Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia

Abstract

A chronic stress paradigm comprising exposure to predation, tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some, but not all, animals. Here, we sought to extend our behavioural studies to investigate how susceptibility (sucrose preference<65%) or resilience (sucrose preference>65%) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes. All chronically stressed animals, displayed increased level of anxiety, but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions. These changes were not present in resilient or acutely stressed animals. Compared to resilient animals, susceptible mice showed elevated expression of tumour necrosis factor alpha (TNF) and the 5-HT transporter (SERT) in the pre-frontal area. Enhanced expression of 5HT(2A) and COX-1 in the pre-frontal area was observed in all stressed animals. In turn, indoleamine-2,3-dioxygenase (IDO) was significantly unregulated in the raphe of susceptible animals. At the cellular level, increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals. Consequently, the susceptible animals display a unique molecular profile when compared to resilient, but anxious, animals. Unexpectedly, this altered profile provides a rationale for exploring anti-inflammatory, and possibly, TNF-targeted therapy for major depression.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

“…This potential link is supported by findings from preclinical studies in rodent models that directly link proinflammatory cytokines with brain 5-HTT availability through activation of MAPK pathways (Baganz and Blakely, 2013;Couch et al, 2013;Katafuchi et al, 2006;Malynn et al, 2013;Morikawa et al, 1998;Ramamoorthy et al, 1995;Samuvel, 2005;Tsao et al, 2008).…”

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

“…In our study, we extended these findings by determining that changes in cognition and anxiety-like behavior were still present 48 h after LPS administration, although the peak effects of LPS-induced behavioral changes may have been missed due to the delay between LPS treatment and behavioral analyses. The exact mechanisms whereby inflammation induces neurological symptoms are not yet clearly understood (Cavailles et al, 2013;Chandarana et al, 1987;Couch et al, 2013), and in the present study, the anxiety-like effects of LPS appear to be partially dependent on TNF-a, as anxiety-like behavior on the EZM could be reduced by central administration of etanercept. Although these effects were significant for head dip and stretch-attend measures only, time spent in open arms showed the same trend across groups, suggesting the effects of LPS and etanercept are consistent across measures.…”

“…However, it is uncertain whether central blockade of TNF-a is efficacious in preventing CNS manifestations of peripheral inflammatory diseases. Furthermore, although research into the effects of centrally and peripherally administered TNF-a blockade on cognition and depressive symptoms has improved our understanding of cytokine actions in the CNS (Couch et al, 2013;Tobinick and Gross, 2008), little work has been undertaken to enhance our knowledge on the effects of TNF-a blockade on anxiety behaviors. This is surprising as peripheral inflammatory conditions, such as RA and psoriasis, involving TNF-a upregulation are commonly associated with anxiety Salim et al, 2011), although the exact mechanisms whereby inflammation induces psychiatric symptoms are unclear (Chandarana et al, 1987;Couch et al, 2013).…”

“…Furthermore, although research into the effects of centrally and peripherally administered TNF-a blockade on cognition and depressive symptoms has improved our understanding of cytokine actions in the CNS (Couch et al, 2013;Tobinick and Gross, 2008), little work has been undertaken to enhance our knowledge on the effects of TNF-a blockade on anxiety behaviors. This is surprising as peripheral inflammatory conditions, such as RA and psoriasis, involving TNF-a upregulation are commonly associated with anxiety Salim et al, 2011), although the exact mechanisms whereby inflammation induces psychiatric symptoms are unclear (Chandarana et al, 1987;Couch et al, 2013). It is suggested that peripheral inflammation can cause upregulation of TNF-a, which in turn activates macrophages peripherally and microglia centrally (Qin et al, 2007) and is further linked to the development of anxiety-like behavior (Wohleb et al, 2011).…”

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…Mice susceptible to stress-induced anhedonia show elevated expression of TNF-a and SERT in the prefrontal area (Couch et al 2013) and SSRIs inhibit the secretion of TNF-a in human T lymphocytes (Taler et al 2007). …”