Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA 1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the bloodbrain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucoseand glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells. V C 2015 Wiley Periodicals, Inc.Key words: lactate; volume transmitter; cAMP; hippocampus L-lactate, pyruvate, and the ketone bodies bhydroxybutyrate and acetoacetate are monocarboxylates that are carried across different cell membranes by monocarboxylate transporters (MCTs; Poole and Halestrap, 1994;Bergersen et al., 1999Bergersen et al., , 2001Pierre et al., 2000; for review see Bergersen, 2007Bergersen, , 2015Halestrap, 2013). Llactate is the most abundant MCT substrate in the brain, and its cerebral concentration varies based on, for instance, metabolic rate, oxygen availability, neuronal firing, and serum lactate levels. The MCTs mediate facilitated cotransport of monocarboxylate anion and proton, meaning that they serve to equilibrate substrate concentrations across cell membranes, with the combined concentration gradients of monocarboxylate and proton as the driving force. Hence, L-lactate and other MCT substrates migrate from sites of production toward sites of consumption, such as between different cells within an organ or among different organs via the blood stream. The equilibrating diffusion of lactate via MCTs between cells and the extracellular space provide a basis for lactate acting as a "volume transmitter" because it allows lactate

No 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.