Probes for INS

Individuals frequently differ in their behavioral and cognitive responses to stress. However, whether motivation is differently affected by acute stress in different individuals remains to be established. By exploiting natural variation in trait anxiety in outbred Wistar rats, we show that acute stress facilitates effort-related motivation in low anxious animals, while dampening effort in high anxious ones. This model allowed us to address the mechanisms underlying acute stress-induced differences in motivated behavior. We show that CRHR1 expression levels in dopamine neurons of the ventral tegmental area (VTA)-a neuronal type implicated in the regulation of motivation-depend on animals' anxiety, and these differences in CRHR1 expression levels explain the divergent effects of stress on both effortful behavior and the functioning of mesolimbic DA neurons. These findings highlight CRHR1 in VTA DA neurons-whose levels vary with individuals' anxiety-as a switching mechanism determining whether acute stress facilitates or dampens motivation.

Fear-associated memories and behavior are often expressed in contexts/environments distinctively different from those in which they are created. This generalization process contributes to psychological disorders, particularly PTSD. Stress-related neurocircuits in the basolateral amygdala (BLA) receive inputs from hypothalamic orexin (Orx) neurons, which mediate neuronal activity by targeting orexin 1 (Orx1R) and orexin 2 (Orx2R) receptors via opposing functions. In BLA, inhibition of Orx1R or activation of Orx2R ameliorate stress responsiveness and behavior. We discovered that most Orx1R+ cells also express CamKIIα, while a majority of Orx2R+ cells are colocalized with GAD67. Further, Orx1R gene Hcrtr1 expression was positively correlated, and Orx2R gene Hcrtr2 expression was negatively correlated, with freezing in a phenotype-dependent fashion (Escape vs Stay) in the Stress Alternatives Model (SAM). The SAM consists of 4-days of social interaction between test mice and novel larger aggressors. Exits positioned at opposite ends of the SAM oval arena provide opportunities to actively avoid aggression. By Day 2, mice commit to behavioral phenotypes: Escape or Stay. Pharmacologically manipulating Orx receptor activity in the BLA, before Day 3 of the SAM, was followed with standard tests of anxiety: Open Field (OF) and Elevated Plus Maze (EPM). In Stay mice, freezing in response to social conflict and locomotion during SAM interaction (not home cage locomotion) were generalized to OF, and blocked by intra-BLA Orx1R antagonism, but not Orx2R antagonism. Moreover, patterns of social avoidance for Escape and Stay mice were recapitulated in OF, with generalization mediated by Orx1R and Orx2R antagonism, plus Orx2R stimulation.