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BANG '02 Abstracts

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1. Dominic Mangiardi, Kara May, Douglas A. Cotanche, David C. Mountain 

Boston University / Cbildren's hospital



Speaker: Dominic Mangiardi | Contact: mangiard@bu.edu



Comparison of Apoptotic Pathways Employed by Gentamicin and Acoustic Trauma in the Avian Cochlea

We have explored the expression of proteins involved in the apoptotic pathway of hair cells dying from both gentamicin treatment and acoustic trauma. The timing and location of proteins involved in early and late stages of apoptosis were examined in whole mount immunocytochemical preparations of the chick basilar papilla. TIAR, an early marker of apoptosis, can be identified 12 to 24 hours after a single subcutaneous injection of gentamicin (300 mg/kg). From studies using fluorescently labeled gentamicin it appears that gentamicin takes 6 to 9 hours to reach cochlear hair cells following systemic injection. Later events in the apoptotic cascade, such as cytochrome c release and activation of caspase-3 are first observed 30 to 36 hours after the gentamicin injection, concurrent with the appearance of hair cell damage and ejection from the sensory epithelium. Using a 1500 Hz pure tone sound exposure at 120 dB SPL, TIAr translocation begins 6 hours after the onset of the exposure, and reaches its maximal extent at 15 to 18 hours after the onset of the tone. Cytochrome c release from mitochondria is seen from 15 to 24 hours after the onset of the tone, which is concurrent with hair cell ejection from the basilar papilla. Caspase-3 is seen in some hair cells during ejection, but not in all cells. Both gentamicin and acoustic trauma exhibit a similar cascade of events in the apoptotic pathway, indicating that these traumatizing insults induce hair cell apoptosis in a similar manner. However, the timing of the apoptotic response seems to be compressed for the case of acoustic trauma when compared directly to the gentamicin treatment.

Keywords and Comments:

Hearing

2. Louis J. Toth,John A. Assad

Boston University Medical School, Harvard Medical School



Speaker: Louis Toth | Contact: ljtoth@bu.edu



Behavioral relevance dynamically increases color selectivity in LIP

A general function of cerebral cortex is to allow the flexible association of sensory stimuli with specific behaviors. Many neurons in parietal, prefrontal and motor cortical areas are activated both by particular movements and by sensory cues that trigger these movements, suggesting a role in linking sensation to action. For example, neurons in the lateral intraparietal area (LIP)encode both the location of visual stimuli and the direction ofsaccadic eye movements. LIP is not believed to encode non-spatial stimulus attributes such as color. Here we investigatedwhether LIP would encode color if color was behaviorallylinked to the eye movement. We trained monkeys to make an eyemovement in one of two directions based alternately on the coloror location of a visual cue. When cue color was relevant fordirecting eye movement, we found a substantial fraction of LIPneurons selective for cue color. However, when cue location wasrelevant, color selectivity was virtually absent in LIP. Theseresults demonstrate that selectivity of cortical neurons canchange as a function of the required behavior.

Keywords and Comments:

Primate

3. Fiala, JC, Ostroff, L, Cooney, J, Feinberg, MD, Allwardt, BA and Harris, KM. 

Boston university



Speaker: Kristen M. Harris | Contact: harrisk@bu.edu



Long-term potentiation in developing hippocampus leads to sdMSBs from spine outgrowth and more polyribosomes in spines with larger synapses.

A key question has been whether the expression of long-term potentiation (LTP) involves the formation of new synapses or an enlargement of existing synapses. This question was investigated in acute hippocampal slices from 15-day-old rats. Two stimulating electrodes were positioned 800 microns apart in the middle of stratum radiatum of area CA1. A recording electrode positioned midway between them demonstrated that repeated tetanic stimulation at one stimulating electrode produced saturated LTP, while control stimulation at the other electrode maintained a stable response from the synapses it activated. Two hours after induction of LTP, the slices were prepared for serial electron microscopy. Coded series from neuropil beneath each stimulating electrode were compared with unbiased volumetric analyses and three-dimensional reconstructions. The density of synapses and dendritic protrusions did not differ between the sites, however there were more nonsynaptic protrusions along dendrites at the LTP sites. The nonsynaptic protrusions were generally headless and similar in appearance to filopodia. Synapses were larger at the LTP than the control site. Although the total number of multiple-synapse boutons (MSB) did not differ, synapses from a single dendrite were more likely to share an MSB after LTP. Long axons and other structures extended between these synapses, hence synapses sharing an MSB could not have arisen by perforation and splitting of a pre-existing spine synapse. In a second study, we show that the predominant location of polyribosomes shifts from dendritic shafts under control conditions, into dendritic spines with enlarged synapses during long-term potentiaion.

Keywords and Comments:

Vertebrate

4. T.A. Blute*, Paul B. Cook and W.D. Eldred

Boston University



Speaker: Todd Blute | Contact: blute@bu.edu



ELECTROPHYSIOLOGICALLY STIMULATED NITRIC OXIDE PRODUCTION IN THE RETINA

Nitric oxide (NO) plays many physiological roles and can be produced by every retinal cell type. Our previous study used fluorescent imaging to visualize NO production in specific retinal cell types in response to pharmacological stimulation. In the present study, we determined whether focal electrical stimulation of the retinal circuitry could also alter NO production. We used constant current stimulation through a glass micropipette positioned in the outer plexiform layer in slices of turtle retina that had been previously loaded with the NO sensitive dye, diaminofluorescein. Brief stimuli increased NO in small select populations of neurons, usually closest to the stimulating electrode, consistent with bipolar cell activation followed by increases in ganglion cells and small points in the inner plexiform layer (IPL). Lateral spread of NO production was observed in the outer plexiform layer. Distinct points of activation appeared and disappeared in the IPL on different trials, suggesting that the stimuli were activating discrete circuits. Some changes occurred after many seconds, indicating that NO can be produced on the biochemical time scale. These results indicate that electrical stimulation can be a useful tool for the study of NO in select retinal circuits. This research supported by NIH EY04785 to WDE

Keywords and Comments:

Vertebrate

5. T.Kremin; D.Gerber; S.Y.Huang; S.Tonegawa; M.E.Hasselmo

Boston University



Speaker: Terry Kremin | Contact: tkremin@bu.edu



MUSCARINIC INHIBITION OF HIPPOCAMPAL EPSPs IS ATTENUATED IN MICE LACKING M1 SUBTYPE ACETYLCHOLINE RECEPTORS.

Cholinergic modulation of synaptic transmission is vital to memory processes, and may be responsible for setting network dynamics in the hippocampus appropriate for encoding of information (Hasselmo & Schnell, 1994, J of Neuroscience) While research has demonstrated the involvement of muscarinic acetylcholine receptors (mAChR) in presynaptic inhibition of glutamatergic transmission, the contributions and involvement of the subtypes of receptors has remained less than clear, primarily from lack of highly specific agonists and antagonists: Sheridan & Sutor (1990) found evidence suggesting M1 receptors cause presynaptic inhibition of glutamatergic transmission, while Dutar & Nicoll's (1988) research supports the M2 receptor. To address this issue, we examined muscarinic inhibition of EPSPs in stratum radiatum of mice lacking M1 subtype receptors (KO) compared to wildtype (WT) controls. Analyses of suppression showed a significant difference in suppression between KO and WT (F=9.1, p<.01). 5 micromolar muscarine caused suppression of 44.2% ? 7.0 (KO, n=7) and 66.2%? 4.5 (WT, n=9) and 20 micromolar muscarine caused 58%? 7.3 (KO, n=4) and 80.7% ? 5.1 (WT, n=6), but the difference was not significant with 1 micromolar muscarine (26.1% ? 5.6 and 26.7% ? 5.3). No significant differences were found in paired pulse facilitation. These findings support a significant contribution of the M1 receptor to the inhibition of synaptic transmission.

Keywords and Comments:

Mammal

6. Danqing Xiao and Helen Barbas

Dept. of Health Sciences, Boston University



Speaker: Danqing Xiao | Contact: xiaod@bu.edu



PREFRONTAL CORTICAL EXTENSION OF THE PAPEZ CIRCUIT THROUGH THE ANTERIOR THALAMIC NUCLEI IN THE RHESUS MONKEY

Previous studies indicate that the anterior nuclei are connected with the prefrontal cortices (Dermon and Barbas J. Comp. Neurol. 344:508, 1994). Here we addressed the question of the extent of connections of the anterior nuclei with prefrontal areas that may suggest their participation in circuits associated with emotions. To identify pathways from prefrontal cortices to the anterior nuclei, we used two approaches. First, we studied bidirectional connections between the anterior nuclei and prefrontal cortices by injecting anterograde and retrograde tracers in prefrontal cortices. Second, we studied the sources of cortical and subcortical input to the anterior nuclei by injecting retrograde tracers in the anterior nuclei. The combined approaches showed that prefrontal medial and orbitofrontal limbic cortices were linked with the anterior nuclei to a much greater extent than lateral prefrontal cortices. Second, the hippocampal formation, entorhinal cortex, perirhinal cortex and parahippocampal areas projected to the anterior nuclei. Finally, we observed a robust projection from the ipsilateral mammillary body to the anterior nuclei. Immunostaining studies indicated that projection neurons in the mammillary body directed to the anterior nuclei were not positive for GABA and a subpopulation of these were positive for the calcium binding proteins calbindin or parvalbumin. The results suggest that the anterior nuclei are a common link for distinct orbitofrontal and medial prefrontal areas, medial temporal cortices and the hypothalamic mammillary body in pathways processing both emotional and mnemonic information.(Supported by NIH grants from NIMH and NINDS.)

Keywords and Comments:

Primate

7. David Somers

Boston University



Speaker: Stephanie McMains | Contact: mcmains@bu.edu



Functional MRI investigation of multiple foci of visual spatial attention: More than one spotlight?

BACKGROUND: Visual spatial attention is commonly viewed as a "spotlight" that enhances processing within a unitary, contiguous spatial window (Posner & Snyder, 1980) Recent fMRI studies revealed a physiological correlate of the "attentional spotlight" as retinotopically-specific visual cortical modulation. What happens when you attend to more than one location? Spotlight theory predicts that attention will modulate the locations and intermediate regions. Other evidence suggests more complex spatial windows of attention (e.g. Pylyshyn & Storm, 1988) Here, we investigated visual cortical modulation patterns produced when subjects simultaneously attended to two objects. METHODS: Subjects viewed displays consisting of rapid serial visual presentation (RSVP) at five locations (fovea, 4 quadrants). Two diagonally-opposing quadrant streams were simultaneously monitored in the "attend2" condition; a third quadrant in "attend1"; the fourth quadrant and the foveal stream served as distractors. Attend2 task required that subjects perform a same/different comparison on digits that simultaneously appeared in two monitored letter streams. RESULTS: Retinotopic cortical representations of the RSVP streams were functionally identified for each subject. Activation was compared in these ROIs for attend1, attend 2, and passive viewing conditions (t-test, random effects model, N=5). Attend1 (vs. attend2) produced significant (p < 0.01) modulation only in the representation of the attended quadrant. Attend2 (vs. attend1) produced significant (p<0.01) in the two opposing attended quadrants, but not in the intervening foveal representation. CONCLUSIONS: Retinotopically-specific patterns of human visual cortical attentional modulation are consistent with the existence of multiple spatial spotlights and inconsistent with the unitary spotlight hypothesis.

Keywords and Comments:

Imaging

8. Wei-Li Diana Ma,David C. Mountain

Boston University



Speaker: Wei-Li Diana Ma | Contact: dma@bu.edu



EarLab: species specific modeling of the mammalian auditory system

Numerous features of the auditory system are shared across the mammalian taxonomic order. Similarities in morphology and psychophysical abilities are the basis for comparative studies in audition, which in turn form the foundation for much of our current understanding of auditory system physiology in humans and other animals. Physiological and phenomenological models of auditory systems traditionally follow experimental data; as a result, their predictions are usually limited not only to a class of stimuli but also the species from which the data were taken. Few attempts have been made to develop "scaling factors" between species, so generalizations of model predictions across species are usually made qualitatively.EarLab offers a modular approach to modeling that incorporates computational models of the auditory system controlled by species-specific parameter sets. The auditory system is divided into functional modules, which are modeled independently and connected to other modules. For instance, the model of cochlear mechanics is parameterized by a frequency-place map developed for the species of interest. Likewise, when possible, the middle ear module uses species specific transfer function coefficients. Each module accepts and outputs defined and measurable quantities so that different models for a given structure can be interchanged and predictions can be verified experimentally. Early success in predicting audiograms suggests that it is possible to develop scaling factors to quantitatively transform models of one species into another.Funded by ONR, NIH/NIDCD

Keywords and Comments:

Vertebrate

9. R.H. Loring1, H.Lee1, F.Sala2, S. Sala2, J.J. Ballesta2, and M.Criado2,1Dept. Pharmaceut. Sci., Northeastern Univ., Boston, MA and 2Instituto de Neurociencias, Univ. Miguel Hernandez-CSIC, San Juan de Alicante, Spain.

Dept. Pharmaceutical Science, Northeastern U.



Speaker: Ralph Loring | Contact: r.loring@neu.edu



SURFACE EXPRESSION OF CHIMERIC a7-GFP NICOTINIC RECEPTORS IS CELL TYPE SPECIFIC.

We previously reported that rat a7 subunit expression is limited to 2 cell lines (GH4C1 and SH-EP1) of 5 tested (Sweileh et al., Mol. Brain Res., 2000 75:293-302). Also, surface expression measured by a-bungarotoxin (BGT) binding to GH4C1 cells is more than 10 fold greater than SH-EP1 cells, even though total receptor expression in both cell lines is similar. To further characterize receptor folding, assembly, and transport to the cell surface, we constructed a chimeric rat a7 subunit with green fluorescent protein (GFP) at the receptor C-terminal. Expression of a7-GFP in Xenopus oocytes resulted in currents that were indistinguishable from wild type receptors but were 33% smaller. BGT binding at the oocyte surface was also reduced to 23% of control. Surface fluorescence in oocytes appeared as speckled patches in confocal microscopy. Transfection of a7-GFP into GH4C1 cells produced fluorescence that was less intense than GFP alone, but showed significant BGT binding compared to GFP transfection. Alpha7-GFP transfection in SH-EP1 cells, however, produced fluorescence that was restricted to small intracellular patches, and no surface BGT binding was observed. These data suggest that GFP tagging of a7 subunits decreases the efficiency of receptor folding and/or transport to the cell surface, and the extent of the decrement is cell type dependent. Supported by NIH NS22472 & Spanish Ministry of Education (DGICYT, PM98-0104 & PM98-0097).

Keywords and Comments:

Mammal

10. Yanny Lau, James Cherry, Michael Baum, Shaila Mani, Diana Pankevich

Boston University



Speaker: Michael Baum | Contact: baum@bu.edu



INDUCTION OF FOS IN THE ACCESSORY OLFACTORY SYSTEM BY MALE ODORS IS NOT DISRUPTED IN FEMALE MICE THAT LACK A FUNCTIONAL AROMATASE (CYP 19) GENE

INDUCTION OF FOS IN THE ACCESSORY OLFACTORY SYSTEM BY MALE ODORS IS NOT DISRUPTED IN FEMALE MICE THAT LACK A FUNCTIONAL AROMATASE (CYP 19) GENE. Y.E. Lau1, J.A. Cherry2, M.J. Baum*1, and S.K. Mani3. Departments of Biology1 and Psychology2, Boston University, Boston, MA 02215; Dept. of Molecular and Cellular Biology3, Baylor College of Medicine, Houston, TX 77030.Halem et al. (J. Neurobiol. 39:249, 1999) found that odors in soiled male bedding stimulated neuronal Fos-immunoreactivity (IR) in the mitral and granule cells of the accessory olfactory bulb (AOB), in the posterior-dorsal medial amygdala (MePD), and in hypothalamic regions including the medial preoptic area (MPA) of female mice. Males showed a similar odor-induced Fos induction in the AOB, but not in the MePD or MPA. We tested the hypothesis (Toran-Allerand, Psychoneuroendo. 16:7, 1991) that the female-typical, adult profile of odor-induced neural activation depends on the prior perinatal exposure of the female nervous system to estradiol. Adult sexually naive female mice that lacked aromatase due to a null mutation of the crp 19 gene (ArKO) and wild-type (wt) control females were ovariectomized and injected daily with estradiol benzoate. Subjects were subsequently housed individually for 4 days and then exposed either to soiled bedding from gonadally intact males or to clean bedding for 90 min. prior to sacrifice. Females' forebrains were later sectioned and processed for Fos-IR. In wt and ArKO females, exposure to male odors caused similar, significant increases in the number of Fos-IR cells in the rostral and caudal portions of the AOB granule cell layer, in the MePD, and in hypothalamic regions that receive projections from the MePD including the MPA and the ventrolateral subdivision of the ventromedial nucleus. The female-typical profile of accessory olfactory responsiveness to male odors appears to develop in the absence of estrogen biosynthesis and presumed action during perinatal life. (Supported by MH59200 and MH57442).

Keywords and Comments:

Olfaction

12. Kevin Kelliher, Michael Baum, Robert Coulter-Thurley

Boston University



Speaker: Robert Coulter-Thurley | Contact: rcoulter@bu.edu



Olfactory Cues are Necessary for Heterosexual Partner Selection but not for Consummatory Aspects of Sexual Behavior in Ferrets of Both Sexes.

Olfactory Cues are Necessary for Heterosexual Partner Selection but not for Consummatory Aspects of Sexual Behavior in Ferrets of Both Sexes. Kevin R. Kelliher and Michael J. Baum Dept. of Biology, Boston University, 5 Cummington St. Boston MA 02215 When given a choice between an estrous female and a stud male, gonadectomized male (treated with testosterone proprionate; TP) and female (with estradiol benzoate; EB) ferrets strongly prefer to approach and interact with opposite-sex ferrets. Using a Y-maze for delivering odors and a procedure for bilateral occlusion of the nares, we assessed the role of conspecific odors, visual and auditory signals or physical interaction in heterosexual partner selection by male and female ferrets tested before and after they had received coital experience. The nares of gonadectomized, TP-treated males and EB-treated females were either bilaterally occluded (Occ-) using dental impression material or left open (Sham). Sham females and males showed a significant preference to enter the arm of the Y-maze which emitted odors from opposite-sex ferrets in breeding condition. After mating experience, this odor preference was significantly enhanced in females. Occ-female and Occ-males never preferred to enter the arm of the Y-maze which emitted odors from opposite-sex as opposed to the same-sex stimulus animals even when they were allowed to see, hear or physically interact with these ferrets. In separate tests of coital behavior conducted in a small cage, Occ-females took significantly longer to receive an intromission from a stimulus male; however, all were sufficiently receptive eventually to receive intromissions. In similar tests Occ-males all achieved intromissions. Olfactory cues are required in order for ferrets of both sexes to identify and approach heterosexual partners whereas they are not essential for consummatory aspects of sexual behavior. (Supported by HD 21094 and MH 00392)

Keywords and Comments:

Olfaction

13. Andrew J. Schroeder, Joannella Morales, P. Robin Hiesinger, Patrik Verstreken, David L. Nelson, Bassem A. Hassan, and F. Rob Jackson

Dept. of Neuroscience, Tufts University School of Medicine



Speaker: Andrew Schroeder | Contact: ascho01@emerald.tufts.edu



Fragile-X protein mutants have altered circadian behavior

Deficits for the fragile X RNA-binding protein result in neuronal projection defects and behavioral abnormalities. For example, it has been reported that Fragile X patients show increased variability in sleep time and problems with sleep maintenance (Gould et al., Am J Med Genet. 95, 307-315, 2000). Such behavioral alterations might be due to an underlying circadian defect. To test the hypothesis that Fragile X protein has a circadian function, we characterized Drosophila melanogaster Fragile X (dfxr) mutants. The Drosophila Fragile X protein has significant similarity to the mammalian homologs, in particular within the KH RNA-binding domain; it is missing in dfxr mutants. Similar to the human cognate, the fly protein is expressed within neurons, including the circadian pacemaker cells, and not in glia. To assay circadian behavior, we monitored rhythms in adult eclosion and adult locomotor activity in dfxr null mutants (homozygotes) and in control heterozygous siblings (dfxr/+). Those studies revealed obvious defects in the circadian control of both rhythms. Whereas control heterozygous siblings had robust activity rhythms with an average circadian period in the wild-type range, homozygous mutants exhibited weak and erratic rhythmicity or were statistically arrhythmic. Some of the homozygotes also showed multiple rhythmic activity components in free-running conditions (i.e., in DD). Only a few of the mutants (3/36) displayed a single dominant periodicity with significant "strength". Interestingly, the adult eclosion rhythm exhibited normal free-running periodicity in the mutant (i.e., circadian period is normal), indicating that the circadian oscillator is intact. However, peaks of eclosion were phase delayed in the mutant by as much as 6-8 h, relative to heterozygous (control) siblings. Such a phenotype is consistent with an effect on rhythmicity that occurs downstream of the clock mechanism. Similar to Fragile X patients, fly dfxr mutants also exhibited aberrant neuronal projections, including subtle defects of the clock neurons. Thus, the rhythm defect of dfxr mutants might be a consequence of a subtle developmental abnormality. Alternatively, the absence of Fragile X protein within the clock cells may lead to a perturbation of neuronal function (e.g., a defect in the release of the clock output peptide PDF). [Supported by NIH HL59873]

Keywords and Comments:

Invertebrate

14. J.A.Clark2*; S.Steele1; C.F.Chabris2; I. Aharon2; H.Tager-Flusberg4;,N.Makris3;,G.J.Harris2,1. U. of Illinois, Chicago ,2 Radiology, 3 Neurology, MGH, Charlestown,,MA,4. Boston University, Boston, MA,,

MGH NMR Center



Speaker: Jill Clark | Contact: jclark@nmr.mgh.harvard.edu



SEMANTIC VS NONSEMANTIC WORD ACTIVATION IN AUTISTIC VS CONTROLS

An fMRI study at 1.5T examined activation for a semantic (SM) vsnonsemantic (NSM)task in autism (AS) vs control subjects (CS). Over 4 scans, subjectsviewed blocks ofsingle word presentations interspersed with fixation. For the first 2scans, subjectswere asked if they thought the words were 'positive' or 'negative' (SMtask). For thesecond 2 scans, subjects were asked if the same words were in uppercaseorlowercase letters (NSM task). Fixed effects analyses using SPM99produced thefollowing. SM VS NSM activation for AS was observed in the bilateralinferiorprefrontal cortex, bilateral posterior medial temporal cortex andbilateral occipitalarea. Whereas, CS activation was only observed in left inferiorprefrontal area. NSMvs SM analyses showed AS with right superior parieto-occipital and rightorbito-frontal activation and CS with bilateral superiorpariteto-occipital and bilateralsuperior temporal activation. The list of words consisted of concrete(CC) andabstract (mental state (MS) and metaphysical (MP)) words. Within the SMtask, CC vs[MS & MP] activation for AS is in the posterior cingulate, andangular/supramagrinalareas and for the CS in the left medial temporal area in addition to thetwo areas forthe AS. These findings suggest differential activation for processingsemantic vsnonsemantic words for AS and CS and may reflect decreased locationspecificity forsemantic processing as well as decreased emotional and perceptual memoryassociations in response to concrete versus abstract words for autisticsubjects.

Keywords and Comments:

Imaging

15. T. Allana and J-W. Lin

Biology Department, Boston University, Boston, MA 02215



Speaker: T. Allana and J-W. Lin | Contact: tallana@cns.bu.edu



Effect of Mg2+ and w-Aga IVA toxin on Release at the Crayfish Neuromuscular Junction

Though the importance of Ca2+ in release is well documented, questions concerning the spatial profile of Ca2+ to which synaptic vesicles respond still remain unanswered. Using broad action potentials (AP), we probed release by either homogeneously (10mM Mg2+) or non-homogeneously (1nM w-Aga IVA toxin) blocking Ca2+ channels. We found that while Mg2+ did not affected the overall shape of the AP, w-Aga IVA toxin does tend to slow the repolarization phase to some extent, leading to the further broadening of the AP. Ca2+ influx, measured with the fluorescent dye Magnesium Orange, is reduced in Mg2+ conditions (89±3% of control, n = 9), but this is not statistically different from the effect of w-Aga IVA toxin (96±13% of control, n = 5). The rising phase of the Ca2+ transients are also quite similar. Synaptic delay was significantly different (p<0.01) in Mg2+ (0.2±0.05msec, n = 8) and w-Aga IVA (0.44±0.1msec, n = 5) conditions. Overall release, on the other hand, was similar in Mg2+(77±5% of control, n = 11), and w-Aga IVA toxin (69±5% of control, n = 4) suggesting that the differences in synaptic delay are not attributable to changes in probability of release. Specific mechanisms to account for these changes in synaptic delay are currently under investigation.

Keywords and Comments:

Crustacean Ca2+

16. Alexia Pollack

University of Massachusetts-Boston



Speaker: Alexia Pollack | Contact: alexia.pollack@umb.edu



PRIMING OF D2 DOPAMINE-MEDIATED ROTATION AND STRIATAL FOS EXPRESSION IN 6-HYDROXYDOPAMINE LESIONED RATS

Rats with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway show response sensitization upon repeated treatment with dopamine agonists, a phenomenon called "priming". Experiments in my laboratory examine the priming of D2 dopamine responses in 6-OHDA rats. In these studies dopamine-mediated contralateral rotational behavior (behavioral activation) is measured in conjunction with dopamine-mediated Fos expression (cellular activation) in an attempt to correlate changes in motor behavior with activation of various populations of striatal output neurons. Our results demonstrate that priming with the D1-D2 agonist apomorphine enhances D2-mediated rotational behavior and permits the D2 agonist quinpirole to induce the expression of Fos in D1-receptor expressing striatoentopeduncular ("direct pathway") neurons. Priming of these D2 responses is long lasting, and requires concomitant NMDA glutamate receptor stimulation during both the induction and the expression phases of priming. In addition, while priming with either the D1 agonist SKF33839 or the D2 agonist quinpirole enhances D2-mediated rotational behavior to a similar extent, only D1 priming permits a subsequent challenge with D2 agonist to activate Fos in striatoentopeduncular (direct pathway) neurons. These results suggest that D1 and D2 priming of D2-mediated responses involves different molecular adaptations occurring in separate populations of striatal output neurons.

Keywords and Comments:

Behavior

17. Isaac Kurtzer, Paul A. DiZio, James L. Lackner

Ashton Graybiel Lab, Brandeis University



Speaker: Isaac Kurtzer | Contact: kurtzer@brandeis.edu



TERMINAL CORRECTIONS AND ADAPTATION TO A DYNAMIC FORCE PERTURBATION EXAMINED WITH AN "ISOVOLITIONAL" INSTRUCTION

Paradigms utilizing dynamic force perturbations have been increasingly adopted to study motor control. These experiments commonly assume that the subject's corrective behavior to a perturbation primarily reflect involuntary mechanisms. Further, they implicitly assume that adaptation is intrinsic to these involuntary spatially sensitive mechanisms. However, the published movement times, instructions, and subjective reports all suggest that subjects change their voluntary status within the reach. The following experiment required subjects to fix their voluntary state, "keep your effort profile the same"; thereby, any online corrections or adaptation to dynamic force perturbations would be attributable to involuntary mechanisms. It is assumed that "effort" reflects a voluntary state, i.e. unconscious or involuntary "effort" is rare or nonexistent. Six of eight subjects showed no spatial corrections to a transient dynamic force perturbation. Fixing the voluntary controller had the effect of producing severely and chronically deviated trajectories with an additional force field. Also, with removal of the perturbing field these subjects did not display an aftereffect for any of the measures used. It is concluded that on-line spatial corrections and adaptation to a dynamic force perturbation require a high-level spatial goal.

Keywords and Comments:

Behavior

18. C. Egles, T. Claudepierre, W.J. Brunken, and D.D. ,Hunter

Tufts University School of Medicine



Speaker: Dale Hunter | Contact: dale.hunter@tufts.edu



The laminin beta2 chain plays an active role during synaptogenesis in the CNS.

Synapses are stabilized by concerted interactions of pre-, intra-, and post-synaptic components. Here, we show that laminins containing the laminin beta2 chain are components of the intrasynaptic matrix of the CNS. Mice lacking the beta2 chain have a marked reduction in synapsin I levels in their CNS that corresponds with a reduction in synaptic density. Hipppocampal synapses that do form in the absence of the beta2 chain have striking anomalies in vivo that are recapitulated in vitro, where synapse-stabilizing laminins are provided by the post-synaptic neuron. These results strongly support a role for laminins in the structural integrity of central synapses.

Keywords and Comments:

Brain

19. Minhua Luo, Jennifer Broderick, Meltem Cevik Arikan, Qing-Sheng Gao, Junning Wang, Karen Li, John Memmott, Mei-Ling Wei and Athena Andreadis

Shriver/UMass Medical School



Speaker: Athena Andreadis | Contact: Athena.Andreadis@umassmed.edu



Modulation of Tau (Dys)function by Regulated Alternative Splicing

Our genes define us as a species, but our neuronal synapses define us as individuals. Normal brain development is a complex process that requires the coordinated expression of many genes. Understanding this regulation is prerequisite to elucidating the genetic causes of abnormal brain development. Our lab examines alternative splicing, a gene regulatory mechanism vital for the proper functioning of the entire organism, and the nervous system in particular. Alternative splicing, which occurs in 30% of vertebrate genes, results in the production of multiple variants from a single gene and is a major contributor to proteomic complexity.Our chosen model is the human tau gene, whose product is instrumental in the function of the axon. Via minutely regulated alternative splicing, tau produces multiple protein isoforms that control axonal morphology and stability. Disturbances in tau splicing result in disruption of the axon and formation of pathological tau structures called neurofibrillary tangles. Dementia sufferers display these tangles which correlate with the severity of the dementia. The second most common dementia after Alzheimer's, frontotemporal dementia with Parkinsonism, is directly caused by misregulations in tau alternative splicing. Finally, tau also plays an important role in development: tau null mice display learning disabilities and muscle defects.Our dissection of the tau system has begun to clarify the role of tau variants in the fate of neurons, the identity of molecules that interact with tau and the regulators which modulate its splicing. All these molecules control nervous system function. This research will give insights into the regulatory cascades within the brain, with the long term view of preventing or curing neuronal loss. This type of research forms part of the bottom-up approach in answering one of the major questions within and beyond science: how the brain creates a mind (the Binding Problem).

Keywords and Comments:

Primate

20. Jason Kass and Isabelle Mintz

Boston University School of Medicine



Speaker: Jason Kass | Contact: kass@bu.edu



VOLTAGE DEPENDENT INACTIVATION OF THE PLATEAU POTENTIAL IN NEURONS OF THE SUBTHALAMIC NUCLEUS

The subthalamic nucleus (STN) releases glutamate to specific subregions within the basal ganglia providing excitatory modulation in processing and transmitting cortical motor signals to the thalamus. Excessive excitation or inhibition of the STN interferes with motor coordination and produces many of the dysfunctional symptoms seen in pathologies of either extreme (Parkinson's and Huntington's disease). Individual STN neurons are reported to display complex firing properties which include Na+ dependent action potentials, low threshold Ca2+ spikes and robust plateau potentials that sustain long lasting, high frequency firing of action potentials beyond an initial depolarization. We first report that these STN neurons indeed have distinct firing properties. Pharmacological treatment with calcium and sodium channel blockers confirms that Na+ channels are responsible for single spike firing and L-type Ca2+ channels sustain the plateau potential.

Our main finding is that the duration of the plateau potential displays an unusual voltage-dependent sensitivity. Using current-clamp recordings we report that 80% (33/41) of the cells tested display a unique voltage-dependent disappearance of the plateau potential. When these cells are depolarized, beyond a critical membrane potential, they can fire low frequency single spikes, but not plateau potentials. We propose that this disappearance is consistent with inactivation of the underlying L-type Ca2+ conductances. Reappearance of the plateau potential following hyperpolarization of sufficient duration is consistent with a recovery from inactivation of these high threshold voltage-gated channels. The remaining 20 % (8/41) of the cells tested display a voltage-dependent sensitivity similarly observed in other central neurons. Progressive depolarizations extend the plateau potential duration and a disappearance is not observed. We propose that these cells are controlled by the same ionic mechanisms as the larger population in the STN, however these L-type Ca2+ channels require a much greater depolarization and the inactivation is not observed. These findings provide a simple mechanism explaining how the plateau potential may participate in the complex firing pattern of neurons in the STN.

Keywords and Comments:

Vertebrate Basal Ganglia

21. Yukhananov* R.Y, Loguinov A.V.#, Crosby* GJ,*Neurogenomic Laboratory, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, #Department of Nutritional Sciences and Toxicology, University of California Berkeley, CA.,

Harvard medical School



Speaker: rus yukhananov | Contact: ryyukhan@zeus.bwh.harvard.edu



The differential gene expression in PKC gamma knockout following chronic morphine administration.

The development of opioid dependence is mediated by several intracellular pathways that produce tolerance and withdrawal reaction following chronic administration of opioid. There are evidence that important role in this process belongs to protein kinase C (PKC), but the specific isoforms involved are unknown. Using PKCgamma knockout mouse we found that implantation of morphine pellet produces the analgesic tolerance that are not different in two control strains and PKC knock-out mice, whereas naloxone-precipitated withdrawal reaction is practically absent in the mutant strain of mice. Using DrugAbuse cDNA array we have studied the gene expression in medial striatum following tolerance development in these strains of mice. The differential gene expression was determined using regression clustering. The majority of genes remain at the same level in control and experimental strain, whereas there are a group of genes related to cytoskeletal proteins that were differentially expressed in mutant mouse compare to control strain. These data suggest that activation of PKC pathway is not required for the tolerance development but is important for expression of withdrawal reaction following chronic administration of opioids that may be mediated by activation of the specific cytoskeletal pathway.

Keywords and Comments:

Mammal

22. Jeffrey R. Cottrell and Elly Nedivi

MIT



Speaker: Jeffrey R. Cottrell | Contact: cottrell@mit.edu



CPG2 localizes specifically to dendritic spines and interacts with the actin cytoskeleton

The activity-regulated gene cpg2 was isolated in a differential screen for seizure-induced genes in the rat hippocampus (Nedivi et al., 1993). Its sequence predicts a protein with homology to members of the spectrin/dystrophin family of structural proteins, several of which have been localized to dendritic spines. To test whether CPG2 is localized to spines, polyclonal antiserum was generated against a CPG2-specific peptide. In western blots, this antiserum recognizes exclusively doublet bands that run at about 110 kD, the predicted size of CPG2. Cultured hippocampal neurons labeled with this antibody show a punctate staining pattern along dendrites. Additional immunocytochemistry defined these sites to be exclusively excitatory synapses on excitatory neurons. Localization of CPG2 at the synapse is postsynaptic and is confined to the base of dendritic spines where it colocalizes with actin. Exposure of neurons to the filamentous actin (F-actin) depolymerizing compound latrunculin A results in the removal of CPG2 as well as F-actin from spines that retain PSD-95, indicating an interaction between F-actin and CPG2. In an F-actin cosedimentation assay, CPG2 pellets with F-actin filaments under actin polymerizing conditions, but remains in the supernatant in non-polymerizing conditions. These data indicate that CPG2 localizes to dendritic spines of excitatory synapses where it directly interacts with the actin cytoskeleton. As the product of an activity-regulated gene, CPG2 may function to modify dendritic spines during plasticity.

Keywords and Comments:

Mammal

23. J.E. Crandall; J.Q. Ren; B.E. Kosofsky; P.G. Bhide

Shriver Center at UMass Med. Sch.



Speaker: Jim Crandall | Contact: james.crandall@umassmed.edu



PRENATAL COCAINE EXPOSURE DECREASES GABAERGIC CELL POPULATIONS IN THE DEVELOPING MOUSE CEREBRAL CORTEX

Recent investigations on the origin of GABAergic neurons in the forebrain suggest that many arise from the ganglionic eminences and migrate tangentially into other regions of the developing telencephalon. Exposure of the immature brain to cocaine results in disruption of forebrain structure and function. We hypothesized that prenatal cocaine exposure would disrupt the maturation of the GABAergic cell population in the embryonic forebrain. Coronal sections from E15 mice exposed either to saline or cocaine from E8 onwards were immunoreacted for GABA, and GABAergic profiles were sampled from 3 different litters from 3 different forebrain regions: medial prefrontal cortex, somatosensory cortex, and olfactory bulb. Treatment groups in addition to cocaine- and saline-exposed litters included nutritional controls (saline pair-fed and a lower dose of cocaine). Both cocaine-exposed litters showed a significant deficit by approximately 50 percent in the number of GABAergic profiles in medial prefrontal and somatosensory regions compared to controls. These differences were most pronounced in the intermediate zone. The number of GABAergic cells in the marginal zone did not differ between groups. Furthermore, the average width of each embryonic cerebral layer was similar. Interestingly, the number of GABAergic cells in the olfactory bulb was not significantly different between groups. Thus, it appears that prenatal cocaine exposure dramatically and selectively reduces GABAergic cells in the developing mouse forebrain by presumably altering neurogenesis in and/or tangential migration from the ganglionic eminences. 

Keywords and Comments:

Vertebrate

24. Bill Adolfsen, J. Troy Littleton

MIT



Speaker: Bill Adolfsen | Contact: billa@MIT.edu



Characterization of the Drosophila Synaptotagmin family

Chemical transmission, mediated through secretion of neurotransmitter,is a fundamental property of neurons thought to subserve higher nervoussystem functions. The process can be simplistically envisioned to encompass two main events; 1) release of neurotransmitter by a presynaptic neuron initiated by calcium influx and 2) reception of that chemical signal by postsynaptic receptors. In recent years, biochemical and genetic studies of synaptotagmin I (syt I) have indicated an intimate role for this protein in the neurotransmitter release process. Extensive biochemical dissection of the syt I protein has uncovered a number of biochemical functions that suggest a role in various aspects of vesicle cycling, however evidence indicating which of these numerous biochemical interactions is physiologically relevant is still lacking. Genetic studies have also begun to provide valuable insight into syt I's function in vivo, however direct interpretations from these studies have been hindered by the observation that several synaptotagmin isoforms are present in higher eukaryotes. Recent completion of the Drosophila genome has made it possible to identify all the members of the synaptotagmin gene family within an organism.We have identified seven synaptotagmins, in addition to three C2 domain proteins that show overall domain organization similiar to these synaptotagmins. Apart from mutations in mouse syt I and syt IV and fly syt I, few other genetic manipulations of synaptotagmins have been reported. Thus the precise role of these isoforms is not known. In order to start to identify the functions of these additional syt isoforms, we report here the expression analysis of various members of the syt I gene family.

Keywords and Comments:

Invertebrate

25. Karin Schon, Sule Tinaz, Seth J. Sherman,, & Chantal E. Stern

Boston University



Speaker: Karin Schon | Contact: kschon@bu.edu



An fMRI study of object and spatial working memory

INTRODUCTION: It is widely accepted that the lateral prefrontal cortex (PFC) is actively engaged in working memory. However, one current controversy is, whether the dorsolateral PFC (DLPFC) is specific to working memory in the spatial domain (Funahashi et al., 1989; Belger et al., 1998), or whether it is process-specific, and is recruited when information being held in working memory needs to be monitored or manipulated regardless of stimulus domain (Owen et al., 1996, 1999). Furthermore, this study investigated interactions between the PFC and medial temporal lobe regions in working memory. METHODS: In this study, we examined working memory using 2 types of stimuli, objects (pictures of birds and fish) and locations (n=10). In addition, we constrasted highly familiar vs. novel objects to examine WM when interference is high (familiar) vs. low (novel). Eleven subjects performed both a visuospatial and a nonspatial object delayed-matching-to sample (DMTS) task with either highly familiar or trial-unique objects. RESULTS: Preliminary results revealed that, during the object DMTS task, when contrasted with the spatial DMTS task, the posterior hippocampus is selectively engaged bilaterally during the delay period when novel stimuli are used, and the anterior hippocampus is recruited bilaterally when the stimuli are highly familiar. In addition, the anterior cingulate area and the pre-SMA showed delay period activity during the DMTS task for spatial locations using familiar stimuli. The DLPFC showed delay-period activity during both task delays when contrasted with control-task delays, but only when the stimuli used were highly familiar. The DLPFC was not selectively engaged during the spatial DMTS tasks, but was active during both spatial and object WM tasks, suggesting that this area is not specific to the spatial domain. CONCLUSIONS: These preliminary results are consistent with the view that the DLPFC is recruited when interference between highly familiar stimuli is expected and task-relevant stimuli need to be monitored (Owen et al., 1996; Stern et al., 2001). This study extends previous work in that this activity can be attributed to the active maintenance (i.e., the delay period in DMTS tasks) of working memory.

Keywords and Comments:

Imaging

27. Yiping Shen, Karina Meiri

Department of Anatomy & Cell biology, Tufts University



Speaker: Yiping Shen | Contact: yiping.shen@tufts.edu



GAP-43 is required for netrin-DCC induced neurite outgrowth and axon guidance of developing cortical neurons, but not developing spinal cord neurons

GAP-43, is a major growth cone protein whose phosphorylation by PKC in response to extracellular guidance cues can regulate F-actin behavior. GAP-43 is essential for successful axon guidance by both cortical afferents and efferents: When it is genetically deleted somatosensory, auditory and visual somatotopic maps fail to form and telencephalic commissural axons fail to cross the midline, supporting the notion that it is functional in a signaling pathway enabling cortical axons to respond to extracellular guidance cues. Here we show a requirement for GAP-43 in a pathway that generates DCC-mediated responses of neocortical neurons to netrin-1. We used 3-D collagen gel co-cultures to show that both recombinant netrin-1, expressed by transfected COS7 cells, and endogenous netrin-1, expressed by the spinal cord floor plate, stimulate neurite outgrowth and axon guidance of neocortical axons. In stark contrast netrin-mediated neurite outgrowth and axon guidance were both significantly inhibited in neocortical axons from GAP-43 (-/-) mice. Interestingly, neither netrin-stimulated neurite outgrowth nor guidance of dorsal spinal cord commissure axons was affected in GAP-43 (-/-) mice, consistent with the normal formation of the spinal cord commissure in GAP-43 (-/-) mice. The results suggest fundamental differences in the way that neocortical and spinal cord axons respond to netrin-1. The results demonstrate previously unappreciated diversity in how different classes of neurons respond to the same extracellular signals.

Keywords and Comments:

Vertebrate

28. N. Otmakhov, S. Carpenter, R. Conti, J.E. Lisman

Brandeis University



Speaker: Stephen Carpenter | Contact: stevec@brandeis.edu



Measuring CaMKII binding affinity in synaptic spines of living neurons

CaMKII is critically involved in long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Previous studies showed the abundance of the kinase in the postsynaptic density. Recent work suggests that CaMKII may only transiently translocate into synapses during periods of synaptic activation. To further understand the localization of CaMKII and it activity-dependent movement, we expressed GFP-fused CaMKII in neurons in hippocampal slice cultures. GFP-CaMKII alpha expression was mostly homogeneous in dendrites and spines with only occasional clustering in spines. GFP-CaMKII beta, however, was mostly restricted to spines, with little expression in dendrites. This distribution is consistent with the notion that only CaMKII beta but not alpha is bound to actin, which concentrated mostly in spines. To assess the affinity of the kinase binding to synaptic structures we bleached the fluorescence in spines and measured how fast the fluorescence recovered. We found that the recovery time differed dramatically in different spines and depended on the subunit expressed. In general, GFP-CaMKII alpha recovered faster (within seconds/minutes) than GFP-CaMKII beta, which in many cases did not recover even in an hour after bleaching. Our data indicate that CaMKII must be strongly bound to internal structures in some spines. Currently we are testing if this strong binding is activity dependent. NIH grant # 2 RO1 NS27337.

Keywords and Comments:

Mammal Other Keywords: CaMKII, hippocampus, LTP, synaptic plasticity

29. Woodley, Sarah K. and Baum, Michael J.

Dept. Biology, Boston University



Speaker: Woodley, Sarah K. | Contact: swoodley@bu.edu



Mating-induced Fos-immunoreactivity in retrogradely labeled projection neurons to the medial preoptic area of female ferrets.

Ferrets are induced ovulators in which receipt of an intromission induces a plasma LH surge and stimulates Fos-immunoreactivity (Fos-IR) in mediobasal GnRH neurons of females, but not of males. These neuroendocrine events are correlated with sex differences in the responsiveness of non-GnRH neurons to sensory inputs. Thus after intromission or exposure to conspecific odors, ferrets of both sexes had increased Fos-IR in the medial amygdala (MA); however, only females had increased Fos-IR in the medial preoptic area (mPOA) (Wersinger and Baum, 1997). We sought to identify afferent projections to the female's mPOA that are activated by the receipt of an intromission. A retrograde tracer, cholera toxin b (CTb), was injected into the mPOA of female ferrets. Seven days later females were mated and 90 min later brains were collected and brains were processed for CTb-IR and Fos-IR. Retrogradely labeled CTb-IR cells were present in the MA, bed nucleus of the stria terminalis (BNST), ventrolateral hypothalamus (VLH), and midbrain subparafascicular nucleus (SPF), confirming previous reports in the male rat (Coolen et al., 1998). The percentage of CTb-IR neurons that contained nuclear Fos-IR averaged 30% in the medial SPF, 18% in the VLH, 12% in the BNST, and 4% in the MA. These results correlate with the predominant role of genital somatosensory (conveyed via the SPF), as opposed to olfactory (conveyed via the MA), inputs in eliciting the female's LH surge (Bakker et al., 2001). They also provide a basis for further comparisons of the ability of genital versus olfactory stimuli to activate neurons that project to the mPOA in the two sexes. (supported by NIH F32 DC0042-02 and HD21094 )

Keywords and Comments:

Vertebrate

30. W. L. Bi, C. Keller-McGandy, D. G. Standaert & S. J Augood

MGH and Harvard Medical School



Speaker: Sarah J. Augood, Ph.D. | Contact: augood@helix.mgh.harvard.edu



Molecular Profile of Cellular Vulnerability in Huntington's Disease

Huntington's Disease (HD) is a hereditary autosomal dominant neurodegenerative disorder with full penetrance and is caused by a triplet (CAG) repeat expansion (> 38 repeats) within the IT15 gene, encoding huntingtin protein. The primary site of neurodegeneration is the striatum (caudate and putamen). However, IT15 mRNA has a ubiquitous distribution throughout the body which does not correlate with the regions of degeneration. The neuroanatomical hallmark of HD is the differential loss and sparing of specific cell populations in the striatum as the disease advances. Specifically, medium spiny projection neurons degenerate whilst specific populations of interneurons are selectively spared. Of these spared interneuron populations, cells expressing neuronal nitric oxide synthase (nNOS)/ somatostatin (SOM) are most resistant. Furthermore, differential striatal cellular vulnerability is observed not only in human HD, but also after intrastriatal injection of excitotoxins in the rat, suggesting that excitotoxicity may play a role of HD pathogenesis. The underlying basis for this differential vulnerability among the various striatal neuron populations is yet unknown. We hypothesize that cellular vulnerability/resistance to Huntington's disease is reflected by differential expression of genes for receptors, peptides and other proteins. To test this hypothesis directly we have used Laser Capture Microdissection (LCM) to isolate different striatal cell populations, specifically medium-sized spiny projection neurons (vulnerable) and nNOS/SOM interneurons (resistant) and then processed the samples for differential gene expression using cDNA microarrays and real-time RT-PCR. We have used this system to compare differential transcriptional levels of various receptors related to the excitotoxic model proposed for cellular dysfunction in Huntington's disease. By contrasting the profiles of selectively vulnerable versus spared populations at a transcriptional level, we hope to gain insights as to the molecular basis of cellular dysfunction in HD.

Keywords and Comments:

Brain

31. S Sheremata, Y Chen

McLean Hospital



Speaker: Summer Sheremata | Contact: sheremat@mclean.harvard.edu



Effects of Atypical Antipsychotic and Antidepressant Interaction on Visual Processing in Schizophrenia

OBJECTIVE: Atypical antipsychotics (APDs) are classified based on a combined antagonism of serotonin and dopamine. Co-administration of other medications that affect pharmacological activity at these receptors, such as antidepressants, is common. Interactions between such drugs are not definitively understood. In this study, we investigated the combined effect of antidepressants and APDs on visual processing in schizophrenia. METHOD: Schizophrenia patients taking both APDs and antidepressants (n=7) and taking only APDs (n=9) performed two visual tasks. In a contrast detection task, a sinusoidal grating appeared at one of two intervals at decreasing contrast levels per trial, and subjects were asked to maintain visual signals across the two intervals. Subjects then indicated during which of the two intervals the moving grating appeared. The subjects also performed a direction discrimination task using identical stimuli in which they indicated the direction of the gratings as they appeared, therefore not requiring maintenance of visual signals across two intervals. RESULTS: For the detection task, patients taking both APDs and antidepressants showed higher thresholds than those taking just APDs. For the direction task, there was no significant difference in the two medication groups (p<0.01). CONCLUSIONS: Because both tasks used contrast as variables, deficient contrast processing alone cannot explain the poor performance in the contrast detection but not in the direction task. Given that antidepressants interfere with APDs stimulation of D1 receptors, the results suggests that co-administration disrupts the perceptual processes requiring retention of sensory information by interfering with serotonergic and dopaminergic activity.

Keywords and Comments:

Behavior

32. B. Yang, J. M. Hinterneder, J. D. Slonimsky, S. J. Birren

Brandeis University



Speaker: Jeanine M. Hinterneder | Contact: jhint@brandeis.edu



Multiple Independent Mechanisms Regulate Neurotransmitter Release in Sympathetic Neurons

Sympathetic neurons can undergo a developmental switch from a noradrenergic to a cholinergic phenotype in response to target-derived cues. One factor that can induce such a change in vitro is ciliary neurotrophic factor (CNTF). Over several days in culture CNTF induces the expression of cholinergic markers and decreases the expression of noradrenergic markers. Here we show that CNTF also promotes a functional change in sympathetic neurotransmitter release, resulting in a switch to inhibitory cholinergic transmission onto cultured cardiac myocytes. The functional change in neurotransmission requires three weeks and is further characterized by the localization of the vesicular acetylcholine transporter (VAChT) to discrete puncta within the sympathetic neurons. While functional changes in neurotransmission require a period of several weeks, CNTF-mediated induction of mRNAs for acetylcholine biosynthetic and packaging proteins takes place within three days. This suggests that the evoked release of acetylcholine (ACh) is dependent upon additional factors that act over a longer time period. The time course of the CNTF-induced cholinergic switch is in marked contrast to the rapid appearance of functional cholinergic transmission following acute treatment with brain-derived neurotrophic factor (BDNF). The timing of cholinergic regulation along with evidence that BNDF modulates cholinergic transmission through a p75-mediated mechanism suggests that the regulation of functional cholinergic transmission can take place through multiple independent mechanisms.

Keywords and Comments:

Mammal This poster was previously presented at SFN 2001 in San Diego

33. Chaelon Myme, Ken Sugino, Gina Turrigiano, Sacha Nelson

Brandeis University



Speaker: Chaelon Myme | Contact: myme@brandeis.edu



Relative Contributions of NMDA and AMPA Receptors to EPSCs in Layer 2/3 Pyramidal Cells of Rat Medial Prefrontal and Primary Visual Cortex

Recent models of persistent activity during working memory in primate prefrontal cortex (PFC) posit NMDA receptor (NMDAR) mediated synaptic current as a mechanism for sustained recurrent excitation. We compared NMDAR contribution in PFC to an area assumed to have less persistent activity, the visual cortex (VC). Whole cell voltage clamp responses were recorded in brain slices from layer 2/3 pyramidal cells of the medial PFC and VC of rats p16-p21. Mixed mEPSCs having AMPAR and NMDAR mediated components were isolated in 0 Mg++ ACSF. Averaged mEPSCs were well-fit by double exponentials. No significant differences in the NMDA/AMPA ratio (mPFC: 21% ± 7%; VC: 22% ± 7%), peak mEPSC amplitude (mPFC: 18.8 ± 0.9 pA; 17.4 ± 0.7 pA), NMDAR decay kinetics (mPFC: 68 ± 7 ms; VC: 66 ± 5 ms), or degree of correlation between NMDAR and AMPAR mediated mEPSC components, were found between the areas (PFC: n = 30; VC: n = 31). Recordings from older rats (p26-29) also showed no differences. EPSCs were evoked extracellularly in normal Mg++ at holding potentials of -90 and +50 mV; the average NMDA/AMPA ratio was again similar in the two regions. In 0 Mg++ and in the presence of CNQX, spontaneous activation of NMDAR increased recording noise and produced a small tonic depolarization which was similar in both areas. We conclude that for the ages studied there is no discernable difference between NMDAR contribution to EPSCs in the mPFC as compared to the VC.

Keywords and Comments:

Mammal

34. RH Cudmore, SB Nelson, GG Turrigiano

Brandeis University



Speaker: Robert Cudmore | Contact: cudmore@brandeis.edu



High Frequency Firing of Rat Visual Cortex Neurons Causes a Long Term Increase In Intrinsic Excitability

Mechanisms of synaptic plasticity have been widely studied, but less is known about how activity modifies the intrinsic firing properties of neurons. Here we show that short periods of high frequency firing produce long lasting increases in neural excitability. Whole cell current clamp recordings were made from visual cortical pyramidal neurons in both dissociated culture and acute slice, with synaptic currents blocked. Current injections (500 ms; 150 pA) that elicit high frequency action potentials (30 Hz) injected every 2 sec for 4 min caused a long lasting increase in the number of spikes evoked by a low amplitude 500 ms depolarizing current injection (before: 2.5 0.5 spikes, 20 min after: 4.1 1.2 spikes, n = 6, p < 0.05). Control recordings showed no change in spike number over the same time period (4.1 1.4 and 4.0 1.2, n = 4, p > 0.89). High frequency firing also produced a decrease in the threshold current to generate an action potential (before: 44 4.9 pA, 20 min after: 26 6.7 pA, n = 5, p < 0.005) and both the number of spikes and the instantaneous spike frequency was increased over a wide range of current injection amplitudes (10 pA to 200 pA). Resting membrane potential and resting input resistance did not change significantly. Rapid changes in a neuron's intrinsic properties based on recent activity could be a powerful mechanism by which neurons tune themselves to recent activity regimes. In addition to synaptic plasticity, this form of intrinsic plasticity could be involved in learning and memory.

Keywords and Comments:

Mammal This poster was previously presented at SFN '01 in San Diego CA.

35. M. Misra1, T. Katzir-Cohen2, J. Clark3, M. Wolf2, R.A. Poldrack3,1. Psychology, 2. Child Development, Tufts University, Medford, MA, 3. Radiology, MGH-NMR Center, Charlestown, MA,

Tufts University



Speaker: Maya Misra | Contact: mmisra@emerald.tufts.edu



Neural Systems for Rapid Automatized Naming Identified Using fMRI

Rapid automatized naming (RAN) tasks require quick serial naming of stimuli. The RAN letters task has been found to be a successful predictor of reading ability. This task involves perceptual, cognitive, and linguistic processes that are shared with reading. The RAN objects task requires similar skills, but has not been found to predict reading in skilled readers and does not appear to be as automatized as letter-naming. Using fMRI methods in conjunction with behavioral measures we attempted to determine the neural correlates of the RAN tasks. In two scans during the same testing session, participants covertly rapidly named either objects or letters presented in a 9 by 4 matrix or passively viewed a matrix of plus signs. Letter-naming was more highly automatized, as reflected in faster naming rates. For both letters and objects compared to fixation, activation was found in the bilateral inferior frontal cortices, bilateral anterior insula, left inferior parietal cortex, and bilateral intraparietal sulcus. A comparison of letters versus objects showed significant activation in left inferior temporal cortex (BA 37) which may reflect letter-specific retrieval processes. In addition, bilateral activation in or near area MT was observed, consistent with engagement of magnocellular processes in reading. For objects versus letters, significant activations were observed in the bilateral fusiform gyri and lateral/dorsal occipital cortices, and bilaterally in the body of the caudate. This difference in striatal activation could reflect differential automaticity for processing letters versus objects.

Keywords and Comments:

Imaging

36. Vanee Pho, James Cherry

Boston University



Speaker: Vanee Pho | Contact: vpho@bu.edu



Exposure to odors or the PDE4 inhibitor rolipram induces phosphorylation of CREB in the mouse olfactory bulb

In the brain, increases in cAMP can result in phosphorylation of the cAMP-responsive binding protein (pCREB), leading to consequent changes in gene expression and synaptic plasticity. However, in the olfactory system, long term effects of cAMP induction following exposure to odors are largely unknown. We examined whether pCREB could be induced in the mouse olfactory system after either exposure to odors or pharmacological elevation of cAMP by administration of the PDE4 inhibitor rolipram. Male mice were injected with 0.5 mg/kg rolipram or saline 30 min before being exposed to 2% ethanol (control) or a mixture of hexanol, euglenol and citronellol in 2% ethanol for 20 min. Olfactory tissues were then quickly isolated and processed for Western blotting using anti-pCREB antibodies (NEB). Consistent with previous results in the rat (Moon et al., PNAS 96:14605, 1999), olfactory epithelium (OE) in saline-treated mice showed elevated pCREB levels in response to odorants (p<0.005); however, rolipram had no effect on pCREB levels in the OE of odor- or ethanol-exposed subjects. By contrast, in the olfactory bulb (OB), pCREB levels were increased following either odor exposure (p<0.005) or rolipram administration (p<0.03) relative to controls. However, rolipram treatment did not further increase the levels of pCREB in the OB seen in response to odors. These results indicate that elevation of cAMP after exposure to odors induces pCREB in both the OE and OB of mice. Rolipram treatment alone mimicked the effect of odors on pCREB levels in the OB, but not the OE. Supported by DC03019.

Keywords and Comments:

Vertebrate

37. M.Drottar, M. L. Leski, L. A. Hassinger, S. L.Valentine, J. D. Baer and J. T. Coyle. Laboratory of Molecular,Neuroscience, Department of Psychiatry, McLean Hospital and Harvard,Medical School, Belmont, MA 02478.,

McLean Hospital



Speaker: Marie Drottar | Contact: mdrottar@mclean.harvard.edu



L-TYPE CALCIUM CHANNELS REDUCE ROS GENERATION IN CEREBELLAR GRANULE

Cerebellar granule cells (CGC) deprived of serum or trophic factors develop sensitivity to kainate neurotoxicity that is mediated by the AMPA subtype of glutamate receptors. The L-type voltage-gated calcium channel blocker nifedipine increases the potency of kainate 50-fold.Thus, one goal of this laboratory is to determine the underlying protective mechanism triggered by calcium influx through this channel.The cell permeable iron chelator deferoxamine effected complete protection against kainate treatment in the presence of nifedipine. The chelatable heavy metal pool decreased ~70% immediately following treatment with kainate, but did not change following kainate/nifedipine treatment. TMRE fluorescence, an indicator of mitochondrial membranepotential, decreased ~70% following kainate treatment but displayed a more modest decrease (~15%) when CGC were treated with kainate/nifedipine. ROS formation decreased in CGC immediately following kainate treatment but was slightly elevated following kainate/nifedipine treatment. Electron microscopic examinations of the CGC indicated severe swelling and distortion of mitochondria immediately following kainate/nifedipine treatment and the appearance of mitochondrial herniations, whorls and bridges 2 hours later, features that were rarely observed following kainate treatment. These results indicate that calcium entry through L-type VGCCs protects CGC during kainate treatment by lowering the chelatable heavy metal pool and the mitochondrial membrane potential, thereby mitigating the formation of ROS.Supported by: NIH grant number 5-RO1 MH51290-07 and the VaughanFoundation.

Keywords and Comments:

Mammal

38. Cecilia S. Lu, Mai-dung Ngyuen, Gisela F. Wilson, Zheng Wang, and Leslie C. Griffith

Griffith Lab/Brandeis University



Speaker: Cecilia S. Lu | Contact: slu@brandeis.edu



Camguk (Cmg), the Drosophila Homologue of CASK/Lin-2 MAGUK Protein Interacts with Ca2+/CaM-dependent Protein Kinase II

Camguk (Cmg)/CASK/Lin-2 is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins that organize multi-protein complexes at epithelial junctions and neuronal post-synaptic densities. Cmg/CASK/Lin-2 differs from other MAGUKs in that it has a CKII sub-domain highly homologous to CaMKII. Previous studies have shown that Cmg associates with the C-terminal cytoplasmic domain of fly potassium channel ether-a-go-go (Eag) via multiple sites in vitro and that Eag is a phosphorylation substrate of CaMKII in vitro and in vivo. We now present evidence that Cmg binds to CaMKII. This association may play a role in providing a scaffold for CaMKII/Eag interaction. Cmg co-immunoprecipitates with CaMKII in a 1:1 stoichiometry when co-expressed in mammalian tSA201 cells. Using gel filtration column chromatography, Cmg and CMKII were found to co-fractionate at ~660 kD, a size corresponding to a 4:4 Cmg/CaMKII complex. Results from GST pull-down indicate that the CKII and GUK sub-domains of Cmg mediate the interaction with CaMKII and that can be dynamically regulated by ATP. ATP binding to an activated CaMKII was shown to promote Cmg/CaMKII association while its subsequent hydrolysis drives the dissociation. Anti-Cmg antibodies co-immunoprecipitate CaMKII from the adult fly heads where both proteins are abundantly expressed. The interaction between Cmg and CaMKII was not observed in eag sc29 flies in which no Eag protein is expressed suggesting the involvement of Eag in forming a multi-protein complex with Cmg and CaMKII in adult fly heads. The functional consequences of Cmg/CaMKII complex are currently under investigation.

Keywords and Comments:

39. N.J. Fortin, K.L. Agster, J.M. Tourigny, S.E. Rubin, S.P. Wright, L.M. Griffith, A.F. Ceriales, A.L. Cahill and H.B. Eichenbaum

Boston University



Speaker: Norbert Fortin | Contact: nfortin@bu.edu



The Hippocampus and Sequence Learning: Memory for Temporal Order vs Recognition of Events.

Recent models of hippocampal function emphasize its potential role in encoding and retrieving sequences of events that compose episodic memories. Here it was found that hippocampal lesions result in a severe and selective impairment in the capacity of rats to remember the temporal ordering of a series of odors, independent of an intact capacity to recognize the odors.These findings support the hypothesis that hippocampal networks encode the temporal context of events that constitute an episodic memory.

Keywords and Comments:

Mammal Hippocampus and memory section

40. Aron Troen, Barbara Shukitt-Hale, Jacob Selhub and Irwin H. Rosenberg 

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University



Speaker: Aron Troen | Contact: atroen@hnrc.tufts.edu



Behavioral impact of nutritional hyperhomocysteinemia in Apolipoprotein E - deficient mice.

High levels of homocysteine in blood are a risk factor for cardiovascular, including cerebrovascular disease. Recent epidemiological data show that mildly elevated homocysteine is also significantly associated with dementia as well as with cognitive decline in the elderly. Homocysteine, a sulfur-containing amino acid, generated as a metabolic by-product of biological methylation reactions, is thought to be toxic to endothelial cells and neurones, and is disposed through reactions that require folate and vitamins B12 and B6 as cofactors. A recent study showed that Apolipoprotein E (ApoE)-null mice fed a B-vitamin deficient diet and supplementary methionine (a precursor of homocysteine) developed premature vascular lesions. We used this model to determine whether nutritionally induced hyperhomocysteinemia would also accelerate age-related neurological changes characteristic of these mice. 4-week old ApoE-null mice were fed control, B-vitamin (folate, B12 & B6) deficient, B-vitamin deficient and methionine supplemented, and B-vitamin and methionine supplemented diets for eight weeks. Wild type C57/Bl mice fed a control diet were used to establish behavioral and biochemical reference values. After eight weeks, mice underwent behavioral testing that included a series of psychomotor tests, the Morris Water Maze test of spatial memory and learning, and measurement of home-cage exploration and open-field behavior. While no differences in behavioral function were observed between ApoE-null and wild-type mice fed control diets, hyperhomocysteinemia markedly reduced performance on the Morris Water Maze in ApoE-null mice without affecting psychomotor performance, while B-vitamin supplementation appeared to increase home-cage exploration and open-field activity.

Keywords and Comments:

Mammal

41. Zhuo Guan, Bill Adolfsen and J. Troy Littleton

MIT



Speaker: Zhuo Guan | Contact: zguan@mit.edu



Microarray Analysis of Activity-Regulated Gene Expression in the Drosophila Nervous System

Epilepsy is a recurrent seizure syndrome caused by pathological synchronized firing of subpopulations of neurons and is one of the most common neurological disorders in humans. To begin to address the downstream consequences on neuronal function and connectivity induced by increased activity, we have generated a collection of conditional seizure mutants in Drosophila. We find that increasing neuronal activity via disruption of resting membrane potential or action potential repolarization leads to an overproliferation of synaptic connections, indicating activity-dependent rewiring occurs in Drosophila as observed in mammalian epilepsy models. To analyze genome-wide alterations in gene expression resulting from the transcriptional program activated by enhanced neuronal activity, we performed DNA microarray analysis using six Drosophila seizure models and four seizure induction paradigms, allowing us to compare over 100 different activity states in the fly brain. We find substantial alterations in genes involved in metabolism, neuronal connectivity, membrane excitability, and neuronal signaling whose expression are differentially modulated depending upon the cellular mechanisms leading to altered neuronal activity. We have also analyzed mutants that block neuronal activity to determine the effect of neuronal silencing on gene transcription. Using these approaches, we have identified a group of activity-regulated genes that may underlie cellular forms of behavioral plasticity by modulating neuronal function or connectivity as a consequence of activity.

Keywords and Comments:

Gene regulation

42. Dan Hu, Yasuo Kubota, Ann M. Graybiel

MIT



Speaker: Yasuo Kubota | Contact: ykubota@mit.edu



Successive Resculpting of Task-related Activity Patterns in the Striatum during Action-sequence Procedural Learning, Extinction and Relearning

We previously reported a reorganization of task-related unit activity recorded in the rat sensorimotor striatum with tetrodes during acquisition of a T-maze procedural task. We now have recorded ensemble unit activity in this striatal region during extensive over-training, extinction and re-acquisition of the tone discrimination T-maze task. During acquisition training (6-21 sessions), responses to the click warning cue (earliest indicator of task start), opening of the start gate, locomotion onset and goal reaching increased while activity at tone onset and during turning declined. Thus, by the end of training, patterns resembled those reported earlier (Jog et al., 1999), highlighting start and goal-reaching. Over-training (10 sessions) decreased training-induced responses at start and goal reaching. Extinction (5-11 sessions) decreased activity at locomotion onset and goal reaching further, but increased gate- and turn-related discharges. Retraining (5-10 sessions) tended to reinstate the activity patterns expressed during over-training. The persisting plasticity of neuronal activity in the sensorimotor striatum suggests that the activity is related not only to motor acts, but also to previous and current stimulus-response associations. We conclude that learning sculpts striatal activity to form chunked representations of entire action sequences appropriate for the current learning context. Supported by: R01 MH60379 and R03 MH57878

Keywords and Comments:

Mammal

43. Marian Haburcak and Emmanuel N. Pothos

Tufts University School of Medicine



Speaker: Marian Haburcak | Contact: marian.haburcak@tufts.edu



CHOLECYSTOKININ MODULATES CATECHOLAMINE QUANTAL SIZE IN MOUSE ADRENAL CHROMAFFIN CELLS

The neuroactive peptide cholecystokinin (CCK) is known for its physiological functions in the intestine, pancreas, gallbladder and the CNS. Its neuroanatomical profile implicates CCK in the regulation of food intake and certain catecholamine-related disorders including schizophrenia, drug addiction and Parkinson's disease. However, the CCK-catecholamine interactions at the cellular level are still not well understood.We studied the effects of sulfated cholecystokinin octapeptide (CCK-8S) and selective CCK-A and CCK-B receptor antagonists on the evoked release of catecholamines in single quanta from mouse adrenal chromaffin granules. Monoquantal events were monitored after stimulation with 80 mM K+ with carbon fiber microelectrodes. Exposure of adrenal chromaffin cultures to 100 nM CCK-8S for 45 minutes significantly decreased the average catecholamine quantal size from 678380+- 61341 (mean±SEM) molecules to 521356±74691 molecules per vesicle (25 % reduction). The reduction in quantal size appears to be a result of a significant reduction in spike amplitude (from 22.2 pA to 13.5 pA). No significant changes were observed after CCK-8S exposure for 5 and 30 minutes. The CCK-B antagonist L-365,260 (1 uM) significantly increased quantal size by 50% after 30 min, while the CCK-A antagonist L-364,718 (1 µM) did not have any effect. Therefore, any effects of CCK-8S on quantal size appear to be CCK-B receptor mediated. Both CCK-A and CCK-B receptors are present on adrenal chromaffin cultures as established by RT-PCR. The results suggest that catecholamine quantal size (number of neurotransmitter molecules released by a single vesicle during exocytosis) is regulated by the CCK-B receptor through a relatively slow mechanism that may implicate changes in tyrosine hydroxylase activity, monoamine vesicular transporters or second messenger systems.

Keywords and Comments:

Vertebrate

44. Reickhof, G.E., Yoshihara, M. and Littleton, J.T. 

MIT



Speaker: Troy Littleton | Contact: troy@mit.edu



Analysis of the role of N-type calcium channels in synaptic transmission, synapse formation and gene transcription.

Voltage-gated calcium channels are essential for coupling changes in membrane potential to intracellular functions regulated by calcium, including neurotransmitter release and changes in gene expression. Drosophila contains three a-subunit genes, including homologs of the mammalian T-type, L-type (Dmca1D), and N-type (Dmca1A) channels. We have identified three seizure-inducing temperature-sensitive paralytic mutations that disrupt the N-type calcium channel (Dmca1A). Sequence analysis has shown that the most severe allele (NT27) is caused by a replacement of the second arginine to a cysteine in the S4 voltage sensor in the third set of six transmembrane domains of the N-type calcium channel. NT27 mutants have defective neurotransmitter release and reduced synaptic proliferation at the neuromuscular junction. The reduced synapse proliferation in NT27 mutants in not secondary to defective synaptic transmission, as synaptobrevin and syntaxin hypomorphic mutants show a more profound defect in evoked release but do not alter synaptic development. Although null mutations in the N-type calcium channel abolish evoked vesicle fusion, they do not disrupt the initial formation of the synaptic field. Thus, defective calcium entry through N-type calcium channels disrupts the normal developmental proliferation of synapses that occurs during growth of the NMJ, suggesting presynaptic calcium may be an important modulator of synapse proliferation. Microarray analysis of NT27 mutants has revealed altered expression of several downstream targets that may transduce presynaptic calcium signals into alterations in synaptic connectivity.

Keywords and Comments:

Electrophysiology

45. M Seney, H Walker, AM Davis, E Bless, G Schwarting, and S Tobet

UMass Medical School



Speaker: Marianne Seney | Contact: marianne.seney@umassmed.edu



Development of cellular organization in brain regions related to neuroendocrine function.

The preoptic area and hypothalamus contain important clusters of neurons deep in the center of the brain that controls a diverse array of functions ranging from homeostatic mechanisms (e.g., body temperature regulation) to reproductive competence and motivated behaviors (e.g., feeding and drinking). These neurons also play major roles in regulating many sex-dependent functions, such as ovulation in females. These brain regions also contain several cell populations with sex differences in distribution, organization, and/or chemical phenotype. We are characterizing several subgroups chemically and anatomically, and tracing their development in embryos. We also examine factors that influence cell migration patterns and ultimately the final positioning of these migrating cells. Time-lapse video microscopy is used to observe cell movements in slices of embryonic brain tissue. A unique aspect of these regions is that cells come from multiple sites, including the nasal compartment (e.g., neurons that make gonadotropin releasing hormone - GnRH or LHRH). Learning how this exquisitely complex region develops and functions provides a basis for understanding a host of issues ranging from infertility to social behaviors, as well as disorders such as Kallmann and Prader-Willi Syndromes which may be derived, in part, from fundamental problems involving the development of cells in the preoptic area and hypothalamus.

Keywords and Comments:

Mammal

46. Hauser, E.C. 1, dÍAzzo, A. 2, and Seyfried, T.N. 1,

1. Biology Dept., Boston College, Chestnut Hill, MA, USA, 2. Genetics Dept., St. Jude ChildrenÍs Res.Hosp., Memphis, TN, USA



Speaker: Eric C. Hauser | Contact: hauserer@bc.edu



Inheritance of brain beta-galactosidase activities and gangliosides in crosses of DBA/2 and knockout mice

GM1-gangliosidosis is a progressive neurological disease caused by deficiencies in lysosomal acid beta-galactosidase (b-gal) and involves CNS accumulation and storage of ganglioside GM1 and its asialo form (GA1). In humans, this disease is characterized as infantile, juvenile, or adult onset. Similar to the infantile/juvenile human diseases, b-gal knockout (ko) mice express residual brain b-gal activity and elevations of GM1/GA1 and total brain gangliosides. Previous studies suggested that inbred DBA/2 (D2) mice may model the adult human disease since total brain gangliosides and GM1 were higher and b-gal activity was lower (by 70-80%) in D2 mice than in inbred C57BL (B6) mice. An analysis was conducted to determine if the b-gal genes in the D2 and the ko mice were functionally allelic and if the reduced brain b-gal activity in D2 mice could account for elevations in GM1 and brain gangliosides. D2 mice (bgald/bgald, d/d) were crossed with B6/129sv mice (bgal+/bgal-, +/-) to generate d/+ and d/- offspring. The relative specific activity (nmol/mg protein/hr) of whole brain b-gal in 21 day-old +/+, +/d, d/d, d/-, and -/- mice was 65 + 4, 45 + 4, 18 + 1, 14 + 2, and 2 + 0.2, respectively (n = 4). These results show that the D2 and ko genes are allelic. The average brain ganglioside sialic acid concentration (ug/100 mg dry wt) in the 21 day-old +/+, d/d, d/-, and -/- mice was 425, 468, 443, and 597, respectively. The ratio of GM1 to GD1a in these mice was 0.2, 0.4, 0.3, and 1.1, respectively. Furthermore, GA1 was present only in ko mice. These results suggest that the reduced brain b-gal activity in D2 mice cannot alone account for the elevation of total gangliosides and GM1 in these mice.

Keywords and Comments:

Mammal Other Keywords: gangliosides, lysosomal acid beta-galactosidase, GM1-gangliosidosis

47. Steven F. Stasheff,Richard H. Masland

Harvard Medical School



Speaker: Steven F. Stasheff | Contact: sfs@massmed.org



INHIBITORY MECHANISMS IN DIRECTION SELECTIVE RETINAL GANGLION CELLS THAT DRIVE OPTOKINETIC NYSTAGMUS.

We describe new features of "null inhibition" that help explain the function of direction selective retinal ganglion cells (DSGCs), which generate the earliest visual input driving optokinetic nystagmus (OKN; Oyster et al, 1972). This asymmetric wave of inhibition shadows a moving stimulus on its "null" side (Wyatt and Daw, 1975). We recorded DSGCs in the rabbit retina in vitro while stimulating with single or paired moving bars of light, showing that 1) a bar moving through the receptive field in the preferred direction strongly inhibits the response to a second bar following it; and 2) the spatial extent and duration of this inhibitory wave correspond to prior predictions, to the known spatial and temporal frequency tuning of DSGCs, and to the velocity tuning of OKN. This suggests that the same inhibition may govern direction selectivity as well as the spatial and temporal response properties of these cells, and hence of OKN. From our experiments, further insights into this inhibitory mechanism include: 1) it is likely postsynaptic; 2) interactions between dendritic layer-specific ON and OFF inputs, activated by leading and trailing edges of moving bars, contribute to null inhibition and likely are mediated by a multistratified amacrine cell; and finally 3) the total amount of inhibition conferred on the cell, measured by probing with a stationary flashing spot, is the same for stimuli moving in the preferred or null direction. Thus, in contrast to classic "integrate and fire" neurons, the DSGC must compute motion direction within local dendritic subunits. A histological examination of the spatial relationship between excitatory and inhibitory synapses within the dendritic arbor of a DSGC revealed no systematic arrangement (such as alignment of synapses along the preferred-null axis), so identifying the precise nature of local dendritic interactions that mediate this asymmetric inhibition is an avenue for future study.Supported by NIH grant NS-01701-08.

Keywords and Comments:

Mammal retina, direction selectivity, inhibition

48. C.D. Acker(1,3), J.S. Haas(1,3), N.Kopell(2,3), and J.A.White(1,3). (1)Dept. of Biomedical Engineering, (2)Dept. of Mathematics, and (3)Center for BioDynamics, Boston University; Boston, MA 02215. 



Speaker: Julie Haas | Contact: jhaas@bu.edu



PREDICTING SYNCHRONY IN THE OSCILLATORY STELLATE CELLS OF THE ENTORHINAL CORTEX

Layer 2 Stellate cells (SCs) of the entorhinal cortex are intrinsic neuronal oscillators that participate in the theta rhythm, a 4-12 Hz rhythm associated with learning and memory. In studying synchronization properties of SCs, we have developed a method for predicting spike times, using models of SCs. These spike time response maps (STRMs) can be used to predict synchrony between coupled pairs of SCs. STRMs are straightforward to measure in a model, and allow us to study the relationship between biophysical properties of cells and their behavior in a network. In models, STRMs also account for counterintuitive results of varying coupling strengths between cells. Slow conductances in these cells, including Ih and possibly a slow potassium conductance, seem to play a large role in the synchronization via excitation. Neuronal noise participates in synchronization as well. We have developed a method for experimentally measuring STRMs in SCs, which account for variability introduced by adaptation and frequency wobble, and our results match the models' predictions in general features. We also investigate the effects of blocking various constituent currents on the cells' STRMs. Future work includes implementation of a symmetrical two-cell SC network in a dynamically clamped setup, to directly verify the models' predictions.

Keywords and Comments:

Electrophysiology

49. Cleane Medeiros, UFPB,Eddie Rowan, University of Strathclyde, Glasgow,Alan L. Harvey, University of Strathclyde,

Federal University of Paraiba, School of Medicine, Campina Grande



Speaker: Cleane Medeiros | Contact: CleaneMedeiros@aol.com



Electrophysiological effects of BgK, a potassium channel blocker

BgK is a K+ channel blocking toxin from the Caribbean sea anemone Bunodosoma granulifera. It is a small protein composed of 37 amino acids that are crosslinked by three disulfide bridges. BgK adopts a novel folding pattern unrelated to scorpion toxins such as ChTx and AgTx2, and different from others sea anemone toxins such as ShK. The functional effects of BgK were investigated by using its alanine substituted mutants on B82 cells expressing cloned Shaker rKv1.2 channel using whole cell patch clamp experiments. BgK blocked K+ currents without affecting the midpoint of channel activation and steepness of the curve. Its effect was voltage- and concentration-dependent. BgK also affected the gating properties of rKv1.2 channels by decreasing the activation time constant and increasing the deactivation time constant compared with control. Different amino acid residues are responsible for the effect of BgK on activation (K7, E8, R12, K15, S16, L17, K25 and N29) and deactivation (W5, F6, L17 and R21). It suggested that the effect of BgK on activation could be centered on three sites of the toxin, each of them centered on a lysine, which are K7-E8, K15-S16-L17, and K25. Apart from L17, the residues W5, F6 and R21 seems to be involved on BgK's effect on deactivation, which suggest that BgK has several non overlapping sites responsible for its effect on gating properties of rKv1.2 channel.

Keywords and Comments:

Electrophysiology

50. C.E. Higgins, C.T. Burket, S. Hubbard and E.F. Ryder 

Worcester Polytechnic Institute



Speaker: Christina Higgins | Contact: thiggins@wpi.edu



Characterization of dig-1, a gene involved in adhesion of sensory neuron processes in C. elegans

Mutations in the gene dig-1 cause morphological defects in the sensory processes of several types of ciliated sensory neurons in C. elegans. Mutant processes deviate from their usual straight paths and sometimes fail to reach their normal destinations in the nose. dig-1 mutant animals also exhibit additional characteristics consistent with a developmental defect in cell adhesion. dig-1 has been mapped to a region on chromosome III near sma-3. A candidate adhesion molecule in this region is predicted by Genefinder (P.Green and L. Hillier, unpublished) to have a cDNA of approximately 40 kb. BLAST analysis revealed three distinct protein domains encoded by the candidate gene: a region at the 5' end containing Ig and Fn Type III repeats, a highly repetitive middle region, and a region at the 3' end containing a Von Willebrand factor Type A motif. One dig-1 mutant allele is a point mutation near the 5' end of the repeated region, while another dig-1 allele is a rearrangement involving 900 base pairs toward the 3' end of the repeated region. Interestingly, the point mutation causes a more severe mutant phenotype than the rearrangment. RT-PCR was used to amplify segments along the whole dig-1 gene. Results were consistent with the idea that dig-1 encodes a single, large transcript, although alternative splicing of the gene may also occur. Investigation into dig-1 expression continues by means of northern blotting techniques and through production of antibodies to the three domains of the putative dig-1 protein.Supported by: NSF CAREER grant 9984662

Keywords and Comments:

Invertebrate

51. Alan D. Dorval,John A. White

Boston University



Speaker: Alan Dorval | Contact: bionic@bu.edu



General Purpose Dynamic Clamp for Constructing Virtual Ion Channel Conductances in Living Neurons

We introduce an inexpensive, flexible and powerful means to add artificial conductances to living neurons. Our dynamic clamp system measures membrane potential and calculates the current that would be provided by a user-defined membrane mechanism if its physical analogue were inserted into the neuronal membrane. The current is calculated and passed back to the cell in real time at frequencies of up to 40kHz.We have implemented a variety of conductance-based models. Ion channel populations (intrinsic and synaptic) have been simulated both as deterministic Hodgkin-Huxley style equations and more accurately as voltage dependent Markov processes exhibiting stochastic gating. In addition to membrane conductances, entire dendrites can be constructed and attached to living cells. Passive and active artificial dendrites with nonlinear voltage dependence are presented.We explore several of these conductance models in conjunction with an artificial cell membrane circuit composed of a physiologically realistic resistance and capacitance in parallel. The ability of our dynamic clamp to simulate fast, nonlinear conductances in real time is examined through a variety of examples, which illustrate the general usefulness of this method for a number of potential experiments. End-users with basic programming skills can easily build customized artificial membrane mechanisms. The hardware required by the system is standard in electrophysiology labs. Our dynamic clamp software is available for free on our web site, http://www.bu.edu/ndl/rtldc.html. This work was supported by grant #BES-0085177, National Science Foundation.

Keywords and Comments:

Electrophysiology

52. Eaton, M.E., Dudman, J.D., Ripoll, L.H., Taher, M. and Konradi, C.

McLean Hospital, Harvard Medical School



Speaker: Molly E. Eaton | Contact: mollyeaton@mclean.harvard.edu



Neuroplasticity by the Antipsychotic Drugs Haloperidol and Clozapine

One approach to understanding the mechanisms by which psychiatric disorders occur in the brain is to look at effective therapies and to determine their mechanisms of action. Several antipsychotic agents have been determined to be effective in treating schizophrenia. Neuronal adaptations such as synaptic plasticity and neurogenesis are thought to underlie their mechanisms of therapeutic action. It has been proposed that the plastic changes generated by antipsychotic drugs lead to the formation and stabilization of synaptic connections, thus counteracting the inadequate synaptic organization that has been associated with schizophrenia.We focus on the conventional antipsychotic drug, haloperidol, and the atypical antipsychotic, clozapine. We will present new evidence of neuronal plasticity in response to treatment with these agents. We will show how exposure to antipsychotic drugs leads to the activation of signal transduction pathways and transcription factors. In addition, we will show gene array analyses of the effects of chronic antipsychotic treatment on gene expression. Finally, we have used BrdU labeling of hippocampal neurons to assess neurogenesis by antipsychotic drugs.This work was supported by NIDA (DA07134) and by NARSAD.

Keywords and Comments:

Gene regulation

53. Judith Chapman, Alison Barnstable, and Andrea Simmons

Brown University



Speaker: Andrea Simmons | Contact: Andrea_Simmons@Brown.edu



Regeneration in the adult vertebrate n.VIII: Behavioral and genetic response

Bullfrogs (Rana catesbeiana) are known to regenerate their eighth cranial nerve (nVIII) after crush lesion. The purpose of this experiment is to examine patterns of gene expression correlated with regeneration and recovery of auditory/vestibular function. We expect to find changes in mRNA expression in regenerative tissues; patterns of mRNA expression should vary depending on stage of recovery. In addition, vestibular function should vary along with mRNA expression.  Frogs' nVIII were subjected to unilateral or bilateral crush lesion via a ventral approach. Sham surgical animals served as controls. Posture and response to rotational motion were monitored daily. Animals were sacrificed at varying time points and nVIII, including medullary targets, were separated and processed for differential display.

Keywords and Comments:

Vertebrate

54. Jill M. Grimes and Richard H. Melloni, Jr. Ph.D.

Northeastern University



Speaker: Jill M. Grimes | Contact: grimes.j@neu.edu



Adolescent Anabolic Steroids, Serotonin and Aggression in Hamsters

Chronic anabolic-androgenic steroid (AAS) treatment during adolescence facilitates offensive aggression in male Syrian hamsters (Mesocricetus auratus). The current study assessed whether adolescent AAS-facilitated offensive attack was modulated by serotonin and if AAS exposure during this developmental period influenced serotonin innervation to the aggression areas of hamster brain. In a first experiment, hamsters were administered high dose AAS throughout adolescence and then scored for offensive attack following the systemic administration of saline or fluoxetine, a selective serotonin reuptake inhibitor. Saline-treated hamsters showed high levels of offensive attack, while treatment with fluoxetine attenuated the AAS-facilitated aggressive response. In a second experiment, hamsters were administered high dose AAS or sesame oil throughout adolescence, tested for offensive aggression, and then examined for differences in serotonin innervation to areas of the hamster brain implicated in aggressive responding. Aggressive AAS-treated hamsters showed significant reductions in the number of serotonin immunoreactive varicosities and fibers in several aggression areas, most notably the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. However, no differences in serotonin afferent innervation were found in other aggression areas, such as the bed nucleus of the stria terminalis and lateral septum. Together, these results support a role for altered serotonin innervation and function in adolescent AAS-facilitated offensive aggression.

Keywords and Comments:

Vertebrate

56. K.R. DeLeon, J.M. Grimes and R.H. Melloni, Jr. Ph.D.

Northeastern University



Speaker: Jill M. Grimes | Contact: grimes.j@neu.edu



Adolescent Cocaine, Serotonin and Aggression in Hamsters

Repeated low dose cocaine treatment (0.5 mg/kg/day) during adolescence facilitates offensive aggression in amle Syrian Hamsters (Mesocricetus auratus). the current study assessed whether adolescent cocaine-facilitated aggression was inhibited by serotonin treatment and if cocaine exposure during this developmental period influencced serotonin development in the anterior hypothalamus, a primary aggression area of hamster brain. In a first experiment, hamsters were administered low dose cocaine throughout adolescence and then scored for offensive aggressionfloowing IP injections of vehicle or fluoxetine, a selective serotonin reuptake inhibitor. Vehicle-treated hamsters showed high levels of offensive aggression, while treatment with fluoxetine inhibited the cocaine-facilitated aggressive response. In a second experiment, hamsters were administered low dose cocaine or saline throughout adolescence, tested for offensive aggression, and then examined for differences in serotonin innervation to the anterior hypothalamus. Aggressive cocaine-treated hamsters showed significant reductions in the number of serotonin immunoreactive varicosities when compared to saline controls. These results support a role for altered serotonin development and function in adolescent cocaine-facilitated offensive aggression.

Keywords and Comments:

Vertebrate

58. Motojiro Yoshihara and J. Troy Littleton

Center for Learning Memory at MIT



Speaker: Motojiro Yoshihara | Contact: motojiro@mit.edu



A three stage model for calcium triggered SNARE-mediated vesicle fusion by synaptotagmin I.

The fundamental aspects of neurotransmission have long been studied at the electrophysiological level and were expounded upon by Katz (1969) in which he introduced the "calcium hypothesis" of neurotransmitter release. Calcium (Ca2+) influx into the presynaptic terminal triggers synaptic vesicle fusion through activation of the SNARE complex fusion machinery. Although it is unknown how Ca2+ influx is coupled to SNARE-mediated fusion, one hypothesis is that Ca2+ acts through the synaptic vesicle protein, synaptotagmin, which contains two Ca2+ binding C2 domains (C2A and C2B). We have performed an electrophysiological analysis of complete and partial loss-of-function alleles of Drosophila synaptotagmin I. Our results suggest a three stage model for Ca2+ triggered SNARE-mediated fusion by synaptotagmin I. These include: 1) a non-Ca2+-cooperative step, likely mediated by the Ca2+-dependent binding of the C2A domain to plasma membrane lipids; 2) a Ca2+-cooperative step that requires an intact C2B domain to allow synaptotagmin to form high affinity interactions with SNARE complexes; and 3) multimerization of synaptotagmin I via Ca2+-dependent oligomerization through the C2B domain. Our studies indicate that Ca2+ binding to synaptotagmin mediates both cooperativity of calcium action (by promoting the formation of synaptotagmin-SNARE interactions) and sensitivity to Ca2+(by promoting lipid association and oligomerization). Synaptotagmin also suppresses asynchronous neurotransmitter release in sustained calcium by promoting rapid and synchronous vesicle fusion. Our findings suggest synaptotagmin I is a highly efficient Ca2+ sensor in vivo and may trigger fusion pore formation by binding and clustering SNARE complexes and mediating local lipid rearrangements at the site of fusion.

Keywords and Comments:

Invertebrate

59. John A. White, Biomedical Engineering Department, BU,,Nancy Kopell, Mathematics Department, BU

Program in Neuroscience, Boston University



Speaker: Jason Ritt | Contact: jritt@math.bu.edu



Neuronal Responses to Aperiodic Stimuli

Motivated by experimental and theoretical studies of the reliabilityof neuronal responses to repeated presentations of a stimulus, wepresent a dynamical model for the entrainment of neurons toaperiodic stimuli. Our goal is to extend previous results availablefor inputs which are weak and/or periodic in time. We are particularlyinterested in short-time responses to transients.

Keywords and Comments:

Modeling

60. Concepcion Sanchez-Moreno, Dayong Wu, Simin Nibbin Meydani, ,and Antonio Martin.

Tufts University



Speaker: Antonio Martin | Contact: amartin@hnrc.tufts.edu



EFFECT OF THE PROINFLAMMATORY CYTOKINE TNFa ON PHOSPHOLIPASE A2 AND COX-2 EXPRESSION, AND ITS IMPACT ON PGE2 SYNTHESIS.

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain. Cumulated over many years, direct effect of the inflammatory processes is likely to exacerbate the pathogenesis processes that give rise to AD. Prostaglandins (PGs) are synthesized in the CNS and modulate several complex brain functions, however, PGs have also been implicated in the pathogenesis of AD. Increased levels of PGE2 have been detected in the cerebrospinal fluid of AD patients.Cultured human astrocytes (HA) were employed to investigate the role of phospholipase A2 (PLA2) and cyclooxygenase (COX-1 and COX-2) on PGE2 synthesis upon exposure to cytokines. HA exposed to Tumor Necrosis Factor (TNFa) at concentration of 10 ng/mL increased the synthesis of PGE2 by 850%, from 210±28 pg/mL to 2000±246 pg/M, (p=0.0001). However, when cells were pretreated with aspirin (500 µmol/L) for 1 hr before being exposed to TNFa, the levels of PGE2 decreased to 53±30 pg/mL, (p=0.0001). HA incubated with TNFa caused a 15% reduction in 20:4(n-6) fatty acid concentration, (p=0.035) compare with the untreated control cells. When we examined the expression of cPLA2, we observed a 122% increase. However, in cells pretreated with aspirin, TNFa-induced increase in cPLA2 expression was abolished. No effect of TNFa on COX-1 expression was observed. However, expression of COX-2 was increased by 46% following exposure to TNFa. We conclude that TNFa causes a large increase in PGE2 synthesis, which appears to be regulated by cPLA2 and COX-2 in a "two-component" model. Pre-treatment of the HA with nonstereoidal anti-inflammatory drugs (NSAID) preserved 20:4(n-6) levels in cells, suggesting that the 20:4(n-6) fatty acid was not released from membrane phospholipids or it was not used for the synthesis of 20:4(n-6)-derived prostaglandin PGE2 during the inflammatory process. Thus, reduction of the inflammatory response by NSAIDs and/or a combination of NSAIDs and antioxidants may be relevant to reduce neuronal damage. (Supported by USDA Intramural)

Keywords and Comments:

Glia

61. Meghan M. Searl, Haline E. Schendan, Rebecca J. Melrose, Chantal E. Stern

Boston University



Speaker: Meghan Searl | Contact: mmsearl@bu.edu



A FMRI STUDY OF THE ROLE OF THE MEDIOTEMPORAL LOBE IN IMPLICIT AND EXPLICIT SEQUENCE LEARNING

fMRI was used to investigate the neural substrates underlying implicit and explicit sequence learning. During both implicit and explicit learning, six people (18 - 27 years; 3 female) performed a serial reaction time (SRT) task, pressing the key at the same location (four possible) as on the screen. Twelve-item second-order conditional sequences either repeated or were pseudo-random in alternate blocks. For implicit learning, participants were naive about the repeating pattern of locations, whereas for explicit learning, they were asked to memorize the repeating sequence. There were four scanning runs (3T Siemens, TR=2 s, flip angle=90o, 21 slices of 5 mm, 0.2 skip, 184x256, 1250 ms per trial) each of implicit and explicit learning. Explicit memory was assessed using generationand recognition tests following completion of all implicit or explicit runs. Explicit knowledge was also queried after all implicit runs were completed. RESULTS: Behavioral analyses revealed clear evidence of explicit memory for the repeating sequence following explicit learning but little or no evidence following implicit learning. fMRI analyses (SPM99) using contrasts of repeated versus random sequence blocks showed activation of frontal, parietal, cingulate and subcortical regions implicated in previous SRT studies. In addition, we report the novel finding of anterior mediotemporal lobe (MTL) involvement during SRT learning. These findings are consistent with animal studies that suggest MTL structures are important for temporal sequence learning.

Keywords and Comments:

Vertebrate

62. L. Davis, D. Kraemer, P. Holcomb, D. Abrams, J. Choi, Y. Han, S. Hofflich

Tufts University



Speaker: Laura Davis | Contact: ldavis@neurocog.psy.tufts.edu



ERP Evidence for Semantic Congruity Effect in Environmental Sound Processing

ERPs elicited by congruous or incongruous environmental sound sequences show a component similar to the N400 reported in language studies. Results from many ERP language studies support the relationship of N400 amplitude to an on-line integration process. With word or sentence stimuli, increases in N400 amplitude can be explained with the semantic integration hypothesis: more integration effort is needed when less supporting context is available. Context is established as each associated word meaning becomes activated and integrated into a higher level representation, creating expectations for following ideas. This representation can facilitate recognition of subsequent words that are congruous but will impede recognition of incongruous words. A traditional N400 in sentence processing will be more negative for semantic anomalies than for context-appropriate words. Familiar non-linguistic sounds may involve activation of stored meanings and also require a similar on-line integrator. To investigate this, 66 environmental sound sequences were divided into context-building and target sounds. Two conditions were created: target sounds were either congruous or incongruous with the immediately preceding context. Sound pairs were presented through headphones while subjects were engaged in a 'makes sense' / 'doesn't make sense' judgement task about each pair. ERPs for incongruous targets have greater negativity than congruous targets. This suggests the N400 component is truly a reflection of the cognitive processes used during higher level semantic integration and is not limited to linguistic stimuli.

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Electrophysiology

63. Hyman, J. M., Goyal, V., Wyble, B. P., & Hasselmo, M. E. 

Boston University



Speaker: James Hyman | Contact: hyman@bu.edu



Phasic relationships of LTP and behavior to the theta rhythm in the rodent hippocampus.

Computational modeling suggests that the hippocampal theta rhythm may play a functional role in separation of encoding and retrieval dynamics (Hasselmo et al., 2001). During encoding, entorhinal input should be strong, but the excitatory connections within the hippocampus should be weak while undergoing LTP. During retrieval, entorhinal input should be weak, but the excitatory connections within the hippocampus should be strong while undergoing LTD. This model has certain physiological requirements: 1.) for an effective encoding phase, long-term potentiation of EPSPs in stratum radiatum of region CA1 should be strongest at the time of weakest transmission in stratum radiatum (peak of the local theta wave), 2.) for effective behavior, relevant sensory input should arrive at the time of the peak of the EEG in s. radiatum, while behavioral response should be generated at the trough of the EEG in s. radiatum.We have performed experiments testing these requirements. It has been shown that in hippocampal slices and in vivo recordings from anesthetized animals, that EPSP's can either be potentiated or depotentiated by stimulating on the peak or the trough of the local theta wave, respectively. We examined LTP induction in the awake behaving rat and showed that LTP can be induced (mean EPSP increase for slope=19%; amplitude=18%; n=4) by delivery of three high frequency bursts at the peaks of local theta activity, while delivery of the same frequency and amplitude HFS at the troughs of local theta results in decreased EPSP's (mean decrease for slope=21%; amplitude=15%; n=4).

Keywords and Comments:

Electrophysiology

64. J.C. King, A.M. Zardetto-Smith, L.L. Haak, E.M. Weerts, J.B. McCormick, ,

Tufts University School of Medicine



Speaker: Joan C. King, | Contact: joanking@concentric.net



WOMEN IN NEUROSCIENCE - A BRIEF HISTORY

Women in Neuroscience (WIN) is an international organization, founded in 1980 for the purpose of fostering the development and career advancement of women scientists in the field of neuroscience.In the past 20 years, WIN has advocated for women scientists by providing resources for networking and professional advancement. The organization has sponsored educational workshops and seminars at the annual Society for Neuroscience meetings since 1981. These seminars and workshops focus on personal and professional development skills. WIN awards travel stipends each year, aided by a yearly grant from Eli Lilly. Postdoctoral, graduate, and undergraduate students receive these awards to attend and present their research at the Society for Neuroscience annual meeting. WIN encourages local groups to establish and nurture chapters, especially in cities in which there is a cluster of research institutes. You can find out more about WIN by contacting one of the current executive board members and/or by visiting the WIN website . 

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Last update: Mon, Mar 4, 2002.

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