Contrasting Responses to Stress Elicited Through Activity of Specific Orexin Receptor Subtypes in the Basolateral Amygdala

Jazmine Yaeger, University of South Dakota

Abstract

Stress-induced disorders, like PTSD and depression, arise through physiological and psychological changes in neurocircuitry. Pro- and anti-stress signaling cascades impact several brain structures; however, the basolateral amygdala (BLA) serves as a convergence point where stress-related learning, motivation, and decision-making is interpreted and converted into instructions for behavioral output. While several neural factors have the capacity to influence stress responses, the orexin (Orx) system uniquely regulates BLA microcircuits. Orexins (Orx_A and Orx_B) are neuropeptides produced in the lateral/dorsomedial-perifornical (LH/DMH-PeF) region of the hypothalamus. Two receptor subtypes relay signals to target neurons with the type 2 (Orx₂) receptor exhibiting high binding affinity for both Orx_A and Orx_B, and the type 1 (Orx₁) receptor showing a similar binding affinity for Orx_A as Orx₂, but a lower (10-100x) affinity for Orx_B. Our lab has demonstrated that acute antagonism of intra-BLA Orx₁ can eliminate stress-related behavioral deficits in mice displaying a vulnerable phenotype in a preclinical social stress model. These animals experience rehabilitation of maladaptive responses compared to vehicle-treated mice of the same phenotype, exhibiting increased active avoidance, enhanced motivated behaviors, and diminished fear responses. In contrast, transient stimulation of intra-BLA Orx₂ promotes similar behavioral responses, suggesting Orx₁ and Orx₂ systems in the BLA function in an opposing fashion. Interestingly, genetic knockdown of intra-BLA Orx₁ (Orx₁-shRNA) and Orx₂ (Orx₂-shRNA) prior to stress resulted in reduced maladaptive behavior, including heightened active avoidance, enhanced motivation, and decreased fear freezing, once animals were exposed to social stress. This suggests plasticity within the BLA microcircuits involves Orx system adjustments that likely play a role in directing stress-induced behavioral output. We further investigated cell-specific relationships within the BLA, identifying glutamatergic pyramidal cells as possessing Orx₁ and GABAergic neurons expressing Orx₂. Together the results expose a contrasting, but malleable, influence of the Orx system on stress responses.