Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition

Elena I Zakharova; Zinaida I Storozheva; Andrey T Proshin; Mikhail Yu Monakov; Alexander M Dudchenko

doi:10.3390/brainsci11010012

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition

Brain Sci. 2020 Dec 24;11(1):12. doi: 10.3390/brainsci11010012.

Authors

Elena I Zakharova¹, Zinaida I Storozheva², Andrey T Proshin³, Mikhail Yu Monakov¹, Alexander M Dudchenko¹

Affiliations

¹ Laboratory of General Pathology of Cardiorespiratory System, Institute of General Pathology and Pathophysiology, Baltiyskaya, 8, 125315 Moscow, Russia.
² Laboratory of Clinical Neurophysiology, Serbsky' National Medical Research Center for Psychiatry and Narcology, Kropotkinsky per., 23, 111395 Moscow, Russia.
³ Laboratory of Functional Neurochemistry, P.K. Anokhin Institute of Normal Physiology, Baltiyskaya, 8, 125315 Moscow, Russia.

Abstract

(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of 'light' and 'heavy' synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the 'light' synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed.

Keywords: PNU-282987; adaptation to severe hypoxia; brain structures; cholinergic forebrain projections; dimethyl sulfoxide; synaptic membrane-bound choline acetyltransferase.