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bioRxiv · 10.1101/2020.03.29.015115

Suppression of cortico-striatal circuit activity improves cognitive flexibility and prevents body weight loss in activity-based anorexia in rats

Milton, L. K.·Mirabella, P. N.·Greaves, E.·Spanswick, D. C.·van den Buuse, M.·Oldfield, B. J.·Foldi, C. J.
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Abstract

BackgroundThe 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. MethodsUtilizing the activity-based anorexia (ABA) rat 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. ResultsDREADD-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. ConclusionsBoth attenuation of weight loss in ABA and improved cognitive flexibility following suppression of mPFC-AcbSh activity aligns 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.

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Milton, L. K., Mirabella, P. N., Greaves, E., Spanswick, D. C., van den Buuse, M., Oldfield, B. J., Foldi, C. J.. 2020-03-30. Suppression of cortico-striatal circuit activity improves cognitive flexibility and prevents body weight loss in activity-based anorexia in rats. https://doi.org/10.1101/2020.03.29.015115

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