A group from the University of the Negev, Israel, has investigated the role of the regulatory neuropeptides, orexins (ORXs) in stress-related disorders. The team determined four principal findings, which indicates that the orexinergic system plays an active role in the response to stressors and could underpin the pathophysiology of post-traumatic stress disorder (PTSD) in some individuals.
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The findings were as follows:
- Rats exhibiting the PTSD phenotype relative to those whose behaviors were minimally disrupted showed an increased level of the neuropeptide ORX-A and ORX-B.
- When mice received intracerebroventricular microinfusion of ORX-A prior to predator-scent stress (PSS) exposure, the PTSD phenotype was reduced relative to those that received artificial cerebrospinal fluid or almorexant
- Mice treated with almorexant displayed an elevated PTSD phenotype relative to those who were untreated.
- The ORX upregulation was found to activate a feedforward mechanism; levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were upregulated. The team speculated that this formed a regulatory system for the adaptive stress response as this is mediated by BDNF and NPY. Therefore, intervention by ORX-A diminishes the incidence of the PTSD phenotype, encouraging activation of the adaptive phenotype.
ORXs are produced by post-translational proteolytic cleavage in the hypothalamus, generating ORX-A and ORX-B. These stimulate various neuroendocrine and behavioral responses, including the stress response. Therefore, an upregulation of the ORXigenic system is associated with a PTSD phenotype.
The team hypothesized that the ORXergic system is implicated in the neurobiological response to PSS, and intervening with ORX-A reduces the incidence of the PTSD response. Instead, ORX-A promotes adaptive phenotypes relative to ORX antagonists. The adaptive response to stress was hypothesized to be the result of the stimulation of BDNF and NPY secretion.
To test this hypothesis, the level of ORX-A, ORX-B, and c-Fos in the paraventricular nucleus (PVN) of the hypothalamus and lateral hypothalamus (LH) before and at several time points after PSS exposure, were determined. In addition, the team measured the effect on expression levels of ORX-A and ORX-B in the PVN and LH in rats. Finally, the effect of an ORX agonist or antagonist administered 30 mins before stress on the NPY and BDNF levels were measured.
The group measured the ORX pattern and time course in response to PSS and the relationship between the behavioral response pattern 7 days following exposure to PSS and expressions of ORXs. To achieve this, c -Fos expression was measure; this is a marker reflecting the excitability of orexinergic neurons.
Cohen et al. found that ORX-A in the PVN and both ORX-A and ORX-B levels in the LH were upregulated in the PVN immediately after PSS exposure. This is associated with the arousal of auditory, visual, olfactory and other sensory systems. The cumulative effect of this upregulation is the facilitation of the animal’s ability to evaluate and respond in an optimal manner. To test this, the team administered either an agonist or an antagonist of ORX.
Cohen et al. found that downregulation of ORX-A and ORX-B occurred in animals with the extreme behavioral response (EBR) phenotype 8 days after PSS stimulation, but not in the control and minimal behavioral response (MBR) rats. This downregulation in ORX levels was also correlated with an increase in anxiety-associated behavior.
The intracerebroventricular microinfusion of ORX-A intervention disrupted the behavioral stress response, reduced prevalence rates of the PTSD phenotype, shifting the behavior to an adaptive behavioral response. This was accompanied by BDNF and NPY upregulation.
These neuropeptides increase synaptic plasticity and stabilize the connections between synapses, phenotypically expressed as resilience to the stressor. In contrast, the antagonist increased the susceptibility of the mice to anxiety-related behaviors. The cause of this was attributed to disrupted BDNF and NPY expression in the hypothalamus.
The ORXergic system activates the hypothalamo-pituitary-adrenal (HPA) axis, also associated with stress. ORX neurons both trigger and accelerate stress response. This aids in coordinating and maintaining processes involved in adaptive stress-related behavioral responses.
In sum, these findings suggest that the ORXergic system is related to the pathophysiology that is associated with PTSD. The appropriate activation of the ORXergic system in response to stress serves to facilitate a subject’s response to stressors as well as accelerate recovery. The team concludes that “Further studies are needed to establish the connection between orexinergic activity and threat attention.”
Cohen, S. et al. (2020) Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder. Nature. doi: 10.1038/s41398-020-0698-9