Ketamine Reverses Depressive-Like Behavior Induced by Optogenetic Stimulation of Glutamatergic Neurons in the Dorsal Hippocampus

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Abstract

The hippocampus is one of the brain structures whose functions and morphology are impaired in depression. The fast-acting antidepressant ketamine reverses these impairments, but the mechanisms of its action are still not fully understood. Optogenetic stimulation of glutamatergic neurons in the CA1 region of the dorsal hippocampus of rats with the preliminary introduction of vectors expressing photosensitive channelrhodopsin led to the manifestation of a sign of depressive-like behavior – an increase in the time of immobility in the tail suspension test, compared to control animals. Immunohistochemical analysis of the expression of the early response protein c-Fos in the CA1 region of the hippocampus confirmed the activation of pyramidal neurons under the influence of light, revealing their involvement in the development of depressive-like behavior. Administration of a subanesthetic dose of ketamine prevented the manifestation of depressive-like behavior trait induced by optogenetic activation of glutamatergic neurons in the CA1 region of the dorsal hippocampus and abolished the increase in c-fos mRNA levels induced by optical stimulation. Thus, we demonstrated for the first time the ability of ketamine to reverse depressive-like behavior trait induced by optogenetic stimulation of the activity of dorsal hippocampal glutamatergic neurons. Overall, the results indicate the important role of dorsal hippocampal glutamatergic neurons in the regulation of psychoemotional behavioral responses and their sensitivity to ketamine administration.

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About the authors

U. S. Drozd

Institute of Cytology and Genetics, Siberian Branch of RAS

Author for correspondence.
Email: drozd@bionet.nsc.ru
Russian Federation, Novosibirsk

E. V. Sukhareva

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: drozd@bionet.nsc.ru
Russian Federation, Novosibirsk

V. V. Bulygina

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: drozd@bionet.nsc.ru
Russian Federation, Novosibirsk

T. S. Kalinina

Institute of Cytology and Genetics, Siberian Branch of RAS; Novosibirsk State University

Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

N. N. Dygalo

Institute of Cytology and Genetics, Siberian Branch of RAS; Novosibirsk State University

Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

D. A. Lanshakov

Institute of Cytology and Genetics, Siberian Branch of RAS; Novosibirsk State University

Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

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2. Fig. 1. Experimental schemes: a – study of the effect of optogenetic activation of glutamatergic neurons on the manifestation of depressive-like behavior; b – study of the effect of ketamine on the effects of optogenetic stimulation of the hippocampus.

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3. Fig. 2. a – Average immobility time during 3 min of optostimulation and without it in the tail suspension test; * – p < 0.05 compared to the ChR2(H134R)-EYFP groups without optostimulation and EGFP groups with optostimulation; b – average intensity of the red fluorescent signal corresponding to c-Fos immunohistochemical staining in the CA1 region of the dorsal hippocampus after optostimulation of glutamatergic neurons of the dorsal hippocampus; * – p < 0.05 compared to the EGFP group; c – panoramic micrograph illustrating vector expression in the hippocampus; g – representative micrographs of immunohistochemical staining of c-Fos and expression of fluorescent reporter proteins in the CA1 field of the dorsal hippocampus after optostimulation of glutamatergic neurons of the dorsal hippocampus in the tail suspension test; scale bar – 100 µm.

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4. Fig. 3. a – Total immobility time during 3 min of optostimulation and without it in the tail suspension test 1 h after ketamine administration; * – p < 0.05 compared to all groups with optostimulation: EGFP – Saline, EGFP – Ketamine, ChR2(H134R)-EYFP – Ketamine; b – c-fos mRNA level in the hippocampus after ketamine administration and optostimulation of the dorsal hippocampus; ** – p < 0.01 compared to the EGFP – Saline and ChR2(H134R)-EYFP – Ketamine group; c – number of c-Fos-expressing cells in the CA1 region of the hippocampus after ketamine administration and optostimulation of the dorsal hippocampus; * – p < 0.05 compared to the EGFP – Saline groups. p-r and ChR2(H134R)-EYFP – Sat. solution; g – representative micrographs of immunohistochemical staining of c-Fos and fluorescent vector EGFP or СHR2(H134R)-EYFP in the CA1 region of the dorsal hippocampus after ketamine administration and optostimulation; scale – 200 µm.

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