Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche

Abstract

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell‐extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ‐olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4‐fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus‐related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.

Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain

“…These data imply that NE might be a putative humoral factor involved in the physiological decrease of neural stem/progenitor cell proliferation during prenatal development. Consistently, we recently detected a similar role of NE in the adult brain with inhibitory effects on the proliferative activity of adult neural stem cells in the consecutive neurogenic regions (Weselek et al, 2020 ). However, the physiological significance of our present findings needs to be determined by functional studies, for example by pharmacologic or genetic manipulation of DA and/or NE levels during the various development stages of the brain.…”

“…periventricular neurogenic regions with their NE levels. These results are backed by our recent findings of direct negative effects of NE on the proliferation of adult periventricular neural stem/progenitor cells (Weselek et al, 2020). Our data provide the first framework to further study the potential functional importance of catecholamines-particularly NE-in regulating neural stem and progenitor cell proliferation and differentiation during mammalian brain development.…”

“…The lethal phenotype without NE supplementation during crucial developmental stages however makes it impossible to accurately study embryonic/fetal brain development under NE depletion in this model. Nevertheless, these data in the fetal brain are in strong agreement with the inhibitory effects of NE on neural stem/progenitor cell proliferation within the periventricular regions of the adult mouse brain most likely also mediated through direct stimulation of β-adrenoceptors (Weselek et al, 2020).…”

“…neural stem cells in the consecutive neurogenic regions (Weselek et al, 2020). However, the physiological significance of our present findings needs to be determined by functional studies, for example by pharmacologic or genetic manipulation of DA and/or NE levels during the various development stages of the brain.…”

“…The lethal phenotype without indirect NE supplementation during crucial developmental stages makes it impossible to accurately study embryonic/fetal brain development under NE depletion in this model. These data together with the recently described role of norepinephrine as a negative regulator of neural stem cell proliferation in the adult brain (Weselek et al, 2020) raised the question of whether catecholamines show analogous trophic actions during embryonic brain development beyond cortical development. We therefore comparatively determined the catecholaminergic innervation and the neural stem/progenitor cell proliferation capacity of the ventricular zone/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from E14.5 until postnatal day zero (P0).…”