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Title page for ETD etd-07192018-110359


Type of Document Dissertation
Author Turner, Brandon David
Author's Email Address brandon.d.turner@vanderbilt.edu
URN etd-07192018-110359
Title Plasticity of afferent-specific synapses in the nucleus accumbens
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Sachin Patel Committee Chair
Brad Grueter Committee Member
Ralph DiLeone Committee Member
Roger Colbran Committee Member
Keywords
  • Accumbens
  • plasticity
  • addiction
  • cannabinoids
  • metabotropic glutamate receptors
Date of Defense 2018-06-28
Availability restricted
Abstract
The nucleus accumbens has been repeatedly identified as a central node in reward processing. Plasticity of synaptic connections within the accumbens at the molecular and cellular level is well understood to serve a pivotal function in coordinating motivation for natural rewards as well as the persistent maladaptive behaviors seen in substance abuse and addiction. Here, I have investigated these synaptic changes and their relationship to drug-related behaviors. Specifically, this work has focused on delineating synaptic changes with respect to isolated synaptic inputs onto distinct populations of medium spiny neurons using channelrhodopsin and whole-cell electrophysiology combined with both in vivo and ex vivo drug exposure. This dissertation describes the function of two major G-protein coupled receptor (GPCR) signaling pathways: 1) Group I metabotropic glutamate receptors (mGlus) and 2) cannabinoid type-1 receptors (CB1Rs) with respect to their function at cortical and thalamic inputs into the accumbens and their subsequent alteration by exposure to the psychostimulant cocaine. I applied both global and region-specific pharmacological and genetic approaches to interrogate the necessity of their function and/or expression for the development of cocaine-related behaviors. I found that Group I mGlu subtypes mGlu1 and mGlu5 regulate cortical and thalamic inputs into the accumbens, respectively, and that mGlu5 regulation of thalamic inputs is uniquely inhibited by prior exposure to cocaine. Additionally, I demonstrated that the expression of CB1Rs in the cortex is necessary for the generation but not expression of cocaine-environment associations and that lacking these receptors prevents adaptations of cortex-accumbens connections induced by ex vivo cocaine. Finally, I showed that the expression of CB1Rs in distinct populations of striatal neurons is necessary for the generation and expression of cocaine-associated behaviors. With this, I have generated several models describing mechanisms by which cocaine remodels striatal reward circuitry via multiple GPCR signaling cascades and how they may facilitate cocaine-induced behavioral changes. This work refines the field of addiction research by taking a nuanced approach to dissecting reward circuit function and highlights the potential for targeting a subset of synaptic regulatory cascades as a therapeutic intervention for drug abuse.
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