MicroRNAs as biomarkers of resilience or vulnerability to stress.

Identifying novel biomarkers of resilience or vulnerability to stress could provide valuable information for the prevention and treatment of stress-related psychiatric disorders. To investigate the utility of blood microRNAs as biomarkers of resilience or vulnerability to stress, microRNAs were assessed before and after 7days of chronic social defeat in rats. Additionally, microRNA profiles of two important stress-regulatory brain regions, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA), were assessed. Rats that displayed vulnerability to subsequent chronic stress exhibited reductions in circulating miR-24-2-5p, miR-27a-3p, miR-30e-5p, miR-3590-3p, miR-362-3p, and miR-532-5p levels. In contrast, rats that became resilient to stress displayed reduced levels of miR-139-5p, miR-28-3p, miR-326-3p, and miR-99b-5p compared to controls. In the mPFC, miR-126a-3p and miR-708-5p levels were higher in vulnerability compared to resilient rats. In the BLA, 77 microRNAs were significantly altered by stress but none were significantly different between resilient and vulnerable animals. These results provide proof-of-principle that assessment of circulating microRNAs is useful in identifying individuals who are vulnerable to the effects of future stress or individuals who have become resilient to the effects of stress. Furthermore, these data suggest that microRNAs in the mPFC but not in the BLA are regulators of resilience/vulnerability to stress.

Optogenetic examination identifies a context-specific role for orexins/hypocretins in anxiety-related behavior.

Maladaptation to stress is associated with psychopathology. However, our understanding of the underlying neural circuitry involved in adaptations to stress is limited. Previous work from our lab indicated the paraventricular hypothalamic neuropeptides orexins/hypocretins regulate behavioral and neuroendocrine responses to stress. To further elucidate the role of orexins in adaptation to stress, we employed optogenetic techniques to specifically examine the effects of orexin cell activation on behavior in the social interaction test and in the home cage as well as orexin receptor 1 internalization and ERK phosphorylation in brain regions receiving orexin inputs. In the social interaction test, optogenetic stimulation of orexin neurons decreased time spent in the interaction zone while increasing the frequency of entries into the interaction zone. In addition, optogenetic stimulation of orexin neurons increased the total distance traveled in the social interaction arena but had no effect on their home cage behavior. Together, these results suggest that orexin release increases anxiety in the social interaction test while increasing the salience of novel but not familiar environmental stimuli. Consistent with activation of orexin neurons, optogenetic stimulation increased orexin receptor1 internalization and ERK phosphorylation in the paraventricular thalamus (PVT) and locus coeruleus (LC), two regions heavily innervated by orexin neurons. Together these results show for the first time that elevation of orexin activity, possibly in the PVT and LC, is associated with increased anxiety, activity, and arousal in a context-specific manner.

Putative genes mediating the effects of orexins in the posterior paraventricular thalamus on neuroendocrine and behavioral adaptations to repeated stress.

Exposure to repeated stress is often associated with psychopathology. However, our understanding of the underlying neural circuitry that regulates responses to repeated stress is limited. The posterior paraventricular thalamus (pPVT) is a brain region responsible for transmission of multimodal sensory information to limbic structures that regulate responses to both acute and repeated stress. Orexin-containing cells originating in the hypothalamus heavily innervate the pPVT. Our previous work has shown that activation of orexin1 receptors in the pPVT during repeated swim stress is important for facilitation of the hypothalamic-pituitary-adrenal (HPA) axis response to subsequent novel restraint. However, the genes responsible for these orexin-mediated adaptations to repeated stress are not known. Using a custom PCR array we examined the expression of 186 specific mRNAs in the pPVT of animals exposed to repeated swim stress (4 days of 15min swim/day) with or without direct pPVT microinfusion of the orexin1 receptor antagonist SB334867 prior to each daily swim stress. Tissue was collected the next morning under basal non stressed conditions. Repeated stress and/or orexin receptor blockade significantly altered expression of only 9 specific genes including growth factors (Vegfa, Bax and Mt3), G-protein coupled receptors (Adora2a, Grm2 and Crhr1), immune-related genes (Ptgs2 and Cx3cr1) and an epigenetic-related gene (Hdac5). These genes represent potential targets for further characterization of orexin-mediated adaptations to repeated stress in the pPVT.