Controlling stress circuitry to enhance post-stroke recovery: targeting HPA Axis activation

Abstract

Ischemic stroke (IS) significantly impacts long-term health and quality of life, due in part to stress-induced hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Elevated corticosterone and hypercortisolism after stroke exacerbate neuronal injury and delay recovery. However, the dynamics of stress-responsive neuronal activity following IS, and how these changes contribute to stroke outcomes, remain understudied. We hypothesize that stress-responsive neuronal activity in corticotropin-releasing factor (CRF)+ neurons of the hypothalamic paraventricular nucleus (PVN) and GAD+ neurons of the bed nucleus of the stria terminalis (BNST) are progressively altered after ischemic stroke. Additionally, we hypothesize that targeted chemogenetic modulation of these neuronal populations during the acute recovery period reduces neuronal damage and improves functional outcomes. Using mouse models of transient middle cerebral artery occlusion (tMCAO), we first investigated temporal patterns of neuronal activity within PVN CRF+ and BNST GAD+ neurons. Fiber photometry was utilized to longitudinally monitor neuronal activity and synaptic input across acute and subacute post-stroke periods. Next, we used chemogenetic modulation (DREADDs) of these neuronal populations during the critical post-stroke recovery window (days 1-7). Functional outcomes assessed included infarct size, hippocampal neuronal integrity, plasma corticosterone levels, and behaviors indicative of anxiety and cognitive deficits. These experiments clarify how stroke alters activity in stress-related neuronal circuits and whether targeted modulation during recovery can improve functional outcomes. These insights could lead to novel strategies for mitigating stroke-induced neuronal damage and enhancing long-term functional recovery.