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Chronic Social Defeat Stress Effects On Neural Activation, Vasopressin Levels and Anxiety-Like Behaviors in a Social Investigation Model

Thomas Adams ('11); Yoav Litvin*; Gen Murakami*; Camille Fontaine*; Donald W. Pfaff* Mentor: Nicole Weekes
*The Rockefeller University, New York City, NY

Abstract: A behavioral model of (chronic) social defeat in mice is used to study the genetic and epigenetic precursors of stress-related psychopathologies in humans. The neuropeptide arginine vasopressin (AVP) has been shown to play multiple significant roles in mammalian responses to stressful challenges. For example: along with corticotropin-releasing factor (CRF), AVP controls the activity of the hypothalamicpituitary- adrenal (HPA) axis. We studied the effects of social defeat on the expression of AVP and activation of AVP-containing neurons (via Fos staining) in the paraventricular nucleus (PVN) of the mouse hypothalamus; additionally, we studied its effects on fear- and anxiety-like behaviors displayed by mice in a novel social investigation experiment. Results indicate a significant increase in fear- and anxiety-like behaviors and in activity of AVP-containing neurons in the PVN after social defeat, suggesting a role for AVP in specifically social anxiety.
Funding provided by Pomona College SURP

Ethanol influences synaptic transmission via a postsynaptic mechanism and modestly inhibits motor activity in Drosophila larvae

Sean Chung ('12); Srishti Nayak ('12 HMC) Mentor: Karen Parfitt

Abstract: Although alcoholism is a vital issue, the molecular mechanisms of action of ethanol still remain unclear. We have been characterizing the effects of ethanol on synaptic transmission by intracellular electrophysiological recording of miniature excitatory junction potentials (EJPs) from the neuromuscular junctions of third instar Drosophila larvae. We employed a solutionchange apparatus to introduce ethanol (60 mM) to the neuromuscular junctions to explore the effect of ethanol on the frequency and amplitude of the mini EJPs. The ethanol modestly suppressed the amplitudes of mini EJPs compared to those collected in control saline, without significantly changing the frequency of mEJPs. This suggests a post-synaptic action of ethanol. Motor assays revealed that higher concentrations (120mM) of ethanol also slightly decreased locomotion in Drosophila larvae.
Funding provided by The Paul K. Richter and Evalyn E. Cook Richter Award

HS2ST (?) and slit localizations in Drosophila

Meredith Course ('12); Steven Chau ('12); Mentor: Karl Johnson

Abstract: Secreted guidance molecules are vital to proper nervous system development. Heparan sulfate proteoglycans (HSPGs) are required to mediate the interactions between some of these secreted ligands and their respective receptors. It is not well understood, however, which portions of the HSPGs are necessary for successful mediation. This experiment looks at Drosophila strains lacking heparan sulfate 2-O-sulfotransferase (Hs2st), an enzyme that sulfates heparan sulfate (HS) chains on the second oxygen. If the HS side chains are responsible for proper functioning of the HSPGs, our mutants should exhibit defects in their ventral nerve cords. We show here that in one mutant case, Hs2st deletion seems to affect the localization of the guidance molecule Slit as depicted by abnormalities in the ventral nerve cord.
Funding provided by The Fletcher Jones Foundation (MC), The Rose Hills Foundation (SC)

The Role of Synbindin in the Development of Neuromuscular Junctions

Rachel Ekaireb ('12); Mentor: Karl Johnson

Abstract: A nervous system must be able to form precise connections between neurons and modulate the strength of these synapses. Heparansulfate proteoglycans (HSPGs) play a fundamental role in regulating the formation and maintenance of synapses. A novel protein, synbindin (sbd), binds to syndecan-2’s cytoplasmic domain in the mouse hippocampus. In this project we examined synbindin’s role in the development of neuromuscular junctions (NMJs) in Drosophila using RNAi techniques to eliminate synbindin in various tissues. UAS sbd-RNAi flies were crossed with flies containing various Gal-4 drivers. Progeny larva were dissected and fluorescently stained in order to quantify the size of the synapses between muscles 6&7 of the A2 segment. Flies lacking synbindin in muscles had significantly smaller synapses than wild-type, supporting the claim that synbindin promotes synapse development by acting as a downstream effector of syndecan in muscle tissue. Future experiments using myc-tagged synbindin will further elucidate synbindin’s role at the NMJ.
Funding provided by The Fletcher Jones Foundation

Varying time courses of chronic mild stress reduce long-term potentiation in CA1 region of rat hippocampus

Meghan Flanigan ('11); Jennifer Liao ('11); Rachel Lown-Hecht ('11); Cara Hall ('11); Mentor: Jonathan King

Abstract: Recent research has suggested that clinical depression may be the result of impairments in neuroplasticity when faced with external stimuli such as chronic stress. In congruence with this hypothesis, stress induced impairments in synaptic plasticity are rescued by treatment with antidepressants. Although chronic severe stress has been commonly shown to alter synaptic plasticity, it has been suggested that the application of unpredictable chronic mild stress (CMS) is more indicative of the stressors that implicate depression in daily life. We investigated the effects of varying time courses of CMS (2-4 days, 1-2 weeks) on long term potentiation (LTP) in the CA1 region of the rat hippocampus, hypothesizing that CMS would decrease LTP in a time-dependent manner. Our results show that CMS did decrease LTP, however longer exposure to stress did not result in a greater reduction in LTP. This study has important implications for understanding stress, depression and neuroplasticity.
Funding provided by The Fletcher Jones Foundation (MF, CH), The Norris Foundation (RLH), 5- C Neuroscience Fellowship (JL)

Developing an animal model to study fetal alcohol syndrome

Lateece Griffin ('11); Jonas Kwok ('13); Julia Gleichman ('10); Mentor: Jonathan Matsui

Abstract: Fetal alcohol syndrome (FAS) is caused by alcohol consumption during pregnancy and affects approximately 1 in every 100 live births in the U.S., 90% of which display ocular defects. The zebrafish (Danio rerio) is an animal model for studying the effects of early ethanol (EtOH) exposure on the development of the vertebrate eye. In this study, eggs from AB strain zebrafish were raised in 0%, 1%, or 1.5% ethanol in order to assess the effects of dose and time exposure. Microphthalmia (small eye), one of the hallmarks of FAS, can be measured by comparing the ratio of area to full-body length. Dose dependent decreases in relative eye size compared to the control were recorded at 5 days post-fertilization. These results indicate that ethanol disturbs the normal growth of the zebrafish eye and causes at least one of the ocular deficits described in FAS children.
Funding provided by 5-C Neuroscience Fellowship (LG), The Fletcher Jones Foundation (JK)

Developing methods to administer drugs to zebrafish retinas and to asses visual function

Alex Groth ('12); Julia Gleichman ('10); Joshua Cameron*; Mentor: Jonathan Matsui
*Western University of Health Sciences, Pomona, CA

Abstract: The zebrafish (Danio rerio) has recently emerged as an animal model to study vision. Zebrafish respond to a variety of stimuli including red, green, blue and ultraviolet light starting around five days post-fertilization. Retinosa pigmentosa (RP) is a genetic disease that leads to irreversible blindness in humans. Aminoglycoside antibiotics are effective in decreasing the effect of premature termination codons in cell lines with the same genetic mutation underlying RP. This summer we developed a method to deliver aminoglycosides to the zebrafish retina. Ultimately, we would like to slow the progression of RP in a mutant zebrafish using aminoglycosides. We are also in the process of improving the optokinetic response (OKR) which is a behavioral assay used to measure zebrafish vision.
Funding provided by The Norris Foundation

Psychological Stress, Hormonal Contributions and Brain Activity

Natalie Guerrero ('11); Mentors: Nicole Weekes, Richard Lewis

Abstract: Evidence suggests that there are sex differences in the prevalence of a variety of psychological disorders, including clinical depression. One of the most recent proposed theories to explain this difference is that women and adolescent girls both experience greater numbers of stressors and demonstrate greater sensitivity (or reactivity) to those stressors than do men. Stressor reactivity has been measured in a number of ways, including EEG prefrontal asymmetry. It has been shown that when subjects are more stressed, there is greater right prefrontal activity than when they are less stressed. Sex differences have also been observed both in the relationship between EEG asymmetry and stressor reactivity, and between EEG asymmetry and dépression. In this study, we investigate sex differences in the reactivity of EEG prefrontal asymmetry in response to a laboratory stressor.
Funding provided by The Fletcher Jones Foundation

Chronic Mild Stress and Sex Differences in Synaptic Plasticity

Cara Hall ('11); Rachel Lown-Hecht ('11); Meghan Flanigan ('11); Jennifer Liao ('11); Mentor: Jonathan King

Abstract: Major depression is a disorder that is linked to the exposure of major life stressors. Women are more susceptible than men to suffer from major depression. Chronic mild stress (CMS) is an established model of depression in rodents. In previous studies, female rodents display enhanced performance over male rodents in a series of behavioral tests conducted after periods of stress. Changes in neuronal plasticity could account for these sex differences. The current study investigated whether CMS produced sex differences in synaptic plasticity. Male and female rats were subjected to a variety of daily stressors for two weeks and long-term potentiation (LTP) in the CA-1 region of the hippocampus was measured. We hypothesized that the females would show increased LTP and the males would show decreased LTP when compared with controls. Contrary to our predictions, our findings revealed that CMS increased LTP in males while decreasing LTP in females.
Funding provided by The Fletcher Jones Foundation (CH, MF), The Norris Foundation (RLH) , 5-C Neuroscience Fellowship (JL)

Examining the role of Syndecan during Synapse Formation in Drosophila

Jared Kopelman ('11); Mentors: Nicole Weekes, Richard Lewis

Abstract: Depression is a common psychiatric disorder that affects approximately ten percent of the population. While the causes of depression are varied, genetics are thought to play a key rôle. More specifically, selective polymorphisms related to the serotonergic and dopaminergic systems have been implicated. In addition, higher right prefrontal EEG activity is seen in both depressed patients and in individuals at risk for dépression. Finally, this EEG préfrontal asymmetry pattern may be related to some of the same genes involved in predisposing individuals to dépression. In this study, we investigate how genetic markers relate to both depressive symptoms and prefrontal asymmetry. We predict that polymorphisms associated with depression will also be associated with greater right frontal activity. In addition to genetics, stress is also thought to be a major cause of depression.
Funding provided by The Fletcher Jones Foundation

Examining the role of Syndecan during Synapse Formation in Drosophila

Rachel Lee ('12); Mentor: Karl Johnson

Abstract: Syndecan (Sdc), a cell-surface heparan sulfate proteoglycan, plays a key role in the Robo- Slit chemo-repellent pathway and has also been implicated in synapse formation. We studied the Drosophila NMJ, which is analogous to vertebrate CNS excitatory synapses, to observe the effects of selectively suppressing expression of Sdc in specified locations. The UAS/GAL4 system was used for targeted knockdown of Sdc, and immunohistochemistry protocols were followed to examine the synapses. Our results showed a decrease in synapse size compared to the wildtype phenotype for the mutants lacking Sdc in either the pre-synaptic cell or post-synaptic cell, demonstrating the need for the presence of Sdc at the synapse for proper synaptogenesis; however, discrepancies in the data, such as the decreased synapse size caused by a lack of Sdc at the glial cells, can be explained by errors in protocol and will need to be rectified.
Funding provided by The Fletcher Jones Foundation

The effects of short-term chronic mild stress on anxiety and depressive-like symptoms in rats

Jennifer Liao ('11); Meghan Flanigan ('11); Rachel Lown-Hecht ('11); Cara Hall ('11); Mentor: Jonathan King

Abstract: Major depression is a chronic mental disorder that is often onset by exposure to multiple, stressful life events. Many studies have reported the validity of the chronic mild stress (CMS) model of depression in rodents. The current study investigated whether a short-term application of CMS would induce depressive-like behavior as indexed by the novelty suppressed feeding (NSF) test and forced swim test (FST) (two behavioral assays used to assess symptoms of depression). Male rats were exposed to CMS for one or two weeks. Following CMS, they were subject to the NSF test and the FST. Our results show that control rats spent less time immobile compared to the CMS rats in the FST. However, they had a longer latency to feed compared to CMS rats in the NSF test. Results suggest that short-term chronic stress may induce behavioral despair but reduce anxiety.
Funding provided by The Fletcher Jones Foundation (MF, CH), The Norris Foundation (RLH), 5-C Neuroscience Fellowship (JL)

Chronic mild stress for two weeks does not produce behavioral changes in male or female rats

Rachel Lown-Hecht ('11); Cara Hall ('11); Jen Liao ('11); Meghan Flanigan ('11); Mentor: Jonathan King

Abstract: Stress-related disorders such as depression disproportionately affect women, but most rodent studies use only males to model the effects of stress. In this study, the effects of chronic mild stress (CMS) on anxiety-related behavior and object memory were investigated in male and female rats. After two weeks of CMS exposure, rats were tested in the novel suppressed feeding (NSF) and novel object recognition (NOR) test. Our results show no significant difference between sexes or controls in the NSF or NOR test. Additionally, there were no differences in weight between control and CMS rats. The lack of significant differences between control and CMS groups, which has been previously studied using 6 weeks of CMS, suggests that 2 weeks of CMS was not long enough to alter feeding patterns, anxiety-like behavior or memory function. Six weeks of CMS procedure may be needed to observe sex differences between male and females.
Funding provided by The Norris Foundation (RLH), The Fletcher Jones Foundation (CH, MF), 5-C Neuroscience Fellowship (JL)

Psychological Stress and Hormone Levels in African American Subjects

Fatima Traore ('11); Mentors: Nicole Weekes, Richard Lewis

Abstract: African Americans have the largest health disparities among all minorities. With stress being a risk factor in almost all health-related outcomes, the chronic exposure to psychosocial stressors experienced by blacks may increase their susceptibility to a large range of diseases by permanently altering their physiological functioning. While previous research has focused on some measures of stress (including heart rate and blood pressure), very little attention has been given to the racial/ethnic differences in hormonal reactivity (HPA axis) despite its prevalent role in many health outcomes such as dysfunctions of the immune system. Furthermore, several studies have documented the effects of racial identity as a possible moderator of psychological and physiological (hormonal) responses in the African American population. Therefore, in our study we investigate the hormonal and psychological responses to laboratory stressors in African Americans, and want to determine if individual differences in levels of ethnic identity moderate these responses.
Funding provided by The Fletcher Jones Foundation

Research at Pomona