dc.creator | Turner, Brandon David | |
dc.date.accessioned | 2020-08-22T17:39:22Z | |
dc.date.available | 2020-08-06 | |
dc.date.issued | 2018-08-06 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-07192018-110359 | |
dc.identifier.uri | http://hdl.handle.net/1803/13278 | |
dc.description.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. | |
dc.format.mimetype | application/pdf | |
dc.subject | Accumbens | |
dc.subject | plasticity | |
dc.subject | addiction | |
dc.subject | cannabinoids | |
dc.subject | metabotropic glutamate receptors | |
dc.title | Plasticity of afferent-specific synapses in the nucleus accumbens | |
dc.type | dissertation | |
dc.contributor.committeeMember | Brad Grueter | |
dc.contributor.committeeMember | Roger Colbran | |
dc.contributor.committeeMember | Ralph DiLeone | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Neuroscience | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2020-08-06 | |
local.embargo.lift | 2020-08-06 | |
dc.contributor.committeeChair | Sachin Patel | |