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Neuroscience

Serotonin has a context-specific ability to modulate altruistic punishment

Yi Li (2014); Mentor(s): Jorge Barraza; Karl Johnson

Abstract: Serotonin plays a crucial role in facilitating cooperative behavior, but in the case of third party punishment, its effect is heavily context dependent. Recent research suggests that serotonin reduces punishment when the individual is personally harmed, but not when others are harmed. Here, we further investigate how the role of serotonin in cooperative behavior differs depending on the group identification of the individuals involved using an acute tryptophan depletion treatment, minimal group paradigm, ultimatum game, and third party punishment tasks. We found that serotonin modulates punishment of unfair behavior both by reducing punishment of fair behavior and by facilitating punishment of unfair behavior in a context-dependent way. While serotonin did not mediate differential punishment of ingroup and outgroup participants engaging in the same behavior, the effects of serotonin on altruistic punishment were sensitive to group identification: Serotonin reduced punishment of fair offers when members of their own ingroup were involved, but exacerbated punishment of unfair behavior when the sender or receiver was a member of the outgroup. Taken in totality, the results suggest that serotonin’s ability to modulate third-party punishment is context-specific.
Funding Provided by: Paul K. Richter and Evelyn E Cook Richter Memorial Fund; Pomona College Department of Neuroscience

Increased Insular Volume is Associated with a Reduced Future Oriented Time Perspective

Cesia Dominguez Lopez (2014); Mentor(s): Louise Cosand

Abstract: In the past few decades, the insula has become the focus point of investigation for representation of bodily states and is thought to play a role in maintaining addiction, making decisions (based on present vs. future outcomes), and in interoceptive abilities. Notably, lesions to insula have been associated with abrupt cessation of smoking and cravings. The present study examined insular volume in cigarette smokers. Because aberrant decision making in addiction generally favors the present, insula volume was compared with present/future orientation as measured by self-report questionnaire (Zimbardo Time Perspective Iventory; Zimbardo, 1999) in 17 male cigarette smokers. Anatomical region of interest volumes were drawn on structural MRI images for each participant. Insular volume was inversely related to future oriented thinking (r=-.504, p= .039). These results may suggest that larger insular cortices correspond to a sensitivity to present visceral states, such as craving, at the cost of sensitivity to long-term outcomes.
Funding Provided by: Kenneth T. and Eileen L. Norris Foundation

The Role of Copy Number Variation in fbxc-5, an F-box protein, on Food Choice Preference in C. elegans

Patrick Liu (2014); Student Collaborator(s): Lillian Haynes (2013 HMC); Mentor(s): Elizabeth Glater

Abstract: A key question in neuroscience is how genetic and biological variation can ultimately influence behavioral phenotypes. The Glater Lab is currently interested in the genetic and neuronal basis for bacterial food choice preference in C. elegans. Two strains of C. elegans demonstrate a marked difference in their naïve preference for S. marscecens, a pathogenic bacteria, and E. coli. Specifically, the N2 strain shows a strong preference for S. marscecens over E. coli whereas the Hawaiian strain shows a much weaker preference. Through genomic substitution lines, the fbxc-5 genes, a set of F-box proteins which differ in copy number between the N2 (5 copies) and Hawaiian (3 copies) strains, have been implicated in mediating this difference. To study the effect of copy number variation of the fbxc-5 gene on the choice preference between N2 and Hawaiian, we utilize a technique called Mos-1 mediated single copy insertion (MoSCI) (Jorgenson 2008) to introduce a single copy of the fbxc-5 gene into the Hawaiian genome and observe its effects on the worm’s choice behavior. Better understanding of these effects will help us understand the role of genetic variation in mediating difference in food choice behavior.
Funding Provided by: Howard Hughes Medical Institute

Identification of Chondroitin Sulfate Proteoglycans (CSPGs) in Drosophila melanogaster

Kevin Guttenplan (2014); Mentor(s): Karl Johnson

Abstract: Proteoglycans are a class of large, negatively-charged proteins with many sugar side-chain modifications. Heparan Sulfate Proteoglycans (HSPGs) are well characterized in Drosophila and are implicated in nervous system development. Chondroitin Sulfate Proteoglycans, proteins similar to HSPGs but with CS rather than HS sugar side chains, have been identified in animals ranging from humans to C. Elegans. Nevertheless, though CS and HS sugars have identical attachment sites and CS sugars are known to exist in Drosophila, no Drosophila CSPGs have been definitively found. Thus, we sought to identify novel CSPGs in Drosophila.
Funding Provided by: National Science Foundation #IOS-0841551

Characterization and Identification of Chondroitin Sulfate Proteoglycans in Drosophila melanogaster

Lauren Kershberg (2015); Student Collaborator(s): Estela Sanchez (2017); Mentor(s): Karl Johnson

Abstract: Chondroitin sulfate proteoglycans (CSPGs) are sugar modified proteins found in a variety of organisms. They affect neural development and axon growth. However, CSPGs have never been found in Drosophila despite evidence of their existence. The identification of CSPGs in Drosophila would allow for an in depth study of the neural mechanisms of CSPGs. In this two part project, bioinformatics approaches were first used to identify four candidate Drosophila CSPGs in three genes: slit, collagen, and tok. Next, experimental techniques are being utilized to locate, identify, and characterize the CSPGs. These experiments are still in progress.
Funding Provided by: National Science Foundation #IOS-0841551

The Role of DAD in Syndecan Localization at the Drosophila Synapse

Tafadzwa Mtisi (2015); Mentor(s): Karl Johnson

Abstract: The precise regulation of synaptic growth is critical for the proper formation of neural circuits. Previous studies have identified a number of molecular signals involved in the regulation of synaptic growth in the Drosophila neuromuscular junction (NMJ). The heparan sulfate proteoglycans (HSPGs) Syndecan (Sdc) and Dallylike interact with the receptor phosphatase LAR to regulate synaptic development. Sdc is a transmembrane protein with highly conserved cytoplasmic domains about which, little is known. Past Johnson lab students conducted a yeast two-hybrid screen on Drosophila embryonic cDNA to identify potential binding partners for the cytoplasmic domains of Sdc (SdcCD). Among the target interactors was Daughters Against Decapentaplegic (DAD), an inhibitory Smad protein in the decapentaplegic signaling pathway. It was hypothesized that DAD’s Pdz domain binds to Sdc’s C2 EFYA cytoplasmic domain. This research was aimed at identifying the role of DAD in localizing Sdc at Drosophila NMJ synapse. A dose-dependent knockout of DAD was used by means of RNA interference and the temperature sensitive Gal 4 system. We hypothesized that the more time third instar larvae spend at 25°C the more DAD is knocked out and the less Sdc localizes at the synapse. Immunoflorescent images of DAD knockout after 3 days at 25°C showed some Sdc still localized at the synapse. Further imaging and quantifying are yet to be done for larvae with higher dose of DAD knockout under the confocal microscope.
Funding Provided by: Koe Family Fund

The Effect of Hey on Axon Guidance in Drosophila melanogaster

Ryan Randle (2014); Mentor(s): Karl Johnson

Abstract: During the development of the CNS in Drosophila, axons rely on conserved guidance cues in order to innervate their appropriate targets. In a forward genetic screen of the 8941 and 7537 deletions, mutants that cause axons to ectopically cross the midline, we attempted to identify novel contributors to axon guidance at the Drosophila midline. Within these deletions lie the transcription factor Hey, previously described as a target of Notch signaling. The midline defects present in the Heyf06656 loss of function mutant are similar to those found in the genetic screen. In light of this, we hypothesized that Hey may have a novel role in canonical midline crossing during CNS development. In order to determine whether Hey was a novel contributor to axon guidance at the Drosophila midline, we scored stage 17 embryos for the number of midline crossing defects (ectopic crossings) in crosses between these mutants, and assayed for the distribution of key guidance molecules. Statistical analysis of the number of defects between each cross showed that Hey indeed is responsible for the defects seen in the screen. However, due to the presence of both Slit and Robo, it is unlikely the defects are accomplished through some previously uncharacterized interaction between Hey and these two guidance molecules. We concluded that it is likely the defects are caused by Hey's role as a target of notch delta signaling. Specifically, the Hey mutant acts to suppress asymmetric differentiation of midline glial cells. Continuing this research may confirm Hey's indirect effect on axon guidance.
Funding Provided by: Fletcher Jones Foundation

Environmental Enrichment Restores Chronic Mild Stress Induced Impairments in Synaptic Plasticity but not Behavior

Hannah DeWeerth (2014); Student Collaborator(s): Jenny He (2014); Yuni Kay (2015); Mentor(s): Jonathan King

Abstract: Stress and depression have a profound effect on cognitive performance. Chronic mild stress (CMS), a series of unpredictable mild stressors, has been shown to induce depressive-like behaviors and impair synaptic plasticity. Environmental enrichment (EE) has been shown to rescue depressive-like behaviors, enhance plasticity and promote neurogenesis. In the current study, we examined whether EE could counteract impairments caused by stress. Rats were subjected to 5 weeks of CMS or assigned as control rats and divided into EE or non-EE conditions. The forced swim test (FST) and the novelty suppressed feeding test (NSF) were used to assess the effects of CMS and EE on behavior. Anhedonia was measured by sucrose preference. Electrophysiological recordings from hippocampal slices were used to examine differences in synaptic plasticity as measured by long-term potentiation (LTP). Our results show that CMS had an effect on food consumption as measured by the NSF test. Rats that were subjected to CMS and EE together showed a higher level of LTP than rats subjected to CMS alone. These data show that EE facilitated recovery of CMS induced impairments in synaptic plasticity. Other parameters measured by the FST and NSF tests were not sensitive enough to detect differences using this paradigm. This study provides evidence that chronic mild stress and environmental enrichment may modulate similar circuits in the brain that affect synaptic plasticity and EE may be beneficial for cognitive function.
Funding Provided by: Paul K. Richter and Evelyn E. Cook Richter Memorial Fund

Gender Identity, Sexual Orientation and the Prenatal Androgen Theory: Re-evaluating definitions, cognitive tests and somatic markers

Zachary Schudson (2013); Student Collaborator(s): Alexis Takahashi (2013); Zoey Martin-Lockhart (2014 PIT); Mentor(s): Rachel Levin

Abstract withheld upon request.
Funding Provided by: Rose Hills Foundation

Neuroplasticity-based cognitive training in schizophrenia: predicting patient responses using a neurological marker

Sean T. Pianka (2014); Additional Collaborator(s): Gregory A. Light (University of California, San Diego); Veronica B. Perez (University of California, San Diego); Mentor(s): Richard Lewis

Abstract: Prevailing pharmacologic treatment paradigms do little to address the neurocognitive deficits in memory, attention, and verbal information processing experienced by a majority of schizophrenia (SZ) patients. Recent studies show that neuroplasticity¬based, procognitive training interventions targeting early perceptual processes may help to ameliorate neurocognitive deficits in some SZ patients. Neurological biomarkers capable of predicting individual patient responses to procognitive training are needed to hone and efficiently implement these resource-intensive treatment protocols. The current study in a cohort of 22 SZ patients utilizes EEG and computational analyses to investigate the effects of a single dose of Targeted Cognitive Training (TCT) on an electrophysiological biomarker known as mismatch negativity (MMN). TCT is a neuroplasticity-based, procognitive training intervention designed to improve auditory information processing. MMN is an automatic, preattentive neurological response to deviant auditory stimuli presented amid a sequence of standard tones. Patterned changes in MMN response may serve as a dynamic index of auditory system neuroplasticity. MMN responses to several deviant stimuli were collected before and after a 1.5-hour session of TCT. Preliminary findings suggest that greater improvements in TCT performance correspond with enhanced MMN responses. Studies further elucidating the efficacy of MMN as a predictive biomarker for patient responses to TCT are currently under way.
Funding Provided by: Claremont Colleges Summer Research Fellowships in Neuroscience

Comparing Neurofibrillary Tangles in Alzheimer's Disease and Progressive Supranuclear Palsy

Alexandria (Ali) Valdrighi (2015); Mentor(s): Izumi Maezawa (UC Davis -Department of Pathology)

Abstract: Alzheimer’s disease is a prevalent neurodegenerative disorder in the United States affecting approximately 5.5 million Americans. Neurofibrillary tangles are a hallmark of Alzheimer’s disease created by hyperphosphorylation of 3R and 4R tau isoforms. Neurofibrillary tangles are also observed in the neurodegenerative disorder Progressive Supranuclear Palsy (PSP), but PSP is only associated with 4R tauopathies. Superresolution Microscopy is a newly developed microscopy technique that is able to resolve images at approximately 100 nm resolution. It can be used to generate detailed, 3D images of neurofibrillary tangles which offer clues to their structures. Superresolution microscopy can be used to image Alzheimer’s and PSP tangles. It is anticipated that the shapes can then be compared to develop a quantitative method of distinguishing the two types of tangles. Distinguishing the tangles quantitatively would allow post-mortem diagnosis of Alzheimer’s and PSP which would be beneficial in clinical research. It may also illuminate structural differences between 3R and 4R tauopathies. Alzheimer’s tangles were observed to have a greater curvature than PSP tangles. Alzheimer’s tangles were also more prevalent in the hippocampus and larger than PSP tangles. A quantitative method to distinguish the shapes of these tangles would need to be developed and statistically validated to apply these findings to the broader research setting.
Funding Provided by: Edmonson Fellowship Program (UC Davis-Health System)

Dopamine receptor 1 neurons mediate food timing on circadian time scales

Emily Meyer (2014); Student Collaborator(s): Mari Purpura (2015 PIT); Christina Chang (2016 CMC); Catherine Chiang (2016 SCR); Mentor(s): Andrew Steele (W.M. Keck Science Center of the Claremont Colleges)

Abstract: Mice, like humans, have a built-in timekeeping system – or circadian rhythm – that revolves around a 24-hour day. This system is dependent on light:dark cycles but also on feeding schedule. When fed a calorie-restricted diet consisting of one meal at the same time each day, mice show abnormally high activity for two to three hours before that meal. This behavior is commonly referred to as food anticipatory activity (FAA). In mice with genetically removed dopamine receptor 1 (D1R), this entrainment to scheduled feeding does not occur, indicating that dopamine is involved in the development of FAA. This summer, the relationship between dopamine and FAA will be further examined by both activating and blocking D1R receptors pharmacologically instead of genetically. Additionally, brain and tissue samples from D1R knockout mice will be investigated for signs of circadian rhythm entrainment. These studies may shed light on aberrant feeding behaviors in humans.
Funding Provided by: Howard Hughes Medical Institute; W.M. Keck Science Center of the Claremont Colleges; Claremont McKenna College

M1 and M2 genes in drosophila hemocytes: what are they doing?

Jennifer Chai (2015); Mentor(s): Junryo Watanabe

Abstract: Macrophages are professional phagocytes of the mammalian immune system, and they adjust their surface receptors as well as their secreted products in response to the environmental cues and local stimuli. Classically activated macrophages, or M1 macrophages, perform anti-microbial functions and secrete proinflammatory cytokines. In contrast, alternatively activated macrophages, or M2 macrophages, are involved in mechanisms such as tissue regeneration and release anti-inflammatory / cytokines. Macrophage-mediated clearance of apoptotic debris is crucial for regeneration of peripheral nervous system after injury. It is hypothesized that M2 macrophages are mediating this clearance much in the same way M2 macrophages aid in the repair and regeneration in muscle and liver organs. In Drosophila, hemocytes act as professional phagocytes, and they are responsible for disposal of all apoptotic and pathogenic microorganisms. The mechanism by which hemocytes recognize and engulf apoptotic debris is poorly understood and whether a similar or parallel M1/M2 phenotype exists in fly hemocytes is currently unknown. However, several genes, such as draper and croquemort, have been identified as been required for phagocytosis of apoptotic cells. Thus, it is hypothesized that hemocytes from M2 deficient flies can phagocytose pathogens but not apoptotic debris, and the reverse should hold for M1 gene deficient hemocytes. Here we investigate similarities and differences between signaling in mammalian M1 macrophages and hemocytes exposed to Escherichia coli using genomic and in vitro systems.
Funding Provided by: Pomona College SURP

Stress Reactivity and Depressive Symptomatology

Nicholas Lawson (2014); Student Collaborator(s): Stephanie Njau; (2014) Additional Collaborator(s): Roxanna Salim; Mentor(s): Nicole Weekes; Richard Lewis

Abstract: The purpose of this study was to investigate the relationship between depressive symptomatology and shifts in prefrontal asymmetry in response to a stressor. There is an abundance of evidence to suggest that individuals who have experienced high levels of childhood trauma and those who have experienced an accumulation of stressors are at higher risk for developing depression. Furthermore, there is evidence to suggest that a combination of higher stressor exposure and greater stress reactivity interact in producing higher risk of depression, such that individuals who are exposed to the highest levels of stressors and respond to such stressors with the highest levels of stress reactivity will experience the highest levels of risk. 75 subjects (15 of which were tested in the summer of 2013) have been tested. Each subject was exposed to a stressor protocol and had stress reactivity measures assessed before and after the stressor. Subjects also provided information about their levels of depressive symptomatology. Subjects testing will continue through the 2013-2014 academic year. We predict that those individuals who respond to a stressor with greater shifts toward right prefrontal activity will be at greater risk for depression. Research ongoing.
Funding Provided by: Rose Hills Foundation

Research at Pomona