Differential Effects of Acute Stress on Motivation in High vs. Low Anxiety
Post by Elisa Guma
The takeaway
Acute stress negatively impacts motivation in high anxiety individuals but improves motivation in low anxiety individuals. These opposing effects are mediated by the modulation of mesolimbic dopamine release via corticotrophin-releasing hormone.
What's the science?
The effects of acute stress on motivation tend to vary between individuals. Anxiety has been shown to moderate the effects of acute stress in learning, and may, in part, explain the variability observed in motivated behaviours by stress. These behaviours may share a common neurobiological mechanism via the action of corticotrophin-releasing hormone (CRH) action on CRH receptor 1 (CRHR1) in the mesolimbic dopamine neurons that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). This week in Science Advances Zalachoras and colleagues investigate the mechanisms underlying differences in motivation in response to stress in an outbred strain of rats by combining behavioural, genetic, electrophysiological, histochemical and molecular analyses.
How did they do it?
The authors used outbred (genetically diverse) Wistar rats to model natural variation in trait anxiety. Rats were classified into either low anxiety or high anxiety phenotypes according to their performance on the elevated plus maze task. The authors tested the rats’ motivation using an operant conditioning task, in which rats had to nose-poke in an appropriate port to receive a palatable food reward. This task was then repeated, with the introduction of an acute stress exposure.
To investigate whether the CRH system was a good target for these motivation differences, the authors examined CRH receptor (CRHR1) expression levels in VTA dopamine neurons in the VTA of low and high anxiety rats and assessed variation in a single-nucleotide polymorphism associated with the CRHR1 gene in low, medium, and high anxiety rats. To investigate whether CRH actions on VTA neurons can mimic the effects of acute stress on motivation, the authors infused CRH (or a control; vehicle) into the VTAs of both low or high anxiety rats and tested motivated behaviour. They also measured dopamine levels in the target region of those VTA neurons, the NAc using microdialysis following CRH infusion.
To better understand the cellular properties of the VTA dopamine neurons in response to CRH, the authors performed ex vivo patch clamp recordings from dopamine neurons in low and high anxiety rats, as well as in a mouse model in which CRHR1 genes were specifically knocked out in dopamine VTA neurons. Behavioural and patch-clamp experiments were repeated in low anxiety rats for whom VTA CRHR1 levels had been downregulated, or in high anxiety rats where CRHR1 was overexpressed selectively in DA neurons in the VTA.
What did they find?
No baseline differences in motivation were observed in low and high anxiety rats, however, following exposure to acute stress, low anxiety rats had increased motivation relative to high anxiety rats. Low anxiety rats had significantly higher expression of CRHR1 in VTA dopamine neurons compared to high anxiety rats and showed variation in the distribution of a known single-nucleotide polymorphism for the CRHR1 gene, indicating that the CRHR1 gene could be mediating this behaviour.
Consistent with the acute stress effects, CRH infusion into the VTA had an opposite effect on motivation for high and low anxiety rats: it improved motivation for low anxiety and impaired it for high anxiety rats. CRH infusion in the VTA also increased dopamine release in the NAc in the low anxiety group relative to the high anxiety group. These results were mirrored by the ex vivo patch-clamp recordings: firing rates of VTA cells were increased following the application of CRH in low anxiety rats, while the opposite effect was observed in high anxiety rats. Similarly, the CRH increased NAc dopamine release in low, but not high anxiety rats.
Downregulation of CRHR1 levels in the VTA of low anxiety rats abolished the improvement in motivation due to acute stress exposure and increased spontaneous firing in DA neurons of the VTA. In contrast, overexpression of CRHR1 significantly improved motivation both under normal and under stress conditions. The same effects were observed in the mouse model in which CRHR1 was knocked out of dopamine cells specifically, suggesting that the effects observed in the rat may be dopamine cell-specific.
What's the impact?
Acute stress exposure was found to facilitate motivated behaviour in low anxiety rats and impair motivated behaviour in high anxiety rats, mediated by the CRHR1. This research sheds light on how stress impacts motivation differently, depending on anxiety levels.
