1989 — 1990 |
Huntley, George W. |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Ontogeny of Transmitter Specific Cells in Primate Cortex @ University of California Irvine |
0.919 |
1996 — 2000 |
Huntley, George W. |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Mechanisms Underlying Motor Cortex Plasticity @ Mount Sinai School of Medicine of Nyu
DESCRIPTION: (Applicant's abstract) The goal of this project is to determine the role of identified connections and specific glutamate receptors in the plasticity of adult motor cortex (MI) representations. The first hypothesis is that the forelimb/vibrissa border region contains overlapping distribution of output neurons to the spinal cord and facial nerve nucleus which could represent the anatomical basis for intracortical microstimulation (ICMS)-defected border shifts. Anterograde labelling from vibrissa cortex will be used to localize corticospinal terminations arising from vibrissa sites exhibiting a forelimb border shift. The second hypothesis is that the horizontal connections which cross between motor representations form an anatomical basis for rapid border shifts. A combination of ICMS and anterograde and retrograde tracer injections into the forelimb/vibrissa border region will be used to correlate the origin and topography of horizontal connections that cross map borders with respect to the location and limits of border shifts. This proposal will provide a comprehensive anatomical and functional basis of motor cortex plasticity which incorporates identified axonal pathways and specific glutamate receptor subunits.
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0.991 |
2001 — 2005 |
Huntley, George W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Cortical Synaptic Plasticity @ Mount Sinai School of Medicine of Nyu
DESCRIPTION (provided by applicant): The long-term goal is to elucidate anatomical and molecular mechanisms enabling functional plasticity of representational maps in cerebral cortex. Our current focus is on determining the role of adhesion molecules in establishing the synaptic cortical circuitry upon which topographic maps of the sensory-motor periphery are based. The model system we use is the thalamic projection to rodent somatosensory (barrel) cortex, where two different thalamic inputs (VB and POrn) converge onto layer IV, terminate in mutually exclusive domains, and thereby establish the barrel center/septal organization. We investigate the role of the cadherin family of adhesion proteins in guiding the development and synaptic specificity of these two converging inputs, since cadherins are bona fide adhesion proteins located at the synapse, and have been implicated in synaptic targeting and plasticity. Initial studies showed N-cadherin was present at VB thalamocortical synapses during the period of thalamic axon ingrowth and formation of whisker-related clustering, and suggest that cadherin-8 plays a similar role in establishing the POrn input to septa. We hypothesize that N-cadherin and cadherin-8 provide a dual, adhesive code for specifying these converging inputs. To extend this work, Aim 1 tests functional roles of N-cadherin in establishing the VB thalamocortical projection. Cocultures combined with N-cadherin blocking reagents test roles in axon ingrowth, laminar targeting to layer IV, and synapse formation. In vivo studies test roles in map formation and in modulating neurophysiological properties of thalamocortical synapses. In Aim 2, we have three sets of studies to test the role of cadherin-8 in development of the POrn thalamic input. First, we will describe the normal development of POrn inputs, since this has never been investigated and will provide a solid foundation for subsequent molecular analyses. Second, we combine immunolocalization methods and direct labeling of POrn thalamic axons and terminals to investigate the relationship between cadherin-8 localization and development of the thalamic input and of barrel center/septal architecture. These studies will provide an essential anatomical framework for investigating functional roles of cadherin-8, which is the experimental focus of the third set of studies. Here, we use cocultures and cadherin-8 blocking reagents to begin investigating functional roles of cadherin-8 in development of the POrn input. Taken together, our studies will provide three significant advances: first, new details of the mechanisms by which cadherins orchestrate the development of highly organized cortical synaptic circuits in a mammalian model of cortical map formation; second, new, normative details about how the thalamic whisker maps develop, which will provide fundamental information on a model system which is an archetype for cortical development and plasticity; third, results will lay the groundwork for advancing our understanding of the role of cadherins in axon growth and synaptic remodeling which may underlie long-term cortical map plasticity during learning or resulting from injury.
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0.991 |
2003 — 2005 |
Huntley, George W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cadherin Adhesion Proteins in Spinal Cord Plasticity @ Mount Sinai School of Medicine of Nyu |
0.991 |
2007 — 2011 |
Huntley, George W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Matrix Metalloproteinases in Synaptic Plasticity @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): The long-term goal is to understand mechanisms of synaptic functional and structural plasticity in brain. This is important because such plasticity represents cellular mechanisms enabling memory. Matrix metalloproteinases (MMPs) are a family of extracellular peptidases whose targets include extracellular matrix (ECM). Canonically, they function to remodel the pericellular microenvironment. Here, we address the novel hypothesis that in brain, regulated MMP-mediated extracellular proteolysis coordinates synaptic signaling and remodeling during synaptic and behavioral plasticity. In Aim 1, regulation and activation of MMP-9 during synaptic plasticity is studied in vivo using electrical stimulation protocols and field recordings to elicit different forms of synaptic plasticity in area CA1. Pharmacological methods are used to establish the timecourse over which levels of MMP-9 protein and proteolytic activity are regulated;gain- and loss-of- function approaches are used to establish functional roles of MMP-9 in synaptic physiology and plasticity;novel reagents and methods including the use of fluorescently tagged MMP active-site directed probes are used to determine if MMP-9 is activated globally during plasticity or locally in relationship to plastic synapses. In Aim 2, effects of active MMP-9 on neuronal form and function are tested. Gain- and loss-of- function approaches combined with two-photon time-lapse imaging of living dendritic spines and whole-cell recording will be applied to acute hippocampal slices to: a) characterize changes in spine motility, morphology and actin dynamics in relationship to MMP-mediated potentiation;and b) determine the relationship between MMP-9 mediated structural plasticity and integrin activation. In Aim 3, a hippocampal- dependent learning and memory task will be used in conjunction with subsequent biochemical, anatomical and loss-of-function approaches in order to determine: a) the timecourse and localization of learning-induced MMP-9 activation;and b) the effects of neutralizing proteolytic activity on strength of memory. The experiments will reveal new, fundamental roles for MMPs in normal brain function, and provide new insight into molecular mechanisms that regulate synaptic and behavioral plasticity.
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1 |
2012 — 2013 |
Benson, Deanna L [⬀] Huntley, George W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Sema7a in Functional Organization of Neocortex @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): Disorders of cognitive, social and perceptual functions are associated with abnormalities of cortical synaptic circuit development and plasticity. There is a strong genetic disposition to such diseases, but the precise causes are unknown. Microdeletions in chromosome 15q24 are associated with a syndrome that features autism. A recent study of 15q24 microdeletion syndrome identified a minimal deletion interval that contains only four genes that are expressed in brain, among which, SEMA7A stands apart as highly relevant to sensory dysfunctions associated with the syndrome. Sema7A is an atypical member of the Semaphorin family of guidance cues: it is membrane-anchored by a GPI-linkage; it is expressed principally postnatally in the nervous system; and it can promote axon extension in a ¿1 integrin-dependent manner. These findings point to the idea that Sema7A has roles in late stages of brain development distinct from the customary Semaphorin-Plexin interactions that generate axon repulsion during embryonic development, but this has not been explored. Our data show that Sema7A is particularly enriched in somatosensory (S1) cortex at a time when synapses develop and sensory experience drives the refinement of connectivity. Accordingly, we hypothesize that Sema7A functions in the maturation and fine-tuning of cortical microcircuitry that occurs during early postnatal development. In mouse S1 barrel cortex our preliminary data show that when Sema7A is genetically ablated thalamocortical axons reach layer IV, but their synapses fail to mature functionally and their postsynaptic dendritic targets fil to orient their arbors appropriately. In contrast, somatosensory maps in subcortical centers are normal. These data outline an entirely novel molecular contribution to the functional and structural development of cortical sensory maps, the absence of which may perturb information processing through cortical microcircuits that in turn, produce symptoms relevant to 15q24 microdeletion syndrome. Our preliminary data serve as the basis for the hypothesis that Sema7A is essential for normal S1 maturation and function.
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1 |
2014 — 2015 |
Huntley, George W. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Molecular Control of Prefrontal Cortical Circuitry in Autism @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) comprise a range of neurodevelopmental abnormalities in cognitive abilities and behaviors associated with dysfunctional circuitry between the prefrontal cortex (PFC) and the neostriatum. Behavioral abnormalities emerge early after birth and are thought to reflect defects in the fine- tuning and plasticity of developing functional synaptic connectivity. We have observed that mRNA encoding cadherin-8 (Cdh8)-a type II, synaptically-localized classic cadherin-is highly enriched in PFC and dorsal striatum during early postnatal development. Moreover, the timing, anatomical distribution, and axon targeting function of Cdh8 suggest strongly that Cdh8 may be crucial for the development and plasticity of PFC->striatal circuitry. This is significant because several recent studies have linked Cdh8 genetically to susceptibility to ASDs. Thus, we hypothesize that cognitive ASD-like phenotypes reflect impaired synaptic development of PFC->striatal direct- and/or indirect-pathway circuitry due to deficient Cdh8-dependent molecular control over these pathways. We will test this hypothesis by combining mouse genetics, anatomy, and electrophysiology. The vertical integration across these objectives (spanning molecules, synapses and circuits) will provide novel insight into molecular control of brain pathways implicated in cognitive deficits associated with ASDs. This is important, because corticostriatal circuit defects are central to a number of aberrant behaviors associated with autism and anxiety disorders, but there is surprisingly little known about the normal development and plasticity of such circuits.
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1 |
2016 — 2020 |
Benson, Deanna L (co-PI) [⬀] Huntley, George W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cdh8-Dependent Circuit Development in Autism @ Icahn School of Medicine At Mount Sinai
? DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) comprise a range of neurodevelopmental abnormalities in cognitive abilities and behaviors associated with dysfunctional circuitry between the prefrontal cortex (PFC) and the neostriatum. Behavioral abnormalities emerge early after birth and are thought to reflect defects in the finetuning and plasticity of developing functional synaptic connectivity. We have shown that mRNA encoding cadherin8 (Cdh8) - a type II, synaptically localized classic cadherin - is highly enriched in PFC and dorsal striatum during early postnatal development. Moreover, the timing, anatomical distribution, and axon targeting function of Cdh8 suggest strongly that Cdh8 may be crucial for the development and plasticity of PFC?striatal circuitry. This is significant because several recent studies have linked CDH8 genetically to susceptibility to ASDs. Thus, we hypothesize that cognitive ASD like phenotypes reflect impaired synaptic development of PFC?striatal direct and/ or indirect pathway circuitry due to deficient Cdh8 dependent molecular control over these pathways. We will test this hypothesis by combining mouse genetics, anatomy, electrophysiology and behavioral assessment. The vertical integration across these objectives (spanning molecules, synapses, circuits and behaviors) will provide novel insight into molecular control of brain pathways implicated in cognitive and behavioral deficits associated with ASDs. This is important, because corticostriatal circuit defects are central to a number of aberrant behaviors associated with autism and anxiety disorders, but there is surprisingly little known about the normal development and plasticity of such circuits.
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1 |
2017 — 2018 |
Huntley, George W. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Susceptibility to Depression by Human Disease-Causing Mutation @ Icahn School of Medicine At Mount Sinai
PROJECT SUMMARY Depression and anxiety are commonly associated with Parkinson's disease (PD), and are often prevalent years before motor impairments upon which clinical diagnosis is made. The circuits and mechanisms underlying PD-related depression are unknown. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of heritable forms of PD. Disease progression in carriers of LRRK2 mutations, including depression, is similar to idiopathic cases suggesting a common mechanism. LRRK2 is enriched in dorsal striatum, the principal target of dopaminergic neurons that degenerate in PD, but paradoxically, its expression peaks developmentally during synaptogenesis, which may indicate that LRRK2 and PD-related mutant forms affect development of excitatory synaptic circuitry within the striatum. This suggests that altered neural circuit function conferred early in life by Lrrk2 mutation could render circuits vulnerable to PD-related depression and anxiety that manifest later in life. In support of this idea, our preliminary data show that in mice harboring the PD-related Lrrk2-G2019S gain-of-kinase function mutation, there is a significant increase in glutamatergic synaptic currents and abnormal spine morphology in developing striatal medium spiny neurons (MSNs) by postnatal day 21, a period that follows a burst in corticostriatal synaptogenesis. This is relevant because elevated glutamatergic signaling and spine abnormalities in ventral MSNs mediate elevated susceptibility to stress-induced depression-like behaviors. Consistent with this, we find in preliminary studies that G2019S mutant mice exhibit heightened sensitivity to social defeat stress, a model of stress-induced depression. Accordingly, our objective is to test the hypothesis that a PD-related Lrrk2 mutation that perturbs excitatory circuitry in striatal reward pathways early in life alters susceptibility to pro- depressive phenotypes by young adulthood. We will test this using mouse Lrrk2 knock-in models in an integrated combination of behavioral assays, whole-cell recording and pharmacological (small-molecule LRRK2 inhibitor) interventional approaches in vivo.
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1 |
2019 — 2020 |
Benson, Deanna L (co-PI) [⬀] Huntley, George W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Impact of Human Disease-Causing Mutation On Striatal Synaptic and Behavioral Plasticity @ Icahn School of Medicine At Mount Sinai
The G2019S mutation is the most common of several mutations in leucine-rich repeat kinase 2 (LRRK2) causing up to 40% of familial Parkinson's disease in certain populations. This pathogenic point mutation is autosomal dominant and increases kinase activity 2-3 fold. Disease progression in both motor and non-motor symptoms of mutant LRRK2 carriers is similar to idiopathic cases suggesting common mechanisms, but progress has been limited because LRRK2 biology is poorly understood and little is known of pathogenic cellular or synaptic actions of G2019S-LRRK2. LRRK2 expression is high in spiny projection neurons (SPNs) of dorsal and ventral striatum, and rises rapidly during axon ingrowth and excitatory synaptogenesis. The timing and location of expression suggests that mutant LRRK2 may be maladaptively influencing development of excitatory circuits that impact striatal function. To begin to test this idea, we probed glutamatergic synaptic function in SPNs in G2019S-LRRK2 knockin mice. We showed that early in postnatal life, G2019S-SPNs in dorsal striatum exhibit a significantly abnormal increase in spontaneous excitatory synaptic currents (sEPSCs) compared to WT mice or mice expressing a LRRK2 kinase-dead knockin mutation (D2017A). Such abnormal excitatory activity was observed in both direct- and indirect-pathway SPNs, was normalized by LRRK2 kinase inhibitors, and was associated with larger SPN dendritic spine-heads and sEPSC amplitudes. Dorsal striatal SPNs receive convergent input from cerebral cortex and control many types of goal- directed behaviors, and the latter are thought to reflect balanced control of bidirectional changes in corticostriatal synaptic strength. The early abnormalities in SPN synaptic function and structure suggest that synaptic plasticity will be altered by G2019S-LRRK2 with consequences for striatally-based behaviors. Preliminary data support both of these ideas. Together, we hypothesize that the normal balance between mechanisms that strengthen or weaken synaptic transmission is altered in SPNs expressing G2019S-LRRK2 in a way that both reveals molecular signaling pathways targeted by mutant LRRK2 and that has predictable consequences for behaviors. The proposed experiments will assess the impact of mutant LRRK2 on synapse strengthening and weakening in subtype-identified SPNs; they will identify the molecular pathways and mechanisms involved; they will determine if mutant LRRK2 alters behaviors associated with SPN synapse plasticity; and they will test whether in vivo LRRK2 inhibition early in life ameliorates maladaptive effects on synaptic and behavioral plasticity documented later in life.
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1 |
2020 — 2021 |
Huntley, George W. |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training Program in Neuroscience @ Icahn School of Medicine At Mount Sinai
PROJECT SUMMARY This is the second renewal of Mount Sinai's Jointly Sponsored Institutional Predoctoral T32 Training Program in Neuroscience. The objective of the Training Program is to provide rigorous, broad-based, individualized and multidisciplinary training to Year 1 and 2 predoctoral students in basic, translational and clinical neuroscience research, thereby enhancing the ability of our trainees to acquire critical skillsets necessary for high-quality doctoral dissertation research and a productive and impactful career in the science- related workforce. To accomplish this, the Training Program leverages the intimate association between the Mount Sinai Hospital and Health System, the Icahn School of Medicine at Mount Sinai and Mount Sinai's Graduate School of Biomedical Sciences, physically embedded together under one leadership, to expose trainees to the enormous breadth of basic, translational and clinical scientific approaches and model systems represented by an outstanding training faculty, ranging from structure/function analysis of individual synapses, to computational modeling of gene, protein and connectivity networks in healthy and diseased brains, to behavioral, electrophysiological and imaging studies of a variety of organisms, including humans. Mount Sinai has undergone an enormous expansion in basic and clinical research infrastructure, neuroscience faculty recruitment and a 3-fold increase in applications to the Neuroscience PhD program. Thus, seven training slots per year are requested. Our trainees participate in an integrated program of Core courses (spanning genes, molecules, cells, synapses, circuits, systems, behaviors and brain pathophysiology) and includes a course with direct patient contact. Courses are team-taught by an exceptional faculty using different teaching styles, including flipped classrooms and other approaches. Additional first-year courses include Responsible Conduct in Research, Rigor and Reproducibiity, an intensive Biostatistics course (with a parallel lab in R-programming) a Journal Club/WIP and research rotations. By the end of the first year, trainees select a thesis lab, and during their second year, commence dissertation research while taking at least two Advanced Electives from a large number of courses offered across the Institution. This allows each trainee to customize their coursework to their particular research and training goal needs. Trainees in our program also benefit from numerous activities that enhance their research experience, including science theme-based Clubs, seminars, career development opportunities, teaching and peer-mentoring activities, an annual retreat and other cohesion-building events. This Neuroscience Training Program T32 is essential to Mount Sinai's mission of providing fundamental neuroscience research training to our students, and serves as the principal research training, mentoring and financial engine driving specifically early-stage predoctoral students seeking a PhD in Neuroscience.
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