_______________________
The Greater Baltimore Chapter
of the Society for Neuroscience
_____________________________
Annual Regional Meeting
November 13, 2015
University of Maryland School of Medicine
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Special Thanks
A very special thanks to the following Departments, Programs and Individuals for their generous
financial contributions, or help in general, in support of this local chapter annual meeting:
National Society for Neuroscience
Department of Anatomy and Neurobiology
University of Maryland, School of Medicine
Chair, Dr. Michael Shipley
Department of Pharmacology
University of Maryland, School of Medicine
Chair, Dr. Margaret M. McCarthy
Department of Physiology
University of Maryland, School of Medicine
Chair, Dr. Scott Thompson
Department of Psychiatry
University of Maryland, School of Medicine
Chair, Dr Bankole Johnson
Department of Neuroscience
Johns Hopkins University, School of Medicine
Director, Dr. Richard Huganir
Undergraduate Program in Neuroscience
Johns Hopkins University
Director, Dr. Linda Gorman
Program in Neuroscience
University of Maryland, School of Medicine
Director, Dr. Michael Shipley
Andor Technology Ltd
Nikon Instruments, Inc.
The Greater Baltimore Society for Neuroscience Executive Committee:
Tom Blanpied, President
Iris Lindberg (Treasurer), Dan O’Connor, Nicholas Marsh-Armstrong, Hey-Kyoung Lee, Sarah
Metzbower, David Foster, Gerald Rameau, Cristina Banuelos and Linda Gorman
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The executive committee would also like to thank Krishna Subramanian from the Hussman Institute for
Autism, Amanda Labuza and the University of Maryland School of Medicine Neuroscience Outreach
and Volunteer Association and Student Training Committee, and the Johns Hopkins **** for all of their
help.
Photo Credits:
Description: Specimen - Dissociated rat hippocampal neuron expressing a GFP-tagged transmembrane protein
(green) and a mCherry-tagged postsynaptic scaffold protein (red); Technique: Spinning disk confocal; Credits:
Tuo Peter Li, Graduate Research Assistant, MSTP, University of Maryland School of Medicine and Dr. Thomas A.
Blanpied, Ph.D., Associate Professor, Department of Physiology, University of Maryland School of Medicine
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Susan Amara, PhD
Scientific Director NIMH IRP
Lab of Molecular and Cellular
Neurobiology
Dr. Amara is currently the Scientific Director of the Intramural Research Program at the National
Institute of Mental Health. Work in her laboratory has focused on the structure, function, and cellular
physiology of neurotransmitter transporters, including glutamate transporters as well as the biogenic
amine transporters, major targets for psychostimulant drugs and antidepressants. She received a BS
from Stanford University, a PhD in Physiology and Pharmacology from the University of California, San
Diego and has previously held faculty positions at Yale University School of Medicine, at the Vollum
Institute in Portland Oregon and as a Howard Hughes Medical Institute Investigator at Yale and in
Oregon. Prior to moving to NIH she served as the Thomas Detre Chair of Neurobiology and
Distinguished Professor at the University of Pittsburgh, School of Medicine. She is a member of the
National Academy of Sciences (2004), a fellow of the AAAS (2007) and a past-President of the Society
for Neuroscience (2011).
Work in Dr. Amara’s laboratory has examined the impact of psychostimulant and antidepressant drugs
on the signaling properties, physiology and acute regulation of biogenic amine transporters. Her group
has also addressed the structure, function and physiology of glutamate transporters. This work has
demonstrated that transporters can serve dual functions as transporters and as substrate-gated ion
channels, revealing additional mechanisms by which carriers regulate neuronal excitability. Dr. Amara’s
laboratory continues to investigate the regulation of transporter function and trafficking by
amphetamines, structure-function relationships in excitatory amino acid transporters (EAATs),
modulation of dopamine transporters (DAT) by GPCRs, and genetic and functional analyses of human
trace amine receptors.
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Photo Credits:
Description: Specimen - Mouse Primary hippocampal cell culture, 7DIV. ICC staining for Neurofilaments
(Alexa568-Red), GFAP (Alexa488-Green) and DAPI (Blue); Technique: Spinning disk confocal; Credits: From the
lab of Dr. Yu-Chih Lin, Ph.D. Investigator, Hussman Institute for Autism, Baltimore and Dr. Michaela Kilander,
Ph.D., Postdoctoral Research Fellow, Hussman Institute for Autism, Baltimore
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11:00am-noon Schedule
11:30am-1:00pm
12:15-3:15pm Outreach session – Room 203
1:00-2:30pm
3:00pm Poster set-up/Registration/Lunch- Elm Ballrooms
3:30
3:45pm Poster Session- Elm Ballrooms
4:45-5:00pm Student Talks- Room 349
Coffee Available- Elm Ballrooms
Opening Remarks- Room 349
Dr. Thomas Blanpied, President
Keynote Address- Room 349
Dr. Susan Amara
Scientific Director of the Division of
Intramural Research Programs
National Institute of Mental Health
“Neurotransmitter transporters & the cellular
mechanisms of amphetamine action”
Poster Awards
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SCHEDULE OF TALKS
1:00pm Haiwen Chen
Distinct organization of evoked and spontaneous vesicle fusion sites within single CNS active zones.
1:15pm Han Tan
GRIP1 is required for homeostatic regulation of AMPAR trafficking.
1:30pm Varun Chokshi
Homer1a signaling in visual cortex plasticity.
1:45pm Chase Francis
EGR3 expression in nucleus accumbens medium spiny neuron subtypes oppositely controls outcomes
of social defeat stress.
2:00pm Lindsay De Biase
Microglia establish region specific phenotypes in the basal ganglia and exhibit variable responses to
normal aging.
2:15pm John Fedota
Nicotine withdrawal induces negative correlation in resting connectivity between insula and executive
control network in smokers.
Description: Specimen - Double-labeled
immunofluorescence of the cerebellar cortex in a
tissue section from a post-mortem young adult
case demonstrated from this confocal image.
Purkinje cells (purple) are labeled for the neuro-
protective enzyme aldolase-C; Purkinje cell
dendrites (green) in the molecular layer are
labeled with excitatory amino acid type 4 (EAAT4).
Excitatory input to the cerebellar cortex may be
altered in autism cases and some GABAergic
Purkinje cells don’t survive which may be due in
part to increased vulnerability.
Credits: Dr. Gene J Blatt, Ph.D., Director of
Neuroscience, Hussman Institute for Autism,
Baltimore
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ABSTRACTS OF TALKS
Haiwen Chen
DISTINCT ORGANIZTION OF EVOKED AND SPONTANEOUS VESICLES FUSION SITES WITHIN SINGLE CNS ACTIVE
ZONES
Haiwen Chen1,2,3, Ai-Hui Tang1,2, Sarah Ransom Metzbower1,2, Thomas A. Blanpied1,2
1Department of Physiology, 2Program in Neuroscience, and 3Medical Scientist Training Program, University of
Maryland School of Medicine, Baltimore, MD 21201, USA
Because glutamate receptors are inhomogenously distributed in the postsynaptic density, the organization of
vesicle docking and fusion sites within single active zones (AZs) will strongly influence synaptic strength.
However, there is extremely limited information about where within the AZ action potentials trigger vesicle
fusion, and even less about the location of spontaneous vesicle fusion. Interestingly, there is controversy over
whether spontaneous and evoked release utilize different vesicle pools, involve different trafficking and fusion
machinery, or activate different groups of receptors. All these factors suggest that spontaneous and evoked
fusion could be organized at spatially distinct regions of the AZ, but this has not been tested.
To address this, we first studied the subsynaptic distributions of key presynaptic proteins likely to define vesicle
fusion sites, including RIM1/2, Munc13, and Bassoon. Using 3D dSTORM on immunostained cultured
hippocampal neurons, we found that all three protein distributions were distinctly heterogeneous with high
local-density peaks (~80-110 nm in diameter), which we identified as nanodomains (NDs). Interestingly, though
these proteins largely overlapped in the AZ, they were distinct in not only cluster volumes, but number and size
of NDs. Compared to the postsynaptic scaffolding protein PSD-95, RIM1/2 had similar size and number of NDs,
while Munc13 had similar size but greater number, and Bassoon had larger size but lesser number of NDs.
Previous work has suggested that these proteins play different roles in evoked and spontaneous release. For
instance, while RIM1α knockout impairs only evoked but not spontaneous release, Munc13 knockout impairs
both. Given the distinct distributions of these proteins, we hypothesized that the evoked and spontaneous
vesicle fusion sites will also differ spatially. To test this, we developed a novel technique to localize single-vesicle
fusion with high spatial resolution in live synapses by adapting single-molecule localization for single-vesicle
fusion signals obtained with vGlut1-pHluorin. We called this approach “pHluorin uncovering sites of exocytosis”
or pHuse. Using pHuse, we compared the pattern of evoked and spontaneous vesicle fusion at individual
presynaptic terminals. This revealed that evoked fusion occurred over a significantly smaller area of the terminal
than spontaneous fusion. We conclude that differential protein organization in the AZ dictates nanometer-scale
distribution of vesicle fusion mode.
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Han Tan
GRIP1 IS REQUIRED FOR HOMEOSTATIC REGULATION OF AMPAR TRAFFICKING
Han L. Tan, Bridget N. Queenan, and Richard L. Huganir
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD
21205
Homeostatic plasticity is a negative feedback mechanism that stabilizes neurons during periods of perturbed
activity. The best-studied form of homeostatic plasticity in the central nervous system is the scaling of excitatory
synapses. Postsynaptic AMPA-type glutamate receptors (AMPARs) can be inserted into synapses to compensate
for neuronal inactivity or removed to compensate for hyperactivity. However, the molecular mechanisms
underlying the homeostatic regulation of AMPARs remain elusive.
In this study, we found that the expression and subcellular distribution of GRIP1, a multi-PDZ (postsynaptic
density 95/discs large/zona occludens) domain AMPAR-binding protein, are regulated during synaptic scaling.
Hyperactivity increases total GRIP1, primarily in the cytoplasmic pool, whereas synaptic GRIP1 is reduced.
Conversely, inactivity decreases GRIP1 expression, reflecting a loss of cytoplasmic GRIP1, and the remaining
GRIP1 protein becomes enriched at synapses. Further, these changes result in altered interaction between
GRIP1 and GluA2 at specific subcellular locations. Further GRIP1 is essential for synapse strengthening during
homeostatic scaling up. GRIP1 knockout neurons have reduced surface AMPARs under basal conditions and are
unable to up-regulate surface AMPARs or synaptic strength during chronic activity suppression.
Our results support the model that GRIP1 regulates AMPAR trafficking by shuttling receptors between the two
distinct pools. Inactivity increases the pool of synaptic GRIP1 and strengthens the association between GRIP1
and synaptic AMPARs, stabilizing surface AMPARs at synapses. Simultaneously, cytoplasmic GRIP1–GluA2
interactions are disrupted to relieve intracellular retention, promoting additional trafficking and accumulation of
AMPARs at the plasma membrane. During elevated activity, GRIP1 is removed from synapses and accumulates
within the cytoplasm, consequently leading to reduced surface AMPARs.
Collectively, our data point to an essential role of GRIP1-mediated AMPAR trafficking during inactivity-induced
synaptic scaling.
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Varun Chokshi
HOMER1A SIGNALING IN VISUAL CORTEX PLASTICITY
Varun Chokshi(1,2), M Gao(4), PWorley(3), and Hey-Kyoung Lee (1,2,3)
(1) Department of biology; (2)Mind Brain Institute, Johns Hopkins University, Baltimore MD; (3) Neuroscience,
Johns Hopkins Med. School, Baltimore, MD; and (4) Div. of Neurol., Barrow Neurolog. Inst., Pheonix, AZ
Visual experience modulates the strength of neuronal transmission in mouse primary visual cortex especially
during the critical period for ocular dominance plasticity (ODP). Both hebbian and homeostatic plasticity of
excitatory synapses are implicated in ODP. We found that metabotropic glutamate receptor mGluR5 signaling is
required for experience-dependent homeostatic regulation of synaptic α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptor mediated miniature excitatory postsynaptic current (mEPSC) amplitude
in the superficial layers of visual cortex. mGluR5s are coupled to synaptic proteins by the long forms of Homer1
(Homer1b/c), which are scaffolding proteins. Its splice variant Homer1a is expressed upon neuronal activity and
displaces the long forms of Homer1 from mGluR5. In Homer1a knock out mice, we observe a deficit in
experience-dependent synaptic scaling. Recent studies suggest that homeostatic synaptic plasticity plays a role
in ODP. To determine whether Homer1a signaling is involved in ODP, we are currently examining whether ODP
is affected in Homer1a KO mice using intrinsic signal imaging.
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Chase Francis
EGR3 EXPRESSION IN NUCLEUS ACCUMBENS MEDIUM SPINY NEURON SUBTYPES OPPOSITELY CONTROLS
OUTCOMES OF SOCIAL DEFEAT STRESS
T.C. Francis (1), R. Chandra (1), L.M. Riggs, P. Konkalmatt, S. Iñiguez, M.K. Lobo (1)
(1) University of Maryland, Batlimore (2) California State University, San Bernardino
The Nucleus Accumbens is a principle integrator of reward related information within the brain and is highly
implicated in depression. The NAc consists primarily of two projection neuron subtypes, medium spiny neurons
(MSNs), which are differentiated by dopamine receptor expression, either dopamine 1 receptors (D1) or
dopamine 2 receptors (D2). Social defeat stress (SDS), a well-validated stress paradigm to induce depression-like
symptoms, promotes dichotomous behavioral, electrophysiological, and molecular outcomes in these MSN
subtypes. SDS produces two distinct behavioral phenotypes: mice susceptible to SDS (i.e., displaying depression-
like symptoms) or mice resilient to SDS. We found repeated high frequency 473 nm optogenetic stimulation
(≥50 Hz stimulation) of NAc D1-MSNs promotes resilience to a 10 day chronic (C)SDS, while repeated stimulation
of D2-MSNs promotes susceptibility to subthreshold (S)SDS. Quantitative real-time PCR revealed repeated
stimulation of either MSN subtype reduces NAc expression of the transcription factor early growth response 3
(Egr3). Egr3 is a primary target of brain-derived neurotrophic factor (BDNF) TrkB signaling. Disrupting this
signaling pathway from the VTA-NAc circuit promotes resilience. Given the known effects of BDNF disruption on
SDS behavior and the opposing outcomes of MSN subtype stimulation, we hypothesized reduction of Egr3
expression in D1-MSN subtypes would promote resilience to SDS and reduction in D2-MSN subtypes,
susceptibility. To mimic stimulation induced down-regulation of Egr3 in cell subtypes, a conditional double
inverted open reading frame (DIO) adeno-associated virus (AAV) expressing an Egr3-miRNA was injected in the
NAc of D1-Cre and D2-Cre mice. Egr3 miRNA knockdown in D1-MSNs enhanced resilience to CSDS, while Egr3
miRNA knockdown in D2-MSNs induced susceptibility to SSDS. These results suggest Egr3 knockdown mimics
MSN subtype-specific stimulation-induced outcomes to SDS. To examine the consequence of enhanced Egr3
expression in MSN subtypes, we injected a DIO-AAV construct to overexpress Egr3. In contrast to knockdown of
Egr3, overexpression of Egr3 in D1-MSNs promoted susceptibility to SSDS, while overexpression in D2-MSNs
produced enhanced resilience to CSDS. Preliminary electrophysiological recordings suggest enhancing Egr3
expression reduce excitatory input to MSN subtypes. Our results suggest Egr3 manipulation in MSN subtypes
oppositely mediates outcomes to SDS. Further, these changes are likely due to alterations in excitatory synaptic
transmission which may underlie the behavioral outcomes to SDS.
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Lindsay De Biase
MICROGLIA ESTABLISH REGION SPECIFIC PHENOTYPES IN THE BASAL GANGLIA AND EXHIBIT VARIABLE
RESPONSES TO NORMAL AGING
Lindsay M. De Biase (1), Zach H. Fusfeld (1), Kornel E. Schuebel (2), Kam-Wing Jair (2), Haiying Zhang (1), Qing-
Rong Liu (1), Raffaello Cimbro (3), Isobel A. Hawes (1), Sissi P. Ribeiro (1), Hui Shen (1), Zheng-Xiong Xi (1), David
Goldman (2), Antonello Bonci (1)
(1) National Institute on Drug Abuse / NIH; (2) National Institute on Alcohol Abuse and Alcoholism / NIH; (3)
Johns Hopkins School of Medicine
Microglia promote brain homeostasis by removing debris from the extracellular space and responding to diverse
CNS insults. Recent studies have shown that microglia also influence synaptic transmission through release of
inflammatory and trophic signaling factors and activity-dependent phagocytosis of synapses. Given their
ubiquitous tissue distribution and gross morphological uniformity, these cells are generally assumed to be
functionally equivalent throughout the CNS. However, this assumption has not been rigorously tested. As we
amplify our understanding of how microglia influence neuronal function, it will be critical to define the nature
and extent of regional heterogeneity within this cell population. We used transgenic mice that express EGFP
within microglia to quantify anatomical, electrophysiological, and molecular properties of these glia within the
basal ganglia (BG), a collection of brain nuclei that regulate goal-directed behaviors and are pathologically
altered during addiction and neurodegenerative disease. Microglial density in the nucleus accumbens (NAc) was
comparable to that reported for cortex, while density in the substantia nigra pars reticulata (SNr) was markedly
elevated and that in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) was significantly
depressed. SNr and NAc microglia also displayed highly complex morphologies compared to VTA and SNc
microglia. Intracellular lysosome content was elevated in SNr microglia, suggesting that microglial phagocytotic
activity or metabolic state varies across BG nuclei. Electrophysiological recordings of microglia revealed that 65%
of microglia within the SNr exhibited delayed rectifier potassium currents, whereas only 9% of VTA and SNc
microglia displayed such currents, which have been linked to altered microglial functional status. Whole
transcriptome RNA sequencing of microglia isolated from distinct BG nuclei revealed broad similarities in gene
expression augmented by region-specific gene expression signatures, with VTA microglia differing most
prominently from microglia in other regions. During the course of normal aging, pronounced increases in
microglial density are observed in the VTA and SNc, while only moderate increases are observed in the NAc and
SNr. In addition, abnormal soma shape and bulbous swellings along cell processes were more frequent in
midbrain as compared to forebrain BG nuclei. Together these findings challenge the idea that microglia
throughout the CNS are functionally equivalent and raise important questions about the impact of this
heterogeneity on neuronal function and susceptibility to neurodegeneration.
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John Fedota
NICOTINE WITHDRAWAL INDUCES NEGATIVE CORRELATION IN RESTING CONNECTIVITY BETWEEN INSULA AND
EXECUTIVE CONTROL NETWORK IN SMOKERS
John R. Fedota(1), Allison L. Matous(1), Betty Jo Salmeron(1), Hong Gu(1), Thomas J. Ross(1), and Elliot A.
Stein(1)
(1) National Institute on Drug Abuse, Intramural Research Program, Neuroimaging Research Branch
The insula plays a central role in detecting internal bodily states (cravings) and salient external stimuli (cues). In
addition, the insula is a primary node of the salience network (SN), a large-scale brain network implicated in
switching between internal and external focus via modulation of connections with the anticorrelated default
mode (DMN) and executive control (ECN) networks. Prior evidence in smokers shows increased connectivity
between the insula and DMN during nicotine withdrawal. However, the down regulated connection predicted
between insula and ECN in withdrawn smokers has not been previously demonstrated. Here, resting state
functional MRI data from 18 smokers was collected in an effort to better characterize the dynamics of large-
scale network connectivity during acute withdrawal. 8 minutes of eyes-open resting-state functional
connectivity data were collected from all participants on two occasions-- during baseline smoking and again
following ~48hrs of full nicotine abstinence. Based on prior evidence, 3 insular regions of interest (dorsal
anterior, ventral anterior, and posterior insula) were identified and served as seeds in an analysis examining the
resting connectivity between each of these ROIs and the SN, ECN, or DMN. The contrast of abstinence-baseline
data identified a significant increase in correlation between insula and DMN connectivity and a significant
decrease in correlation between insula and ECN connectivity across scans. During abstinence, the ventral
anterior insula seed showed a positive correlation with rostral anterior cingulate, a node of the DMN, as well as
a negative correlation with the middle frontal gyrus, a node of the ECN. Thus, as opposed to replacing a strong
insula-ECN connection during baseline smoking with a strong insula-DMN connection during abstinence, the
current results suggest that the magnitude of connection between the insula and both the ECN and DMN are
increased during abstinence, though in opposite directions. These results illustrate the dynamics of large-scale
brain network connection in response to nicotine abstinence and are consistent with a reduced exogenous
attentional focus during withdrawal.
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Photo Credits:
Top: Graphical abstract to the " Epigenetic modulation of BDNF transcription in the valproic acid model of
autism" poster. Credits: Melissa Konopko
Bottom: Image from “Molecular Identity of Periglomerular and Short Axon Cells” The Journal of
Neuroscience, January 20, 2010 • 30(3):1185–1196; Olfactory bulb glomeruli are the initial sites of
synaptic integration of olfactory sensory information. This sensory input is modulated by local
interneurons including, GABAergic and dopaminergic (DA) periglomerular and short axon cells. This
image shows a 3D reconstruction of a biocytin-filled Dopaminergic/GABAergic short axon cell (black)
innervating multiple glomeruli in the olfactory bulb (each glomerulus colored separately). Credits: from
the lab of Dr. Adam Puche Ph.D., Associate Professor, Department of Anatomy & Neurobiology, University of
Maryland School of Medicine
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POSTER INDEX
Poster # Presenter Title
P1 Matthew Albrecht REDUCTION OF PAVLOVIAN BIAS IN SCHIZOPHRENIA: ENHANCED EFFECTS IN
CLOZAPINE-ADMINISTERED PATIENTS
P2 Eric Albuquerque THE TRANSCRIPTION FACTOR SRY SUPPRESSES EXPRESSION OF INFLAMMATORY
MARKERS
P3 Kathryn Argue CB1 and CB2 ENDOCANNABINOID RECEPTORS ACT IN CONCERT TO MODULATE
SEX DIFFERENCES IN THE DEVELOPING AMYGDALA AND SOCIAL PLAY BEHAVIOR
P4 M. Flavia Barbano FEEDING BEHAVIOR AND REWARD ARE DIFFERENTIALLY INDUCED BY
OPTOGENETICALLY ACTIVATING GABAERGIC LATERAL HYPOTHALAMIC
PROJECTIONS TO VTA AT DIFFERENT STIMULATION FREQUENCIES
P5 Benjamin Bell CHARACTERIZATION OF dWAKE; A PUTATIVE CIRCADIAN REGULATOR OF SLEEP
P6 Michelle Bridi SPONTANEOUS NEURONAL SPIKING DURING VISUAL DEPRIVATION DRIVES
METAPLASTICITY
P7 P. Leon Brown THE EFFECTS OF RMTG LESIONS ON THE RESPONSE OF NIGRAL DOPAMINE
NEURONS TO FOOTSHOCK AND HABENULA STIMULATION: AN
ELECTROPHYSIOLOGICAL STUDY IN ANESTHETIZED RATS
P8 Francisco Cervantes Constantino TOP-DOWN NEURAL SYNCHRONIZATION DURING IMAGINED ACOUSTIC
RHYTHM
P9 Haiwen Chen DISTINCT ORGANIZTION OF EVOKED AND SPONTANEOUS VESICLES FUSION
SITES WITHIN SINGLE CNS ACTIVE ZONES
P10 Varun Chokshi HOMER1A SIGNALING IN VISUAL CORTEX PLASTICITY
P11 Corsi, Nicole BELIEVING OR NOT IN TREATMENT’S SIDE-EFFECTS: BEHAVIORAL
OUTCOME AND PERSONALITY TRAITS ASSOCIATED TO A NOCEBO EFFECT IN
MOTOR PERFORMANCE
P12 Heydar Davoudi HIPPOCAMPAL AREA CA3 IS NECESSARY FOR THE INDUCTION OF SHARP-WAVE
RIPPLES IN AREA CA1
P13 Lindsay De Biase MICROGLIA ESTABLISH REGION SPECIFIC PHENOTYPES IN THE BASAL GANGLIA
AND EXHIBIT VARIABLE RESPONSES TO NORMAL AGING
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Poster # Presenter Title
P14 Allison Densmore
P15 Priyanka Desirazu EPIGENETIC MODULATION OF BDNF EXPRESSION IN THE VALPROIC ACID MODEL
P16 John Fedota OF AUTISM
P17 Chase Francis A QUANTITATIVE PROTEOMICS STUDY TO INVESTIGATE KEY PROTEINS INVOLVED
P18 Hana Goldschmidt IN OXIDATIVE PATHWAYS IN PATIENTS WITH ALZHEIMER'S DISEASE
P19 Jonathan Grima
P20 Wei Guo NICOTINE WITHDRAWAL INDUCES NEGATIVE CORRELATION IN RESTING
P21 Utsav Gyawali CONNECTIVITY BETWEEN INSULA AND EXECUTIVE CONTROL NETWORK IN
P22 Chelsea Ho SMOKERS
P23 Mohammad Imran
P24 Byung Woo Kim EGR3 EXPRESSION IN NUCLEUS ACCUMBENS MEDIUM SPINY NEURON SUBTYPES
OPPOSITELY CONTROLS OUTCOMES OF SOCIAL DEFEAT STRESS
P25 Melissa Konopko
P26 Alok Kumar DGKΘ CATALYTIC ACTIVITY IS REQUIRED FOR EFFICIENT RECYCLING OF
P27 Samuel Kwon PRESYNAPTIC VESICLES AT EXCITATORY SYNAPSES
THE ROLE OF NUCLEAR PORE COMPLEXES IN REPEAT EXPANSION
NEURODEGENERATION
IMMUNE ACTIVATION OF ENDOGENOUS PAIN MODULATION AS A MECHANISM
OF BONE MARROW STROMAL CELL-PRODUCED PAIN RELIEF IN RATS
THALAMIC INTRALAMINAR NUCLEI CONTROL OF STRIATAL DOPAMINE RELEASE
AND ACTION REINFORCEMENT
EFFECTS OF R-MODAFINIL AND ITS ANALOGUES IN COMPULSIVE
METHAMPHETAMINE TAKING AND SEEKING
CARDIOVASCULAR EFFECTS OF CLONIDINE IN PATIENTS ON BUPRENORPHINE
MAINTENANCE
VOLTAGE-GATED CALCIUM CHANNELS AND INTRACELLULAR Ca2+
INTRACELLULAR Ca2+ DYSREGULATION AS MECHANISMS OF DISEASE IN
AMYOTROPHIC LATERAL SCLEROSIS Lin28b
THE ROLE OF PLACENTAL SEROTONIN IN THE VALPROIC ACID MODEL OF AUTISM
NOX2 REGULATION OF MICROGLIAL/MACROPHAGE ACTIVATION IN THE TBI
BRAIN: A NOVEL MECHANISM FOR NEUROPROTECTION
CHOICE-AND STIMULUS-RELATED ACTIVITY MAPPED ACROSS L2/3 OF MOUSE S1
AND S2
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Poster # Presenter Title
P28 Amanda Labuza IDENTIFICATION OF SANK1 AS NOVEL SERCA1 REGULATORY PROTEIN IN
SKELETAL MUSCLE
P29 Tara LeGates SYNAPTIC PLASTICITY MECHANISM OF EXCITATORY HIPPOCAMPAL INPUT TO THE
NUCLEUS ACCUMBENS
P30 Elise Lesage NICOTINIC RECEPTOR STIMULATION AFFECTS REVERSAL LEARNING IN SMOKERS
P31 Tuo Peter Li PROTEIN CROWDING WITHIN THE POSTSYNAPTIC DENSITY CAN IMPEDE THE
ESCAPE OF TRANSMEMBRANE PROTEINS
P32 Allison Matous DELAYED RECRUITMENT OF RIGHT INSULA IN SMOKERS DURING PARAMETRIC
MODULATION OF RESPONSE CONFLICT
P33 Sarah Metzbower THE ROLE OF SYNAPTIC NANOSTRUCTURE IN REGULATING NMDA RECEPTOR
ACTIVATION
P34 N.R. Myslinski BRAIN BEE
P35 Norbert Myslinski BRAIN BEE INTERNATIONAL
P36 Mai Nakamura INVESTIGATING THE ROLE OF GDE2 AND GDE3 IN ALZHEIMER’S DISEASE
PATHOGENESIS
P37 Christina Nemeth Mertz NANOPARTICLE THERAPY FOR TARGETED DRUG DELIVERY TO INJURED CELLS
FOLLOWING NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY
P38 Matthew Panicker CORTICAL HIERARCHY GOVERNS CLAUSTROCORTICAL CIRCUIT ORGANIZATION
P39 Mary Patton ETHANOL DISINHIBITS DORSOLATERAL STRIATAL MEDIUM SPINY NEURONS
THROUGH ACTIVATION OF A PRESYNAPTIC DELTA OPIOID RECEPTOR
P40 Janell Payano Sosa HYPOTHALAMIC FUNCTIONAL CONNECTIVITY IN ONGOING PAIN IN HEALTHY
SUBJECTS AND SPONTANEOUS PAIN IN BURNING MOUTH SYNDROME PATIENTS
P41 Julia Peter THE PARK10 GENE USP24 IS A NEGATIVE REGULATOR OF AUTOPHAGY
P42 Lindsay Pickett THE ROLE OF MAST CELLS AND MICROGLIA IN SCULPTING THE SEXUALLY
DIMORPHIC NUCLEUS (SDN) OF THE POA
P43 Jose Jorge Ramirez-Framco PHOGRIN, A LARGE DENSE CORE VESICLE-ASSOCIATED PROTEIN, IS A
NOVEL MARKER OF INTERNEURONS IN THE HIPPOCAMPUS
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P44 Rodriguez, Gabriela CELL AUTONOMOUS AND NETWORK EFFECTS OF NMDA RECEPTORS IN
EXPERIENCE-DEPENDENT HOMEOSTATIC SYNAPTIC SCALING
Poster # Presenter Title
P45 Sarah Rudzinskas EXPLORING THE ROLES OF PROGESTERONE RECEPTOR AND OXYTOCIN
SIGNALING IN THE MECHANISM MEDIATING METHAMPHETAMINE-FACILITATED
SEX BEHAVIOR
P46 Alessandro Scaglione OPTOGENETIC DISSECTION OF MOTIVATIONAL SALIENCE NEURONAL CIRCUITS
IN THE BASAL FOREBRAIN
P47 Lieven Schenk DIFFERENTIAL NEURAL PROCESSING OF TREATMENT AND STIMULUS-
EXPECTANCY
P48 Anne-Christine Schmid BRUSH ALLODYNIA SUSCEPTIBILITY IS RELATED TO BASELINE HEAT PAIN
SENSITIVITY; REGIONAL BLOOD FLOW DIFFERENCES; AND SENSITIZATION-
INDUCED HEAT ALLODYNIA AND MECHANICAL HYPERALGESIA
P49 Sharma, Tanu RESILIENT PROPERTIES OF OLFACTORY ENSHEATHING CELLS AFTER NEURONAL
LOSS
P50 Liu Shuo DISRUPTED AUTOPHAGY AFTER SPINAL CORD INJURY IS ASSOCIATED WITH ER
STRESS AND NEURONAL CELL DEATH
P51 Joyce Silva DOES ANTI-NGT REVERSE SYMPTOMS OF CHRRONIC NEUROPATHIC PAIN?
P52 Nathalie Spita COCHLEAR INNERVATION MEDIATED BY SEMAPHORIN SIGNALING
P53 Ramanujan Srinath CHARACTERIZING GCAMP6F NONLINEARITY USING TWO-PHOTON IMAGING OF
FERRET V1
P54 Vaughn Steele NEURAL MEASURES OF INCORRECT RESPONSES PREDICT COMPLETION OF
SUBSTANCE ABUSE TREATMENT
P55 Monique Stins BRAIN ENDOTHELIAL ACTIVATION AND NEURONAL DAMAGE
P56 Sara Stockman SEX DIFFERENCE IN NEONATAL HIPPOCAMPAL NEUROGENESIS (MAY) IMPACT
EARLY LIFE FORGETTING
P57 Malgorzata Straka INHIBITION AND STIMULUS COMPETITION WITHIN A GABAERGIC NUCLEUS IN
THE MIDBRAIN ATTENTION NETWORK
P58 Aleksandr Talishinsky PSYCHOSTIMULANT DRUG ADMINISTRATION MARKEDLY INCREASES VISUAL
STIMULUS SEEKING BEHAVIOR IN CALORIE-RESTRICTED RATS; UNDERLYING
NEURAL MECHANISMS
18
P59 Han Tan GRIP1 IS REQUIRED FOR HOMEOSTATIC REGULATION OF AMPAR TRAFFICKING
Poster # Presenter Title
P60 Aihui Tang A TRANSSYNAPTIC NANOCOLUMN ORGANIZES SYNAPTIC PROTEIN
DISTRIBUTION TO ALIGN NEUROTRANSMITTER RELEASE WITH RECEPTORS
P61 Michael Tennekoon NEURAL CORRELATES OF WORKING MEMORY PREDICT ACADEMIC SKILLS
P62 Tim Jarvela THE NEURAL CHAPERONE PROSAAS POTENTLY BLOCKS ALPHA-SYNUCLEIN
FIBRILLATION AND NEUROTOXICITY
P63 Tammy Tran THE ROLE OF APOE-4 IN HIPPOCAMPAL HYPERACTIVITY IN AMNESTIC MILD
COGNITIVE IMPAIRMENT
P64 Adam Van Dyke CO-ACTIVATION OF MULTIPLE SEROTONIN RECEPTORS UNDERLIES SUSTAINED
POTENTIATION OF SYNAPTIC TRANSMISSION BY FLUOXETINE IN THE
HIPPOCAMPUS
P65 Jonathan VanRyzin ROLE OF MICROGLIA IN SEXUAL DIFFERENTIATION OF THE AMYGDALA
P66 Michael White MACRO- AND MICROCIRCUIT COMPONENTS OF A PUTATIVE TOP-DOWN
ATTENTIONAL FILTER
P67 Nathan Whitmore UNMASKING LOCAL ACTIVITY WITHIN LOCAL FIELD POTENTIALS BY REMOVING
COMMON DISTAL SIGNALS USING INDEPENDENT COMPONENT ANALYSIS
P68 Joshua Whitt β2-MEDIATED INACTIVATION DRIVES THE DIURNAL DIFFERENCE IN BK CURRENT
LEVELS IN SUPRACHIASMATIC NUCLEUS AND REGULATES CIRCADIAN
RHYTHMICITY
P69 Jessica Whitt EXPERIENCE DEPENDENT PLASTICITY ADULT SENSORY THALAMIC NUCLEI
P70 Olatoundji Yessoufou
P71 Jing Hui Adeline Yong C-TERMINAL PHOSPHORYLATION OF GLUA2 AND GLUA3 IN GLUA3 IN SYNAPTIC
PLASTICITY
19
Photo Credits:
Description: Specimen - Pyramidal Neurons in Cingulate Cortex - Pyramidal neurons were labeled using SMI32
(red) and Dapi (white) staining, in cingulate cortex section of adult mouse brain.
Credits: Dr. Céline Plachez, Ph.D. Investigator, Hussman Institute for Autism, Baltimore
20
P1 Albrecht, Matthew
REDUCTION OF PAVLOVIAN BIAS IN SCHIZOPHRENIA: ENHANCED EFFECTS IN CLOZAPINE-ADMINISTERED
PATIENTS
Matthew A Albrecht (1,2,3), James A Waltz (1), James F Cavanagh (4), Michael J Frank (5,6), James M Gold (1)
1. Maryland Psychiatric Research Center, Department of Psychiatry, School of Medicine, University of Maryland,
Baltimore, Maryland, United States of America 2. School of Public Health, Faculty of Health Sciences, Curtin
University, Perth, Western Australia, Australia 3. Curtin Health Innovation Research Institute - Biosciences,
Curtin University, Perth, Western Australia 4. Department of Psychology, University of New Mexico,
Albuquerque, New Mexico, United States of America 5. Department of Cognitive, Linguistic and Psychological
Sciences, Brown University, Providence, Rhode Island, United States of America 6. Department of Psychiatry and
Brown Institute for Brain Science, Brown University, Providence, Rhode Island, United States of America"
The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL)
deficits likely related to degraded representations of reward values. However, the RL tasks used to date have
required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect
performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and
may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30
demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action
(“Go” or “NoGo”) and the valence of the optimal outcome (reward or punishment-avoidance), such that all
combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL
model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias
that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the
reduction in Pavlovian bias was enhanced. Electrophysiologically, the reduction in Pavlovian bias in the full
sample of SZ patients was accompanied by electrophysiological feedback processing differences at the time of
the P3a component. The reduced Pavlovian bias in patients is thought to be due to reduced fidelity in the
communication within and between striatal regions and frontal cortex and may partially account for previous
findings of reduced “Go-learning” in schizophrenia in studies that have required “Go” responses or Pavlovian
consistent responses to learn reinforcement contingencies. The attenuated P3a component exhibited by
patients is consistent with the view that deficits in operant learning in patients are due to a reduced ability to
adaptively use feedback to update representations of stimulus value.
21
P2 Albuquerque, Eric
THE TRANSCRIPTION FACTOR SRY SUPPRESSES EXPRESSION OF INFLAMMATORY MARKERS
Eric R. Albuquerque, Grace Jiau, Minjun Kim, M., Seung K. Woo
Department of Neurosurgery, University of Maryland School of Medicine
Previous epidemiological and preclinical studies have provided evidence that the magnitude of pain and
inflammatory responses is higher among females than males. Although the sex dimorphism of these responses
cannot be fully explained by hormonal differences, no study has examined whether it can be related to sex-
specific genes. Thus, the present study was designed to test the hypothesis that a male-specific transcription
factor, sex-determining region Y (SRY), inhibits the transcription of genes involved in inflammatory response. In
one set of experiments, quantitative PCR was used to analyze levels of mRNAs encoding the inflammatory
markers COX-2, IL-1β, and TNF-α in wild-type and SRY-overexpressing glioblastoma cells. Overexpression of SRY
in the glioblastoma cells markedly reduced the expression of COX-2 and IL-1β. In another set of experiments, a
luciferase reporter assay was used to examine the roles of SRY in transcription driven by NF-κB and NFAT, which
are known to up-regulate expression of inflammatory markers. Co-expression of SRY markedly reduced the
luciferase activity under the control of tandem repeats of the NF-κB and NFAT transcriptional response elements
in human liver carcinoma cells Hep G2. In conclusion, these results support the hypothesis that SRY suppresses
the expression of inflammatory markers. The present study suggests that sex dimorphism of pain and
inflammatory responses may be, at least in part, determined by the male-specific transcription factor SRY.
22
P3 Argue, Kathryn
CB1 and CB2 ENDOCANNABINOID RECEPTORS ACT IN CONCERT TO MODULATE SEX DIFFERENCES IN THE
DEVELOPING AMYGDALA AND SOCIAL PLAY BEHAVIOR
Kathryn J. Argue (1,2), Jonathan W VanRyzin (1,2), and Margaret M McCarthy (1,2)
(1) Department of Pharmacology and (2) Program in Neuroscience University of Maryland, Baltimore, School of
Medicine, Baltimore, MD, USA
Males of most species display higher levels of juvenile social play behavior compared to females. In rats, this sex
difference is negatively correlated with cell proliferation in the developing amygdala. Both sex differences in
play behavior and cell proliferation are mediated by the endocannabinoid system (PNAS 107; 2010). Further
investigation into involvement of the endocannabinoid receptor types revealed surprising evidence of
cooperation between the two receptors. Neonatal activation of either CB1 or CB2 alone between postnatal days
0-3 was not sufficient to increase female play behavior, however dual-agonist treated newborn females
displayed increased levels of social play when tested as juveniles during postnatal days 27-38 (ANOVA p < 0.05),
and activation of either CB1 or CB2 was sufficient to decrease the number of BrdU+ cells in the female
developing amygdala (ANOVA p < 0.001). Dual-agonist treatment had no effect on play in males. Antagonizing
both receptors in females reduced play behavior (ANOVA p < 0.05). Both CB1 and CB2 are known to mediate cell
proliferation, however traditionally they were thought to be expressed on different cell types. We used a flow
cytometry approach to identify newly proliferating cells in the developing amygdala, and found that neonatal
females contain more newly proliferating cells coexpressing CB1 and CB2 compared to males (t-test p < 0.05).
Together with our behavioral analyses, these data suggest that developmental sex differences in
endocannabinoid receptor expression mediate effects on juvenile social play behavior. Currently we are
performing further characterization of the newly born cells that coexpress CB1 and CB2, and assessing how sex
differences in neuronal morphology in the juvenile amygdala correspond to endocannabinoid-mediated effects
on social play behavior.
23
P4 Barbano, M. Flavia
FEEDING BEHAVIOR AND REWARD ARE DIFFERENTIALLY INDUCED BY OPTOGENETICALLY ACTIVATING
GABAERGIC LATERAL HYPOTHALAMIC PROJECTIONS TO VTA AT DIFFERENT STIMULATION FREQUENCIES
M. Flavia Barbano (1,2), Hui-Ling Wang (1), Roy A. Wise (1), and Marisela Morales (1)
(1) National Institute on Drug Abuse, NIH, Baltimore, MD; (2) Johns Hopkins University, Baltimore, MD
The lateral hypothalamus (LH) is a heterogeneous brain structure that has been classically involved in feeding,
motivation and reward. Optogenetic approaches have recently confirmed that GABAergic LH neurons induce
feeding and reward. It has also been shown that GABAergic projections from the LH to the ventral tegmental
area (VTA) modulate feeding and compulsive sucrose seeking. However, it is still unclear if the same population
of GABAergic lateral hypothalamic neurons that projects to the VTA promotes both feeding and reward. In the
present study, we addressed this question by using a combination of optogenetic, behavioral, and
pharmacological techniques in transgenic male mice expressing Cre recombinase under the regulation of the
vesicular GABA transporter (VGaT::Cre mice). We found that VTA photoactivation of GABAergic LH projections
using low frequencies (5 Hz but not 40 Hz) promoted feeding in food sated mice. This effect was decreased by
the intra-VTA administration of a mix of GABA A and B antagonists. Conversely, photostimulation of the same
pathway was highly rewarding and reinforced instrumental behavior when high frequencies were used (40 but
not 5Hz). The best operant performance was achieved using high frequencies of stimulation (40 Hz). The
motivated operant responses were also reduced by the administration of GABA antagonists. To further
characterize the reinforcing properties of low and high frequencies of stimulation on reward, we conducted a
place conditioning study. Different groups of mice received continuous photostimulation with frequencies
either low (5 Hz) or high (40 Hz) after entering a light-paired chamber on a three chamber apparatus. Only mice
conditioned with the high frequency showed a significant preference for the light-paired chamber during
training and also during subsequent testing, when the light was no longer available. These and similar findings
confirm that activation of GABA fibers originating from the lateral hypothalamus and projecting to the ventral
tegmental area can contribute to the rewarding and feeding-inducing effects long established by electrical
stimulation studies. It is unclear if the differential effectiveness of low and high frequency stimulation reflects
the activation of different subsets of GABA neurons or difference levels of responses by the same group of GABA
neurons.
24
P5 Bell, Benjamin
CHARACTERIZATION OF dWAKE; A PUTATIVE CIRCADIAN REGULATOR OF SLEEP
Benjamin J. Bell (1), Joseph Bedont (2), Qili Liu (3), Sha Liu (3), Seth Blackshaw (2), Mark Wu (3).
(1) Human Genetics, Johns Hopkins Medical Institute; (2) Neuroscience, Johns Hopkins Medical Institute; (3)
Neurology, Johns Hopkins Medical Institute
Introduction: While the molecular gears of the circadian oscillator have been well-described, how this oscillator
regulates sleep is unknown. From a forward genetic screen in Drosophila, we recently identified a novel
molecule, named WIDE AWAKE (dWAKE), which mediates the circadian timing of sleep onset. dWAKE is
expressed in circadian clock neurons (large LNvs) and exhibits cycling expression, peaking near dusk. These
large LNv clock neurons are photorecipient and promote arousal. dWAKE promotes sleep onset by inhibiting
these cells at dusk via upregulation of GABAA receptors. Based upon this work, we set out to identify and
characterize a mammalian homolog of dWAKE.
Methods: In situ hybridization – chromogenic and fluorescent two-color, Time-course qPCR, Cell-culture
transfection and Western blotting, CRISPR, Electroencephalography recording of sleep
Results: Using a bioinformatic approach, we identified a single homolog of dWAKE in mice (mWAKE), which
shares 30% identity with dWAKE. By in situ hybridization, we determined that mWAKE is specifically expressed
in the suprachiasmatic nucleus (SCN), the mammalian master circadian pacemaker. Moreover, mWAKE
expression is restricted within the SCN, where it overlaps with photorecipient neurons delineated by Gastrin
Releasing Peptide expression. Similar to dWAKE, co-transfection of mWAKE in cultured cells results in significant
upregulation of a GABAA receptor. mWAKE levels also cycle over the course of a day, peaking near ZT0, the
beginning of the inactive phase in mice. To carry out genetic analysis of mWAKE, we have used the CRISPR
technique to generate a knockout of mWAKE.
Conclusions: The expression pattern of mWAKE is striking similar to that of dWAKE. They are both expressed in
photorecipient clock neurons and also exhibit cycling expression. Moreover, the function of mWAKE in
upregulating GABAA receptors appears to be conserved. We are now measuring sleep and circadian rhythm
behaviors in our mWAKE knockout mutants behaviorally via electroencephalography."
25
P6 Bridi, Michelle
SPONTANEOUS NEURONAL SPIKING DURING VISUAL DEPRIVATION DRIVES METAPLASTICITY
Michelle C.D. Bridi (1), Roberto de Pasquale (2), Crystal Lantz (3), Elizabeth Quinlan (3), and Alfredo Kirkwood
(1)
(1) Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Blatimore, MD; (2) University of Sao Paolo, Sao
Paolo, Brazil; (3) University of Maryland, College Park, MD
Cortical activity levels are stabilized through homeostatic mechanisms such as synaptic scaling and the sliding
threshold for plasticity, which negatively couple neuronal spiking to synaptic strength. The synaptic scaling
model predicts that decreased neuronal spiking increases the strength (and conversely, increased neuronal
spiking decreases the strength) of all synapses in that neuron by the same factor. Neuronal activity is also
stabilized by the sliding threshold for plasticity, such that neurons favor long-term potentiation (LTP) when
activity is low and long-term depression (LTD) when activity is high. These homeostatic mechanisms have been
modeled in vivo by short (2d) visual deprivation, achieved by exposure to complete darkness. Dark exposure
(DE) increases the strength of excitatory synapses (measured by miniature excitatory postsynaptic potential
(mEPSC) amplitude) and promotes LTP at the expense of LTD in the primary visual cortex (V1) of mice. A
prediction of these models is that further reduction of neuronal activity during DE would cause even larger
compensatory increases in mEPSC amplitude and LTP. Surprisingly, decreasing spontaneous activity during DE
with diazepam did not increases mEPSC amplitude or LTP in V1. Conversely, we performed binocular lid suture
for 2 days, a form of visual deprivation normally too mild to drive synaptic scaling, while increasing spontaneous
activity with flumazenil. Flumazenil combined with binocular lid suture increased mEPSC amplitude and
promoted LTP, whereas binocular lid suture alone had no effect. Activity-dependent changes in NMDA receptor
subunit composition may underlie these findings.
26
P7 Brown, P. Leon
THE EFFECTS OF RMTG LESIONS ON THE RESPONSE OF NIGRAL DOPAMINE NEURONS TO FOOTSHOCK AND
HABENULA STIMULATION: AN ELECTROPHYSIOLOGICAL STUDY IN ANESTHETIZED RATS
Paul D. Shepard, Heather. L. Palacorolla, P. Leon Brown, Dana B. Brady, Robert P. McMahon, Greg I. Elmer
Department of Psychiatry / MPRC, University of Maryland School of Medicine, Baltimore, MD
GABA neurons in the rostromedial tegmental area (RMTg) are an important source of inhibitory input to
dopamine (DA) neurons within the substantia nigra (SN). Dense innervation of the RMTg by glutamatergic
efferents from the lateral habenula (LHb) provide the hodological substrate for a feedforward inhibitory
pathway that underlies the transient inhibition in DA cell firing elicited by aversive stimuli ranging from the loss
of an expected reward to peripheral nociceptive stimulation. Here, we sought to determine (i) the degree of
confluence in the response of individual SN DA neurons to footshock and habenular activation and (ii) whether
excitotoxic lesions of the RMTg altered this response pattern. Extracellular single unit recordings were obtained
from DA neurons in the SN of sham (n= 40 cells) or RMTg lesioned rats (n= 34 cells). 7-14 days prior to the
recordings, rats received a midline injection (110 nl) of quinolinic acid (400 mM) or saline. The number of NeuN
and amphetamine-induced cFos positive neurons in RMTg lesioned rats was reduced by 87% and 92%,
respectively. Spontaneous activity was recorded for several minutes prior to applying brief biphasic constant
current pulses pseudorandomly at 0.5 Hz to the ipsilateral LHb (1 mA, 100 usec) or contralateral footpad (5-7
mA, 1 ms). Neuronal responses were categorized as: inhibition (I), excitation (E), inhibition followed by
excitation (I/E), excitation followed by inhibition (E/I) or no change (N/C). The majority of cells recorded in sham-
treated rats showed a biphasic I/E response to LHb stimulation (36/40). The response to footshock was more
heterogeneous but comprised predominantly of cells exhibiting either an I/E (n = 14) or I (n=19) response.
RMTg-lesioned rats showed significantly greater variability in their response to LHb stimulation with 50% of the
cells characterized by an initial excitation (n=6), NC (n=9) or an indeterminate response (n=2). The increased
heterogeneity was accompanied by a disproportionate reduction in the number of I/E cells in lesioned animals
(11/34). Comparable changes were observed in the response to footshock including a significant reduction in the
proportion of cells characterized by an I/E response (6/34) and a corresponding increase in the NC category.
Notably the proportion of cells exhibiting a monotonic inhibitory response to footshock was not altered by
RMTg lesions (14 vs12). These data suggest that activation of the RMTg by aversive stimulation has a biphasic
effect on SN DA neurons that reflects both the direct and indirect influence of the RMTg.
27
P8 Cervantes Constantino, Francisco
TOP-DOWN NEURAL SYNCHRONIZATION DURING IMAGINED ACOUSTIC RHYTHM
Francisco Cervantes Constantino (1), and Jonathan Z. Simon (1,2,3,4))
(1) Program in Neuroscience and Cognitive Science; (2) Department of Electrical and Computer Engineering; (3)
Institute for Systems Research; (4) Department of Biology
Perceptual filling-in is one mechanism to handle missing sensory information, possibly operating by
interpolation from context cues. These may be static, as is the case for frequency in the auditory continuity
illusion. This work addresses perceptual filling-in mechanisms based on a frequency-modulated sound stimulus
as time-varying dynamic cue. We create conditions to observe an instance of a stimulus-context-driven neural
oscillation, reflecting endogenous neural processes entirely unrelated to acoustics, but associated with
behavioral performance in a detection task.
Auditory steady state responses were recorded with magnetoencephalography (MEG) during presentation of a
long rhythmic pulse train (5 Hz rate). Brief noise masker probes were pseudo-randomly added. In half of the
masker probes, the ongoing rhythmic pulse train was also omitted. 35 listeners reported, shortly after each
probe, whether it had been perceived-rhythmic (pR), or not (pN).
MEG responses showed higher evoked power at the 5 Hz rhythm rate, for incorrect pR trials than correct pN
trials. This contrast accounted for 30% of the variance in detection sensitivity.
We propose that the presence of cortical dynamics synchronized to a sound modulation may lead to the
subjective experience of sound as modulated, even in cases where synchronized dynamics is not supported by
sensory data - in analogy to some auditory illusions or hallucinations. For modulation rates relevant to human
speech communication, as in the rate tested here, the proposed strategy may be underlied by an internal model
generated to extract meaning from complex sound mixtures, as in the problem of active listening to multiple
speakers. The results also raise the question of contextual interpolation as a common-principled strategy found
in other sensory modes."
28
P9 Chen, Haiwen
DISTINCT ORGANIZTION OF EVOKED AND SPONTANEOUS VESICLES FUSION SITES WITHIN SINGLE CNS ACTIVE
ZONES
Haiwen Chen1,2,3, Ai-Hui Tang1,2, Sarah Ransom Metzbower1,2, Thomas A. Blanpied1,2
1Department of Physiology, 2Program in Neuroscience, and 3Medical Scientist Training Program, University of
Maryland School of Medicine, Baltimore, MD 21201, USA
Because glutamate receptors are inhomogenously distributed in the postsynaptic density, the organization of
vesicle docking and fusion sites within single active zones (AZs) will strongly influence synaptic strength.
However, there is extremely limited information about where within the AZ action potentials trigger vesicle
fusion, and even less about the location of spontaneous vesicle fusion. Interestingly, there is controversy over
whether spontaneous and evoked release utilize different vesicle pools, involve different trafficking and fusion
machinery, or activate different groups of receptors. All these factors suggest that spontaneous and evoked
fusion could be organized at spatially distinct regions of the AZ, but this has not been tested.
To address this, we first studied the subsynaptic distributions of key presynaptic proteins likely to define vesicle
fusion sites, including RIM1/2, Munc13, and Bassoon. Using 3D dSTORM on immunostained cultured
hippocampal neurons, we found that all three protein distributions were distinctly heterogeneous with high
local-density peaks (~80-110 nm in diameter), which we identified as nanodomains (NDs). Interestingly, though
these proteins largely overlapped in the AZ, they were distinct in not only cluster volumes, but number and size
of NDs. Compared to the postsynaptic scaffolding protein PSD-95, RIM1/2 had similar size and number of NDs,
while Munc13 had similar size but greater number, and Bassoon had larger size but lesser number of NDs.
Previous work has suggested that these proteins play different roles in evoked and spontaneous release. For
instance, while RIM1α knockout impairs only evoked but not spontaneous release, Munc13 knockout impairs
both. Given the distinct distributions of these proteins, we hypothesized that the evoked and spontaneous
vesicle fusion sites will also differ spatially. To test this, we developed a novel technique to localize single-vesicle
fusion with high spatial resolution in live synapses by adapting single-molecule localization for single-vesicle
fusion signals obtained with vGlut1-pHluorin. We called this approach “pHluorin uncovering sites of exocytosis”
or pHuse. Using pHuse, we compared the pattern of evoked and spontaneous vesicle fusion at individual
presynaptic terminals. This revealed that evoked fusion occurred over a significantly smaller area of the terminal
than spontaneous fusion. We conclude that differential protein organization in the AZ dictates nanometer-scale
distribution of vesicle fusion mode.
29
P10 Chokshi, Varun
HOMER1A SIGNALING IN VISUAL CORTEX PLASTICITY
Varun Chokshi(1,2), M Gao(4), PWorley(3), and Hey-Kyoung Lee (1,2,3)
(1) Department of biology; (2)Mind Brain Institute, Johns Hopkins University, Baltimore MD; (3) Neuroscience,
Johns Hopkins Med. School, Baltimore, MD; and (4) Div. of Neurol., Barrow Neurolog. Inst., Pheonix, AZ
Visual experience modulates the strength of neuronal transmission in mouse primary visual cortex especially
during the critical period for ocular dominance plasticity (ODP). Both hebbian and homeostatic plasticity of
excitatory synapses are implicated in ODP. We found that metabotropic glutamate receptor mGluR5 signaling is
required for experience-dependent homeostatic regulation of synaptic α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptor mediated miniature excitatory postsynaptic current (mEPSC) amplitude
in the superficial layers of visual cortex. mGluR5s are coupled to synaptic proteins by the long forms of Homer1
(Homer1b/c), which are scaffolding proteins. Its splice variant Homer1a is expressed upon neuronal activity and
displaces the long forms of Homer1 from mGluR5. In Homer1a knock out mice, we observe a deficit in
experience-dependent synaptic scaling. Recent studies suggest that homeostatic synaptic plasticity plays a role
in ODP. To determine whether Homer1a signaling is involved in ODP, we are currently examining whether ODP
is affected in Homer1a KO mice using intrinsic signal imaging.
30
P11 Corsi, Nicole
BELIEVING OR NOT IN TREATMENT’S SIDE-EFFECTS: BEHAVIORAL OUTCOME AND PERSONALITY TRAITS
ASSOCIATED TO A NOCEBO EFFECT IN MOTOR PERFORMANCE.
Corsi Nicole(1), Tinazzi Michele(1), Emadi Andani Mehran(1,2), Fiorio Mirta(1)
(1) Department of Neurological and Movement Sciences, University of Verona (Italia), (2) Department of
Biomedical Engineering, University of Isfahan (Iran)
Behavioral evidence shows that believing in the detrimental effects of a treatment leads to a worse motor
performance (nocebo effect). Despite subject’s belief about treatment’s efficacy being crucial for the nocebo
effect, no study until now has tackled this issue. With this study we investigated whether the persistence of
belief and personality traits could account for individual differences in the magnitude of the nocebo response.
27 volunteers were asked to perform a force task with the right index finger, and received a visual feedback of
force. After a training, participants underwent a nocebo procedure, in which a treatment (actually inert) was
applied to the right hand together with verbal instructions about its negative effects on force. In a conditioning
session, subjects were exposed to the (fake) effects of the treatment, by means of a surreptitious reduction of
the visual feedback. Finally, in a test session, subjects received the same treatment and performed the motor
task without reduction of the feedback. Crucially, when asked to report about treatment efficacy, two different
patterns could be observed: some subjects gave higher scores in the test compared to the conditioning session
(high-responders, N=15), whereas other subjects did the opposite (low-responders, N=12). Results showed that
hogh-responders had a stronger nocebo effect, as evidenced by lower levels of force (p < 0.001), higher feeling
of weakness (p < 0.001) and higher sense of effort (p = 0.036), compared to low-responders. Personality
questionnaires revealed that high-responders had lower level of optimism (p = 0.008) and self-directedness (p =
0.048), but higher anxiety trait (p = 0.008), harm avoidance (p = 0.008) and physiological reactivity than low-
responders. These findings show that the magnitude of the nocebo response can be modulated by different
factors, such as the persistence of subject’s belief about the efficacy of the treatment and personality traits.
31
P12 Davoudi, Heydar
HIPPOCAMPAL AREA CA3 IS NECESSARY FOR THE INDUCTION OF SHARP-WAVE RIPPLES IN AREA CA1
Heydar Davoudi (1) and David J. Foster (2)
(1) Department of Biomedical Engineering, (2) Department of Neuroscience, Johns Hopkins University School of
Medicine, Baltimore, MD.
Hippocampal area CA1 local field potential exhibits high frequency (100- 250 Hz) events known as Sharp-Wave
Ripples (SWRs). These events that occur during slow-wave sleep and awake restfulness have been shown to be
important for the consolidation of spatial memory. However, the mechanism of formation of SWRs is not yet
well understood. Although it is hypothesized that projections from the highly recurrent network of the
hippocampal area CA3 might be responsible for the formation of SWRs in CA1, this has not been causally
demonstrated. In a study by Nakashiba et al. (2009), in which CA3’s Schafer Collateral (SC) projections to CA1
were genetically silenced over the time course of a few days, the number of SWRs did not change, while the
peak frequency of a fraction of SWRs decreased. However, the time course of genetic silencing in that study was
sufficient to allow for the possibility of compensatory mechanisms in the development of ripple activity in CA1.
We hypothesized that a more acute shutdown of CA3 input to CA1 might reveal a more significant role.
Therefore, we bilaterally expressed proton pump Arch3.0 in SC of 2-3 months old Long-Evans rats. Here we
report that, using multi-tetrode recording and reversible optogenetic manipulation, the silencing of SC terminals
in CA1 decimates SWRs. In particular, SWRs and their associated spiking activity were abolished when light was
delivered to CA3 terminals in CA1 but intact when light was off. Meanwhile, activities in other frequency bands
were not affected by light. This silencing also significantly suppresses place field activity while animal is running.
These findings shed light on the functional interconnections between hippocampal subregions that support
episodic memory.
32
P13 De Biase, Lindsay
MICROGLIA ESTABLISH REGION SPECIFIC PHENOTYPES IN THE BASAL GANGLIA AND EXHIBIT VARIABLE
RESPONSES TO NORMAL AGING
Lindsay M. De Biase (1), Zach H. Fusfeld (1), Kornel E. Schuebel (2), Kam-Wing Jair (2), Haiying Zhang (1), Qing-
Rong Liu (1), Raffaello Cimbro (3), Isobel A. Hawes (1), Sissi P. Ribeiro (1), Hui Shen (1), Zheng-Xiong Xi (1), David
Goldman (2), Antonello Bonci (1)
(1) National Institute on Drug Abuse / NIH; (2) National Institute on Alcohol Abuse and Alcoholism / NIH; (3)
Johns Hopkins School of Medicine
Microglia promote brain homeostasis by removing debris from the extracellular space and responding to diverse
CNS insults. Recent studies have shown that microglia also influence synaptic transmission through release of
inflammatory and trophic signaling factors and activity-dependent phagocytosis of synapses. Given their
ubiquitous tissue distribution and gross morphological uniformity, these cells are generally assumed to be
functionally equivalent throughout the CNS. However, this assumption has not been rigorously tested. As we
amplify our understanding of how microglia influence neuronal function, it will be critical to define the nature
and extent of regional heterogeneity within this cell population. We used transgenic mice that express EGFP
within microglia to quantify anatomical, electrophysiological, and molecular properties of these glia within the
basal ganglia (BG), a collection of brain nuclei that regulate goal-directed behaviors and are pathologically
altered during addiction and neurodegenerative disease. Microglial density in the nucleus accumbens (NAc) was
comparable to that reported for cortex, while density in the substantia nigra pars reticulata (SNr) was markedly
elevated and that in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) was significantly
depressed. SNr and NAc microglia also displayed highly complex morphologies compared to VTA and SNc
microglia. Intracellular lysosome content was elevated in SNr microglia, suggesting that microglial phagocytotic
activity or metabolic state varies across BG nuclei. Electrophysiological recordings of microglia revealed that 65%
of microglia within the SNr exhibited delayed rectifier potassium currents, whereas only 9% of VTA and SNc
microglia displayed such currents, which have been linked to altered microglial functional status. Whole
transcriptome RNA sequencing of microglia isolated from distinct BG nuclei revealed broad similarities in gene
expression augmented by region-specific gene expression signatures, with VTA microglia differing most
prominently from microglia in other regions. During the course of normal aging, pronounced increases in
microglial density are observed in the VTA and SNc, while only moderate increases are observed in the NAc and
SNr. In addition, abnormal soma shape and bulbous swellings along cell processes were more frequent in
midbrain as compared to forebrain BG nuclei. Together these findings challenge the idea that microglia
throughout the CNS are functionally equivalent and raise important questions about the impact of this
heterogeneity on neuronal function and susceptibility to neurodegeneration.
33
P14 Densmore, Allison
EPIGENETIC MODULATION OF BDNF EXPRESSION IN THE VALPROIC ACID MODEL OF AUTISM
Melissa A. Konopko, Allison Densmore, Clinton D. Roby, Bruce K. Krueger
Use of the drug, valproic acid (VPA) by pregnant women increases the risk of autism in their children. Our lab
has found that administration of a single dose of VPA to pregnant mice during the period of early neurogenesis
causes a transient increase in Bdnf mRNA and protein in the mouse fetal brain. Moreover, research has
suggested that Bdnf dysregulation may be involved in the development of autism. The goal of my research is to
elucidate the mechanistic link between VPA and the increased expression of this neurotrophin. VPA has several
known functions including histone deacetylase inhibition and degradation of DICER, a key enzyme in microRNA
(miRNA) maturation. Additionally, changes in histone acetylation engage in molecular crosstalk with other
epigenetic marks and can result in alterations in DNA methylation. I hypothesize that the increased expression
of BDNF is mediated by epigenetic mechanisms including an increase in activating histone modifications, a
reduction in repressive DNA methylation and a decrease in mature Bdnf specific microRNAs. Histone lysine
acetylation was analyzed using chromatin immunoprecipitation. Our analysis revealed a two to four fold
increase in three different histone acetylation marks. Additionally, we examined two trimethylation marks and
found no change on H3K27, and a significant increase on H3K4 only in female brains exposed to VPA. I next
analyzed DNA cytosine methylation, a repressive modification. We found a significant, but modest impact of
VPA on DNA methylation. Finally, I investigated the impact of micro RNAs (miRs) on Bdnf expression in fetal
brain. I found that VPA decreased levels of miR-10a, a miR that has been demonstrated to inhibit Bdnf
expression. Together, these experiments help to elucidate the epigenetic contributions to VPA’s ability to
increase Bdnf expression in the brains of fetuses exposed to the drug in utero.
34
P15 Desirazu, Priyanka
A QUANTITATIVE PROTEOMICS STUDY TO INVESTIGATE KEY PROTEINS INVOLVED IN OXIDATIVE PATHWAYS IN
PATIENTS WITH ALZHEIMER'S DISEASE
Priyanka Desirazu (1), Abhay Moghekar (1)
(1) Johns Hopkins Bayview Medical Centre
Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease that is characterized by
accumulation of amyloid beta forming senile plaques and the deposition of microtubule-associated tau proteins
into neurofibrillary tangles. It is primarily a disease of synaptic dysfunction and the loss of synapses can be
correlated with cognitive decline. Oxidative stress also has been hypothesized to play an increasingly important
role in pathogenesis of late onset AD. Certain alleles of the gene TOMM40 have been statistically associated
with an increased risk of developing late-onset Alzheimer’s disease. Because TOMM40 is located on
chromosome 19, and is closely adjacent to APOE, studies suggest that the statistically significant correlation of
TOMM40 with Alzheimer's is due to linkage disequilibrium. Using age matched samples from the Baltimore
Longitudinal Study of Aging (BLSA) who are cognitively normal, have mild cognitive impairment (MCI) and those
with dementia we are investigating the role of TOMM40, COX-IV, Synaptophysin and PSD95 by first developing
and optimizing an extraction protocol for these proteomic studies. Samples from the frontal and temporal gyri
are homogenized and soluble extracellular, cellular and insoluble fractions are extracted either using RIPA or
Urea buffers. Using semi-quantitative Western blotting the concentration of these proteins are measured and
correlated with the onset of clinical symptoms of Alzheimer’s disease. Preliminary results indicate that a
combination of sonication and homogenization protocols with the use of Urea buffer yields maximum protein
from samples. MCI patients have larger total protein content than the other groups. TOMM40, Synaptophyisn
and COX-IV were detected in human brain samples by preliminary Western Blots. Comparison of protein
concentration using Mass spectrometry across 3 patient groups will give us a better understanding of the roles
of TOMM40, COX-1V, synaptophysin and PSD95 in AD, correlating temporal relationship of synaptic dysfunction
to onset of cognitive dysfunction in AD patients.
35
P16 Fedota, John
NICOTINE WITHDRAWAL INDUCES NEGATIVE CORRELATION IN RESTING CONNECTIVITY BETWEEN INSULA AND
EXECUTIVE CONTROL NETWORK IN SMOKERS
John R. Fedota(1), Allison L. Matous(1), Betty Jo Salmeron(1), Hong Gu(1), Thomas J. Ross(1), and Elliot A.
Stein(1)
(1) National Institute on Drug Abuse, Intramural Research Program, Neuroimaging Research Branch
The insula plays a central role in detecting internal bodily states (cravings) and salient external stimuli (cues). In
addition, the insula is a primary node of the salience network (SN), a large-scale brain network implicated in
switching between internal and external focus via modulation of connections with the anticorrelated default
mode (DMN) and executive control (ECN) networks. Prior evidence in smokers shows increased connectivity
between the insula and DMN during nicotine withdrawal. However, the down regulated connection predicted
between insula and ECN in withdrawn smokers has not been previously demonstrated. Here, resting state
functional MRI data from 18 smokers was collected in an effort to better characterize the dynamics of large-
scale network connectivity during acute withdrawal. 8 minutes of eyes-open resting-state functional
connectivity data were collected from all participants on two occasions-- during baseline smoking and again
following ~48hrs of full nicotine abstinence. Based on prior evidence, 3 insular regions of interest (dorsal
anterior, ventral anterior, and posterior insula) were identified and served as seeds in an analysis examining the
resting connectivity between each of these ROIs and the SN, ECN, or DMN. The contrast of abstinence-baseline
data identified a significant increase in correlation between insula and DMN connectivity and a significant
decrease in correlation between insula and ECN connectivity across scans. During abstinence, the ventral
anterior insula seed showed a positive correlation with rostral anterior cingulate, a node of the DMN, as well as
a negative correlation with the middle frontal gyrus, a node of the ECN. Thus, as opposed to replacing a strong
insula-ECN connection during baseline smoking with a strong insula-DMN connection during abstinence, the
current results suggest that the magnitude of connection between the insula and both the ECN and DMN are
increased during abstinence, though in opposite directions. These results illustrate the dynamics of large-scale
brain network connection in response to nicotine abstinence and are consistent with a reduced exogenous
attentional focus during withdrawal.
36
P17 Francis, Chase
EGR3 EXPRESSION IN NUCLEUS ACCUMBENS MEDIUM SPINY NEURON SUBTYPES OPPOSITELY CONTROLS
OUTCOMES OF SOCIAL DEFEAT STRESS
T.C. Francis (1), R. Chandra (1), L.M. Riggs, P. Konkalmatt, S. Iñiguez, M.K. Lobo (1)
(1) University of Maryland, Batlimore (2) California State University, San Bernardino
The Nucleus Accumbens is a principle integrator of reward related information within the brain and is highly
implicated in depression. The NAc consists primarily of two projection neuron subtypes, medium spiny neurons
(MSNs), which are differentiated by dopamine receptor expression, either dopamine 1 receptors (D1) or
dopamine 2 receptors (D2). Social defeat stress (SDS), a well-validated stress paradigm to induce depression-like
symptoms, promotes dichotomous behavioral, electrophysiological, and molecular outcomes in these MSN
subtypes. SDS produces two distinct behavioral phenotypes: mice susceptible to SDS (i.e., displaying depression-
like symptoms) or mice resilient to SDS. We found repeated high frequency 473 nm optogenetic stimulation
(≥50 Hz stimulation) of NAc D1-MSNs promotes resilience to a 10 day chronic (C)SDS, while repeated stimulation
of D2-MSNs promotes susceptibility to subthreshold (S)SDS. Quantitative real-time PCR revealed repeated
stimulation of either MSN subtype reduces NAc expression of the transcription factor early growth response 3
(Egr3). Egr3 is a primary target of brain-derived neurotrophic factor (BDNF) TrkB signaling. Disrupting this
signaling pathway from the VTA-NAc circuit promotes resilience. Given the known effects of BDNF disruption on
SDS behavior and the opposing outcomes of MSN subtype stimulation, we hypothesized reduction of Egr3
expression in D1-MSN subtypes would promote resilience to SDS and reduction in D2-MSN subtypes,
susceptibility. To mimic stimulation induced down-regulation of Egr3 in cell subtypes, a conditional double
inverted open reading frame (DIO) adeno-associated virus (AAV) expressing an Egr3-miRNA was injected in the
NAc of D1-Cre and D2-Cre mice. Egr3 miRNA knockdown in D1-MSNs enhanced resilience to CSDS, while Egr3
miRNA knockdown in D2-MSNs induced susceptibility to SSDS. These results suggest Egr3 knockdown mimics
MSN subtype-specific stimulation-induced outcomes to SDS. To examine the consequence of enhanced Egr3
expression in MSN subtypes, we injected a DIO-AAV construct to overexpress Egr3. In contrast to knockdown of
Egr3, overexpression of Egr3 in D1-MSNs promoted susceptibility to SSDS, while overexpression in D2-MSNs
produced enhanced resilience to CSDS. Preliminary electrophysiological recordings suggest enhancing Egr3
expression reduce excitatory input to MSN subtypes. Our results suggest Egr3 manipulation in MSN subtypes
oppositely mediates outcomes to SDS. Further, these changes are likely due to alterations in excitatory synaptic
transmission which may underlie the behavioral outcomes to SDS.
37
P18 Goldschmidt, Hana
DGKΘ CATALYTIC ACTIVITY IS REQUIRED FOR EFFICIENT RECYCLING OF PRESYNAPTIC VESICLES AT EXCITATORY
SYNAPSES
Hana L. Goldschmidt (1), Becky Tu-Sekine (1), Lenora Volk (2), Victor Anggono (3), Richard L. Huganir (2) and
Daniel M. Raben (1)
(1) Department of Biological Chemistry, Johns Hopkins School of Medicine, Hunterian 503, 725 N. Wolfe St,
Baltimore, MD 21205, USA., (2) Department of Neuroscience and Howard Hughes Medical Institute, Johns
Hopkins University School of Medicine, Hunterian 1001, 725 N. Wolfe Street, Baltimore, MD 21205, USA, (3)
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland,
Brisbane, QLD 4072, Australia
Synaptic transmission relies on coordinated coupling of synaptic vesicle (SV) exocytosis and endocytosis. While
much attention has focused on characterizing proteins involved in SV recycling, the roles of membrane lipids and
their metabolisms remain poorly understood. Diacylglycerol, a major signaling lipid produced at synapses during
synaptic transmission, is regulated by diacylglycerol kinase (DGK). Here we report the first functional role for
DGKθ in the mammalian central nervous system in facilitating recycling of presynaptic vesicles at excitatory
synapses. Using synaptophysin- and vGlut1-pHluorin optical reporters, we found that acute and chronic deletion
of DGKθ attenuated the recovery of SVs following neuronal stimulation. Rescue of recycling kinetics required
DGKθ kinase activity. Our data establish a role for DGK catalytic activity and its byproduct, phosphatidic acid, at
the presynaptic nerve terminal in SV recycling. Together these data suggest DGKθ supports synaptic
transmission during periods of elevated neuronal activity.
38
P19 Grima, Jonathan
THE ROLE OF NUCLEAR PORE COMPLEXES IN REPEAT EXPANSION NEURODEGENERATION
Jonathan C. Grima (1), Matthew J. Elrick (1), Ishrat Ahmed (1), Jeannie Chew (2), Laura P. W. Ranum (3), Leonard
Petrucelli (2), Robert H. Brown (4), Ke Zhang (1), Christopher J. Donnelly (1), Rita Sattler (1), Thomas E. Lloyd (1),
Solomon H. Snyder (1), Jeffrey D. Rothstein (1)
(1) Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, (2)
Department of Neuroscience, Mayo Clinic, (3) University of Florida College of Medicine, (4) University of
Massachusetts Medical School
Familial and sporadic Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share a common
genetic mutation in chromosome 9. An expanded hexanucleotide (GGGGCC) repeat within a non-coding region
of the C9orf72 gene is the most common genetic cause of familial and sporadic ALS and FTD. It is also the most
common cause of Huntington disease phenocopies. The repeat expansion leads to the loss of one alternatively
spliced C9orf72 transcript, pathological inclusions of TDP-43 protein, the formation of nuclear RNA foci and
accumulation of cytoplasmic dipeptide repeats. However, the underlying mechanisms by which this bi-
directionally transcribed expanded repeat causes these diseases have not been fully elucidated. Nonetheless, it
is becoming increasingly evident that Nuclear Pore Complex (NPC) dysfunction may be a key pathogenic
contributor.
NPCs are the largest protein assemblies in eukaryotic cells. They span the nuclear envelope, consist of multiple
copies of 30 different proteins called nucleoporins, and serve as the only transport conduit between the nucleus
and cytoplasm. These molecular machines not only regulate the flow of molecules into and out of the nucleus
but also have transport-independent functions such as regulating genome organization and gene expression.
Work from our lab and others indicate that nucleocytoplasmic transport dysfunction may be a fundamental
pathway for C9orf72 ALS-FTD pathogenesis. Proteins in this pathway are potent genetic modifiers of GGGGCC
repeat expansion-mediated cytotoxicity in a drosophila model and in iPS neurons derived form C9orf72 patients.
Our ongoing studies suggest that products of the C9orf72 repeat expansion are likely to disrupt
nucleocytoplasmic transport at the NPC. To this end, we assessed the integrity of nucleoporins, the basic
building blocks of NPCs, in C9orf72 human tissue, ips neurons, and various transgenic animal models. Our data
using a large cohort of human autopsy brain as well as transgenic mouse tissues and human C9orf72 iPS cell
lines indicate that select nucleoporins with critical functions are severely affected in the disease with
aggregation at the nuclear membrane, altered nuclear to cytoplasmic distribution, and possible degradation.
This study suggests NPC pathology and function are a fundamental defect in the pathway of C9orf72 ALS-FTD
and potentially other repeat expansion neurodegenerative diseases."
39
P20 Guo, Wei
IMMUNE ACTIVATION OF ENDOGENOUS PAIN MODULATION AS A MECHANISM OF BONE MARROW STROMAL
CELL-PRODUCED PAIN RELIEF IN RATS
Wei Guo, Satoshi Imai(1), Jiale Yang, Shiping Zou, Feng Wei, Ronald Dubner, and Ke Ren
Dept. of NPS, Dental School, & Prog. in Neurosci., Univ. of Maryland, Baltimore, MD 21201, (1) Department of
Pharmacy, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
We have shown that intravenous infusion of rat bone marrow stromal cells (BMSC) suppressed pain
hypersensitivity in rat persistent pain models and the effect was reversed by naloxone, an opioid receptor
antagonist. Studies suggest that BMSC produce their therapeutic effects through secretion of chemical
mediators that interact with the body’s immune system. In the present study, we tested the hypothesis that
BMSC produce the pain-relieving effect, or antihyperalgesia, through interactions with immune cells and involve
activation of endogenous opioid system. A rat model of myogenic orofacial pain was produced by ligation of the
tendon (TL) of the masseter muscle. Primary culture of rat BMSC were obtained from donor rats and human
primary BMSC cell line was purchased (STEMCELL Tech.). BMSC were injected (1M cells/rat, i.v.) at 7 d after TL.
We show that the mu opioid receptors (MOR) expression in the rostral ventromedial medulla (RVM), a key
structure in endogenous pain modulation, was upregulated following infusion of both rat and human BMSC.
BMSC’s antihypergesic effect and upregulation of MOR was attenuated by depletion of the
monocyte/macrophage population of immune cells. Direct injection of peripheral blood monocytes (PBMC, 10K
cells) from BMSC-treated rats into RVM attenuated hyperalgesia in TL rats. Interestingly, injection of serum
from BMSC-treated rats into RVM produced similar pain attenuation, suggesting that chemical mediators from
PBMC mediated BMSC’s effect. Antibody array of serum and chemokine array of PBMC derived from BMSC-
treated rats consistently detected an increased CXCL1 chemokine levels in BMSC-treated rats, compared to
control rats. Immunostaining showed localization of CXCR2, the receptor for CXCL1, in RVM neurons, but not
glial cells. CXCR2 expression was also shown in RVM neurons immunoreactive for MOR. Injection of the CXCR2
antagonist SB 225002 (100 pmol) and transfection of Cxcr2 shRNA into the RVM both diminished BMSC-
produced antihyperalgesia. The BMSC-induced upregulation of MOR in RVM was also attenuated after RNAi of
Cxcr2. These results suggest that immune activation of endogenous pain modulation plays an important role in
BMSC-produced antihyperalgesia and monocyte-derived CXCL1 is a critical mediator of BMSC-produced effects.
40
P21 Gyawali, Utsav
THALAMIC INTRALAMINAR NUCLEI CONTROL OF STRIATAL DOPAMINE RELEASE AND ACTION REINFORCEMENT
Utsav Gyawali (1) and Brian N. Mathur (1)
(1) University of Maryland School of Medicine
Survival in a dynamic sensory environment requires attention-driven action adjustments for successful reward
acquisition. Such goal-directed action learning and performance requires dopamine signaling in the dorsal
striatum, the input nucleus of the basal ganglia. In addition to receiving a dopaminergic input, the striatum
receives glutamatergic input from the centromedian/parafascicular nuclei (CM/Pf) complex of the thalamus,
which encodes salient sensory stimuli. How the CM/Pf complex might shape striatal dopamine signaling to
govern attentionaly-driven, goal-directed action adjustments is poorly understood. To this end, we employ
optogenetic drive of thalamostriatal afferents and detection of striatal dopamine transients using fast-scan cyclic
votammetry in brain slices. Our preliminary data suggest that individual intralaminar nuclei form unique striatal
microcircuits to differentially elicit striatal dopamine release upon activation. These results shed new light on
the role of the thalamus in action reinforcement and suggest thalamostriatal circuits as a potential node of
intervention in striatal dopamine-related disorders such as addiction and Parkinson’s disease.
41
P22 Ho, Chelsea
EFFECTS OF R-MODAFINIL AND ITS ANALOGUES IN COMPULSIVE METHAMPHETAMINE TAKING AND SEEKING
Chelsea P. Ho (1), Brooke E. Schmeichel (1), Janaína C. Vendruscolo (1), Brendan J. Tunstall (1), Rachel D. Slack
(2), Jianjing Cao (2), Gianluigi Tanda (2), George F. Koob (1), Amy H. Newman (2), Leandro F. Vendruscolo (1)
(1) Neurobiology of Addiction Section, Integrative Neuroscience Research Branch - IRP/NIDA/NIH; (2) Medicinal
Chemistry Section - Molecular Targets and Medications Discovery Branch - IRP/NIDA/NIH
Methamphetamine is a highly addictive drug and, currently, no pharmacological treatment is available for
methamphetamine use disorders or relapse prevention. Like other psychostimulants, the wake-promoting drug
R-modafinil, blocks dopamine reuptake by binding to dopamine transporters (DAT). However, modafinil has a
lower DAT binding affinity, resulting in a lower abuse potential. Chronic modafinil treatment has been shown to
attenuate both cue- and methamphetamine-induced reinstatement of drug seeking behavior in rats, suggesting
that modafinil might constitute a potential treatment for methamphetamine addiction. The effect of modafinil
on compulsive methamphetamine intake remains to be determined. Here, we tested the effect of modafinil and
two modafinil analogues (JJC8-016 or JJC8-091) on methamphetamine self-administration. Male Wistar rats
were trained to self-administer methamphetamine, intravenously, under short access (1 h; ShA) and long access
(6 h; LgA) conditions to model moderate, “recreational” drug use, and escalated, compulsive-like drug taking,
respectively. Rats were given intraperitoneal injections of vehicle, R-modafinil, JJC8-016 or JJC8-091, and tested
for methamphetamine self-administration. The results show that JJC8-016 and JJC8-091 dose-dependently
decreased methamphetamine self-administration in both LgA and ShA animals, whereas modafinil had no effect.
JJC8-016, but not JJC8-091 significantly decreased locomotion. This preliminary study indicates the potential of
JJC8-016 and, particularly, JJC8-091 to diminish escalated methamphetamine intake.
42
P23 Imran, Mohammad
CARDIOVASCULAR EFFECTS OF CLONIDINE IN PATIENTS ON BUPRENORPHINE MAINTENANCE
Mohammad Imran MD, William J. Kowalczyk PhD, Karran A. Phillips MD, Michelle L.Jobes PhD, A shley P.
Kennedy PhD, Udi E. Ghitza PhD, Daniel A . Agage MD, John P. Schmittner MD, David H. Epstein PhD , Kenzie L.
Preston PhD,.
Objectives: In a randomized clinical trial, we showed that clonidine increased time to lapse and duration of
opioid abstinence in individuals receiving buprenorphine maintenance (Kowalczyk et al., Am J Psychiatry 2015).
Hypotension is a potential adverse effect of clonidine. Here we report on the heart rate and blood pressure
measures collected in the course of the clinical trial.
Method: Randomized double-blind clinical trial was conducted with 208 opioid-dependent patients at an
outpatient treatment research clinic. The 118 participants who maintained abstinence during weeks 5-6 were
continued on buprenorphine and randomly assigned to receive clonidine (up to 0.3 mg/d; N=61) or placebo
(N=57) for 14 weeks. Sitting and standing blood pressures (BP) and heart rate (HR) were measured weekly
during the baseline (12 weeks), placebo/clonidine Induction (2 weeks), intervention (12 weeks), and post-
intervention maintenance (8 weeks) phases of the study. BP and HR data during the intervention phase from
109 participants (N=51, placebo) and (N=58, clonidine) were analyzed. Data of 9 participants was removed from
study due to noncompliance (N=8) and inability to tolerate buprenorphine (N=1). We used SPSS for independent
sample t test and matched paired t test.
Results: There were no significant differences in BP or HR in the clonidine and placebo groups: Clonidine vs
placebo: sitting mean BPs with SDs as 123±11/74±7 mmHg vs 125±12//75±9 mmHg, 0.62 < t(107) < 0.64, p’s >0
.1; standing mean BPs with SDs as - 123±11/80±8 mmHg vs 125±11/81±10 mmHg; 0.870.1; sitting HRs - 75 ±9 vs
75 ±8 BPM, t(107)=0.41, p=0.68; standing HRs - 80 ±8 vs 85 ±10 BPM, t(107)=0.46, p=0.14.
Conclusion: Clonidine did not lower blood pressure at clinically or statistically significant levels when used in
patients on buprenorphine maintenance. Clonidine also had no significant effect statistically or clinically on
heart rate."
43
P24 Kim, Byung Woo
VOLTAGE-GATED CALCIUM CHANNELS AND INTRACELLULAR Ca2+ INTRACELLULAR Ca2+ DYSREGULATION AS
MECHANISMS OF DISEASE IN AMYOTROPHIC LATERAL SCLEROSIS
Byung Woo Kim, Qing Chang, Lee J Martin
Department of Pathology, Division of Neuropathology, Johns Hopkins School of Medicine
Ca2+ ions are highly versatile and universal intracellular second messengers that regulate various cellular
processes, including neuronal excitability, mitochondrial function, plasticity, and cell death. For these processes
to be properly executed, a precise regulation of Ca2+ signaling is required. Ca2+ channels are critical sources of
Ca2+ entry into nerve cells, yet their role in neurodegenerative disease is not understood. ALS is a progressive
neurodegenerative disorder characterized by the gradual degeneration and elimination of motor neurons and
skeletal muscles leading to paralysis, respiratory insufficiency, and death1. We hypothesize that abnormalities in
voltage-gated Ca2+ channels (VGCCs) are key factors contributing to the mechanisms of neuronal death in
familial ALS with hSOD1 mutations. Using patch-clamp electrophysiology, tissue fractionation, and western
blotting, we showed that high voltage-activated (HVA) Ca2+ currents are increased in transgenic mutant hSOD1
mouse spinal motor neurons. Protein expression levels for VGCCs are increased in the brains of mutant hSOD1
transgenic mice, consistent with increased calcium channel activity in the disease. Immunohistochemistry
revealed a novel VGCCs cellular localization in mouse spinal cord that identifies VGCCs associated with the
nucleus and this localization is altered in mutant hSOD1 transgenic mice. Nuclear localization of VGCCs is further
supported by nuclear fractionation of mouse brain and spinal cord followed by western blotting and live cell
imaging of transfected HEK293FT cells with plasmids containing GFP tagged- Ca2+ channels. We conclude that
VGCCs have a novel subcellular function and that channelopathy contributes to disease mechanisms in ALS.
44
P25 Konopko, Melissa
THE ROLE OF PLACENTAL SEROTONIN IN THE VALPROIC ACID MODEL OF AUTISM
Melissa A. Konopko, Allison Densmore, Clinton D. Roby, Bruce K. Krueger
Use of the anti-epileptic and mood-elevating drug, valproic acid (VPA), by pregnant women increases the
incidence of autism in their children. In utero exposure to VPA in mice has been used an animal model for
autism that mimics the behavioral deficits, some neuroanatomical changes and the male sex bias of human
autism. VPA, a histone deacetylase inhibitor, has been assumed to cause its main effect directly on the
developing brain. In contrast, the focus of this research is the placenta which plays a central role in brain
development by being the sole source of serotonin for the developing forebrain. Serotonin functions as a
necessary neurotrophic factor during early gestation. Reduced fetal serotonin alters maturation of pyramidal
neurons in the somatosensory cortex leading to dendritic morphology similar to that seen in autistic brains. Our
preliminary experiments show altered expression of various serotonin related genes. These changes suggest a
decreased ability of the placenta to produce serotonin, leading to a paucity of this biogenic amine in the fetal
brain and potentially dysregulated brain development.
45
P26 Kumar, Alok
NOX2 REGULATION OF MICROGLIAL/MACROPHAGE ACTIVATION IN THE TBI BRAIN: A NOVEL MECHANISM FOR
NEUROPROTECTION
Alok Kumar (1), James P. Barrett (1), Bogdan A. Stoica (1), Alan I. Faden (1), and David J. Loane (1)
(1) Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University
of Maryland School of Medicine, Baltimore, MD, USA.
Microglia can be polarized towards either an M1-like/classical or M2-like/alternative activation status in
response to injury. These phenotypes can mediate neuroinflammation or promote tissue repair, respectively.
Activation of NADPH oxidase (NOX2/gp91phox) is an important mechanism involved in pro-inflammatory
signaling in microglia. We reported that NOX2 is chronically expressed in M1-like microglia in the peri-lesional
area 1 year following controlled cortical impact (CCI) in mice. Here we compared wild-type (WT; gp91phox+/+)
and NOX2-deficient (NOX2-KO; gp91phox-/-) mice to investigate the role of NOX2 in posttraumatic microglial
polarization.
Three-month old WT or NOX2-KO male mice were subjected to CCI (6m/sec, 2mm depth), and cohorts were
followed for 1- 28d post-injury. M1-/M2-like polarization was analyzed by qPCR, flow cytometry, Western blot,
and immunohistochemistry. Motor recovery and histology were assessed using a beam walk test and
stereological methods.
In WT TBI mice, NOX2 was expressed in reactive microglia (CD68+/Clic1+) in peri-lesional cortex through 28d;
NOX2-KO significantly reduced CD68/Clic1 expression at 3 and 7d post-injury. Flow cytometry analysis of
isolated microglia/macrophages revealed that IL-4R-alpha and its downstream signaling pathway (STAT6, JAK3)
were significantly increased in CD45high microglia/macrophages of NOX2-KO TBI mice compared to WT controls.
M2-like polarization (Arg1, Ym1, TGF-beta) was increased at 3d post-injury in NOX2-KO, with effects sustained
through 21d. There was significant reduction M1-like polarized microglia/macrophages (IL-1-beta, TNF-alpha, IL-
12, iNOS, CD16/32) in NOX2-KO TBI mice. M1/M2-like changes were associated with improved motor function
and reduced cortical neurodegeneration at 21d in NOX2-KO.
Thus, after TBI NOX2-KO mice exhibit enhanced IL-4R-alpha-mediated signaling, greater M2-like repolarization,
and reduced neurodegeneration. These data indicate that NOX2 drives the M1-like polarization of
microglia/macrophages after TBI, and that inhibiting this pathway limits tissue damage and may promote tissue
repair."
46
P27 Kwon, Sung E. (Samuel)
CHOICE-AND STIMULUS-RELATED ACTIVITY MAPPED ACROSS L2/3 OF MOUSE S1 AND S2
Sung E. Kwon (1), Hongdian Yang (1), Genki Minamisawa (1), Daniel H. O'Connor (1)
(1) The Solomon H. Snyder Department of Neuroscience & Brain Science Institute, The Johns Hopkins University
School of Medicine
During perceptual decisions, the activity of single sensory cortex neurons and behavioral choices often co-vary,
even when the stimulus is identical. “Choice probability” (CP) is the probability with which an ideal observer can
predict the choice of the animal based on a single-trial neuronal response. CP is frequently studied because it
links neuronal activity and perception.
CP is often higher for neurons with greater stimulus sensitivity. Intuitively, this is consistent with more
informative neurons contributing more to perceptual decisions. However, theoretical studies suggest a key role
for inter-neuronal “noise” correlation (Rsc) in determining CP. The exact relationship between CP, neuronal
sensitivity, and Rsc is unclear. Also unknown are how CP is mapped at cellular resolution across multiple sensory
cortex areas, and to what degree choice is predicted by population activity patterns unobservable when
recording from one or a few neurons at a time.
We trained mice to detect weak deflections of a single whisker. Using cellular resolution 2-photon calcium
imaging during the task, we measured activity across hundreds of L2/3 neurons in whisker areas of primary (S1)
or secondary (S2) somatosensory cortex (S1: 4 mice; S2: 4 mice). Ideal observer analysis quantified how well
each neuron discriminated stimulus presence/absence (“Stimulus probability”, SP) and the choice of the mouse.
SP is a measure of neuronal sensitivity to our stimulus. We also quantified Rsc among neuron pairs.
The fraction of neurons with significantly above-chance SP was greater in S1 than S2 (S1: 47%, S2: 30% of
responsive neurons). S1 neurons also had higher SP (S1 median: 0.57; S2: 0.53, p<0.001, K-S test). Thus, stimulus
representation was somewhat stronger in S1. In contrast, S2 and S1 neurons predicted choice similarly (S1
median CP: 0.56, S2: 0.55, p=0.065, K-S test). Mean Rsc with other responsive neurons was higher for neurons in
S2 vs S1 (0.17 vs 0.09; p<0.001, Wilcoxon rank sum test). Partial correlations revealed that CP depended
separately on a neuron’s stimulus sensitivity and its mean Rsc.
We used a machine learning algorithm to decode the stimulus and choice from populations of hundreds of S1 or
S2 neurons. S1 populations yielded better decoding of the stimulus (S1: 93 ± 3% correct; S2: 75 ± 4%; mean ±
SEM across mice). Mouse performance (78 ± 1%) was similar to that of the S2 decoder. Decoding of choice was
similar in the two areas (S1: 75 ± 4%; S2: 77± 2%).
Could widespread choice- and stimulus-related activity reflect direct S1<->S2 communication? We imaged S1-
>S2 axons (2 mice), and S2->S1 axons (4 mice), and found stimulus- and choice-related activity propagating
bidirectionally.
47
P28 Labuza, Amanda
IDENTIFICATION OF SANK1 AS NOVEL SERCA1 REGULATORY PROTEIN IN SKELETAL MUSCLE
Amanda Labuza (1,2), Patrick F. Desmond (1,3), Joaquin Muriel (1), Michele L. Markwardt (1), Mark A. Rizzo (1),
Robert J. Bloch (1,2)
1 Department of Physiology, 2 Program in Neuroscience, 3. Program in Biochemistry and Molecular Biology
University of Maryland, Baltimore, MD 21201 USA
Small ankyrin (sAnk1) is a transmembrane (TM) protein found in muscle and brain. sAnk1 has been shown to
interact with obscurin and titin in skeletal muscle and to stabilize the network sarcoplasmic reticulum (nSR).
Stabilization of the nSR is essential for normal muscle contraction and relaxation. We have previously reported
that sAnk1 shares homology in the TM domain with sarcolipin (SLN), which binds to the sarco(endo)plasmic
reticulum Ca2+-ATPase (SERCA) via its TM domain to inhibit enzymatic activity. We therefore investigated if
sAnk1 can also regulate SERCA activity via TM interactions.
To study the interaction of sAnk1 and SERCA1 (the isoform expressed in skeletal muscle), we used SR vesicles
isolated from rabbit skeletal muscle and COS7 cells transfected to express these proteins. Through co-
immunoprecipitation experiments and an anisotropy-based FRET (AFRET), we demonstrated that SERCA1
interacts specifically with sAnk1. Mutation of the TM region of sAnk1 to all leucines significantly reduced
association with SERCA1 in both assays. Preliminary data suggest that SERCA1 can interact with both sAnk1 and
SLN simultaneously.
We also studied the effect of sAnk1 on SERCA1. Assays of ATPase activity showed that both SLN and sAnk1
decrease SERCA1 activity by shifting the apparent affinity for Ca2+, but that SLN is the more potent inhibitor.
We are currently studying the association of sAnk1 with SERCA as a function of Ca2+ concentration.
Our results suggest that sAnk1, like SLN, interacts with SERCA1 through its TM domain. This interaction can
regulate SERCA1 activity and thereby modulate the sequestration of Ca2+ in the lumen of the ER and SR.
Identification of sAnk1 as a novel regulator of SERCA1 activity has major implications for the physiology of
muscle and may provide novel therapeutic approaches to treat muscular dystrophies linked to Ca2+
misregulation.
48
P29 LeGates, Tara
SYNAPTIC PLASTICITY MECHANISM OF EXCITATORY HIPPOCAMPAL INPUT TO THE NUCLEUS ACCUMBENS
Tara A. LeGates (1) and Scott M. Thompson (1)
Department of Physiology University of Maryland School of Medicine
The nucleus accumbens (NAc) is a central component of the reward system and is responsible for integrating
information from cortical and limbic brain regions to drive goal directed behavior. The ventral hippocampus
provides excitatory input to the NAc shell, which is thought to be important for modulating NAc activity and
providing contextual information to reward processing. This synapse has received increased attention due to its
potential role in mood regulation, specifically in response to reward and motivation to seek rewards, which are
altered in mood disorders including depression. However, the mechanistic understanding of activity-dependent
synaptic plasticity at this synapse remains limited. We used whole-cell electrophysiological recordings in the NAc
shell to dissect the mechanisms underlying activity dependent synaptic plasticity of the excitatory input from the
hippocampus to the NAc shell. Our data show that this synapse is capable of undergoing activity-dependent long
term potentiation (LTP) via a postsynaptic mechanism. The induction of LTP was blocked by APV and KN62
indicating that this is an N-methyl-D-aspartate (NMDA) receptor - and Ca2+/calmodulin-dependent kinase type II
(CaMKII)-dependent process. Furthermore, we found that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor subunit composition remains unchanged after LTP induction. We verified the specificity of
this response by using optogenetic stimulation of this synapse allowing us to assay the behavioral consequence
of in vivo manipulation of this synapse. These experiments provide the first detailed electrophysiological
characterization of the excitatory input from the hippocampus to the NAc and are crucial for proper
understanding of the dysfunction in these neural circuits that contribute to mood dysregulation.
49
P30 Lesage, Elise
NICOTINIC RECEPTOR STIMULATION AFFECTS REVERSAL LEARNING IN SMOKERS
Elise Lesage (1), Sarah E. Aronson (1,2), Matthew T. Sutherland (1,3), Thomas J. Ross (1), Betty Jo Salmeron (1),
and Elliot A. Stein (1)
(1) Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National
Institutes of Health, Baltimore, MD; (2) University of Maryland, Baltimore, MD; (3) Department of Psychology,
Florida International University, Miami, FL
Introduction: The ability to flexibly update the value of actions in an uncertain environment is important for
human functioning. This ability is captured by probabilistic reversal learning (RL) tasks, where participants must
learn reward contingencies based on uncertain information and adjust their behavior as contingencies change.
RL captures learning from reward and punishment, relies on prefrontal and striatal circuitry, and is modulated
by cholinergic afferents in preclinical models. Here, we investigate the effects of nicotinic receptor stimulation
on probabilistic RL in smokers and non-smokers through the administration of nicotine and varenicline, a partial
agonist/partial antagonist to nicotine at alpha4beta2 receptors.
Methods: 24 smokers participated in 6 fMRI sessions (4 reported herein) during a two-drug (nicotine and
varenicline), placebo–controlled, double-blind crossover study. Subjects performed a probabilistic RL task in the
scanner. Two visual stimuli were presented, one predictive of a reward and the other predictive of a
punishment. The outcome was probabilistic, such that the correct response results in a reward in 75% of trials.
The contingencies reversed throughout the task, and participants adjusted their response (switch or stay) based
on the receipt of a reward (win) or punishment (loss). The effects of PATCH (nicotine or placebo) and PILL
(varenicline or placebo) on RL performance and on neural activity in regions engaged in RL were assessed.
Results: Acutely abstinent smokers (i.e. in the absence of either drug) made fewer lose-stay choices than when
either nicotine or varenicline was in their system. Imaging results during lose-stay events revealed effects of
nicotine on neural activity during a lose-stay choice, such that there was decreased activity in bilateral caudate
and putamen and left amygdala in abstinent but not sated smokers. No significant nicotine-x-varenicline
interactions were observed in the lose-stay events in the smoker group, but trends were observed in anterior
insula and anterior cingulate.
Discussion: These data show that RL performance is affected by nicotinic receptor stimulation in smokers;
acutely abstinent smokers show a showed a decreased tendency to select the previously rewarded stimulus in
the face of negative feedback. These results indicate that cognitive flexibility may be exaggerated in abstinent
smokers, perhaps indicating an exploratory drive state induced by acute withdrawal.
50
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