RESUMO
Severe stress leads to alterations in energy metabolism with sexually dimorphic onset or severity. The locus coeruleus (LC) in the brainstem that mediates fight-or-flight-or-freeze response to stress is sexually dimorphic in morphology, plays a key role in interactions between diet and severe stressors, and has neuronal input to the brown adipose tissue (BAT)-a thermogenic organ important for energy balance. Yet, little is known on how LC coordinates stress-related metabolic adaptations. LC expresses receptors for the neuropeptide PACAP (pituitary adenylate cyclase activating peptide) and PACAP signaling through PAC1 (PACAP receptor) are critical regulators of various types of stressors and energy metabolism. We hypothesized that LC-PAC1 axis is a sex-specific central "gatekeeper" of severe acute stress-driven behavior and energy metabolism. Selective ablation of PAC1 receptors from the LC did not alter stress response in mice of either sex, but enhanced food intake in females and was associated with increased energy expenditure and BAT thermogenesis in male mice. These results show a sexually dimorphic role of the LC-PAC1 in regulating acute stress-related energy metabolism. Thus, by disrupting LC-PAC1 signaling, our studies show a unique and previously unexplored role of LC in adaptive energy metabolism in a sex-dependent manner.
RESUMO
Intense stress precipitates symptoms in disorders such as post-traumatic stress (PTSD) and schizophrenia. Patients with these disorders have dysfunctional sensorimotor gating as indexed by disrupted prepulse inhibition of the startle response (PPI), which refers to decreased startle response when a weak pre-stimulus precedes a startling stimulus. Stress promotes release of norepinephrine (NE) and corticotrophin releasing factor (CRF) within the brain, neurotransmitters that also modulate PPI. We have shown that repeated stress causes sensitization of NE receptors within the basolateral amygdala (BLA) via CRF receptors and promotes long-lasting PPI disruptions and startle abnormalities. The bed nucleus of the stria terminalis (BNST) is another crucial brain region that could be involved in stress-induced alterations in NE and CRF functions to promote PPI changes as this anatomical structure is enriched in CRF and NE receptors that have been shown to regulate each other. We hypothesized that repeated infusions of NE into the BNST would cross-sensitize CRF receptors or vice versa to alter PPI. Separate groups of male Sprague Dawley rats received, CRF (200ng/0.5 µl), NE (20µg/0.5 µl), or vehicle into the BNST, once/day for 3 days and PPI was tested after each infusion. Repeated CRF-or vehicle-treated rats were then challenged with a subthreshold dose of NE (0.3µg/0.5 µl) while repeated NE-treated rats were challenged with CRF (200ng/0.5 µl), and PPI was measured. Surprisingly, initial/repeated CRF or vehicle in the BNST had no effects on PPI. In contrast, initial and repeated NE disrupted PPI. Sub-threshold NE challenge in rats that previously received repeated CRF had no effect on PPI. Interestingly though, intra-BNST challenge dose of CRF significantly disrupted PPI in rats that previously had received repeated NE infusions. Taken together, these results indicate that repeated stress-induced NE release could alter the activity of CRF receptors in the BNST to modulate sensorimotor gating as measured through PPI.
