Lateral Septal Circuits Govern Schizophrenic-Like Effects of Ketamine on Social Behavior

Ruixiang Wang; Zeru Peterson; Nagalakshmi Balasubramanian; Kanza M. Khan; Michael S. Chimenti; Daniel Thedens; Thomas Nickl-Jockschat; Catherine A. Marcinkiewcz

doi:10.1101/2023.08.08.552372

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Lateral Septal Circuits Govern Schizophrenic-Like Effects of Ketamine on Social Behavior

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Lateral Septal Circuits Govern Schizophrenic-Like Effects of Ketamine on Social Behavior

Ruixiang Wang, Zeru Peterson, Nagalakshmi Balasubramanian, Kanza M. Khan, Michael S. Chimenti, Daniel Thedens, Thomas Nickl-Jockschat and Catherine A. Marcinkiewcz

bioRxiv

Cold Spring Harbor Laboratory

08/08/2023

DOI: 10.1101/2023.08.08.552372

PMCID: PMC10441349

PMID: 37609170

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https://doi.org/10.1101/2023.08.08.552372View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine exhibit profound social and sensorimotor deficits as previously reported. Using three-dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naïve mice. We then examined the translatome of LS engram neurons and found that ketamine treatment dysregulated genes implicated in neuronal excitability and apoptosis, which may contribute to LS hypoactivation. A number of ketamine-induced differentially expressed genes (DEGs), including those involved in mitochondrial function and neuroinflammatory pathways, were shared with human schizophrenia and mouse models of neurodevelopmental disorders. Chemogenetic activation of LS engram neurons induced downstream activity in the ventral part of the basolateral amygdala, subparafascicular nucleus of the thalamus, intercalated amygdalar nucleus, olfactory areas, and dentate gyrus, and may also reduce connectivity of the LS with the piriform cortex and caudate-putamen. In sum, schizophrenia-like social deficits may emerge via changes in the intrinsic excitability of a discrete subpopulation of LS neurons that serve as a central hub to coordinate social behavior via downstream projections to reward, fear extinction, motor and sensory processing regions of the brain.

Details

Title: Subtitle: Lateral Septal Circuits Govern Schizophrenic-Like Effects of Ketamine on Social Behavior
Creators: Ruixiang Wang - University of Iowa
Zeru Peterson - University of Iowa
Nagalakshmi Balasubramanian - University of Iowa
Kanza M. Khan - Daemen College
Michael S. Chimenti - University of Iowa
Daniel Thedens - University of Iowa
Thomas Nickl-Jockschat - University of Iowa
Catherine A. Marcinkiewcz - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
Publisher: Cold Spring Harbor Laboratory
DOI: 10.1101/2023.08.08.552372
PMID: 37609170
PMCID: PMC10441349
Language: English
Date posted: 08/08/2023
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Psychiatry; Neuroscience and Pharmacology; Electrical and Computer Engineering; Iowa Institute of Human Genetics; Radiology; Iowa Neuroscience Institute
Record Identifier: 9984456077102771

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