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Del Monte Institute for Neuroscience Pilot Awards

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    Mayer-Pröschel Research

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    Freedman and Majewska Research

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    Gelbard Research

Since 2015, the pilot program at the Del Monte Institute for Neuroscience has been funding research that opens new doors of understanding of the brain and central nervous system. This program is maintained by philanthropic support, and it has generated more than $31-million in external research support to date.

2021 Pilot Award Recipients

The role of nuclear inhibitor of protein phosphatase-1 (NIPP1) in neuronal excitability and CNS myelination

Houhui XiaPI: Houhui Xia
Funding Source: The Schmitt Program in Integrative Neuroscience
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​Our brain relies on neurons to perform its functions while communcations between neurons is important for neuron's function in the brain. Neurons use axons to contact the dendrites of another neuron. Electrical signal will degrade along the long axonal processes. Oligodendrocyte cells in the CNS has many processes which wrap around axons to form lamellar structure, called myelin sheath, and prevent this degradation. Myelination is thus essential to our brain function.  We found that deleting a gene called NIPP1 in the mouse brain led to a myelination deficit. Interestingly, we found that deleting NIPP1 in oligodendrocytes, the cells directly responsible for myelination, did not have an effect on myelination. On the other hand, deleting NIPP1 gene in neurons led to a myelination deficit. Moreover, we found that neuron's ability to communciate to other cells is decreased in the KO mice. We will elucidate the neuronal mechanisms regualted by NIPP1, for example PSD93 and sk2, in determining NIPP1's function on neuron's communciation ability and CNS myelination. The proposed work will elucidate the critical role of NIPP1 gene in neuron-glia interaction and CNS myelination.

Mechanisms of CGRP signaling bias in pain perception

Ian DickersonPI: Ian Dickerson
Funding Source: The Schmitt Program in Integrative Neuroscience
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Calcitonin gene-related peptide (CGRP) is a neurotransmitter that plays a critical role in chronic, migraine, and inflammatory pain.  CGRP’s effect on pain is mediated by intracellular signaling pathways, but the regulation of these pathways is unclear.  We have recently discovered that a protein named CGRP-receptor component protein (RCP) can control the signaling at the receptor for CGRP.  We have recently developed the first mice that lack RCP, and these transgenic mice will be used in this proposal to establish an animal model for the function of RCP in migraine and inflammatory pain.   Successful completion of these aims will determine if our in vitro biochemical findings are recapitulated in vivo models, and if so will provide new non-opioid therapeutic targets.

Dopamine-driven substrates of hallucinations​

Julie FudgePI: Julie Fudge
Funding Source: The Schmitt Program in Integrative Neuroscience
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Hallucinations, or 'hearing voices', are  a core symptom of schizophrenia.  These symptoms are relieved by antipsychotic drugs, which modulate the neurotransmitter dopamine.  Although there are hints from human brain imaging studies about the brain regions involved in hallucinations, little is known about how and where brain wiring goes awry. This pilot grant will support and extend our recent work in an animal model closer to the human (monkey) investigating  the 'caudal ventral striatum', a region reliably dysregulated in humans experiencing 'voices'.  We will  delineate connections from auditory cortex, and from specific dopamine neurons that modulate information flow in this region of the striatum.​​

​​​Natural speech processing, the influence of expectations, and auditory hallucinations in early-stage ​schizophrenia

Judy Thompson, Ph.D.PI: Judy Thompson
Funding Source: The Schmitt Program in Integrative Neuroscience
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Auditory hallucinations (AH) are experienced by approximately 60-80% of individuals with schizophrenia (SZ). These symptoms are often associated with distress and disability, and in many cases, do not respond adequately to standard treatments. A barrier to the development of novel therapeutics for AH is lack of clarity regarding underlying neural mechanisms. Recent models of psychosis suggest that AH may result from a pathological overweighting of expectations relative to incoming sensory signals during perception. It has further been proposed that sensory processing impairments in SZ may drive this overweighting of expectations, and thus contribute to the development of AH. Our aim is to investigate these potential AH mechanisms by leveraging recent advances in electroencephalography (EEG) methods. Specifically, EEG will be used to evaluate whether AH in early-stage SZ are associated with 1) impaired auditory processing of speech; and 2) alterations in the effects of prior knowledge regarding speech content on this auditory processing. Focusing on the early stages of SZ for this project will help minimize the influence of factors associated with longstanding psychotic illness that may confound our results, such as prolonged medication exposure. We will recruit 20 young people with early-stage SZ, specifically 10 with and 10 without AH (AH+/AH-), along with 10 matched healthy controls. EEG will be recorded as participants listen to narrative speech segments, and neural responses will be modeled to derive measures of auditory processing of speech, and the effects of prior knowledge on this processing. We hypothesize that AH in early-SZ will be associated with impaired auditory encoding of speech and a greater influence of prior knowledge on this encoding, and that within AH+, these two alterations will be related. The results from this work will be used to support the application of an NIH proposal for a larger-scale investigation of AH mechanisms.

​​​Interactions between microglial dynamics and the brain extracellular matrix

Edward Brown, Ph.D.PI: Edward Brown
Funding Source: The Schmitt Program in Integrative Neuroscience
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Microglia are immune cells of the brain, where they constantly probe their environment with long thin highly motile arms called “processes". The involvement of these microglial processes is known to be important in the development of new connections between brain cells and hence in the formation of new memories. The spaces between brain cells are filled with numerous filamentous proteins forming a network. We believe that when a microglial process probes and penetrates an area it 'loosens' that protein network. This is important because changes to that protein network will affect the ability of other brain cells to reach out and make connections. Hence, we believe that microglial probing loosens the protein network between brain cells and thereby affects learning and memory. To explore this idea, we will use chemicals to make microglial processes enter a specific region of the brain, or leave it, and study the resultant effects on the protein network in between brain cells. Specifically we will measure the speed with which tracer molecules can move through that network as a measure of that network's ability to hinder motion, and do so with tracers of different sizes to understand the size of the 'pores' in the network. Tracers larger than the pore size will move very slowly, while tracers smaller than the pore size will move rapidly. This study will provide preliminary data for a larger study on the detailed effects of the movement of microglial processes on the material between brain cells, and the subsequent impact on learning and memory.​​

Use of intracortical microstimulation to determine the role of VLPFC in audiovisual working memory​

Lizabeth Romanski, Ph.D.PI: Lizabeth Romanski
Funding Source: The Schmitt Program in Integrative Neuroscience
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We propose to use stimulation of brain activity during working memory to enhance performance and to alter neural activity in the ventrolateral prefrontal cortex.  This finding can help us understand what precise role the ventrolateral prefrontal cortex plays in memory and cognition.  Moreover, this type of brain stimulation may be a way to introduce therapeutic brain stimulation for future treatment of neurological impairments.  Since the area we are targeting is involved in processing and integrating social communication information we hope that this technique could provide a sort of therapeutic enhancement to lagging social communication brain circuits in the future.​​

Development of an APOE4 homozygous model of the human neurovascular unit​

James McGrath, Ph.D.PI: James McGrath
Funding Source: The Schmitt Program in Integrative Neuroscience
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Patients with pre-existing neurodegenerative diseases known such as Alzheimer’s Disease, Multiple Sclerosis, and Parkinson’s Disease, are particularly vulnerable to cognative decline following episodes of systemic infection including sepsis . The mechanisms underlying this decline are unknown and studies in mouse models are not good representatives of human inflammatory disease. New stem cell technologies combined with microfludic 'tissue-on-a-chip' platforms are allowing the development of human tissues in the laboratory that are derived entirely from the cells of a patient. These technologies not only overcome the limitations of animal models, they are an important tool for a new era in patient-specific medicine. Thus our project seeks to develop a 'brain-on-a-chip' model of Alzheimer's with the goal of being able to develop approaches that can protect this most vulnerable population. The project will develop the model using cells carrying the genetic risk factor for Alzheimers and test it against a healthy model that does not carry the genetic risk factor. ​

Microglia: Synapse interactions in brain radiation injury​

M. Kerry O'Banion, M.D., Ph.D.PI: M. Kerry O'Banion
Funding Source: Rochester Center for Alzheimer’s Disease Research and the Sally J. States Pilot Fund
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Despite advances in the use of targeted radiotherapy, whole brain radiotherapy remains a part of current treatment and prevention plans for metastatic cancer. Moreover, even with tumor focused radiotherapy, normal brain tissue is exposed to ionizing radiation and cognitive dysfunction remains a major late complication, particularly in children and young adults. Recent evidence from multiple laboratories, including our own, indicates that radiation causes loss of connections between neurons in the brain, and that this loss may be responsible for cognitive dysfunction. The immune cells of the brain, known as microglia, play important roles in removing connections between neurons, both as part of normal development and in disease states such as Alzheimer's. Thus, we tested whether microglia might be playing a role in the loss of neuron connections after radiation. We found that blocking the ability of microglia to remove connections prevented cognitive dysfunction after brain radiation exposure in mice. These findings suggest a possible therapeutic strategy for preventing brain radiation effects in patients receiving radiation treatment. To better understand the timing and involvement of microglia as key effectors of brain radiation injury, we plan to carry out additional studies that: 1) quantify molecular markers of these brain changes as a function of time after radiation exposure; 2) use special microscopes to visualize interactions between microglia and neuronal connections; and 3) determine whether we can establish a “smoking gun", namely test whether microglia actually ingest neural connections after radiation. Together, evidence generated from the pilot proposal will help us to submit a much larger grant focused on developing novel therapies to prevent CNS radiation injury.​

Developing a mouse model of alcohol exacerbation of Alzheimer’s pathology to probe microglial contributions​​​

Ania Majewska, Ph.D.PI: Ania Majewska
Funding Source: Rochester Center for Alzheimer’s Disease Research and the Feinberg Family Fund
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Alzheimer's disease is the most common age-related dementia, accounting for the progressive cognitive impairment and compromised life quality of approximately 5.8 million people in the United States. A number of lifestyle factors can increase the risk of Alzheimer's disease including the abuse of alcohol. Alcohol use is prevalent in our society, ranging from infrequent social drinking, through moderate consumption and all the way to chronic and lifelong abuse. These different drinking patterns have been shown to differentially impact the brain and modulate cognitive processes. While it is clear that alcohol use can impact the risk of developing Alzheimer's dementia, the mechanisms by which alcohol affects the brain that impact this risk are currently unknown. This is largely due to the fact that few animal models exist that accurately reflect both human drinking and clinical features of Alzheimer's disease. In this proposal we will develop and test a common mouse model of Alzheimer's disease based on mutations that have been associated with the disease in humans, coupled with an alcohol exposure paradigm that retains many features of human alcohol use, to test a candidate mechanism that may link Alzheimer's disease and alcohol. We will focus on the brain immune cell, the microglia, which is uniquely susceptible to disruptions of the environment (such as the presence of alcohol and its metabolites in the brain) and which is known to have multifaceted and important roles in modulating Alzheimer's disease progression. We believe this new model and the results of our study will yield important insights into the process by which alcohol affects Alzheimer's disease and may lead to future therapeutic avenues for treatment of patients with a history of drinking alcohol. ​  ​

Using optogenetics to define tau oligomer dynamics in the context of Alzheimer’s disease

Gail Johnson, Ph.D.PI: Gail Johnson
Funding Source: Rochester Center for Alzheimer’s Disease Research
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​In Alzheimer’s disease (AD) a protein called tau becomes sticky and forms clumps called “oligomers” which then join to form large accumulations in nerve cells called “neurofibrillary tangles” (NFTs). When the large NFTs were first discovered, it was thought that they were what killed the nerve cells. However, recent research has shown that the NFTs are not what make the nerve cells sick, but rather the oligomers which are smaller clumps of tau. Although it is now clear that these oligomers are toxic to nerve cells, how and why they form is not well understood.  A major problem with studying tau oligomer formation is that there has not been a good way to study how they form, and thus processes that may be able to reduce their formation or stability remain unknown. Therefore, the first goal of this proposal is set up a unique and state-of-the-art system to study tau oligomer formation. To do this we attach a “module” to tau called “Cry2olig” that is sensitive to blue light and put it in nerve cells that are grown on a dish. When you shine blue light on it causes it to interact with it another Cry2olig which pulls the tau proteins together to form the oligomers.  We are then able to monitor this process using microscopy and determining how fast the tau forms the oligomers. Once we take away the light, the tau oligomers disassemble, and we can determine how fast that happens. With this new system, we can determine the effects of other proteins on tau oligomer formation and disassembly. In the future this system, has the potential to be used to test drugs or molecules that may prevent tau oligomer formation as possible treatments for AD.​​

Mouse models of Sez6L2 autoantibody-associated cerebellar ataxia​​​

Jennetta Hammond, Ph.D.PI: Jennetta Hammond
Funding Source: Harry T. Mangurian Jr. Foundation
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When the immune system attacks the cerebellum, the brain region responsible for coordinating movement, it can lead to symptoms of ataxia such as stumbling, falling, incoordination, and slurred speech.  Therapeutics aimed at suppressing the immune system in this autoimmune condition may be beneficial if treatment is started early.  However, often it is not clear if the ataxia is immune-mediated or has other causes.  Antibodies that target specific proteins in the cerebellum have been shown in some cases to be excellent biomarkers for diagnosis of immune-mediated ataxias.  More research is needed to identify new antibody biomarkers of ataxia and to characterize how the immune system specifically damages the cerebellum when these problematic antibodies are present.  Antibodies targeting a protein called Sez6L2 have recently been reported in six patients with ataxia. In this proposal, we are generating two different mouse models to understand how immune attack against Sez6L2 damages the cerebellum leading to ataxia.  One model will focus on potential damaged caused directly by the Sez6L2 antibodies.  The second model will investigate whether a full-immune attack against Sez6L2 better models the human disease.  In both models, we will analyze mouse motor functions and look at brain histology for neuron death and multiple immune markers.  These studies, coupled with the previously reported human case studies, should encourage prompt and routine screening for Sez6L2 antibodies in suspected immune-mediated presentations of ataxia. We anticipate the results from these studies will also help doctors decide which available therapies will best suppress the immune system to protect the cerebellum against attacks linked to Sez6L2. ​​

Modeling protein phosphatase-1-related human intellectual developmental disorder in mouse​​​

Houhui Xia, Ph.D.PI: Houhui Xia
Funding Source: Harry T. Mangurian Jr. Foundation
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Protein phosphatase 1 (PP1), an enzyme, has been dubbed as a molecule of forgetfulness based on studies performed on a transgenic mouse model. PP1 is thought to play its important role in memory via its role in communication among neurons. However, PP1 has three different isoforms, PP1α, PP1β, and PP1γ, each encoded by a different gene. It is thought that PP1γ is the PP1 isoform playing roles in synaptic plasticity.   Whole exome sequencing, a new technology of sequencing the gene coding portion of human genome, can diagnose the genetic basis of intellectual developmental disorder (IDD) in patients whose parents are normal. One of the genes mutated in IDD patients is PP1β. It is surprising because this isoform of PP1 was only known to play a role in heart development in the past.   We are using transgenic knockout (KO) or knockin (KI) mouse models to study the roles of PP1γ, PP1β as well as PP1β's human mutation in brain functions. We have obtained conditional PP1β KO mouse line from our collaborator Dr. Nairn (Yale). We have also generated a conditional KI mouse line which carries a corresponding human mutation in PP1β gene.   We will turn on the KO or mutation at specific cell type (CA1 pyramidal neurons in hippocampus) to examine the communication between CA3 and CA1 pyramidal neurons. We will also examine synapse formation. We will also introduce the human mutation in PP1β gene starting at sperm/egg stage, exactly mimicking what happens in the human patients. The effect of mutation on synaptic functions and cognition will be examined by imaging, electrophysiology recording and behavioral assays. We anticipate that PP1β KO or human mutation will lead to deficits in synapse formation, synaptic plasticity, and spatial learning and memory. ​

A comparative modeling approach to exploring speech processing in the human visual system

Edmund Lalor, Ph.D.PI: Edmund Lalor
Funding Source: Ernest J. Del Monte Institute for Neuroscience Research Pilot and Feasibility Program
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Interpersonal communication is central to human life. For most people, such communication typically involves spoken language. As such, neuroscience research has dedicated enormous effort to understanding how our brains transform speech sounds – even for different speakers and accents – into syllables, words, and, ultimately meaning. But speech doesn't rely only on sound. Most communication between people involves face-to-face communication where information from a speaker's face and gestures help us to understand what they are saying. Compared with our knowledge about how brains convert sounds to speech, we know relatively little about how our brains extract visual information from a speaker's face and gestures to help with speech comprehension. Our project aims to address this issue. It aims to do so by collecting EEG brainwave signals from human subjects and examining how those brainwave signals relate to different kinds of speech, including silent videos of a talker, audio speech clips with no video, and audio and video together. Importantly, our project aims to do this for a variety of participants, including people with typical hearing, as well as deaf individuals, and deaf individuals who use a cochlear implant. By exploring the brain data across these groups, we hope to be able to cleanly distinguish brain signals that reflect the processing of visual speech information from signals that reflect the processing of audio speech. With a team made up of members with complementary expertise in brain signal analysis and language processing in deaf individuals, we hope to make important new discoveries about how the human brain extracts useful information from visual speech. In turn, this will be useful for future research aimed at improving the effectiveness of cochlear implants and for a greater understanding of language processing in deaf individuals. ​​

Predicting semantics in the perspective-taking brains of romantic couples: How perspective-taking ability contributes to relationship strength

Andrew Anderson, Ph.D.PI: Andrew Anderson
Funding Source: Ernest J. Del Monte Institute for Neuroscience Research Pilot and Feasibility Program
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A healthy human society is built upon healthy interpersonal relationships. In absence of these people are prone to depression, anxiety, ill health, and even early mortality. Among the most important relationships to keep healthy are those with our romantic partners. This relies in part on the ability to put oneself in one's partner's shoes – to know their tastes, experiences and views, and how they differ from one's own. This ability is underpinned by a complex network of brain systems collectively referred to as the “theory of mind" network. Whilst advances in brain scanning technology have broadly identified the whereabouts of this network in the brain, less is known about how detailed information is represented within it, and how this contributes to romantic relationship quality. Indeed, the ability to record from the brain what one envisions their partner's perspective to be, and computationally match that to brain activity recorded from the partner contemplating the same subject would be transformative for relationship and clinical science. Progress has been obstructed because it has been unclear that contemporary technology can measure sufficient brain signal to even discern interpersonal differences in personal perspectives. In recent work we introduced computational methods showing that brain scans capture person-specific elements of experience (of things like shopping). We now seek to deploy these methods to explain brain activation elicited as couples envision items and activities like chocolate, wine, dogs and shopping from each other's perspectives. We will test whether brain activity elicited when imagining one's partner's perspectives predicts that partner's actual perspectives, and how this reflects their relationship satisfaction. Success would be an exciting step toward brain-based assessments of relationship health.​​

Microstimulation of the nucleus basalis: A neuromodulatory source of theta-rhythmic sampling during selective attention?

Ian Fiebelkorn, Ph.D.PI: Ian Fiebelkorn
Funding Source: Ernest J. Del Monte Institute for Neuroscience Research Pilot and Feasibility Program
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​Survival depends on detecting behaviorally relevant information in complex, dynamic environments. The primate brain largely gathers information from the visual environment through a combination of two interacting functions: spatial attention (enhanced sensory processing) and saccades (exploratory shifts of gaze). A shared network of brain regions, the “attention network,” directs both of these functions, prompting the following fundamental question: how does a single network control both the sensory (i.e., spatial attention) and the motor (i.e., saccades) functions of environmental sampling? Recent research indicates that these competing functions are temporally isolated in the attention network, alternating over time at a frequency in the theta range (~4–6 Hz). That is, recent research indicates that environmental sampling is characterized by two rhythmically alternating attentional states, with the first promoting sampling (i.e., sensory functions of the attention network) and the second promoting shifting (i.e., motor functions of the attention network). Neurophysiological evidence indicates that these attentional states are coordinated by theta-rhythmic neural activity in the attention network, with distinct patterns of neural activity characterizing the sampling and shifting states. Yet the neural source of transitions between these theta-rhythmic attentional states remains unknown. A synthesis of previous research strongly suggests cholinergic innervation from the nucleus basalis (NB) as a potential source. The NB is the primary source of acetylcholine (ACh) in cortex, and the neuromodulatory enhancement of ACh is critical to selective attention. In addition, neurons in the NB fire at theta frequencies and are associated with theta-rhythmic neural activity in cortex. Here, we will utilize microstimulation and neuropharmalogical manipulations in macaques, while simultaneously recording from cortical nodes of the attention network. We will test the hypothesis that transitions between theta-rhythmic attentional states in cortical nodes of the attention network are attributable to ACh-inducing neural activity in the NB.​

Targeting brain enriched orphan G protein coupled receptors​

Cesare Orlandi, Ph.D.PI: Cesare Orlandi
Funding Source: Ernest J. Del Monte Institute for Neuroscience Research Pilot and Feasibility Program
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​​In mammals, G protein coupled receptors (GPCRs) form the largest family of cell surface receptors and are involved in the regulation of every aspect of neurophysiology. GPCRs sense the presence of neurotransmitters, hormones, changes in pH, levels of light, and many other fluctuations in the extracellular environment, and they translate it into intracellular messages leading to appropriate cellular responses. Because of their role as powerful regulators, GPCRs are the most exploited molecular target by currently available drugs. Surprisingly, what activates ~100 members of the GPCR family is still unknown, hence these receptors are named orphans. Nonetheless, human and animal studies revealed relevant physiological roles for many orphan GPCRs, especially in the brain. Orphan GPCRs represent therefore unexploited pharmacological targets for the treatment of a variety of neuropsychiatric disorders. The goal of the proposed study is to build an innovative assay to identify what activates four orphan GPCRs (GPR137b, GPR156, GPR158, and GPR179) that are enriched in the central nervous system and are involved in disorders such as depression and night blindness. This deorphanization process will be completed by screening a library of biologically active molecules whose targets are unknown. With our work, we expect to identify the endogenous ligands activating these orphan GPCRs, or, at least, to find synthetic compounds that are able to modulate their activity. The identification of orphan GPCR ligands will expand our knowledge on the biology of these receptors, and, at the same time, it will boost the development of new therapeutics targeting a variety of diseases including depression, addiction, blindness, and other major neuropsychiatric disorders.

Specific and selective neural mechanisms of transcranial electrical stimulation for affecting cognition​

Adam Snyder, Ph.D.PI: Adam Snyder
Funding Source: Ernest J. Del Monte Institute for Neuroscience Research Pilot and Feasibility Program
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Application of minute electrical currents to the scalp (transcranial electrical stimulation; TES) has been shown to affect brain activity and, separately, has been shown to affect behavior. Thus, TES has potential to treat mental illnesses, since it can influence brain dynamics. So far, our understanding of the effects of TES is quite basic. We know that electrical stimulation can increase the excitability of nearby neurons, for example, or that it can speed learning of some simple motor tasks. For TES to be most effective as a therapy, we need a better understanding of how to affect brain dynamics in detailed and nuanced ways. The research will combine TES with direct recording of groups of neurons in multiple brain areas in subjects performing a visual-motor task requiring cognitive control. Cognitive control is an important brain function required for flexible task performance (e.g., ``task switching''), and it is affected in illnesses such as psychosis and depression. By systematically measuring the relationship of TES on neural activity and behavior simultaneously, we will improve our understanding of the neural mechanisms of TES, and hopefully develop specific and selective methods to improve cognitive control performance.

Validation of chronic pain biomarkers in a clinical setting using brain imaging​​​

Paul Geha, M.D.PI: Paul Geha
Funding Source: Ernest J. Del Monte Institute for Neuroscience Research Pilot and Feasibility Program
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Chronic pain is a major health crisis in the United States. It is estimated that 100 million Americans live in chronic pain with an annual cost reaching between $500-600 billion dollars.  The mechanisms of chronic pain are poorly understood hence there are no objective biomedical tests that are specific or sensitive to a specific chronic pain condition. We address this problem by developing specific brain-based tests to diagnose patients suffering from chronic-low back pain, since this condition is one of the most common chronic pain condition and the number 1 cause of disability worldwide. Besides, existing diagnostic tests, like spine imaging for low-back pain are expensive, non-specific and often lead to unnecessary procedures like spine surgery. Our group has developed highly reproducible brain-based tests to diagnose patients with chronic low-back pain. These measures are obtained using magnetic resonance imaging of the brain.   An obstacle to the translation of these tests into clinical use remains, however.  While these tests were shown to be valid at separating patients from healthy non-pain controls using a research scanner their validity was not directly compared between a research and a clinical scanner like the ones used in routine diagnostic testing in a hospital setting. Therefore, in this proposal we will test the validity of our chronic low-back pain brain based diagnostic testing and develop the method of disease detection further using a hospital scanner at the University of Rochester clinical imaging facility.  The same patients and healthy controls will be scanned both on a research scanner and on a clinical non-research scanner and the validity of the diagnostic tests compared between the two data acquisition protocols. ​

Microsaccade differences in psychosis and their contribution to abnormal vision

Brian Keane, Ph.D.PI: Brian Keane
Funding Source: Friends of Del Monte Funds
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There are over 1000 articles on eye movements in schizophrenia (SZ), but it remains almost completely unknown whether people with this disorder differ in their microsaccades, which are miniature, rapid eye movements.  A major goal of this grant is to establish that such differences exist (Aim 1).  We elicit group differences in microsaccades via three tasks: steady fixation, visual acuity, and reading.  The latter two tasks were chosen since each is plausibly impaired among psychosis patients, each is highly dependent on microsaccades, and each is important for normal everyday functioning.  To ensure that discovered group differences do not owe to poor mental health, our comparison “control” group will have an anxiety, mood, or substance use disorder but no psychosis   To ensure that group differences are not owing to poor general health, psychosis patients will all be younger, within five years of their first psychotic break. In contrast to possibly all prior psychosis studies, we will use cutting-edge, high-precision eye-tracking equipment and calibration procedures. Our second goal is to consider whether abnormal microsaccades can potentially explain well-documented reading or visual acuity deficits in psychosis (Aim 2).  A possibility is that microsaccades in psychosis are intrusive; that is, they are less precise and accurate and cannot be controlled or suppressed when needed, leading to impairments in high-acuity vision and reading.  Our project, if successful, could yield a novel marker for psychosis and clarify how the oculomotor system differs in early illness stages.  This project could also offer a novel explanation for poor visual acuity and reading in psychosis, which in turn might suggest new treatments focused on the oculomotor system.  Pilot data from this pilot project will increase the chances of success for a subsequent grant application to the NIH. ​

​Identification of a brain glucose sensor that may explain the pathology of potentially fatal​​ hypoglycemia-unawareness in diabetes​​

Kavaljit Chhabra, Ph.D.PI: Kavaljit Chhabra
Funding Source: Friends of Del Monte Funds
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​​​How our brain senses glucose is not well defined. Moreover, high blood glucose levels in diabetes compromise the ability of the brain to sense glucose. Consequently, when individuals with diabetes are faced with life-threatening low blood glucose levels (hypoglycemia) due to overdose of insulin or other medical complications (iatrogenic), their brains fail to sense this hypoglycemia. Without any interventions to restore their blood glucose levels, these individuals may experience seizures, loss of consciousness, coma, and even death. Mechanisms underlying this phenomenon of hypoglycemia unawareness and/or impaired ability of the brain to enhance the protective counter-regulatory glucose response in diabetes are unclear. Therefore, to explain how diabetes compromises the ability of the brain to sense glucose, we produced innovative reagents in our lab and identified a glucose-binding protein (receptor) in the brain. In our preliminary experiments, we have observed that this receptor may be important for glucose sensing, and diabetes compromises the function of the receptor. In this proposed project, we will establish the role of the glucose-binding protein in brain glucose sensing and whether this protein can be targeted to improve hypoglycemia awareness and/or the brain’s response to fight hypoglycemia in diabetes. Findings from our project will help mitigate a significant problem of life-threatening iatrogenic hypoglycemia in individuals with diabetes.​

Prior Years Pilot Award Recipients

Adolescent plasticity of the frontal dopamine circuit: cellular mechanisms and behavioral functions

Dr. WangPI: Kuan Hong Wang
Funding Source: Del Monte Institute for Neuroscience
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Neuroscientific research has identified adolescence as a critical period where key neurotransmitter systems are still developing, offering an important therapeutic window for interventions in psychiatric disorders. Previous work in our lab and others points to increased adolescent plasticity in dopamine signaling. Dopamine is a critical neurotransmitter which impacts reward, motivation, and cognitive processing. The protracted development of dopamine circuits in the brain aligns with the timeline of psychiatric disease progression, offering an important disease relevant developmental process to target. Our research seeks to understand how dopamine circuit plasticity during development occurs within the brain. Our proposed research will help to determine what mechanisms impact adolescent dopamine plasticity and how changing these signals could give rise to psychiatric abnormalities. With better disease understanding research can design more targeted therapeutics for neuropsychiatric patients.

Do impairments in prediction underlie perceptual and social processing deficits in schizophrenia?

Ed LalorPI: Ed Lalor
Co-Investigator: David Dodell-Feder
Funding Source: Del Monte Institute for Neuroscience
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Schizophrenia is essentially defined by the symptoms displayed by patients, with the underlying cause still not being known. Our project aims to study how people with schizophrenia perceive their world and understand social interactions with others. We aim to do so by recording electrical brain wave activity from people with schizophrenia (and healthy control subjects) while they watch episodes of the TV show The Office. This will allow us to analyze the brain wave data in terms of how the brain responds to sounds and speech in the TV show – giving us measurements of their perception. And, given the nature of the show, it will also allow us to analyze how the brain wave data changes for scenes that are more or less socially awkward – allowing us to obtain measurements of how they understand social interactions. By comparing the results from people with schizophrenia and healthy controls, we hope to obtain basic measures of brain function that will help us understand the underlying causes of this terrible, debilitating disorder.

Age-dependent immune cell atlas for an orthopedic model of postoperative delirium

Harris GelbardPI: Harris Gelbard
Co-Investigator: Niccolo Terrando, Dept of Anesthesia, Duke University Medical Center
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Operations like hip repair in the elderly are frequently associated with postoperative delirium, which can lead to increased sickness, decreased quality of life, dementia and premature death. We have developed a mouse model of this type of delirium and shown that brain inflammation and cognitive abilities can be treated with an experimental drug, URMC-099 we have developed. In this project, we will use a technique to define which proteins in immune cells present in the body and brain can be returned to normal functions by treatment with URMC-099, and in so doing, provide a strong justification for advancing it to clinical trials.

Oxidation-induced hyper-activation of c-Cbl is critical in amyloid-ß1-42 oligomer

Mark NoblePI: Mark Noble
Funding Source: Rochester Center for Alzheimer’s Disease Research
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The overarching goal of this proposal is to provide a new molecular understanding of how toxic oligomers of amyloid beta peptides disrupt cellular function, a major contribution to the pathology of Alzheimer’s disease (AD). Our particular focus is on enabling protective strategies that rationally combine protective agents to achieve greater benefits than can be obtained by attacking individual targets To this end, our therapeutic strategies are focused on compounds suitable for rapid movement from the laboratory to the clinic. In addition, our studies also may help better understand the white matter damage that has long been observed in Alzheimer’s disease (AD), and may be an early component of this disease. On a molecular level our studies provide new insights into how metabolic changes, such as increased oxidation, and activation of the signaling molecule Fyn kinase, cause AD-related damage to the cells that are required for generating and repairing myelin.

Multidisciplinary studies of a novel lncRNA that regulates nervous system development

Doug PortmanPI: Doug Portman
Co-Investigator: David Matthews
Funding Source: The Schmitt Program in Integrative Neuroscience
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“Model systems" like the tiny nematode C. elegans have played outsized roles in neuroscience by allowing the identification of genes that control the development and function of the brain in all animals, including humans. In recent work, we have discovered a previously unknown C. elegans gene that is essential for the functional maturation of its nervous system during juvenile development. Excitingly, this gene does not act to make a protein, like most genes do; instead, it functions as an RNA molecule. This class of genes, called long non-coding RNAs (lncRNAs), have attracted a great deal of attention in recent years, but very little is known about their functions in brain development and neurological disease. We have good reason to believe that mammals, including humans, have a version of the nematode gene we have identified, but lncRNA genes are notoriously difficult to study using traditional approaches. In this project, we will combine the expertise of two labs, one that focuses on C. elegans neurogenetics, and another which uses computational approaches to studying RNA. Together, these two groups will work to identify candidate mammalian versions of the gene we have discovered in C. elegans. Such a discovery could have fascinating implications for understanding the molecular mechanisms that build the human brain and could provide new opportunities for the diagnosis and treatment of neurological and psychiatric disorders.

Indexing the electrophysiology of music along the auditory system

Ed LalorRoss MaddoxPIs: Ed Lalor and Ross Maddox
Funding Source: The Schmitt Program in Integrative Neuroscience
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Combining expertise from our two labs, we will study and compare music and speech processing from the earliest parts of the auditory system (Experiment 1) to the more complicated later parts (Experiment 2). The first part will focus on natural speech sounds and music sounds as well as sonic “textures” whose statistics match those of speech and music, but are distinctly not either. In the second experiment we will present piano music naturally played and with all the notes out of order so that we can determine how predictability in music effects its processing, even when the acoustics of the sounds are the same. This project will not only tell us how music is processed by the brain, but will also tackle more fundamental questions like “what makes music music?”

Understanding how alcohol affects microglial function in the adolescent brain

Ania MajewskaPI: Ania Majewska
Funding Source: The Schmitt Program in Integrative Neuroscience
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Drinking in adolescence profoundly affects brain function in the long-term, with increased propensity for alcohol use disorder, depression and cognitive deficits in adults who abused alcohol as adolescents. We have recently shown that intoxication changes microglia-immune cells-in a way that may impact their interactions with neurons. In this proposal, we will use a mouse model of adolescent binge drinking to examine how alcohol affects microglia. By selectively removing microglia only during the adolescent period when animals are exposed to alcohol, we will be able to test whether “alcohol-exposed" microglia cause long-term changes in brain or whether these deleterious effects are mediated by other cell types in the brain. This information will provide a spring board from which to understand the biological underpinning of the effects of alcohol use during adolescence.

Retinal biomarkers of concussive and subconcussive head injury

Steven SilversteinPI: Steven Silverstein
Co-Investigators: Jeff Bazarian, Rajeev Ramchandran, Brian Keane, Ben Chapman
Funding Source: The Schmitt Program in Integrative Neuroscience
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At present, there are no non-invasive markers of brain changes associated either with concussions or repetitive milder head hits. We therefore propose to examine the ability of changes in the retina – the neural tissue in the eye – to signal the emergence of brain changes related to hits to the head. We will examine collegiate football players before the season, immediately after the season, and then 4 months post-season. We will determine whether there are changes in retinal structure and functioning across the 3 time points, and whether these predict changes in brain structure and thinking skills across the same period. Our long-term goal is to develop rapid, non-invasive methods for detecting significant brain trauma in the immediate aftermath of a head hit, as well as tests that can be used to screen for longer-lasting or progressive changes that would require lifestyle alterations and possibly treatment to prevent further worsening of the condition.

Nanolocalization of synaptic acid-sensing ion channels

David MacLeanPI: David MacLean
Funding Source: The Schmitt Program in Integrative Neuroscience
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Within the brain, billions of nerve cells are constantly communicating with one another by hurling chemicals across the tiny gap between them. This gap, known as a synapse, is less than one ten millionth of a meter or about one thousand times smaller than the width of a human hair. Using super resolution microscopes, we have learned that within the incredibly tiny region of a synapse certain classes of receptor proteins are precisely aligned right across from where neurotransmitter chemicals get released. These receptors appear well situated for hyper efficient chemical communication. Other types of receptors site on the edge of synapse, positioned to detect greater levels of neurotransmitter or barrages of chemical signals. Using the University of Rochester’s new super resolution microscope, we will determine where a particular receptor class, the acid-sensing ion channel, sits within the synapse. Understanding the exact location of these acid-sensing receptors at synapses will give important clues about their functions within our brain.

Impact of radiation dose to the amygdala and hippocampus on depressive symptoms in brain tumor patients receiving partial brain radiation

Sara HardyPI: Sara Hardy
Co-Investigators: Michelle Janelsins, Michael Milano, Giovanni Schifitto
Funding Source: The Schmitt Program in Integrative Neuroscience
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Depression is frequent for patients with brain tumors, and often under-recognized. It is not known whether radiation to specific parts of the brain can contribute to depression. The amygdala and hippocampus are structures that have a known role in depression. In a preliminary study, we evaluated a small group of patients with brain tumors who received radiation treatment. In this group, patients who had increased radiation dose to the amygdala and hippocampus had more symptoms of depression. We are interested in expanding our cohort to confirm these findings and create a model that takes into account other factors that are related to depression in order to validate this result. We also plan to look at brain MRI to examine changes in the amygdala and hippocampus and their connections to the rest of the brain. Should these findings be confirmed, future studies will evaluate interventions such as reducing radiation dose to these structures using advanced radiation techniques and creating interventions for patients at higher risk of depression after brain radiation.

The implications of CSF flow in mild cognitive impairment: An MRI study

Arun VenkataramanPI: Arun Venkataraman
Co-Investigators: Jianhui Zhong, Feng Vankee Lin
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Factors such as Β-amyloid deposition and tau neurofibrillary tangles have been implicated in the pathogenesis of Alzheimer’s disease (AD). It is, however, unclear what initiates the cascade of events that leads to a vulnerability to such factors. It has recently been speculated that cerebrospinal fluid (CSF) flow may be implicated in this type of pathology. Research in the murine model has suggested that an important component of CSF flow is toxin clearance from the brain. We hope to study the relationship between CSF flow measured on PC-MRI and MCI disease metrics such as brain volume, surface thickness, and White matter (WM) connectivity metrics in patients with amnestic Mild cognitive impairment (MCI).

Evaluation of microstructural integrity in HIV-infected individuals with and without cerebral small vessel disease using microscopic fractional antisotropy and myelin water imaging

Giovanni SchifittoPI: Giovanni Schifitto
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Understanding the effects of in-plane acceleration and simultaneous multi-slice on structural connectome analyses

Zhengwu ZhangPI: Zhengwu Zhang
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Biometric sensors as a tool for objective measurement of rehabilitation efforts in stroke patients

PI: Ania Buza
Funding Source: Del Monte Institute for Neuroscience
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When a person has a stroke, part of their brain is damaged. Depending on the size and location, the brain injury can cause new weakness that leaves the person disabled. Studies on animals suggest that exercising the weak part of the body after a stroke can help recover strength, and that more exercise leads to better recovery. We think this is also true in people, but it’s difficult to study because it is hard to know how much exercise each person did. In this project, we are using new sensors (made by MC10, Inc.) that measure movement (accelerometry and gyroscopy) and muscle activity (electromyography). Using information collected by these sensors we are developing a system that automatically tracks the number of rehab exercises a person has done with their weak arm. We will use the new system to measure the amount of exercise different people do after a stroke, and use this information to answer questions about how exercising affects stroke recovery. Ultimately, we hope this information will contribute to identifying better ways to help people regain their strength and independence after a stroke.

Comparative effectiveness studies for treatment strategies in Parkinson's disease

Ashkan ErtefaieCharles VenutoPIs: Ashkan Ertefaie and Charles Venuto
Funding Source: Del Monte Institute for Neuroscience
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Parkinson’s disease (PD) manifests a heterogeneous clinical syndrome and this variability in the clinical phenotype highlights the need to tailor the type and/or the dose of treatment to the specific needs of individuals living with PD. The main goal of individualized, or precision, medicine is to use patient characteristics to determine an individualized treatment strategy (ITS) to promote wellness. This research is motivated by the PPMI (Parkinson’s Progression Markers Initiative) observational study. The data set includes longitudinal measurements of patients’ characteristics and treatment history and provide an excellent opportunity to construct data-driven ITSs. Existing guidelines for symptomatic drug therapy for PD can best be described as "permissive". The relative lack of comparative evidence for different classes of drugs has created challenges in devising recommendations to follow any specific therapeutic strategy; indeed, there remains substantial heterogeneity in the choice of treatment strategies. The study aims to fill this important gap.

Pilot study of RNA biomarkers in CSF for myotonic dystrophy type 1 (DM1)

Johanna HamelCharles ThorntonPIs: Johanna Hamel and Charles Thornton
Funding Source: Del Monte Institute for Neuroscience
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Animal models of sensory hypersensitivity

Farran BriggsPI: Farran Briggs
Funding Source: Del Monte Institute for Neuroscience
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Function and structure of auditory processing networks in Rett Syndrome

Edward FreedmanPI: Ed Freedman
Funding Source: Del Monte Institute for Neuroscience
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Predictive coding in ASD: Testing competing hypotheses using electrophysiological modeling of neural responses to natural speech

Edmund LalorPI: Ed Lalor
Co-Investigators: John Foxe and Ed Freedman
Funding Source: Del Monte Institute for Neuroscience
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The goal of this study is to adjudicate between two competing hypotheses – derived from predictive coding theory – as to the mechanisms underlying atypical perceptual processing in ASD. One hypothesis characterizes autistic perception in terms of reduced top-down influences on perception. While the other proposes that bottom-up sensory-perceptual processes are enhanced. We aim to test these two hypotheses using experiments involving natural speech – allowing us to link the essential RDoC constructs of perception and language. Our approach will involve using state-of-the-art methods for indexing the neurophysiology of hierarchical speech processing, while manipulating the fidelity of sensory input and the strength of prior information. Access to interpretable measures of hierarchical processing will be critical for adjudicating between the two hypotheses.

Using MoBI to identify biomarkers of cognitive decline in Alzheimer’s disease

Edward FreedmanPragathi BalasubramaniAnton PorsteinssonPIs: Ed Freedman, Pragathi Balasubramani, Anton Porsteinsson
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Here, for the first time, we will use the novel Mobile Brain/Body Imaging (MoBI) system in populations with an amnestic mild cognitive impairment (aMCI), Alzheimer’s disease (AD), and in age-matched healthy older adults to evaluate event-related potentials (ERPs) while stressing available cognitive resources using dual-task walking paradigms. Using electroencephalography (EEG) it was recently shown that visual evoked potentials (VEPs) can distinguish groups of older adults with an aMCI from those with AD, and from older adults that were not cognitively impaired. Our recent work using the novel MoBI EEG-based system has demonstrated that older adults show less flexibility in the reallocation of cognitive resources during dual-task walking. In addition, the risk of falling in people with AD is 2-3 times higher than in healthy older adults. We will compare neurophysiological responses in these groups while they are sitting, standing and walking on the treadmill. The overarching hypothesis that we will test in the proposed experiments is that both ERPs and gait parameters will correlate with cognitive impairment measures. MoBI and high density EEG are non-invasive tools that may lead to earlier diagnosis of aMCI/AD as well as point toward training paradigms that could stave off conversion from health to aMCI and also from aMCI to AD.

Control of tolerance to opiates: The role of CGRP, RCP and inflammation

Ian DickersonJean BidlackPIs: Ian Dickerson and Jean Bidlack
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Latent human herpesvirus 6 as a modulator of Alzheimer pathology

Margot Mayer-ProschelGail JohnsonChristoph ProschelPIs: Margot Mayer-Pröschel, Gail Johnson, and Christoph Pröschel
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Understanding adrenergic signaling in microglia in the context of Alzheimer’s disease

Ania MajewskaM Kerry ObanionPIs: Ania Majewska and Kerry O’Banion
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Gut permeability, systemic inflammation, and penumbral collapse in acute ischemic stroke

Marc HaltermanGiovanni SchifittoPIs: Marc Halterman, Giovanni Schifitto
Funding Source: The Schmitt Program in Integrative Neuroscience
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To explore the potential link between acute stroke, intestinal injury, and delayed expansion of the stroke core during the early phase of hospitalization, this collaborative effort between basic and clinical investigators will test the hypothesis that systemic inflammatory responses to pathological brain-gut coupling adversely affects the perfusion of 'at-risk' tissue within the ischemic penumbra that contributes to delayed core expansion. Paired blood specimens will be collected from patients presenting with AIS at the time of ED presentation and following hospital admission. Analyses will include acute measurement of leukocyte activation and serum-based markers of brain injury, gut injury, and systemic inflammation. These data will be analyzed in conjunction with data on stroke lesion growth extrapolated from acute CT and delayed MRI-based imaging obtained in the course of routine neurological care.

Mapping semantic information flow in the brain during natural speech production

Andrew AndersonEdmund LalorDavid Dodell-FederPIs: Andrew Anderson, Edmund Lalor, David Dodell-Feder
Funding Source: The Schmitt Program in Integrative Neuroscience
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To date it is unclear how studies of the neural bases of language relate to inter-personal communication. Our long-term research goal is to harness functional Magnetic Resonance Imaging and Electroencephalography to chart the neural exchange of meaning between peoples’ brains during spontaneous conversation. Obviously, this depends on the ability to measure meaning in the brains of both speaker and listener. Recent scientific advances including those made by the current team have made strides toward solving this problem on the listener’s side. This project seeks to newly introduce computational methods that map out how meaning is processed in the speaking brain. This presents a challenge to discover the timeline that meaning is converted to outgoing speech, as opposed to incoming speech being converted to meaning.

Electroencephalography (EEG) during auditory perception in children with autism spectrum disorder: an investigation of the predictive coding hypothesis

Leona OakesPI: Leona Oakes
Co-Investigator: John Foxe
Funding Source: The Schmitt Program in Integrative Neuroscience
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Recent evidence suggests that individuals with Autism spectrum disorder (ASD) have poor prediction capabilities. Given that social communication is highly dependent on prediction and that individuals with poor prediction may prefer more repetitive environments, a deficit in predictive skills could explain many of the core symptoms associated with ASD. This study explores this hypothesis using EEG during an auditory mismatch negativity (MMN) paradigm. The MMN paradigm consists of playing a tone in a set rhythm pattern in most trials, and then creating a “deviant tone” by making an adjustment in the timing of a tone (e.g., making the tone come more quickly or slowly). When an individual detects a deviant tone, they demonstrates an MMN response. The MMN response to deviant tones varying in complexity will be compared between individuals with and without ASD. Additionally, the amplitude of the MMN (i.e., intensity of response) in individuals with ASD will be correlated with their symptom severity. We hypothesize that 1) individuals with ASD do not respond as dramatically to deviant tones and respond less as complexity increases and 2) the less an individual with ASD responds, the more severe their other ASD symptoms.

Amygdala-prefrontal interactions involved in social communication

Lizabeth RomanskiPI: Liz Romanski
Funding Source: The Schmitt Program in Integrative Neuroscience
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The focus of this project is to understand how groups of neurons in the amygdala encode social communication information and transmit it to the prefrontal cortex for evaluation, and cognitive processing. Deficits in communication and social interaction are hallmarks of autism spectrum disorders and we propose that understanding the amygdala-prefrontal circuits will help us to understand the neural basis of these deficits. Results from these studies will help us understand the processing and integration of socio-emotional information at the cellular and network level which will help us in our understanding of disorders in which these processes are disrupted.

The role of fragile X mental retardation protein in the auditory brainstem

Hitomi SakanoPI: Hitomi Sakano
Funding Source: The Schmitt Program in Integrative Neuroscience
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We are investigating the role of Fragile X Mental Retardation Protein (FMRP) in the auditory brainstem. FMRP is an RNA binding protein and its absence results in Fragile X Syndrome (FXS), the most common cause of inherited autism spectrum disorder and mental retardation. We believe that FMRP has wide spread effects on gene expression and that these genes may play a role in neuroplasticity in the auditory brainstem. We will be analyzing the effects of FMRP on gene expression in the auditory brainstem by comparing the normal mouse to the FXS mouse model. Specifically, we will utilize laser capture microdissection technology to isolate specific areas of the auditory brainstem and perform RNA-seq next-generation sequencing analysis. Of the genes whose expression is altered, we will identify those that are directly controlled by FMRP through mRNA binding, versus those that are indirectly affected by other mechanisms. We will also determine if these genes are clustered in particular cellular pathways. Finally, we will test if any of these pathways are affected by deafening or loss of hearing. Results will reveal how FMRP regulates genes important in neuroplasticity to maintain normal hearing, and reveal potential therapeutic targets for symptoms of FXS such as auditory hypersensitivity.

Optogenetic identification and manipulation of cortico-cortical feedback in a non-human primate, the common marmoset

Kuan Hong WangJude MitchellPIs: Kuan Hong Wang, Jude Mitchell
Funding Source: The Schmitt Program in Integrative Neuroscience
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The expansion of the cerebral cortex among primates has supported higher-level planning through specializations in frontal, parietal, and motor areas. Elucidating how these higher-level cortical areas interface with the rest of the brain remains one of the key challenges for understanding human intelligence and how aberrations in brain structure give rise to devastating disorders such as schizophrenia and autism. A major anatomical feature of higher-level cortical areas is that they make extensive feedback projections to earlier sensory areas that are involved in perception. At the behavioral level, higher level planning and movement control can have a profound influence on external perception and self-awareness, presumably through these feedback projections. However, the role of feedback at the neural level has remained elusive, in part because we lack the tools necessary to manipulate it in behaving animals, particularly in primates where the brain organization is similar to our own. The current project will develop an intersectional viral strategy based on pilot studies in mice to label and manipulate cortical feedback projection pathways in the marmoset monkey. These studies will help build a more general approach for understanding how higher-level cortical circuits in the primate interface with the rest of the brain.

Early visual cortex plasticity and white matter changes associated with growth hormone and insulin-like growth factor in acromegaly patients

David PaulPI: David Paul
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Beyond the classic VTA (Dopamine)

Julie FudgePI: Julie Fudge
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Exploring the electrophysiology of Batten disease in human participants

Edward FreedmanPI: Ed Freedman
Funding Source: Del Monte Institute for Neuroscience
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Exploring the electrophysiology of a murine model of Batten disease

Krishnan PadmanabhanPI: Krishnan Padmanabhan
Funding Source: Del Monte Institute for Neuroscience
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Using virtual agents to study the neural bases of live social interaction

David Dodell-FederEhsan HoquePIs: David Dodell-Feder, Ehsan Hoque
Funding Source: Del Monte Institute for Neuroscience
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Using MoBI to identify biomarkers of cognitive decline in Alzheimer’s disease

Edward FreedmanPragathi BalasubramaniAnton PorsteinssonPIs: Ed Freedman, Pragathi Balasubramani, Anton Porsteinsson
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Here, for the first time, we will use the novel Mobile Brain/Body Imaging (MoBI) system in populations with an amnestic mild cognitive impairment (aMCI), Alzheimer’s disease (AD), and in age-matched healthy older adults to evaluate event-related potentials (ERPs) while stressing available cognitive resources using dual-task walking paradigms. Using electroencephalography (EEG) it was recently shown that visual evoked potentials (VEPs) can distinguish groups of older adults with an aMCI from those with AD, and from older adults that were not cognitively impaired. Our recent work using the novel MoBI EEG-based system has demonstrated that older adults show less flexibility in the reallocation of cognitive resources during dual-task walking. In addition, the risk of falling in people with AD is 2-3 times higher than in healthy older adults. We will compare neurophysiological responses in these groups while they are sitting, standing and walking on the treadmill. The overarching hypothesis that we will test in the proposed experiments is that both ERPs and gait parameters will correlate with cognitive impairment measures. MoBI and high density EEG are non-invasive tools that may lead to earlier diagnosis of aMCI/AD as well as point toward training paradigms that could stave off conversion from health to aMCI and also from aMCI to AD.

Rejuvenating microglia in a mouse model of Alzheimer’s disease

Ania MajewskaJohn OlschowkaPIs: Ania Majewska and John Olschowka
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Supernormal structural connectomes: lessons for Alzheimer’s disease

Zhengwu ZhangTim BaranPIs: Zhengwu Zhang and Timothy Baran
Funding Source: Rochester Center for Alzheimer’s Disease Research
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Cellular plasticity in the amygdala during critical periods for social learning

Julie FudgePI: Julie Fudge
Co-Investigator: Alexandra McHale
Funding Source: The Schmitt Program in Integrative Neuroscience
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This proposal develops ideas that we have been building on for some time, namely, whether the immature amygdala can add circuits during postnatal life, and if so, how the environment shapes that process. Depending on our results, we hope to use tract tracing to examine variability in amygdala circuit formation in maternally deprived monkeys compared to control. The project is entirely post-mortem work in monkeys.

NeuroTag: Team-based undergraduate research for identifying novel targets for CNS diseases

Marc HaltermanSara KnowldenPIs: Marc Halterman and Sara Knowlden
Funding Source: The Schmitt Program in Integrative Neuroscience
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This project blends a bench-based drug discover project with a vertically integrated team-based program that will provide University of Rochester undergraduate Neuroscience students research experience in a fast-paced, cross-disciplinary laboratory environment. The students will be trained in the laboratory on the essential techniques required to perform location proteomics to identify potential new drug targets in neuronal ER-stress pathways. One goal of our project is to establish a sustainable program that will expose undergraduate students to discovery science early in their academic careers and foster in them an appreciation for the rewards of collaborative science and exploration. The project will also establish a pipeline for functional gene analysis that in the future can be used to identify functional signaling nodes in other disease-relevant paradigms.

The Sez6 family and complement dependent synapse pruning

Jennetta HammondPI: Jenetta Hammond
Co-Investigator: Harris Gelbard
Funding Source: The Schmitt Program in Integrative Neuroscience
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This study is aimed at understanding whether complement dependent synapse pruning is involved in the molecular neuropathology of autism (using mouse models) and whether the Sez6 gene family regulates this process. We hypothesize that the activity of complement regulatory proteins may be key to understanding why certain subsets of synapses are more vulnerable to synaptic pruning by glial cells than others during development and in the context of heightened inflammation. Enhanced pruning could lead to disrupted connectivity and neurological functions in individuals with autism spectrum disorders.

The role of outer hair cell motility for cochlear fluid homeostasis

Jong-Hoon NamPI: Jong-Hoon Nam
Co-Investigator: Kenneth S. Henry
Funding Source: The Schmitt Program in Integrative Neuroscience
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The objective of this research is to observe how acoustic stimuli affect mass transport within the cochlear fluid. The hypothesis of the full-blown R01 proposal is that the outer hair cells’ motility contributes to cochlear fluid homeostasis. We will investigate the micro-fluid dynamics within the the organ of Corti (OoC), which has been largely overlooked because there have been few means to observe it until very recently. There are three aims with different scopes toward obtaining an integral set of preliminary data, such as the time taken for mass transport along the cochlear length in vivo (Aim 1), micro-mechanics of the OoC in vitro (Aim 2), and theoretical prediction in silico (Aim 3). Aims 1 and 2 are used to validate the theoretical study of Aim 3. Aim 3 will predict the cochlear fluid homeostasis under different natural/pathological conditions.

Small molecule activation of ERBB signaling pathways to promote hearing restoration after noise exposure

Patricia WhiteAnne LuebkePIs: Patricia White, Anne Luebke
Funding Source: The Schmitt Program in Integrative Neuroscience
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The loss of cochlear sensory cells, termed hair cells, is a primary cause of hearing loss in mammals. Surprisingly, spontaneous regeneration of lost cochlear hair cells occurs in birds, yet this does not occur in mammals. In regenerating animals, cochlear supporting cells, which are adjacent to hair cells, proliferate and differentiate into new hair cells, with restoration of auditory discrimination in 1-2 months. Supporting cells in the young mouse cochlea retain the capacity for regeneration, however, knowledge of how regeneration is regulated is still lacking. Efforts to manipulate these pathways in mice in order to improve cochlear responses after noise exposure are still in the early stages. We have investigated a potential role for ERBB family receptors in inner ear regeneration. We hypothesize that the activation of ERBB signaling pathways using WS3 will drive cochlear supporting cell-to-hair cell differentiation and improve auditory responses in mice after noise exposure.

MRI Atlas of CSF drainage pathways in the aging Alzheimer's disease brains

Rashid DeanePI: Rashid Deane
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Three-dimensional in-vivo measurement of lumbar spine segmental motion using UTE MRI-ultrasound Registration

Edmund KwokPI: Edmund Kwok
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Auditory processing in mouse model of Autism Spectrum Disorders (ASD)

Anne LuebkeJ. Chris HoltPIs: Anne Luebke, Chris Holt
Co-Investigator: Christine Portfors
Funding Source: The Schmitt Program in Integrative Neuroscience
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Auditory processing is important for communication and it has been shown that children with Autism spectrum disorder (ASD) have deficits in auditory function at the cochlear level. Additionally, difficulty in filtering relevant auditory information in background noise can significantly impair a person’s social communication abilities. We, and others, have demonstrated that children with ASD have impaired abilities to hear in the presence of background noises, but exhibit no differences in quiet.

Mouse models are essential to advance understanding of the mechanistic basis of ASD, as well as to test potential therapies. In this proposal we will examine three different mouse models of ASD (16p11.2 duplication, Cntnap2, and Shank3) that have the greatest construct and face validity, and have also been backcrossed many generations onto C57B6 strain to eliminate potential strain effects. While these mouse models exhibit differences in their output of social vocalizations and thus show communication deficits, it is not known whether they also show auditory processing deficits.

Investigating convergent strategies for population coding of natural images during locomotion in rodents and non-human primates

Krishnan PadmanabhanJude MitchellPIs: Krishnan Padmanabhan, Jude Mitchell
Funding Source: The Schmitt Program in Integrative Neuroscience
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The goal of this project is to use high-density recordings of neuronal populations to investigate how anatomical circuits in the brain give rise to canonical computations across different species.

The mammalian neocortex encodes features of the sensory world through the coordinated activity of large populations of neurons (REF%). While many of the general features of neocortex are well conserved across mammals, such as the six-layered structure (REF%) and primary excitatory and inhibitory cell classes (REF%), other features such as columnar organization (REF%) and foveal overrepresentation vary considerably between species (REF%). As a result, some features of single neuronal responses to sensory stimuli are preserved across diverse species (tuning of cells to oriented bars of light REF%), while others vary between species (saccades in non-human primates REF%).

Understanding these differences in the context of neuronal coding is made more complicated by the fact that computations often reflect the joint activity of networks of neurons (REF%); computations that can be obscured when either single neurons are analyzed in isolation or when the activity of units in averaged over multiple trials. As a result, it is unclear to what extent structural differences in neocortex reflect underlying differences in neural coding. These issues could be resolved by examining the patterns of activity across large neuronal populations using comparable stimulus and behavioral conditions.

Developing drugs to inhibit the toxic RNA-mediated disease mechanism in Spinocerebellar Ataxia type 10 neurons

Tatsuaki KurosakiPI: Tatsuaki Kurosaki
Co-Investigators: Lynn Maquat, Christoph Proschel and Charles Thornton
Funding Source: The Schmitt Program in Integrative Neuroscience
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Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by a unique combination of progressive ataxia, seizures and anticipation. SCA10 is associated with expansion of an ATTCT repeat in intron 9 of the ATXN10 gene. While the normal repeat size is 10-22, the disease-associated repeat size is 800-4500. Given that earlier work has shown that repeat expansion does not affect ATXN10 mRNA or protein expression, the molecular mechanism of SCA10 is unlikely attribute to a simple loss of ATXN10 gene function. Based on my unpublished data, I postulate that a novel RNA-mediated gain-of-function mechanism contributes to SCA10 pathogenesis. In this mechanism, the expanded AUUCU RNA repeats accumulate in cell nuclei and sequester nuclear RNA-binding proteins, including the well-studied pre-mRNA splicing mediator poly-pyrimidine tract binding protein 1 (PTBP1). To examine this hypothesis, I propose to (1) generate human induced pluripotent stem cell (iPSC)-derived neuronal cells using SCA10-patient cells, and (2) test the ability of antisense oligonucleotides (ASOs) to block the sequestration of AUUCU-binding proteins from ATXN10 mRNA harboring expanded repeats without affecting ATXN10 mRNA harboring a normal number of repeats.

Cerebellar hypoplasia and saccadic adaptation in Autism Spectrum Disorder

Edward FreedmanJohn FoxePIs: Edward Freedman, John Foxe
Funding Source: The Schmitt Program in Integrative Neuroscience
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The conceptual framework for this new collaboration rests on the principle that visual orienting behaviors can be used as accurate predictors of neural dysfunction in developmental disorders such as Autism and Dyslexia, as well as in degenerative diseases like Alzheimer’s disease and also in discrete injuries like mild traumatic brain injury. Combining understanding of neural underpinnings with analyses of structural integrity and also with neurophysiological measures of function in these patient populations will produce insight into the disorders, help identify biomarkers for early diagnosis and define subpopulations for targeted remediation. While future work will be directed at other developmental disorders and degenerative diseases, in the experiments described in detail below we seek to identify a subphenotype of Autism Spectrum Disorders (ASD) based on the structure of the cerebellum and the ability to adapt the amplitude of saccadic eye movements in response to persistent visual errors.

Limitations underlying perceptual processing in ASD: Integration across domains

Duje TadinLoisa BennettoPIs: Duje Tadin, Loisa Bennetto
Co-Investigator: Paul Allen
Funding Source: The Schmitt Program in Integrative Neuroscience
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Given these gaps in knowledge, the overarching goal of this study is to quantitatively estimate different sources of noise that limit perceptual processing in ASD using psychophysical and computational methods to test the main hypothesis that internal additive noise is broadly elevated in individuals with ASD. Given the high prevalence of inconsistent sensory responses in ASD, it is critical to test this hypothesis in a range of perceptual domains. Our study will integrate our parallel lines of work to focus on visual and auditory domains. In addition, we will employ a novel approach that dramatically increases data collection efficiency, allowing us to use a paradigm that was previously impractical to implement with non-expert participants.

Indexing the dynamic encoding of natural speech at the semantic level

Edmund LalorRajeev RaizadaPIs: Edmund Lalor, Rajeev Raizada
Co-Investigator: Andrew Anderson
Funding Source: The Schmitt Program in Integrative Neuroscience
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The overarching aim of this study is to determine whether or not EEG responses to natural speech can be decoded based on the semantic content of that speech. The underlying hypothesis is that EEG reflects the encoding of speech based on its semantic content. More specifically, we hypothesize that the semantic processing of speech involves relating that speech to components of experience, and that this process produces discriminable patterns of activation on the scalp that are particular to the content of the specific speech input.

A feasibility pilot study on the effects of exercise on chemotherapy-induced peripheral neuropathy and interceptive brain circuitry

Ian KlecknerPI: Ian Kleckner
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Multisensory integration in children with dyslexia

Ciara MolloyPI: Ciara Molloy
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Fluoxetine for visual recovery after ischemic stroke

Bogachan SahinPI: Bogachan Sahin
Funding Source: Center for Advanced Brain Imaging and Neurophysiology
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Novel methods for treating and studying lysosomal storage disorders

Mark NoblePI: Mark Noble
Co-Investigators: Christoph Proschel, Jonathan Mink, John Foxe
Funding Source: Del Monte Institute for Neuroscience
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Genetic and neuroscience studies across the spectrum of developmental brain disorders

Alex PaciorkowskiPI: Alex Paciorkowski
Funding Source: The Schmitt Program in Integrative Neuroscience
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This proposal combines genomic and neuroscience methods to investigate the genetic and cellular mechanisms underlying the developmental brain disorders autism, intellectual disability, and epilepsy with specific emphasis on the MEF2CARC synaptic activation response pathway. Additionally, this proposal through its use of whole exome sequencing makes use of the excellent resources of the Genomic Research Center, as well as the Center for Integrative Research Computing. Taken as a whole, this proposal will increase the collaborative use of methods in genomics, bioinformatics, cellular neuroscience, as well as developmental medicine and will allow the ongoing collaboration between the co-investigators and my research group to mature in new directions.

Transglutaminase 2 facilitates neuronal survival: “Seq-ing” the targets

Gail JohnsonPI: Gail Johnson
Co-Investigator: Alex Paciorkowski
Funding Source: The Schmitt Program in Integrative Neuroscience
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The purpose of this project is to identify response elements and genes regulated by transglutaminase 2 (TG2) which promote neuronal survival and attenuate ischemic-induced cell death. TG2 is mainly a cytosolic protein, however a small but significant proportion of TG2 is found in the nucleus in basal conditions, and in response to hypoxia in neurons, TG2 moves into the nucleus. This is of significance because nuclear TG2 promotes cell survival. In primary neurons TG2 attenuates ischemic-induced cell death, an effect that is independent of its transamidating activity. Neuronal expression of human TG2 in mice significantly decreases stroke volume in a permanent middle cerebral artery (MCA) ligation model, and knockdown of endogenous TG2 in neurons potentiates ischemic-induced cell death. These data are extremely exciting and strongly support our hypothesis that TG2 attenuates ischemic-induced neuronal cell death.

Dynamics and mixed selectivity of prefrontal populations maintaining stimulus features and their locations during working memory tasks

Tatiana PasternakAdam SnyderPIs: Tatiana Pasternak, Adam Snyder
Co-Investigator: Albert Compte, Rubén Moreno-Bote
Funding Source: The Schmitt Program in Integrative Neuroscience
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In everyday perceptual experience stimulus features and their locations are largely inseparable. Despite this apparent inseparability, physiological recordings from the lateral prefrontal cortex (LPFC) aimed at the neural mechanisms of working memory for features and their locations have used different behavioral paradigms; representation of stimulus features in working memory was often examined in tasks requiring comparisons between current and remembered stimuli, while memory for location, was usually studied with paradigms involving making eye movements to remembered locations. With these tasks, single cell recordings in prefrontal cortex revealed different types of delay activity: sustained stimulus-selective delay activity in memory for location tasks and transient stimulus selective activity in tasks requiring retention of stimulus features. The sustained location-specific delay activity in spatial tasks has been thought by many to represent the substrate of sensory working memory, giving rise to the widely accepted biophysical attractor models of working memory. The absence of such activity during non-spatial tasks suggests either that this difference is a reflection of distinct mechanisms underlying maintenance of stimulus features and their locations, or that it is a consequence of the difference between behavioral tasks used to study the two types of working memory. In either case, there is a need to identify in LPFC network activity the specific dynamical processes, other than sustained activity, which can support working memory, as recently proposed in theoretical models.

Disrupted protein translation causes astrocyte dysfunction in Vanish White Matter disease

Christoph ProschelSina GhaemmaghamiPIs: Chris Proschel, Sina Ghaemmaghami
Funding Source: The Schmitt Program in Integrative Neuroscience
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This project studies a genome wide proteomic and transcriptomic analysis in neural cells of Vanishing White Matter (VWM) patients to identify disease mechanism and novel markers. VWM disease is an IDD with known genetic cause but poorly understood disease etiology. While mutation in the proteins translation initiation factor EIF2B are known to cause VWM, the lack of suitable biological systems has hampered the study of cell biological deficits in neural lineage cells. Here we develop VWM-derived pluripotent stem cells to study to generate human neural stem cells and astrocytes with EIF2B subunit mutations from VWM patients. While EIF2B mutations affect protein translation changes at the posttranslational level have not been studied. Our genome comparison of proteome by tandem mass spectroscopy in human cells therefor provides the first attempt to study the sequelae of EIF2B mutations in this IDD. Our studies provide a unique opportunity to identify distinctive biomarkers and possible therapeutic targets.

Micro Array recordings of ensemble activity in the primate ventral prefrontal and premotor cortex during complex behaviors

Lizabeth RomanskiMarc SchieberPIs: Liz Romanski, Marc Schieber
Funding Source: The Schmitt Program in Integrative Neuroscience
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A collaborative effort to understand the localization of brain function across the ventral frontal lobe, and to combine and to leverage the PIs individual skillsets and technical expertise to realize each other’s respective neurophysiological goals. PI Schieber has used micro arrays in his recordings across a large expanse of the primate motor cortex. This cutting edge technology, which allows for the recording of > 100 neurons simultaneously, requires skill in surgically implanting the subdural micro electrode arrays and quantitative expertise in analyzing the multiple, simultaneous neuronal signals that they yield. PI Romanski has successfully recorded from difficult-to-reach ventral prefrontal cortical regions but has performed only single and dual electrode recordings. The single electrode method is extremely limiting and does not allow for the recording of ensembles of cells. In this collaboration Romanski and Schieber will combine their expertise to 1) Record many cells simultaneously from the ventral prefrontal cortex using floating micro arrays while nonhuman primates perform audiovisual mnemonic and integrative tasks and 2) Record mirror neurons from the ventral premotor and prefrontal cortex while nonhuman primates perform reach, grasp, and manipulation tasks.

A unique model of glial resistance to hypoxic injury

Margot Mayer-ProschelPI: Margot Mayer-Proschel
Co-Investigator: Vera Gorbunova
Funding Source: The Schmitt Program in Integrative Neuroscience
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Studies of SIK1 epilepsy mutations in human neuronal cells

Alex PaciorkowskiPI: Alex Paciorkowski
Co-Investigator: Chris Proschel
Funding Source: The Schmitt Program in Integrative Neuroscience
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Putative role of fluoxetine in post-stroke recovery of visual function

Bogachan SahinPI: Bogachan Sahin
Co-Investigators: Zoe Williams, Brad Mahon
Funding Source: The Schmitt Program in Integrative Neuroscience
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The effects of arousal on microglial behavior during stroke

Ania MajewskaPI: Ania Majewska
Co-Investigator: Mark Halterman
Funding Source: The Schmitt Program in Integrative Neuroscience
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Resting state functional connectivity MRI in musicians with Embouchure Dystonia

Jonathan MinkPI: Jonathan Mink
Co-Investigator: Joel Perlmutter
Funding Source: The Schmitt Program in Integrative Neuroscience
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High efficiency injection of biomolecules into utricle cells by carbon nanotube arrays

Ian DickersonPI: Ian Dickerson
Co-Investigator: Michael Schrlau, Patricia White
Funding Source: The Schmitt Program in Integrative Neuroscience
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