Brain activation induced by chronic psychosocial stress in mice

Abstract

Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of ∆FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of ∆FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.Psychosocial stress increases the risk for both somatic and psychiatric diseases and worsens their prognosis 1-4 . This term refers to a broad range of experiences, including lack of normative care, abuse, and problems in peer relationships such as bullying 5 . Stress-related mental disorders like major depressive disorder (MDD) and anxiety disorders are associated with altered activation of specific brain regions. For example, neuroimaging has revealed that resting-state activity is reduced in the prefrontal cortex (PFC) 6 and increased in the hippocampus 7 while task-related reactivity is decreased in the hippocampus 8 and nucleus accumbens 9 of MDD patients. Interpretation of the human imaging findings is difficult as activation patterns in tasks carried out during brain imaging may differ from those occurring during naturalistic chronic stress exposure. Because patients enrolled in these studies also tend to have an extensive history of symptoms and medication use, it is challenging to reveal direct consequences of chronic psychosocial stress itself. In contrast, animal models allow investigation of specific stressors in a controlled manner to establish the mechanisms connecting chronic psychosocial stress exposure, brain activation, and subsequent emotional and social behaviour.Chronic social defeat stress (CSDS) is a rodent model of psychosocial stress, which produces many behavioural features similar to the symptoms of human anxiety and mood disorders, such as social aversion, anhedonia (decreased sucrose-preference) and increased self-administration of drugs of abuse 10,11 . These behavioural phenotypes...

Chronic stress exacerbates acute stress-induced neuronal activation in the anterior cingulate cortex and ventral hippocampus that correlates with behavioral deficits in mice

“…Although we confirmed enhanced activation of the ACC and vHPC, we did not fully replicate findings from studies using long-lasting IEG markers that demonstrate sustained activation by chronic stress in HPA-sensitive regions, such as the amygdala, PAG, and BNST [81][82][83] . These differences likely reflect our approach to measure functional response to acute stress vs. changes in baseline activity levels, but may have also been influenced by the type or intensity of stressors applied.…”

How much fear is in anxiety?

“…Other than expression of immediate early genes or accumulation of radioactive derivates of glucose which measure phasic changes in neuronal activity upon acute exposure to a threatening situation, repeated injections of MnCl 2 are expected to result in intracerebral accumulation of Mn 2+ also in cells with tonic (i.e., lasting) changes in neuronal activity. Importantly, MEMRI has the potential to non-invasively map whole-brain activity ( Bangasser DA, 2013; Bissig and Berkowitz, 2009; Chen et al, 2013, 2007; Eschenko et al, 2010; Hoch et al, 2013; Laine et al, 2017; Tang et al, 2016 ). Mn 2+ enters active neurons through voltage-gated calcium channels ( Drapeau and Nachshen, 1984 ) (e.g.…”

Early-life experiences altered the maturation of the lateral habenula in mouse models, resulting in behavioural disorders in adulthood

“…17,36 The dentate gyrus and basolateral amygdala are known to be activated by stress, and these plastic changes are correlated with anxiety-or depression-like behaviours. [37][38][39][40][41] However, we found no effect on neuronal activity as observed by Zif268/ Egr1 cells in the dentate gyrus and PV neurons in the dentate gyrus and basolateral amygdala in adults from the repeated maternal deprivation (P10-20) group (Figure 3K, 4H and 4K). In contrast, in adults in the repeated maternal deprivation (P10-20) group, we observed behavioural changes (anxiety and depression) and elevated neuronal reactivity in the lateral habenula (Figure 3, 4 and 5).…”