Central CRF and acute stress differentially modulate probabilistic reversal learning in male and female rats.

Acute stress can have variable and sometimes sex-dependent effects on different executive functions, including cognitive flexibility, some of which may be mediated by increased corticotropin releasing factor (CRF). Previous studies on the effects of stress and CRF on cognitive flexibility have used procedures entailing deterministic rewards, yet how they may alter behavior when outcomes are probabilistic is unclear. The present study examined how acute stress and increased CRF activity alters probabilistic reversal learning (PRL) in male and female rats. Rats learned to discriminate between a 'correct' lever rewarded on 80 % of trials, and an "incorrect" lever delivering reward on 20 % of trials, with reward contingencies reversed after 8 consecutive correct choices. Separate groups received either intracerebroventricular infusions of CRF (3 µg) or restraint stress prior to a PRL session. Experiments examined how these manipulations affected learning when given prior to a one-day acquisition test or during performance in well-trained rats. Exogenous CRF, and to a lesser extent acute stress, impaired motivation across sexes, slowing deliberation times and increasing the number of trials omitted, particularly following a switch in reward contingencies. Neither manipulation significantly altered errors or reversal performance. However, increased CRF activity reduced negative feedback sensitivity. Across manipulations, females showed increased omissions and choice latencies, and were less sensitive to feedback than males. These results reveal the complexity with which stress, CRF, sex, and experience interact to alter aspects of motivation and probabilistic reinforcement learning and provide insight into how CRF activity may contribute to symptoms of stress-related disorders.

Differential effects of corticotropin-releasing factor and acute stress on different forms of risk/reward decision-making.

Acute stress and corticotropin-releasing factor (CRF) have been show to perturb cost/benefit decision making involving effort costs. However, previous studies on how stress manipulations affect decisions involving reward uncertainty have yielded variable results. To provide additional insight into this issue, the current study investigated how central CRF infusion and acute restraint stress alter different forms of risk/reward decision-making guided by internal representations of risk/reward contingencies or external informative cues. Male rats were well-trained on one of two tasks that required choice between a small/certain or a large/risky reward. On a probabilistic discounting task, the probability of obtaining the larger reward increased or decreased systematically over blocks of trials (100-6.25%). On a cue-guided Blackjack task, reward probabilities (50% or 12.5%) were signaled by discriminative auditory cues. CRF (1 or 3 µg) was infused intracerebroventricularly (ICV) or one-hour of restraint stress was administered prior to behavioral testing. Neither CRF nor acute stress altered risky choice on probabilistic discounting, but did increase trial omissions in the latter part of the session. Conversely on the Blackjack task, CRF reduced risky choice on good-odds trials (50%), whereas acute stress increased reward sensitivity. CRF but not acute stress also slowed decision latencies across tasks. These data reveal complex and differential manners in which increased CRF activity and acute stress alter distinct forms of risk/reward decision-making, particularly those guided by external cues.

Corticotropin-Releasing Factor (CRF) circuit modulation of cognition and motivation.

The neuropeptide, corticotropin-releasing factor (CRF), is a key modulator of physiological, endocrine, and behavioral responses during stress. Dysfunction of the CRF system has been observed in stress-related affective disorders including post-traumatic stress disorder, depression, and anxiety. Beyond affective symptoms, these disorders are also characterized by impaired cognition, for which current pharmacological treatments are lacking. Thus, there is a need for pro-cognitive treatments to improve quality of life for individuals suffering from mental illness. In this review, we highlight research demonstrating that CRF elicits potent modulatory effects on higher-order cognition via actions within the prefrontal cortex and subcortical monoaminergic and cholinergic systems. Additionally, we identify questions for future preclinical research on this topic, such as the need to investigate sex differences in the cognitive and microcircuit actions of CRF, and whether CRF may represent a pharmacological target to treat cognitive dysfunction. Addressing these questions will provide new insight into pathophysiology underlying cognitive dysfunction and may lead to improved treatments for neuropsychiatric disorders.

Alterations in effort-related decision-making induced by stimulation of dopamine D1, D2, D3, and corticotropin-releasing factor receptors in nucleus accumbens subregions.

RATIONALE: Nucleus accumbens (NAc) dopamine (DA) plays an integral role in overcoming effort costs, as blockade of D1 and D2 receptors reduces the choice of larger, more-costly rewards. Similarly, the stress neuropeptide corticotropin-releasing factor (CRF) modulates DA transmission and mediates stress-induced alterations in effort-related choice. OBJECTIVES: The current study explored how excessive stimulation of different DA receptors within the NAc core and shell alters effort-related decision-making and compared these effects to those induced by CRF stimulation. METHODS: Male Long Evans rats were well-trained on an effort-discounting task wherein they choose between a low-effort/low-reward and a high-effort/high-reward lever where the effort requirement increased over blocks (2-20 presses). Dopamine D1 (SKF 81297, 0.2-2 µg), D2/3 (quinpirole, 1-10 µg), or D3 (PD 128,907, 1.5-3 µg) receptor agonists, or CRF (0.5 µg), were infused into the NAc core or shell prior to testing. RESULTS: Stimulation of D2/3 receptors with quinpirole in the NAc core or shell markedly reduced the choice of high-effort option and increase choice latencies, without altering preference for larger vs smaller rewards. Stimulation of D1 or D3 receptors did not alter choice, although SKF 81297 infusions into the shell reduced response vigor. In comparison, core infusions of CRF flattened the discounting curve, reducing effortful choice when costs were low and increasing it when costs were high. CONCLUSIONS: Excessive stimulation of NAc D2 receptors has detrimental effects on effort-related decision-making. Furthermore, CRF stimulation induces dissociable effects on decision-making compared with those induced the effects of stimulation of different DA receptors.

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor.

Acute stress activates numerous systems in a coordinated effort to promote homeostasis, and can exert differential effects on mnemonic and cognitive functions depending on a myriad of factors. Stress can alter different forms of cost/benefit decision-making, yet the mechanisms that drive these effects, remain unclear. In the present study, we probed how corticotropin-releasing factor (CRF) may contribute to stress-induced alterations in cost/benefit decision-making, using an task where well-trained rats chose between a low effort/low reward lever (LR; two pellets) and a high effort/high reward lever (HR; four pellets), with the effort requirement increasing over a session (2, 5, 10, and 20 presses). One-hour restraint stress markedly reduced preference for the HR option, but this effect was attenuated by infusions of the CRF antagonist, alpha-helical CRF. Conversely, central CRF infusion mimicked the effect of stress on decision-making, as well as increased decision latencies and reduced response vigor. CRF infusions did not alter preference for larger vs smaller rewards, but did reduce responding for food delivered on a progressive ratio, suggesting that these treatments may amplify perceived effort costs that may be required to obtain rewards. CRF infusions into the ventral tegmental area recapitulated the effect of central CRF treatment and restraint on choice behavior, suggesting that these effects may be mediated by perturbations in dopamine transmission. These findings highlight the involvement of CRF in regulating effort-related decisions and suggest that increased CRF activity may contribute to motivational impairments and abnormal decision-making associated with stress-related psychiatric disorders such as depression.

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats.

The stress response is essential to the survival of all species as it maintains internal equilibrium and allows organisms to respond to threats in the environment. Most stress research has focused on the detrimental impacts of stress on cognition and behavior. Reversal learning, which requires a change in response strategy based on one dimension of the stimuli, is one type of behavioral flexibility that is facilitated following some brief stress procedures. The current study investigated a potential mechanism underlying this facilitation by blocking glucocorticoid receptors (GRs) during stress. Thirty-seven male Long Evans rats learned to discriminate between two images on a touchscreen, one of which was rewarded. Once a criterion was reached, rats received stress (30 min of restraint stress or no stress) and drug (GR antagonist RU38486 or vehicle) administration prior to each of the first 3 days of reversal learning. We expected that stress would facilitate reversal learning and RU38486 (10 mg/kg) would prevent this facilitation in both early (<50% correct in one session) and late (>50% correct in one session) stages of reversal learning. Results showed that stressed rats performed better than unstressed rats (fewer days for late reversal, fewer correction trials, and fewer errors) in the late but not early stage of reversal learning. RU38486 did not block the facilitation of RL by stress, although it dramatically increased response, but not reward, latencies. These results confirm the facilitation of late reversal by stress in a touchscreen-based operant task in rats and further our understanding of how stress affects higher level cognitive functioning and behavior.