Inter-individual variability amplified through breeding reveals control of reward-related action strategies by Melanocortin-4 Receptor in the dorsomedial striatum

Abstract

In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals’ response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors.

Of Mice and Men: The Inter-individual Variability of the Brain's Response to Drugs

“…For instance, inter-individual differences in baseline anxiety-like behavior (ALB) in Wistar rats affected subsequent amygdala kindling in that only rats with increased baseline ALB before kindling exhibited a lasting increase in ALB after kindling ( Adamec and Shallow, 2000 ). Similar observations have been reported for various other behavioral phenotypes ( Pitychoutis et al, 2011 ; Armario and Nadal, 2013 ; Freund et al, 2013 ; Theilmann et al, 2016 ; Dellu-Hagedorn et al, 2018 ; Allen et al, 2022 ). Thus, as in humans, the development of pathologies in laboratory rodents is related to individual differences determining either vulnerability or resilience.…”

“…It is noteworthy that stress may also play a role in inter-individual variability in epilepsy ( Jhaveri et al, 2023 ). As in our study in the kindling model of DRE ( Ebert and Löscher, 1999 ), selective breeding has been used to examine the potential mechanisms of inter-individual variability in models of psychiatric disorders ( Allen et al, 2022 ).…”

Associations between nesting, stereotypy, and working memory in deer mice: response to levetiracetam

“…In operant conditioning procedures, young rats favor habit-based response strategies even under conditions that induce goal-seeking behavior in adults, suggesting that young organisms are more prone to use habit-based action strategies [ 52 ]. Allen, Heaton [ 53 ] capitalized on this propensity to identify highly habit-prone mice for later selective breeding for habit bias. Relatedly, Moin Afshar, Keip [ 54 ] revealed that the capacity for goal-based action strategies develops across juvenile and adolescent development, crystalizing only in young adulthood [ 54 ].…”

The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs

“…Intra-VTA infusion of the selective MC3R agonist γ-MSH, on the contrary, increases responding for sucrose under a progressive ratio schedule of reinforcement [ 343 ]. MC4R in the dorsomedial striatum appears to propel reward-seeking behavior [ 344 ].…”