Suppression of Corticostriatal Circuit Activity Improves Cognitive Flexibility and Prevents Body Weight Loss in Activity-Based Anorexia in Rats

Laura K Milton; Paul N Mirabella; Erika Greaves; David C Spanswick; Maarten van den Buuse; Brian J Oldfield; Claire J Foldi

doi:10.1016/j.biopsych.2020.06.022

Suppression of Corticostriatal Circuit Activity Improves Cognitive Flexibility and Prevents Body Weight Loss in Activity-Based Anorexia in Rats

Biol Psychiatry. 2021 Dec 15;90(12):819-828. doi: 10.1016/j.biopsych.2020.06.022. Epub 2020 Jul 2.

Authors

Laura K Milton¹, Paul N Mirabella¹, Erika Greaves², David C Spanswick³, Maarten van den Buuse⁴, Brian J Oldfield¹, Claire J Foldi⁵

Affiliations

¹ Department of Physiology, Monash University, Clayton, Victoria, Australia; Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
² Department of Physiology, Monash University, Clayton, Victoria, Australia.
³ Department of Physiology, Monash University, Clayton, Victoria, Australia; Warwick Medical School, University of Warwick, Coventry, United Kingdom.
⁴ School of Psychology and Public Health, La Trobe University, Bundoora, Victoria, Australia.
⁵ Department of Physiology, Monash University, Clayton, Victoria, Australia; Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. Electronic address: claire.foldi@monash.edu.

PMID: 32892984
DOI: 10.1016/j.biopsych.2020.06.022

Abstract

Background: The ability to adapt behavior to changing environmental circumstances, or cognitive flexibility, is impaired in multiple psychiatric conditions, including anorexia nervosa (AN). Exaggerated prefrontal cortical activity likely underpins the inflexible thinking and rigid behaviors exhibited by patients with AN. A better understanding of the neural basis of cognitive flexibility is necessary to enable treatment approaches that may target impaired executive control.

Methods: Utilizing the activity-based anorexia (ABA) model and touchscreen operant learning paradigms, we investigated the neurobiological link between pathological weight loss and cognitive flexibility. We used pathway-specific chemogenetics to selectively modulate activity in neurons of the medial prefrontal cortex (mPFC) projecting to the nucleus accumbens shell (AcbSh) in female Sprague Dawley rats.

Results: DREADD (designer receptor exclusively activated by designer drugs)-based inhibition of the mPFC-AcbSh pathway prevented weight loss in ABA and improved flexibility during early reversal learning by reducing perseverative responding. Modulation of activity within the mPFC-AcbSh pathway had no effect on running, locomotor activity, or feeding under ad libitum conditions, indicating the specific involvement of this circuit in conditions of dysregulated reward.

Conclusions: Parallel attenuation of weight loss in ABA and improvement of cognitive flexibility following suppression of mPFC-AcbSh activity align with the relationship between disrupted prefrontal function and cognitive rigidity in AN patients. The identification of a neurobiological correlate between cognitive flexibility and pathological weight loss provides a unique insight into the executive control of feeding behavior. It also highlights the utility of the ABA model for understanding the biological bases of cognitive deficits in AN and provides context for new treatment strategies.

Keywords: Activity-based anorexia; Anorexia nervosa; Chemogenetics; Cognitive flexibility; Nucleus accumbens; Prefrontal cortex.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anorexia*
Cognition
Female
Humans
Prefrontal Cortex*
Rats
Rats, Sprague-Dawley
Weight Loss