Estrous phase during fear extinction modulates fear relapse through a nigrostriatal dopamine pathway

Abstract Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce renewal, but the mechanisms remain unknown. Ovarian hormones modulate dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by a DA D1 receptor agonist into the dorsolateral striatum (DLS). The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse. In cycling female, Long-Evans rats, fear extinction during proestrus or estrus (Pro/Est; high hormones) resulted in less relapse (renewal and spontaneous recovery) compared to males or females in metestrus or diestrus (Met/Di; low hormones). This effect was mimicked by estradiol (E2) administration to ovariectomized rats. Females in Pro/Est had greater fear extinction-induced cFos within SN DA neurons compared to males. Similarly, fast scan cyclic voltammetry revealed that electrically-evoked DA release in the DLS is potentiated by E2 and is greater during Pro/Est compared to Met/Di. An inhibitory intersectional chemogenetic approach targeting the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, chemogenetic stimulation of the SN-DLS pathway during extinction reduced fear renewal in males. These data suggest that levels of ovarian hormones present during fear extinction modulate relapse through a SN-DLS pathway, and that the SN-DLS pathway represents a novel target for the reduction of fear relapse in both sexes.