Acute stress diminishes M-current contributing to elevated activity of hypothalamic-pituitary-adrenal axis

Abstract

Acute stress stimulates corticotrophin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), which is an essential component of hypothalamic-pituitary-adrenal (HPA) axis. However, the cellular and molecular mechanisms remain unclear. The M-channel is a voltage-dependent K+ channel involved in stabilizing the neuronal membrane potential and regulating neuronal excitability. In this study, we tested our hypothesis that acute stress suppresses expression of Kv7 channels to stimulate PVN-CRH neurons and the HPA axis. Rat PVN-CRH neurons were identified by expressing enhanced green fluorescent protein driven by Crh promoter. Acute restraint stress attenuated the excitatory effect of Kv7 blocker XE-991 on the firing activity of PVN-CRH neurons and blunted the increase in plasma corticosterone (CORT) levels induced by microinjection of XE-991 into the PVN. Furthermore, acute stress significantly decreased the M-currents in PVN-CRH neurons and reduced PVN expression of Kv7.3 subunit in the membrane. In addition, acute stress significantly increased phosphorylated AMP-activated protein kinase (AMPK) levels in the PVN tissue. Intracerebroventricular injection of the AMPK inhibitor dorsomorphin restored acute stress-induced elevation of CORT levels and reduction of membrane Kv7.3 protein level in the PVN. Dorsomorphin treatment increased the M-currents and reduced the firing activity of PVN-CRH neurons in acutely stressed rats. Collectively, these data suggest that acute stress diminishes Kv7 channels to stimulate PVN-CRH neurons and the HPA axis potentially via increased AMPK activity.

Corticotropin-Releasing Hormone Signaling in the Oval Bed Nucleus of the Stria Terminalis Mediates Chronic Stress-Induced Negative Valence Behaviors Associated with Anxiety

“…Our results show that CVMS-induced decreased M-currents in ovBNST are accompanied by a more depolarized cellular resting membrane potential (Fig.2F), indicating enhanced neuronal excitability. Acute restraint suppresses M-currents and increases cellular activity in CRH neurons in the hypothalamic PVN, which may contribute to HPA hyperactivation after acute stress (64). However, whether chronic stress modulates M-currents was previously unknown.…”

Selective targeting of M‐type potassium Kv7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression‐like behaviour

“…The role of VTA dopaminergic neurons in the development of depression raises another question: could the reduced expression or activity of K + channels (including that of K v 7 channels induced, e.g. by stress) (Zhou et al, ) be a causative factor in the altered firing of VTA dopaminergic neurons and the depression‐like behaviours related to such altered firing? The results found thus far suggest that this may be the case.…”

Functional Status of Hypothalamic–Pituitary–Thyroid and Hypothalamic–Pituitary–Adrenal Axes in Hospitalized Schizophrenics in Shanghai

“…Hence, compared to T3, T4 is a more moderate adjustment for overall thyroid function. The main adrenal function, as we know, activates to boost metabolism and to increase excitability of the central and peripheral nervous systems (20). Moreover, type II iodothyronine 5′ deiodinases catalyzes the conversion of T4 to T3 (21), and chronic physiological COR increase may result in a decline in T3 by inhibiting this enzyme in schizophrenia (22).…”