Hypoxic preconditioning in rats with low and high prepulse inhibition of acoustic startle is implemented through topographically different sensory inputs. Working hypothesis

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Abstract

The neurotransmitter and network mechanisms of hypoxic preconditioning are practically unknown. Previously, in rats, we identified the key role of the hippocampus and its cholinergic projections in the preconditioning mechanism of single-exposure of moderate hypobaric hypoxia (HBH) based on the association between the efficiency of HBH and the magnitude of Prepulse Inhibition of Acoustic Startle (PPI). This study presents the first data on PPI-dependent neuronal networks of hypoxic preconditioning and their cholinergic components. The activity of synaptic choline acetyltransferase (ChAT), an indicator of cholinergic function, was used for a correlation analysis of ChAT response to HBH in the hippocampus, cerebral cortex, and caudal brainstem in animals with different levels of PPI. In rats with PPI < 40%, ChAT activity was correlated in the hippocampus, cortex and caudal brainstem, while in rats with PPI > 40% in the hippocampus and cortex. It is hypothesized that HBH is realized through topographically different sensory inputs, namely through respiratory neurons of the brainstem in rats with low PPI and respiratory neurons of the olfactory epithelium in rats with high PPI.

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About the authors

E. I. Zakharova

Institute of General Pathology and Pathophysiology

Author for correspondence.
Email: zakharova-ei@yandex.ru
Russian Federation, Moscow

Z. I. Storozheva

Federal Research Center for Original and Promising Biomedical and Pharmaceutical Technologies

Email: zakharova-ei@yandex.ru
Russian Federation, Moscow

A. T. Proshin

Federal Research Center for Original and Promising Biomedical and Pharmaceutical Technologies

Email: zakharova-ei@yandex.ru
Russian Federation, Moscow

M. Y. Monakov

Institute of General Pathology and Pathophysiology

Email: zakharova-ei@yandex.ru
Russian Federation, Moscow

A. M. Dudchenko

Institute of General Pathology and Pathophysiology

Email: zakharova-ei@yandex.ru
Russian Federation, Moscow

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2. Fig. 1. Individual values of the synaptic ChAT activity in the control and HBH subgroups of rats with PPI values of <40% and >40%. Designations. The ChAT activity is presented in nmol ACh/1 min in 1 g wet weight of the corresponding brain structure. The software package STATISTICA 8.0 (StatSoft., USA) was used to visualize the data. I, hippocampus; II, cerebral cortex; III, caudal brainstem. C, the fraction of light synaptosomes. D, the fraction of heavy synaptosomes. Synaptic membranes, the subfraction of synaptic membranes. Synaptoplasm, the subfraction of the synaptoplasm. Control, the control subgroups of rats. HBH, the subgroups of rats after one-time moderate hypobaric hypoxia (85 mm Hg, equivalent to 11% O2, 60 min). N = 3 for each subgroup. *, the significant differences in ChAT activity values between the paired subfractions of rats with PPI < 40% and PPI > 40%, p < 0.05. #, the significant changes in the ChAT activity values after HBH were compared with the corresponding control subgroup, p < 0.05. Fisher’s exact test (FET criterion).

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3. Fig. 2. Individual values of the protein content in the control and HBH subgroups of rats with PPI values of <40% and >40%. Designations. The protein content is presented in mg in 1 g wet weight of the corresponding brain structure.The remaining designations are the same as those in Figure 1.

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4. Fig. 3. Conjugacy of HBH-initiated changes in the synaptic ChAT activity and Pr content in the hippocampus, cerebral cortex, and caudal brainstem in rats with PPI < 40%. Designations. The ChAT activity and Pr content values are represented as a percentage change (mean ± SEM%) relative to the values in the corresponding control subgroup, which were taken as 100%. Cortex, the cerebral cortex. Stem, the caudal brainstem. C and D, the fractions of light and heavy synaptosomes, respectively, as in Figure 1. SM, the synaptic membrane subfraction. Sp, the synaptoplasm subfraction. The SM and Sp indicators are shown in pairs according to their belonging to a synaptosome fraction. ChAT, top row, the ChAT activity. PROTEIN, bottom row, the Pr content. Accordingly, in each brain structure, changes in mChAT/mPr values are presented in SM, and changes in sChAT/ sPr values are presented in Sp. For better perception, the indicators of different brain structures (Cortex, Hippocampus, Stem) are presented in different colors (different shades of gray). In the Hippocampus, C, the SM column is highlighted in red in the ‘ChAT’ row, as it is a key indicator for the mechanism of hypoxic preconditioning. *, significant differences from the corresponding control subgroups, p < 0.05, n = 3, Fisher’s exact test (FET-criterion), which for ChAT is similar to the ‘#’ marker in Figure 1. Ovals represent a significant correlation between changes in ChAT activity and Pr content in a subfraction (an intrafractional association), Pearson’s test (r-criterion). Horizontal brackets indicate a significant correlation of indicator changes (ChAT or Pr) between different subfractions (an interfractional and interstructural coherence) according to Pearson’s test (r-criterion). +r/ -r, positive/negative correlation, respectively; r*/ r**/ r***, p < 0.05/ p < 0.02/ p < 0.01, respectively; n = 6 for each sample.

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5. Fig. 4. Conjugacy of HBH-initiated changes in the synaptic ChAT activity and Pr content in the hippocampus, cerebral cortex, and caudal brainstem in rats with PPI > 40%. The designations are the same as those in Figure 2.

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6. Fig. 5. Scheme of the sources of cholinergic influences in the cerebral cortex and hippocampus, as well as components of neural networks of hypoxic preconditioning. The scheme is based on the Rat Brain Atlas by Paxinos and Watson (Paxinos, Watson, 1998) and later data on the stereotaxic coordinates of the prefrontal cortex (Sampath et al., 2017; Wirt, Hyman, 2017). Designations. B, nucleus basalis magnocellularis. CA1, CA2, CA3, fields of the hippocampus. Caudal Brainstem, medulla oblongata + pons Varolii. Ent, entorhinal cortex. LDTg, laterodorsal tegmental nucleus. LC, locus coeruleus. MS, medial septal nucleus. mPFC, medial prefrontal cortex. OB, olfactory bulb. Pir, piriform cortex. PPTg, pedunculopontine tegmental nucleus. VDB, nucleus of the vertical limb of the diagonal band. Red ovals with short processes in the cerebral cortex and hippocampus, cholinergic interneurons (predominantly bipolar neurons). Red lines, cholinergic projections from the nuclei of the forebrain and tegmental nuclei of the midbrain. Black lines, projections of other neuromediation (most often glutamatergic). The arrows indicate a direction of projections to a target structure. Where known, a line thickness reflects the relative power of single-color projections. The scheme shows only the brain structures and connecting fibers that are mentioned in the text.

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