L‐lactate induces neurogenesis in the mouse ventricular‐subventricular zone via the lactate receptor HCA₁

Abstract

Aim Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular‐subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular‐subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1‐dependent effects on neurogenesis in the two main neurogenic niches. Methods Wild‐type and HCA1 knock‐out mice received high intensity interval exercise, subcutaneous injections of L‐lactate, or saline injections, five days per week for seven weeks. Well‐established markers for proliferating cells (Ki‐67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular‐subventricular zone. Results We demonstrated that neurogenesis in the ventricular‐subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild‐type, but not in HCA1 knock‐out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. Conclusion Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular‐subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age‐related cognitive decline.

Muscle-to-Brain Signaling Via Myokines and Myometabolites

“…HCAR1 activation led to increased cerebral vascular endothelial growth factor A (VEGFA) expression, a mediator of angiogenesis that is known to improve neurogenesis and cognition [90,117]. The authors found that, similar to high-intensity exercise, subcutaneous injection of L-lactate (to mimic exercise-induced raise in lactate serum levels) leads to higher brain VEGFA levels [116], capillary density [116] and adult neurogenesis [118,119]…”

Lactate as Potential Mediators for Exercise-Induced Positive Effects on Neuroplasticity and Cerebrovascular Plasticity

“…Furthermore, a follow-up study by Morland and colleagues ( Lambertus et al, 2020 ) demonstrated that exercise had a strong HCAR1-dependent effect on adult neurogenesis in the subventricular zone (SVZ). Using the same HIIT paradigm or injection of L-lactate could activate HCAR1 and promote neurogenesis in SVZ.…”

“…There is also controversy about the way lactate affects changes in the brain. Some research results indicate that lactate can activate the PGC1-α/FNDC5/BDNF pathway through SIRT1 or act through NMDA, while some results show it is HCAR1 ( Yang et al, 2014 ; Morland et al, 2017 ; El Hayek et al, 2019 ; Lambertus et al, 2020 ). Even studies reported that lactate promotes choroidal neovascularization by upregulating VEGF expression in macrophages, regardless of the activity of lactate transporter MCT ( Song et al, 2018 ).…”

“…First, we investigate the “lactate paradox.” It is well known that blood lactate levels increase significantly only when exercise intensity exceeds the lactate threshold. Morland et al show that lactate produced by high-intensity exercise mediates the beneficial effects of exercise on the brain ( Morland et al, 2017 ; Lambertus et al, 2020 ). Paradoxically, moderate- and low-intensity exercise that does not increase blood lactate has many beneficial effects on the brain in many studies, including improvements in BDNF levels, nerve regeneration, vascular regeneration, and cognitive function.…”

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia

“…A role of HCAR1 in cell proliferation was previously shown in cancer and osteoblast cell lines 12,13 . A very recent paper also showed HCAR1 dependent neurogenesis after high intensity physical exercise 43 . Similar to our study, this paper found neurogenesis to be HCAR1 dependent in the subventricular zone, but not in the hippocampus.…”