Striatal Melanocortin-4 Receptor Control of Action Flexibility

• Main Author: Heaton, Elizabeth C
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2023
• Subjects: Clinical psychology; Molecular biology; Neurosciences; Pharmacology
• ISBN: 9798381681796

More than half of all individuals in treatment for substance use disorder (SUD) will relapse. Inflexibility in selecting between familiar, habitual behaviors that have been rewarded in the past (drug seeking) and novel strategies that might be more advantageous (rehabilitation) may be a factor that preserves SUD. The dorsomedial striatum (DMS) is a brain region that receives and integrates glutamatergic input from cortical and subcortical regions required for goal-directed action selection. However, the factors in the DMS responsible for coordinating this incoming information remain incompletely understood. This dissertation begins by describing the extrahypothalamic functions of the melanocortin-4 receptor (MC4R), a receptor that is well-positioned in the DMS to control flexible, goal-directed action. Next, I report that MC4R in the DMS appears to propel familiar reward-seeking behavior (habit), even when it is not fruitful, and moderating MC4R presence improves the capacity for goal-directed behavior. I then demonstrate that this process requires inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Then, I further investigate how striatal melanocortin systems propel familiar behaviors, particularly via interaction with the central nucleus of the amygdala (CeA). I demonstrate that MC4R-expressing cells in the DMS are 1) predominantly expressed on dopamine D1-type receptor-expressing medium spiny neurons and 2) are necessary and sufficient for controlling the capacity of mice to arbitrate between actions and habits. I next use site-selective gene silencing and pharmacological techniques to reveal that MC4R presence suppresses goal seeking. I also find that MC4R-expressing neurons are functionally integrated into an amygdalo-striatal circuit that suppresses action flexibility in favor of routinized behaviors. Additionally, I use publicly available spatial transcriptomics datasets to reveal differences in the gene transcript correlates of Mc4r across the striatum, with considerable co-variation in dorsal structures. Guided by these results, I lastly discovered that MC4R function in the dorsolateral striatum complements that in the DMS, here suppressing habitual behavior. Together, these findings provide insight into the molecular and circuit-level mechanisms by which MC4R in the DMS propels habitual behavior. This dissertation thus illuminates mechanistic factors that support the development of automatized routines when flexible decision making is no longer adaptive, which may provide insight into therapeutic targets for neuropsychiatric disorders in which decision making is impaired.