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Neuroscience Program

Neuroscience investigators focus on:

  • The neural, molecular, and genetic mechanisms that underlie nervous system development, learning and memory, addiction, glial responses to neuronal injury, and circadian rhythmicity; 
  • Mechanisms of synaptic neurotransmitter release, analysis of how neurotransmitter receptors and membrane channels operate, and how drugs act on these processes to modify cellular function and behavior; 
  • Magnetic resonance imaging technology to study and map changes in the brain associated with physiological stimuli as well as drugs of abuse; and 
  • Disorders of the central nervous system, with special emphasis on neurodegenerative disorders, autism spectrum disorders, mental retardation and other developmental disabilities. 

REQUIREMENTS FOR SPECIALIZATION

All Basic Biomedical Science students must complete the core curriculum as well as electives required by their program. Students in the Neuroscience program must take 3 elective courses, one of which must be Introduction to Neuroscience, usually in the spring of the first year. In addition, students must take at least one other course in neuroscience. Courses offered by other programs may be taken to complete the final elective requirement.

View PhD Program Schedule  |   View courses

OUR LEADERSHIP & FACULTY

PROGRAM DIRECTOR

David Weaver, PhD
Professor
email Dr. Weaver

OUR FACULTY

The Program in Neuroscience is interdepartmental, administered under the umbrella of the Department of Neurobiology. Participating faculty have primary appointments in several departments, with the largest concentration of faculty coming from the Departments of Neurobiology, Psychiatry, Cell Biology, Physiology and Neurology. 

View the affiliated faculty listing for the Neuroscience Program.

OUR STUDENTS

STUDENT EXPERIENCE

The program maintains a schedule of seminars and intramural research presentations that ensures a cohesive program. This atmosphere is especially conducive to the scientific growth of graduate students obtaining their degrees in neuroscience.

View current and past student listing

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Student and HHMI Gilliam Graduate Fellowship award winner, Kellianne Alexander, speaks about her
research

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Student, Kasturi Biswas, speaks about her experience coming to UMass Chan Medical School from India

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Student, Jenya Kolpakova, speaks about her
experience and interest in the overlap between science and business

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Student, Heather Learnard, speaks about her
research and bringing her own experience and expertise to the lab

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EXTERNAL AWARDS FOR RESEARCH TRAINING (CURRENT)

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    The role of Neurexin in serotonin synaptic function and social behavior

    The goal of this proposal is to examine how presynaptic Neurexins (Nrxns) at serotonin (5-HT) synapses impact 5-HT signaling and social behavior. Extensive 5-HT axon terminal innervation throughout the brain corroborates 5-HT’s modulatory role in numerous behaviors including social behaviors, reward, emotion regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism Spectrum Disorder (ASD). While 5-HT therapeutics are often used to treat ASD, variable improvements in symptomatology require further investigation of 5-HT-mediated pathology. Many different genes contribute to increased ASD susceptibility and clinical presentation variability. Notably, synaptic dysfunction, specifically dysregulation of synaptic excitation and inhibition, remains a hallmark of ASD pathogenesis. Nrxns are presynaptic cell adhesion molecules that are well characterized in maintaining synapse function for proper neural circuit assembly. The three Nrxn genes transcribed from two promoters (α and β) express six principal Nrxn isoforms (αNrxn1-3, βNrxn 1-3). Additionally, mutations in Nrxn1 and Nrxn2 genes have been reported in ASD. In the current literature, the role of Nrxns at 5-HT synapses has yet to be investigated. Given that aberrant Nrxn and 5-HT function independently contribute to signaling pathology and social behavior impairments, it is critical to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying the core deficits of ASD. Here, I will explore how 5-HT signaling mediated through Nrxns regulates social behaviors (Aim 1) and how Nrxns regulate 5-HT circuits relevant to social behaviors (Aim 2). Our group has created a novel mouse model in which the three Nrxn genes are selectively deleted in 5-HT neurons. My preliminary studies indicate that the loss of Nrxns at 5-HT synapses impairs social recognition memory and social reward preference. The hippocampus and nucleus accumbens, respectively, are crucial in these behaviors. In Aim 1, I will determine whether 5-HTergic Nrxns are critical for social behaviors through completion of social (and other complex) behavior studies. In addition, I will explore (i) if and (ii) how 5-HT is necessary for social behaviors using (i) 5-HT therapeutics to augment 5-HT function prior to social behavior studies and (ii) in vivo microdialysis to measure extracellular 5-HT levels during social behavior. In Aim 2, I will perform a mouse breeding and lentiviral rescue approach to determine whether specific Nrxns control social behavior. Furthermore, I will use immunohistochemical and electrophysiological approaches to identity how Nrxn proteins regulate excitatory and inhibitory synapse distribution and physiology. A close examination of Nrxns in 5-HT synaptic function is necessary to shed new light on social behavior disturbances in ASD.

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    Dissecting ADAM10 function in microglia-mediated synapse elimination

    The goal of this proposal is to dissect the molecular signaling between microglia and neurons that regulates synapse elimination in response to changes in sensory experience. Despite compelling evidence that microglia, the resident brain macrophages, play important roles in eliminating synapses in development and disease, the precise neuron-to-microglia molecular signaling that drives this process is poorly understood. I recently discovered a signaling pathway necessary for microglia-mediated synapse elimination by utilizing the well-described circuitry of the mouse barrel cortex circuit as a model to manipulate sensory experience and dampen neuronal activity. Here I found microglia robustly engulf synapses in the barrel cortex following either whisker lesioning or trimming, and that this engulfment is dependent on the microglial CX3CR1 receptor and its canonical neuronal ligand, CX3CL1, but not complement. Using single-cell RNAseq I also found that neuronal Cx3cl1 was not differentially regulated in the cortex following whisker removal, but the protease Adam10, known to cleave membrane-bound CX3CL1 into a soluble form, is increased following lesioning. Importantly, pharmacological inhibition of ADAM10 resulted in synapse elimination defects that phenocopied CX3CR1 and CX3CL1-deficient mice. These data suggest that post-translational modification of neuronal CX3CL1 by ADAM10 is required to regulate microglial synapse elimination in the cortex following whisker removal. Several exciting new questions have now arisen, which I will tackle in this proposal: 1) What is the cellular source of ADAM10 and is it localized to synapses (Aim 1)? 2) Do other subcortical synapses within the barrel circuit remodel via ADAM10-CX3CL1-CX3CR1 signaling and does this differ between whisker lesioning and trimming (Aim 2)? I hypothesize ADAM10 is derived from layer IV excitatory neurons to regulate microglia- mediated synapse remodeling and that ADAM10 signaling is specific for cortical synapse rewiring after whisker trimming and lesioning, but not for sub-cortical synapse remodeling. To test this hypothesis, I have acquired powerful in vivo molecular genetic tools to manipulate ADAM10 function in specific cells. I have also developed collaborations to learn and perform cutting-edge whole tissue clearing by iDISCO to assess structural remodeling of entire circuits. Finally, I have a strong mentoring team that includes my mentor Dr. Dorothy Schafer with expertise in microglial function within neural circuits, my co-mentor Dr. Andrew Tapper with expertise in structural and functional mapping of brain circuits, and collaborators with expertise in iDISCO. Together, I am in a strong position to molecularly dissect how ADAM10 modulates neuron-microglia signaling necessary for remodeling brain circuits. This could be highly relevant for neurodegenerative disease where microglial dysfunction, synapse loss, and ADAM10 have been implicated. In the process, I will receive training in a variety of microscopy and molecular genetic approaches that will provide a foundation for my future career as an independent principle investigator at an academic institution focused on dissecting functions for glial cells within neural circuits.

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    Microglia-derived neuroactive cytokines governing neural circuit excitatory-inhibitory balance

    Elaborate mechanisms exist to establish and maintain the appropriate balance of excitation and inhibition (E/I balance) in the brain. Defects in E/I balance are hypothesized to underlie many core clinical symptoms seen in ASD including repetitive behaviors and seizures. Concomitant with E/I imbalance are increased markers of inflammation in the periphery and brain. Central to this inflammation are microglia, a resident macrophage of the central nervous system. Whether microglial inflammatory state drives E/I imbalance in neuropsychiatric disease remains a critical open question. In this proposal, I will leverage my primary mentor’s (Schafer) expertise in using mouse models to study microglia function at synapses with my co- mentor’s (Frazier) expertise as a physician scientist studying neuroinflammatory processes in ASD patients to explore whether microglia-derived cytokine signaling modulates E/I balance. I will use a mouse model with altered inflammatory cytokine signaling to assess how microglial inflammatory cytokine production modulates neuronal excitability (aim1). Next, I will use human ASD functional imaging data and data from patient serum to identify pro-inflammatory cytokines that are dysregulated in ASD patients and assess how these ASD-specific cytokines affect E/I balance in our mouse models (aim2). To start, I already have one candidate TNF􏰀-alpha. The results from these experiments will help to identify novel targets for treating ASD with inflammatory modulation.

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EXTERNAL AWARDS FOR RESEARCH TRAINING (PAST)

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    Gq Receptor Regulation of Striatal Dopamine Transporters

    Dopamine (DA) neurotransmission is vital for behaviors such as movement and reward, as well as, cognitive functions including mood, learning and memory. Several neuropsychiatric disorders are linked to alterations in DA signaling including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, Parkinson's disease, and addiction. The DA transporter (DAT) is imperative for temporal and spatial control of DA signaling. DAT is located at the presynaptic terminal of DAergic neurons and facilitates the termination of DAergic transmission by rapidly clearing released DA. DAT is the primary target of addictive and therapeutic psychostimulants, which compete for DA binding and block uptake through the transporter, preventing DA clearance and leading to the hyper-locomotive and rewarding behaviors associated with drug use. Given that DAergic signaling is highly sensitive to DAT function, understanding the molecular mechanisms that control DAT function and availability is a critical missing piece of the puzzle in understanding DAergic neurotransmission and dysfunction in DA- related disorders. Over two decades of research support that DAT surface expression is acutely regulated by endocytic trafficking. Protein kinase C (PKC) activation with phorbol esters stimulates DAT internalization and thereby decreases DAT surface expression and function. Although considerable progress has been made to define the molecular mechanisms governing basal and PKC-regulated DAT trafficking, there are significant gaps in our understanding of this process in bona fide DAergic terminals. It is not clear how DAT is regulated in response to the endogenous presynaptic receptors that are activated upstream of PKC, such as Gq-coupled receptors, and how the complex signal events stemming from Gq receptor activation integrate to acutely control DAT surface expression. It is additionally unknown whether regulated DAT trafficking is region-specific, or whether altered DAT surface expression impacts DAergic signaling in the striatum. The proposed studies will leverage chemogenetic receptors to test how Gq activation impacts DAT surface levels in a cell- autonomous manner, in both dorsal and ventral striatum. We will capitalize on a novel conditional, inducible, in vivo gene silencing approach to determine the endocytic mechanisms that are required for Gq-mediated DAT trafficking, by both chemogenetic and endogenous presynaptic receptors. We will further employ ex vivo fast- scan cyclic voltammetry to investigate how presynaptic DAT trafficking impacts DA signaling. I anticipate that at the completion of these studies, we will have gained a more in-depth understanding of the complex mechanisms underlying DAT regulation at presynaptic DAergic terminals, and its potential influence on synaptic DA homeostasis.

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    Fluorescent visualization of complement-dependent pannexin activity in microglia

    The goal of this project is fluorescently visualize ATP release and extracellular accumulation at the surface of stimulated microglia. The development of this innovative technology has the potential to enable spatiotemporal imaging of microglial extracellular signaling. For this project, I am exploiting the presence of the cell's glycocalyx to attach ATP-sensitive biosensors at the sites of ATP accumulation. There are two aims to this project: 1) to synthesize a novel, polyhistidine binding moiety that covalently modifies the glycocalyces of living cells and binds recombinant biosensors to measure ion and metabolite efflux and accumulation; 2) to visualize and measure ATP release from pannexin channels in C5a stimulated microglia. The completion of these aims will yield a transformative set of chemical-biological tools and methodologies to investigate the physiology and pathophysiology of pannexin-dependent activity in glia, and potentially in living animals.

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