Early life adversity accelerates epileptogenesis and enhances depression-like behaviors in rats

Rayiky Rupasinghe; Gabi Dezsi; Ezgi Ozturk; Simone Carron; Matthew R Hudson; Pablo M Casillas-Espinosa; Nigel C Jones

doi:10.1016/j.expneurol.2022.114088

Early life adversity accelerates epileptogenesis and enhances depression-like behaviors in rats

Exp Neurol. 2022 Aug:354:114088. doi: 10.1016/j.expneurol.2022.114088. Epub 2022 Apr 21.

Authors

Rayiky Rupasinghe¹, Gabi Dezsi², Ezgi Ozturk², Simone Carron¹, Matthew R Hudson², Pablo M Casillas-Espinosa³, Nigel C Jones⁴

Affiliations

¹ Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria, 3050, Australia.
² Department of Neuroscience, Central Clinical School, Monash University and Department of Neurology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia.
³ Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria, 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University and Department of Neurology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia.
⁴ Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria, 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University and Department of Neurology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia. Electronic address: nigel.jones@monash.edu.

PMID: 35461829
DOI: 10.1016/j.expneurol.2022.114088

Abstract

Objective: Early life stressors are well-established risk factors for psychiatric disorders, and evidence also suggests that these promote vulnerability to epilepsy. Given the high prevalence of psychiatric disorders in epilepsy, early life stress may represent a common driver for these comorbidities. We used animal modelling to investigate the effects of early life stress on epileptogenesis and depressive behaviors, also exploring HPA axis programming as a potential associative mechanism.

Methods: From post-natal day 2-9, Wistar rat dams (n = 3) and their offspring were exposed to the Limited Bedding and Nesting (LBN) model of early life adversity. Control dams (n = 3) were undisturbed. Maternal care was video-recorded, and behavior scored. As adults, rats (n = 7/group) underwent kainic acid-induced status epilepticus (SE), to trigger epilepsy development. Spontaneous seizures, depression-like behavior and HPA axis function were quantified.

Results: LBN significantly altered aspects of maternal care, including markedly reducing the consistency of care (p < 0.05), compared to control conditions. Following SE, LBN rats exhibited significantly accelerated epileptogenesis (p = 0.01) and greater disease severity (p = 0.001), compared to control rats. Anhedonia and behavioral despair were observed in epileptic rats exposed to LBN. LBN rats showed significantly dampened HPA axis responsivity, but epileptic rats showed greater corticosterone responses to CRH administration (all p < 0.05).

Significance: Early life adversity promotes a vulnerability to experimental epileptogenesis. These two 'hits' (early life stress and epilepsy) interact to create a depressive-like phenotype, but effects on HPA axis are complex and contrasting. This has implications for the mechanisms underpinning the increased prevalence of psychiatric disorders observed in people with epilepsy.

Keywords: DEX-CRH; Depression behavior; Early life stress; Epileptogenesis; HPA axis; Limited bedding and nesting.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adverse Childhood Experiences*
Animals
Corticosterone
Depression / etiology
Disease Models, Animal
Epilepsy*
Humans
Hypothalamo-Hypophyseal System
Pituitary-Adrenal System
Rats
Rats, Wistar
Stress, Psychological / complications

Substances

Corticosterone