El receptor tipo 1 de CRF modula la proyección dopaminérgica nigroestriatal y facilita la flexibilidad cognitiva después de estrés agudo y crónico

Repeated restraint stress (RRS) in rats impairs cognitive flexibility, particularly when faced with additional mild acute stress (AS). We tested the hypothesis that this impairment is associated with altered dopaminergic activity in the dorsal striatum (DS) driven by corticotropin-releasing-factor receptor type 1 (CRFR1) in the substantia nigra pars compacta (SNpc). 62 male rats received RRS or handling for 14 days, before training on a two-action, two-outcome instrumental conditioning task. Initial learning was assessed using an outcome devaluation test. Cognitive flexibility was assessed by reversing the outcome identities and a second outcome devaluation test, with half the rats in each group receiving AS before reversal training. Dopamine and metabolites were quantified in the DS, and CRFR1 mRNA was quantified in the SNpc. In experiment 2, SNpc CRFR1 was pharmacologically blocked unilaterally before AS and reversal training in 32 male and 32 female rats. Increased dopaminergic activity in the DS and SNpc and CRFR1 expression in the SNpc in the left hemisphere were associated with resilience to AS in naïve rats, but with an impairment in RRS+AS rats. Blocking CRFR1 in the left SNpc impaired cognitive flexibility following AS in naïve rats, but restored it following AS in RRS rats. Blocking CRFR1 in the SNpc increased DA availability in the DMS but decreased it in the DLS. The study suggests opposite facilitation in DA availability in the medial and lateral DS by CRFR1 in the SNpc and a left-to-right transition in dopaminergic nigrostriatal projection activity as a protective mechanism following RRS.Significance Statement This study investigated the role corticotropin-releasing-factor receptor type 1 (CRFR1) in the substantia nigra pars compacta (SNpc) in regulating cognitive flexibility following stress. Cognitive flexibility was assessed by the ability to update changes in action-outcome relationships following either chronic, acute or a combination of both stressors. We found an increase in CRFR1 in the SNpc and in markers of dopaminergic activity in the left hemisphere of dorsal striatum associated with resilience to acute stress. In contrast, 14 days of repeated restraint plus acute stress both impaired cognitive flexibility and caused a left-to-right hemisphere transition in both CRF1 and dopaminergic activity. This transition was partly driven by opposing effects of CRFR1 on the nigrostriatal projection from the medial and lateral SNpc.