Chronic Stress Decreases Cerebrovascular Responses During Rat Hindlimb Electrical Stimulation

Abstract

Repeated stress is one of the major risk factors for cerebrovascular disease, including stroke, and vascular dementia. However, the functional alterations in the cerebral hemodynamic response induced by chronic stress have not been clarified. Here, we investigated the in vivo cerebral hemodynamic changes and accompanying cellular and molecular changes in chronically stressed rats. After 3 weeks of restraint stress, the elicitation of stress was verified by behavioral despair in the forced swimming test and by physical indicators of stress. The evoked changes in the cerebral blood volume and pial artery responses following hindpaw electrical stimulation were measured using optical intrinsic signal imaging. We observed that, compared to the control group, animals under chronic restraint stress exhibited a decreased hemodynamic response, with a smaller pial arterial dilation in the somatosensory cortex during hindpaw electrical stimulation. The effect of chronic restraint stress on vasomodulator enzymes, including neuronal nitric oxide synthase (nNOS) and heme oxygenase-2 (HO-2), was assessed in the somatosensory cortex. Chronic restraint stress downregulated nNOS and HO-2 compared to the control group. In addition, we examined the subtypes of cells that can explain the environmental changes due to the decreased vasomodulators. The expression of parvalbumin in GABAergic interneurons and glutamate receptor-1 in neurons were decreased, whereas the microglial activation was increased. Our results suggest that the chronic stress-induced alterations in cerebral vascular function and the modulations of the cellular expression in the neuro-vasomodulatory system may be crucial contributing factors in the development of various vascular-induced conditions in the brain.

Orofacial Neuropathic Pain Leads to a Hyporesponsive Barrel Cortex with Enhanced Structural Synaptic Plasticity

“…Using in vivo intrinsic imaging, we observed that ION ligation induced a decreased haemodynamic response to vibrissae stimulation in the S1BF cortex. This result is consistent with a reduced haemodynamic responsiveness of the primary sensory cortex previously reported in a model of chronic stress and triggered by enhanced iNOS and decreased nNOS and HO-2 expression [67]. However our result was unexpected, since a previous voltage-sensitive dye imaging study had described an increased neuronal response in the primary somatosensory cortex of sciatic nerve-ligated rats, with an enlarged area of activation following electrical stimulation of the hind paw [41,68].…”

Neurovascular Coupling under Chronic Stress Is Modified by Altered GABAergic Interneuron Activity

“…Summarily, chronic restraint stress decreased hemodynamic response to forelimb stimulation. Moreover, these results obtained with a mouse model are consistent with our previous work using a rat model of chronic restraint stress, which also showed reduced hemodynamic response to sensory stimuli (Lee et al, 2015).…”

“…Chronic restraint stress is a well-established protocol that induces anxiety-like behaviors in mice (Buynitsky and Mostofsky, 2009;Lee et al, 2015Lee et al, , 2018. The EPM, which contains both closed and open arms, is used to test the level of anxiety-like behaviors in animal subjects: the longer the time spent in the closed arms, the higher the level of anxiety-like behavior.…”

“…In one instance, the malfunction of inwardly rectifying potassium (K ir ) channels in parenchymal arteriolar myocytes was observed in chronically stressed mice (Longden et al, 2014). Moreover, our previous work with chronically stressed rats revealed reduced cerebrovascular response following sensory stimulation (Lee et al, 2015).…”

“…Previously, we reported that chronically stressed rats exhibit a decrease in cerebral blood volume (CBV) response to a sensory stimulus (Lee et al, 2015). From these observations, we hypothesized that there would be a neuronal activity-originated source that would induce such changes on NVC and modulate vascular tone and function.…”