title: Lipopolysaccharide administration induces sex-dependent behavioural and serotonergic neurochemical signatures in mice.
abstract: Challenging the innate immune machinery with the pro-inflammatory agent lipopolysaccharide (LPS) results in the development of a sickness syndrome characterized by numerous depressive-like behavioural and physiological manifestations, most of which overlap with the clinical symptoms of major depression. Although women are known to mount stronger pro-inflammatory responses during infections and being at higher risk to develop depressive disorders compared to men, the vast majority of experimental studies investigating the neurobiological effects of LPS administration have been conducted in males. Herein, we investigated the behavioural effects of LPS administration (0.83mg/kg) in male and female C57BL/6J mice subjected to tests screening for alterations in locomotor activity (open field test), anorexia (food consumption), anhedonia (sucrose preference test), behavioural despair (forced swim test) and grooming behaviour (splash-test). We further mapped the brain's serotonergic and dopaminergic activity in five limbic brain regions implicated in the pathophysiology of major depression (i.e., prefrontal cortex, hippocampus, striatum, amygdala, and hypothalamus) at two critical time-points post-LPS treatment; at 6h when depression of behavioural activity is maximal, and at 24h when depressive-like symptoms develop independently of obvious locomotor performance impairments associated with acute LPS administration. Our findings indicate that the two sexes present with differential behavioural sensitivity to this immune stressor, as impairment of grooming behaviour in the splash test was more persistent in female mice, and anorexia lasted longer in their male counterparts. Notably, LPS affects the brain's serotonergic neurochemistry in a sex-specific manner, as it induced sustained serotonergic hyperactivity in females at 24h post-LPS administration in all the brain regions examined. Moreover, the kinetics of dopaminergic activation appeared to be sex-differentiated upon LPS challenge. Given the higher prevalence of affective disorders in women, a focus of basic science on sex differences that underlie neuroinflammatory processes is imperative in order to elucidate the neuroimmunological substrate of major depression.
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Sens
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Schneider
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mauch
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Schaffstein
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Mohamed
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Fasoli
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Saurine
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Britzolaki
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Thelen
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320, OH, USA. Electronic address: ppitychoutis1@udayton.edu.
authors.forename: Pothitos M
authors.initials: PM
authors.lastname: Pitychoutis
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005260:Female; D006120:Grooming / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D012727:Sex Characteristics; D013395:Sucrose / Q000008:administration & dosage
chemical_list: D008070:Lipopolysaccharides; D012701:Serotonin; D013395:Sucrose
keywords: Cytokines; Depression; Dopamine; Females; Forced swim test; Gender; Hippocampus; Immune; Prefrontal cortex; Serotonin; Sickness; Splash test; Stress