Research reportCentral CRF and acute stress differentially modulate probabilistic reversal learning in male and female rats
Introduction
The acute stress response orchestrates reactions to real or perceived environmental threats by inducing multiple physiological, neural and behavioral changes via the hypothalamic pituitary adrenal (HPA) axis and other systems. Stress responses are generally thought to be adaptive, yet, acute stress can impair some facets of cognition such as memory retrieval [[1], [2], [3]] and attention [4,5]. In both humans and pre-clinical animal models, acute stress has more variable effects on cognitive functions mediated by the frontal lobes, such as working memory and cognitive flexibility. Thus, different stressors have been reported to either impair or facilitate these functions, depending on multiple factors that include sex differences [[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]. For example, acute stress impairs working memory but is without effect on flexibility in females across species [19,[21], [22], [23]]. Conversely, acute stress either impairs or facilitates working memory and flexibility in males across species [[6], [7], [8],11,14,19,21,23,24], demonstrating the complexity with which stress and sex interact to perturb these aspects of cognition.
Stressors promote the release of corticotropin releasing factor (CRF) which in turn initiates the HPA axis. However, this neuropeptide and its cognate receptors are also widely expressed in brain regions that reside outside of HPA axis circuitry [[25], [26], [27]]. As a consequence, increased CRF activity in other brain regions can by itself mediate many of the cognitive effects of stress [[28], [29], [30]]. Similar to acute stress, central infusion of exogeneous CRF impairs attention and working memory in male rats [31,32]. Likewise, increased central CRF impairs different forms of cognitive flexibility, including reversal learning, entailing shifts between different stimulus-reward contingencies and extradimensional set-shifting [33]. Conversely, acute stress can have variable effects on reversal learning and strategy set-shifting, depending on the stressor used and whether or not stress occurs in the testing context [6,8].
Studies on how acute stress and exogeneous CRF can influence cognitive flexibility have typically used procedures where the outcomes of correct or incorrect choices were deterministic. Yet, real world circumstances often present situations where a “correct” action may not always be reinforced. In this regard, cognitive flexibility involving probabilistic reinforcement has been reported to be altered in individuals with stress-related disorders, such as depression. Individuals with depression are more sensitive to misleading negative feedback or commit more errors during reversal phases of probabilistic reversal learning (PRL) [[34], [35], [36], [37]]. Notably, certain forms of depression are characterized by elevated CRF levels [38,39]. Yet, it is unclear whether alterations in PRL observed in depressed patients are driven in part by increased CRF activity. Moreover, whether acute stress modulates PRL is also unknown. To investigate this, we conducted an exploratory series of experiments to probe how acute stress and enhanced CRF activity affect acquisition and performance of a rodent version of the PRL task that resembles those used with human subjects [[40], [41], [42]]. A secondary aim was to investigate if these manipulations differentially affected behavior in males vs females. Furthermore, in light of the fact that human PRL tasks are typically conducted in a manner where participants learn the initial probabilistic discrimination and reversal in the same session, separate studies examined how stress or exogenous CRF administration prior to acquisition influenced initial learning of the task, as well as how these manipulations affected performance in well-trained rats.
Section snippets
Animals
Squads of 12–24 male and female Long–Evans rats (Charles River Laboratories), weighing 225−275 g at arrival were maintained at 21 °C with a 12 h light/dark cycle. Experiments were performed during the light phase of the cycle between the hours of 9am-3pm. Rat colonies were segregated by sex. Animals were handled 5 min./day in the week prior to training to habituate to this procedure. Following one week of colony acclimatization, animals that would eventually receive one-hour of restraint stress
Acquisition (between-subjects comparisons)
Fifty-six animals were tested prior to PRL acquisition (Fig. 1A) but 7 were removed due to missed placements, leaving 49 animals for the analysis (n = 29 males, 13 vehicle/16 CRF; n = 20 females, 10 per group). When analyzing data from all animals in this experiment, one of our first observations was that CRF markedly increased omission rates. Over the 240-trial session, control rats made 14.1 +/- 5 omissions, whereas those receiving CRF made 50.5 +/- 12 omissions (F(1,45) = 6.05, p < 0.05;
Discussion
The present series of experiments provide insight into how increased CRF activity and acute stress distinctly alter performance on various measures of PRL. Our most striking and consistent finding was that CRF infusion, and to a lesser extent acute stress, reduced motivation to perform the task, indexed by trial omissions and choice latencies. In contrast, neither of these manipulations altered flexibility, although they did change the manner in which reward and negative feedback altered
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
This work was supported by a Discovery Grant (RGPIN-2018-04295) from the Natural Sciences and Engineering Research Council of Canada to S.B.F. and an NSERC Doctoral Fellowship to C.A.B. We thank Nicola Symonds for their assistance with behavioral testing.
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