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The role of corticotropin-releasing and acute stress in modulating cognitive flexibility and decision making : physiological and behavioural interactions with mesolimbic dopamine

University of British Columbia

The stress response is a co-ordinated reaction to real or perceived threats. One arm of the response is the hypothalamic-pituitary-adrenal axis, initiated by corticotropin-releasing factor (CRF). Centrally-active CRF mediates many of the rapid behavioural stress responses. Indeed, CRF mediates, and exogeneous CRF mimics, the acute stress-induced bias away from more valuable rewards requiring greater effort. In Chapter 1, we discuss relevant research comparing acute stress and central CRF infusion at the circuit level and as it relates to different cognitive domains. In Chapters 2 and 3, we examine how acute stress and increased central CRF activity alter cognitive flexibility in both sexes, and risk/reward decision making in males. Using a probabilistic reversal learning (PRL) task, results suggested that acute stress impaired PRL in males, but CRF slightly facilitated flexibility across both sexes, with minimal overall sex differences. Using two decision making tasks, we found that acute stress increased reward sensitivity and CRF impaired optimal risky choice with external cues, whereas neither manipulation altered risky choice when reward contingencies were internally generated. Moreover, CRF markedly reduced motivation in all tasks. When viewed together, we found that CRF hyperactivity altered behaviour in a manner more similar to chronic than acute stress manipulations. In search of potential mechanisms, we probe the role of centrally-active CRF in altering ventral tegmental area dopamine neuron activity in Chapter 4, revealing that CRF increased dopamine neuron population activity. Chapter 5 examines the role of increased mesolimbic dopamine signaling on effort-related decision making. Here, we found increased nucleus accumbens (NAc) D2 receptor activity biased choice away from the more valuable, but more physically onerous, reward in a manner parallel to central CRF treatment. Collectively, these latter results suggest that increased CRF signaling enhances tonic dopamine activity, enhancing mesolimbic dopamine tone acting on NAc D2 receptors to reduce effort choice. Enhanced CRF activity is found in those with depression and other stress-related disorders. Therefore, culmination of these experiments point to a key role in CRF hyperactivity, perhaps via interaction with dopamine signaling, in perturbing behaviour within cognitive domains known to be altered in depression.

Text

2020-03-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/73685

Psychology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/