The ins of the striatum: Utilizing chemogenetics to define the contribution of cortical and thalamic afferents during addiction behaviors
Wunsch, Amanda M.
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Addiction is a chronic neuropsychiatric disorder accompanied by high rates of recidivism that lacks effect treatment, part of which may be due to an incomplete understanding of the brain circuits mediating addiction. Cortico-basal ganglia circuitry is a complex, interconnected network regulating addiction. Aberrant glutamatergic signaling in NAc is particularly important for the development and persistent of addiction, and NAc neurons receive glutamatergic innervation from many structures, with prefrontal cortex (PFC) and midline and intralaminar thalamic nuclei (MTN) inputs predominating. Recently we developed a viral mediated gene transfer approach combined with chemogenetics that allows us to selectively activate Gi/o-signaling cascades to reduce neuronal activity in specifically prefrontal cortex (PFC) or MTN NAc afferents during addiction-related behaviors. Thus, the overall goal of this dissertation was to utilize these novel techniques to more clearly define the role of PFC or MTN neurons projecting to the NAc in the regulation of psychomotor sensitization, drug-self administration, and drug-seeking behaviors in rats. We found that reducing neuronal activity of PFC neurons projecting to NAc attenuated the development of amphetamine sensitization. However, attenuating activity of these neurons during sensitization enhanced conditioned responses during a subsequent challenge session. Furthermore, our corticostriatal manipulation did not alter drug-taking during self-administration, but led to slower rates of extinction and enhanced responding following a priming injection of cocaine. We normalized responding following inhibition of corticostriatal afferents immediately prior to the drug-primed reinstatement test. These results demonstrate that corticostriatal afferents modulate responsiveness to psychostimulant drugs and drug-associated stimuli. Considerably less is known about the relative contribution of MTN to relapse behaviors compared to other sources of NAc glutamate, despite sending dense projections to NAc. First, I demonstrate that reducing activity of MTN attenuates both cue-induced and drug-primed reinstatement of cocaine-seeking, which establishes a role of MTN in relapse behaviors. Then I show that dampening activity of specifically anterior MTN neurons projecting to NAc (MTN-NAc) abolished drug-prime reinstatement, but enhanced cue-induced reinstatement. We found no effect of the same manipulation in posterior MTN-NAc during either reinstatement behavior. These results demonstrate MTN mediate relapse behavior, and MTN-NAc may be particularly important for regulating responses to drug-associated stimuli.