Stress adaptation in rats associate with reduced expression of cerebrovascular K_v7.4 channels and biphasic neurovascular responses

Abstract

Neurovascular coupling ensures rapid and precise delivery of O₂ and nutrients to active brain regions. Chronic stress is known to disturb neurovascular signaling with grave effects on brain integrity. We hypothesized that stress-induced neurovascular disturbances depend on stress susceptibility. Wistar male rats were exposed to 8 weeks of chronic mild stress. Stressed rats with anhedonia-like behavior and with preserved hedonic state were identified from voluntary sucrose consumption. In brain slices from nonstressed, anhedonic, and hedonic rats, neurons and astrocytes showed similar intracellular Ca²⁺ responses to neuronal excitation. Parenchymal arterioles in brain slices from nonstressed, anhedonic, and hedonic rats showed vasodilation in response to neuronal excitation. This vasodilation was dependent on inward rectifying K⁺ channel (K_ir2) activation. In hedonic rats, this vasodilation was transient and followed by vasoconstriction insensitive to K_ir2 channel inhibition with 100 µM BaCl₂. Isolated arteries from hedonic rats showed increased contractility. Elevation of bath K⁺ relaxed isolated middle cerebral arteries in a concentration-dependent and K_ir2-dependent manner. The vasorelaxation to 20–24 mM K⁺ was reduced in arteries from hedonic rats. The expression of voltage-gated K⁺ channels, K_v7.4, was reduced in the cerebral arteries from hedonic rats, whereas the expression of arterial inward-rectifying K⁺ channels, K_ir2.1 was similar to that of nonstressed and anhedonic rats. We propose that preserved hedonic state is associated with increased arterial contractility caused by reduced hyperpolarizing contribution of K_v7.4 channels leading to biphasic cerebrovascular responses to neuronal excitation. These findings reveal a novel potential coping mechanism associated with altered neurovascular signaling.

Keywords:

• Chronic stress
• neurovascular coupling
• major depression
• hedonic state
• K⁺ channels
• cerebral blood flow

Acknowledgments

We thank Jane Holbaek Roenn for technical assistance with Western blot analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Independent Research Fund Denmark – Medical Sciences [Grant nos 8020-00084B and 9149-00003B], the Novo Nordisk Foundation [Grant no. NNF19OC0058460], and the Lundbeck Foundation [Grant no. R344-2020-952].

Notes on contributors

Christian Staehr

Christian Staehr, M.D. recently graduated as a medical doctor from Aarhus University (2021). In his PhD, he studies brain blood flow and neurovascular coupling in health and disease. His research suggests that restoration of balanced neurovascular coupling may be a novel treatment target in numerous neurological disorders.

Elena V. Bouzinova

Elena Bouzinova has PhD in neuroscience from Lomonosov Moscow State University (1998) and PhD in membrane transport from Aarhus University (2007). She is studying the devastating effects of chronic stress and neuronal dysfunction behind it in various animal models.

Ove Wiborg

Ove Wiborg, PhD from Aarhus University (1989). He is an Associate Professor at Aalborg University and has his research interest in neurobiology of Major Depression, Memory Loss, Alzheimer's Disease, and Dementia.

Vladimir V. Matchkov

Vladimir Matchkov has his PhD from Lomonosov Moscow State University (1998) and DMSc from Aarhus University (2010). Since 2010, he is an Associate Professor at Aarhus University, Health. His research addresses the comorbidity of neuronal disorders and disturbances in cerebral perfusion, with a focus of dysbalanced neurovascular coupling signaling.