Role of the lactate receptor HCAR1 as part of neural adaptations to hypoxia in hooded seals (Cystophora cristata)

Abstract

To maintain normal neuronal function, the mammalian brain requires a constant supply of energy. The deep-diving hooded seal (<i>Cystophora cristata</i>) brain exhibits remarkable tolerance to extreme hypoxia, presumably involving a reduction in brain activity to lower energy demand. Thus, some neurons, circuits or even regions in the seal’s brain presumably display a neural protective shutdown response to achieve this. The mechanisms behind this response as yet remain incompletely understood, but there are several factors that may contribute. Lactate, beyond its metabolic role, has been demonstrated to have signaling effects, and the lactate receptor HCAR1 is expressed in the human and rodent brain. Activation of HCAR1 has been observed to slow neuronal firing, inhibit excitatory transmission, and have other beneficial cerebral effects. This thesis investigates the role of the receptor in the hypoxia- tolerant hooded seal. Using qPCR analysis, the HCAR1 was shown to be expressed in several brain regions of hooded seals. Electrophysiological experiments, employing field recordings of excitatory post-synaptic potentials (fEPSP) were conducted to measure synaptic transmission in hippocampal slices from hooded seals. These recordings were performed with and without activating HCAR1 using lactate and non-metabolic agonists. Parallel experiments were conducted in mice to compare possible differences between hooded seals and non- hypoxia-tolerant animals. Both lactate and its agonist 3,5-DHBA demonstrated a suppressing effect on synaptic transmission activity in both hooded seals and mice. The results indicate that during the deep and prolonged dives of hooded seals, when energy is generated anaerobically in the brain, increased lactate levels activate HCAR1, leading to the suppression of synaptic activity. This mechanism potentially contributes to the neural protective shutdown observed in hooded seals.