Investigating behavioral flexibility controlled by the melanocortin-4 receptor in the dorsal striatum Open Access

Seo, Esther (Spring 2022)

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Flexible behavior refers to the ability to update behavior in response to external or internal stimuli – to integrate new information into old patterns of behavior. One brain region necessary for behavioral flexibility is the dorsal striatum. The dorsal striatum is divided into two subregions in rodents: the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Neural activity in the DMS and DLS is directly correlated with whether an action is considered goal-directed or habitual, respectively. The factors in the dorsal striatum responsible for coordinating behavioral flexibility remain incompletely understood. One possible factor is the melanocortin-4 receptor (MC4R), a receptor directly implicated in the regulation of behavioral flexibility. MC4R controls the direction of excitatory neural activity in the DMS and DLS such that MC4R activation decreases neural activity in the dorsal striatum. Administration of a systemic MC4R agonist would be expected to impact MC4R activity simultaneously in the DMS and DLS. However, neural activity in the DMS and DLS is not concurrent and is dependent on the present action (action->outcome or stimulus->response). We found that systemic administration of an MC4R agonist during a period when mice express flexible responding interferes with DMS-dependent behavior, resulting in a bias towards inflexible, habit-like behavior. Meanwhile, we found that systemic administration of an MC4R agonist during the expression of habit blocked DLS-dependent behavior, resulting in goal-directed action selection, when habitual behavior would otherwise occur. These findings could provide novel therapeutic insight for treating neuropsychiatric disorders characterized by maladaptive habit, such as substance use disorders.

Table of Contents

Introduction 1

Current Research 3

Methods 4

Animals 4

Setmelanotide preparation and administration 5

Evaluation of setmelanotide dosage on food intake and locomotion 5

Instrumental conditioning: Short training 6

Instrumental conditioning: Extended training 7

Statistical analyses 8

Results 9

Setmelanotide Dosage Pilot Study 9

Short Training 10

Extended Training 11

Discussion 13

Setmelanotide blocked bias formation towards goal-directed behavior in mice exposed to short training 13

Does setmelanotide have potential for blocking habitual behavior? 14

Implications of setmelanotide in humans regarding behavioral flexibility 15

Conclusion 16

References 17




List of Figures

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