The stress state-dependent noradrenergic modulation of corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus through a retrograde neuronal-astrocytic circuit
Description
Stress is a major determinant of quality of life and chronic stress plays an important contributing role in the occurrence of psychiatric and physiological pathologies. Ascending brainstem noradrenergic afferents provide a critical excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis in response to stress by activating corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). The stimulatory role of noradrenergic synapses on CRH neurons in the regulation of the HPA axis has long been known, but the cellular mechanisms have been perplexing. We demonstrate a retrograde inter-neuronal communication stimulated by norepinephrine that utilizes a trans-astroglial signaling mechanism to activate upstream neurons and recurrent synaptic inputs. We found that NE activates postsynaptic α1-adrenoceptors in PVN CRH neurons, which triggers a calcium response in astrocytes via the dendritic release of vasopressin. Activated astrocytes stimulate upstream glutamate neurons via ATP release and P2X receptor activation, resulting in the recurrent excitation of the CRH neurons. The NE excitation of CRH neurons is strengthened by simultaneous presynaptic α2-adrenoceptor-mediated suppression of GABA release but is restrained at higher NE concentrations by activation of upstream GABAergic neurons via the same postsynaptic α1-adrenoceptor-mediated retrograde neuronal-glial signaling mechanism. Thus, the NE stimulation of CRH neurons in the PVN is mediated by a novel retrograde signaling mechanism that enlists a trans-neuronal-astroglial circuit to activate upstream glutamate and GABA neurons. This mechanism is stress-sensitive. Acute stress desensitizes this α1-receptor mediated circuit via glucocorticoid receptor-dependent signaling. The desensitization of the excitatory circuit, through which NE exerts its major stimulatory drive to CRH neurons, indicates a cellular mechanism or a target site of negative feedback. Chronic stress desensitized the CRH neurons to both α1 and α2-adrenoceptor activation. Thus, the noradrenergic regulation of CRH neurons was lost entirely following chronic stress, rendering the CRH neurons completely insensitive to this major regulatory input. Our research revealed the cellular mechanisms of the NE regulation of CRH neurons under control, acute stress and chronic stress conditions. It fills an important gap in knowledge concerning the noradrenergic excitatory drive to the CRH neurons and the stress-induced glucocorticoid feedback control of the HPA axis.