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Background Major depressive disorder (MDD) is a stress-related psychiatric disorder. A subgroup of MDD patients is characterized by increased inflammatory activation. We aimed to investigate whether increased inflammation particularly occurs in MDD patients with a history of stressful early or later life experiences. Methods Serum levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in N = 214 MDD patients and N = 180 healthy controls (HC). Childhood trauma (Childhood Trauma Questionnaire – CTQ), adverse life events of the past 12 months (List of Threatening Experiences Questionnaire – LTE-Q), and perceived stress in the past month (Perceived Stress Scale – PSS) were analyzed with regard to cytokine levels. Results Pro-inflammatory cytokine levels were not related to global scores of adverse events or perceived stress covering different time points ranging from childhood to the past month. However, in the subgroup of traumatized MDD patients, higher severity of childhood sexual abuse was associated with higher levels of both IL-6 and TNF-α in a linear fashion. Conclusions Our data suggest a linear relationship between childhood sexual abuse and increased pro-inflammatory cytokine levels in MDD patients, while more recent stressful life events were not related to these inflammatory markers.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.44.

Juvenile mice of the DBA/2J strain undergo generalised seizures when exposed to a high-intensity auditory stimulus. Genetic analysis identified three different loci underlying this audiogenic seizure proneness (ASP)-Asp1, Asp2 and Asp3 on chromosomes 12, 4 and 7, respectively. Asp1 is thought to have the strongest influence, and mice with only Asp1 derived from the DBA/2J strain are reported to exhibit ASP. The aim of this study was to characterise more accurately the contributions of the Asp1 and Asp3 loci in ASP using congenic strains. Each congenic strain contains a DBA/2J-derived interval encompassing either Asp1 or Asp3 on a C57BL/6J genetic background. A double congenic C57BL/6J strain containing both Asp loci derived from DBA/2J was also generated. Here, we report that DBA/2J alleles at both of these Asp loci are required to confer ASP because congenic C57BL/6 mice harbouring DBA/2J alleles at only Asp1 or Asp3 do not exhibit ASP, whereas DBA/2J alleles at both loci resulted in increased susceptibility for audiogenic seizure in double congenic C57BL/6 mice.

Tumor necrosis factor alpha (TNF-α) is a vital component of the immune sys tem and CNS. We previously showed that 3-month-old TNF-α and TNF-α receptor knockout mice had impaired cognition, whilst at 12-months-old mice had better cognition. To extend these findings on possible age-dependent TNF-α effects in the brain, we investigated the behaviour of 6-month-old TNF-α knockout mice and their neurobiological correlates. 6-month-old TNF < sup > -/- < /sup > , TNF-R1 < sup > -/- < /sup > and TNF-R2 < sup > -/- < /sup > mice were compared to age-matched WT mice and tested for various behaviours. ELISA hippocampal levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and qPCR mRNA levels of Tnfa, Tnfr1, Tnfr2, Il10 and Il1β were measured. TNF-R1 < sup > -/- < /sup > and TNF < sup > -/- < /sup > mice were found to have lesser exploratory behaviour than WT mice, while TNF-R1 < sup > -/- < /sup > mice displayed better memory than WT and TNF-R2 < sup > -/- < /sup > mice. Both TNF < sup > -/- < /sup > and TNF-R2 < sup > -/- < /sup > mice exhibited significantly lower immobility on the depression test than WT mice. Additionally, TNF < sup > -/- < /sup > mice expressed significantly lower levels of BDNF than WT mice in the hippocampus while TNF-R1 < sup > -/- < /sup > mice displayed significantly lower BDNF levels compared to both WT and TNF-R2 < sup > -/- < /sup > mice. TNF-R2 < sup > -/- < /sup > mice also displayed significantly higher levels of NGF compared to TNF-R1 < sup > -/- < /sup > mice. These results illustrate that TNF-α and its receptors mediate several behavioural phenotypes. Finally, BDNF and NGF levels appear to be regulated by TNF-α and its receptors even under immunologically unchallenged conditions. Refereed/Peer-reviewed

Alterations in immune function of various humoral and cellular factors, including chemokines, secondary to early stress may play a role in the enhanced vulnerability to psychiatric conditions in those with a history of childhood adversity. C57BL/6 (WT) mice and mice deficient for the chemokine receptor type 7 (CCR7(-/-)) were used to determine the effects of maternal separation on a range of behaviours and the biological stress response. Unpredictable maternal separation (MS) was conducted for 3 h daily from postnatal day 1 to 14, with subsequent behavioural testing at 10 weeks of age. Corticosterone was quantified in 11-week-old mice. Maternally separated (MS) CCR7(-/-), but not WT mice, displayed reduced interest in social novelty compared to CCR7(-/-) naive mice. Separated CCR7(-/-) mice also exhibited significantly lower serum corticosterone concentrations compared to non-separated mice. CCR7(-/-) mice spent less time in the centre during an open field test and more time in the closed arm of the elevated zero maze compared to their wild-type (WT) controls suggesting they were more anxious, however, no difference was observed between MS and control mice in either strain or test. Together these findings suggest that CCR7 is involved in mediating social behaviour and stress response following maternal separation, whereas other behaviours such as anxiety appear to be modified by CCR7 independent of maternal separation. The observed altered cell-mediated immune function possibly underlying the behavioural and neuroendocrine differences in CCR7(-/-) mice following maternal separation requires further investigation. Refereed/Peer-reviewed

Tumour necrosis factor-α (TNF-α) plays an important role not only in immunity but also in the normal functioning of the central nervous system (CNS). At physiological levels, studies have shown TNF-α is essential to maintain synaptic scaling and thus influence learning and memory formation while also playing a role in modulating pathological states of anxiety and depression. TNF-α signals mainly through its two receptors, TNF-R1 and TNF-R2, however the exact role that these receptors play in TNF-α mediated behavioural phenotypes is yet to be determined. Methods: We have assessed TNF -/- , TNF-R1 -/- and TNF-R2 -/- mice against C57BL/6 wild-type (WT) mice from 12 weeks of age in order to evaluate measures of spatial memory and learning in the Barnes maze (BM) and Y-maze, as well as other behaviours such as exploration, social interaction, anxiety and depression-like behaviour in a battery of tests. We have also measured hippocampal and prefrontal cortex levels of the neurotrophins nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) as well as used immunohistochemical analyses to measure number of proliferating cells (Ki67) and immature neurons (DCX) within the dentate gyrus. Results: We have shown that young adult TNF -/- and TNF-R1 -/- mice displayed impairments in learning and memory in the BM and Y-maze, while TNF-R2 -/- mice showed good memory but slow learning in these tests. TNF -/- and TNF-R2 -/- mice also demonstrated a decrease in anxiety like behaviour compared to WT mice. ELISA analyses showed TNF -/- and TNF-R2 -/- mice had lower levels of NGF compared to WT mice. Conclusion: These results indicate that while lack of TNF-α can decrease anxiety-like behaviour in mice, certain basal levels of TNF-α are required for the development of normal cognition. Furthermore our results suggest that both TNF-R1 and TNF-R2 signalling play a role in normal CNS function, with knockout of either receptor impairing cognition on the Barnes maze. Refereed/Peer-reviewed

Background Tumour necrosis factor - alpha (TNF-α) is a pro-inflammatory cytokine that combines a plethora of activities in the early stages of an immune response. TNF-α has gained increasing importance given TNF-α upregulation in multiple brain pathologies like neuropsychiatric conditions such as depression, schizophrenia, as well as neuroinflammatory disorder like multiple sclerosis (MS).