2018 — 2021 |
Plotkin, Joshua L |
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. |
Direct Amygdala Modulation of the Dorsolateral Striatum and Compulsive Behaviors @ State University New York Stony Brook
Project Summary/Abstract Compulsive motor behaviors (i.e. repetitive stereotyped, insuppressible behaviors) are a common motor symptom found in a wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders. These motor symptoms interfere with the daily functioning, productivity and quality of life of over 1% of the population, yet treatment options are limited and often ineffective, due to insufficient understanding of the underlying brain circuits and lack of therapeutic targets. The striatum (caudate/putamen), the major input nucleus of the basal ganglia, is a key mediator of compulsive motor behaviors in both humans and rodents. Compulsive motor behaviors commonly co-occur with anxiety disorders, and psychophysical models have proposed that the two are mechanistically linked, suggesting the corresponding brain circuitries may overlap. How limbic-associated inputs converge on the motor portions of the striatum, however, is unclear. The objective of this proposal is to determine how synaptic inputs from the basal and lateral nuclei of the amygdala (BLA) influence dorsolateral striatum function, and if pathological synaptic integration of BLA inputs by the dorsolateral striatum exacerbates compulsive motor behaviors. The dorsolateral striatum contains two types of functionally opposing spiny projection neurons (SPNs), which predominantly receive synaptic inputs from the sensorimotor cortex and thalamus, and ultimately promote or suppress action initiation. A leading hypothesis is that compulsive motor behaviors are due to imbalanced activation of SPN populations, pathologically promoting action initiation. The proposed research will determine how SPNs pathologically integrate synaptic inputs from the BLA in complementary mouse models of compulsive motor behavior (genetically induced by deletion of Slitrk5 or Sapap3, or experimentally induced by repetitive over-activation of BLA inputs to the dorsolateral striatum). This approach will reveal common, model-independent circuit pathologies. Guided by strong preliminary data and cutting edge techniques (2-photon laser scanning microscopy, dendritic calcium imaging, slice electrophysiology, mutant mouse lines containing fluorescently tagged SPN-subtypes, and spatially localized optogenetics in ex vivo slices and in vivo), the proposed research will 1) determine how the dendritic excitability of dorsolateral striatum SPN populations is altered in Slitrk5 and Sapap3 knockout mice, 2) functionally map how SPN dendrites are engaged by the BLA, and how this impacts synaptic integration in mutant mice, and 3) determine the role of repetitive in vivo activation of BLA inputs to the dorsolateral striatum in inducing behavior and circuit pathologies overlapping with and exacerbating those found in mutant mice, and identify the common circuit pathologies corrected by the behaviorally therapeutic (in mice, but only a subset of patients) serotonin reuptake inhibitor fluoxetine. The results from this proposal are expected to reveal both novel pathological loci and the underlying mechanisms of a widely used but imperfect treatment for compulsive motor behaviors, aiding in the development of improved therapies for this common and debilitating symptom.
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2019 |
Plotkin, Joshua L |
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. |
Modulation of Neuronal Acetylcholine Receptors @ State University New York Stony Brook
? DESCRIPTION (provided by applicant): Central cholinergic signaling is implicated in attention, learning and memory processes. Despite substantial progress in understanding molecular and cellular aspects of the function of acetylcholine receptors in the central nervous system, significantly less progress has been made at relating the functions of ACh at the cellular level with the effects of ACh on cognition. The research program supported by NS22061 is dedicated to elucidating the contribution of nAChRs to CNS function and dysfunction. Our current goal is to quantitatively map the role of cholinergic signaling and nAChRs in establishing the activity footprint or engram of emotionally salient memories. We propose to combine state-of-the art genetic tools for engram labeling with electrophysiological, pharmacological and optogenetic methods to address the role of ACh in modulating network function. Specifically we will test the hypothesis that ACh controls the magnitude and indelibility of emotionally salient memories encoded in the basal lateral amygdala; and further that there is a cholinergic engram in the basal forebrain that is associated with specific learning paradigms. Our rationale for posing this hypothesis stems from observations that neurons within the basal lateral amygdala (BLA) are critical for establishing emotionally salient memories. The BLA receives robust cholinergic input from the basal forebrain and we have demonstrated that this cholinergic input is critical for BLA dependent learning and memory, that endogenous ACh increases the excitability of BLA neurons and further that plasticity at cortical-amygdala synapses requires ACh and nicotinic ACh receptors (nAChRs). To test this hypothesis we will address three specific questions: How does endogenous ACh circuit activity affect the BLA fear memory engram? What is the contribution of nAChRs to the cholinergic modulation of the fear memory engram? Does long term nicotine exposure change the cholinergic and BLA fear engrams? If our hypothesis is correct, then one would predict that specific manipulations of nAChR cholinergic signaling could be exploited to adjust the potency and durability of emotionally salient memories. Such alterations could be clinically relevant for selective ablation of memories in individuals with stress-related memory disorders, such as patients with PTSD or for patients with anxiety-disorders. Likewise, these studies could help to better target new therapeutics for restoring positive memories in patients with neurodegenerative diseases resulting in memory loss, such as Alzheimer's and Parkinson's disease.
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