Chronic social stress induces peripheral and central immune activation, blunted mesolimbic dopamine function, and reduced reward-directed behaviour in mice

Abstract

Psychosocial stress is a major risk factor for depression, stress leads to peripheral and central immune activation, immune activation is associated with blunted dopamine (DA) neural function, DA function underlies reward interest, and reduced reward interest is a core symptom of depression. These states might be inter-independent in a complex causal pathway. Whilst animal-model evidence exists for some specific steps in the pathway, there is currently no animal model in which it has been demonstrated that social stress leads to each of these immune, neural and behavioural states. Such a model would provide important existential evidence for the complex pathway and would enable the study of causality and mediating mechanisms at specific steps in the pathway. Therefore, in the present mouse study we investigated for effects of 15-day resident-intruder chronic social stress (CSS) on each of these states. Relative to controls, CSS mice exhibited higher spleen levels of granulocytes, inflammatory monocytes and T helper 17 cells; plasma levels of inducible nitric oxide synthase; and liver expression of genes encoding kynurenine pathway enzymes. CSS led in the ventral tegmental area to higher levels of kynurenine and the microglia markers Iba1 and Cd11b and higher binding activity of DA D1 receptor; and in the nucleus accumbens (NAcc) to higher kynurenine, lower DA turnover and lower c-fos expression. Pharmacological challenge with DA reuptake inhibitor identified attenuation of DA stimulatory effects on locomotor activity and NAcc c-fos expression in CSS mice. In behavioural tests of operant responding for sucrose reward validated as sensitive assays for NAcc DA function, CSS mice exhibited less reward-directed behaviour. Therefore, this mouse study demonstrates that a chronic social stressor leads to changes in each of the immune, neural and behavioural states proposed to mediate between stress and disruption of DA-dependent reward processing. The model can now be applied to investigate causality and, if demonstrated, underlying mechanisms in specific steps of this immune-neural-behavioural pathway, and thereby to identify potential therapeutic targets.

Exploratory and agile behaviors with central dopaminergic activities in open field tests in Formosan wood mice (Apodemus semotus)

“…The DAergic activity in the ST plays an important role in the regulation of locomotor activity (Sershen et al, 1987). Furthermore, the locomotor activity and exploration behaviors in the open field test associated well with DAergic activity in the MPFC and ST, and the activity in the NA in the present study was confirmed by previous studies (Aragona et al, 2007;Bambico et al, 2015;Baskerville and Douglas, 2010;Bergamini et al, 2018;Cabib et al, 1988;Egashira et al, 2005;Sershen et al, 1987).…”

“…The mouse strains (ddY versus C57BL/6J mice), indicators of DA turnover (HVA/DA versus DOPAC/DA ratios) and doses of diazepam (1, 3 and 10 mg kg −1 versus 0.05 and 0.5 mg kg −1 ) were different, but evidence for the role of DAergic activities in the regulation of reward-directed, locomotor, social and even aggressive behaviors has accumulated over the years (Baskerville and Douglas, 2010;Bergamini et al, 2018;Sershen et al, 1987). From findings of neurobiological and behavioral aberrations, the NA and MPFC act as a hub, and their DA signals transmit social motivational, reward and stress adaptations (Aragona et al, 2007;Bergamini et al, 2018). The DAergic activity in the ST plays an important role in the regulation of locomotor activity (Sershen et al, 1987).…”

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

“…CSS leads to reduced reward-directed behavior, 40,41 increased aversion learning, helplessness and fatigue, 38,42,43 increased fMRI restingstate functional connectivity within PFC and between PFC and amygdala, 44 increased amygdala inositol levels 44 and increased immune/inflammatory activation in periphery and amygdala and PFC. 38,41,42 Utilizing this depression-relevant model, the present study shows that CSS in mice leads to reduced expression of a number of oligodendrocyte genes in PFC and amygdala tissue comprising gray and white matter. Furthermore, mice heterozygous for Cnp1, one such oligodendrocyte gene, are more sensitive to CSS in terms of reduced social interaction, whilst Cnp1 +/− and CSS act additively to increase amygdala microglia activation.…”

Making Sense of Rodent Models of Anhedonia

“…The significance of these results is supported by the selective increase in immuno-inflammatory markers in rats showing reduced sucrose intake in the sucrose consumption test, but not in resilient animals ( Rossetti et al, 2016 ). A recent study in mice shows that exposure to a chronic social stress protocol activates the immune-inflammatory system in the periphery and in the VTA-NAc dopaminergic pathway, reducing mesolimbic dopaminergic transmission ( Bergamini et al, 2018 ). At the behavioral level, defeated mice show a decrease in operant responding for sucrose in tests validated as sensitive assays for NAc dopaminergic activity, thus suggesting a possible mechanism for a causal correlation between immuno-inflammatory activation and anhedonic-like behaviors ( Bergamini et al, 2018 ).…”

“…A recent study in mice shows that exposure to a chronic social stress protocol activates the immune-inflammatory system in the periphery and in the VTA-NAc dopaminergic pathway, reducing mesolimbic dopaminergic transmission ( Bergamini et al, 2018 ). At the behavioral level, defeated mice show a decrease in operant responding for sucrose in tests validated as sensitive assays for NAc dopaminergic activity, thus suggesting a possible mechanism for a causal correlation between immuno-inflammatory activation and anhedonic-like behaviors ( Bergamini et al, 2018 ). Recent clinical and preclinical studies suggest that vulnerability to increased immune-inflammatory stimuli after a significant stress could be related to impaired integrity of the brain blood barrier around the NAc and may represent the link between stress exposure and development of depressive symptoms ( Cooper et al, 2018 ).…”