Experimental evidence suggests a role for the immune system in the pathophysiology of depression. A specific involvement of the proinflammatory cytokine interleukin 6 (IL6) in both, patients suffering from the disease and pertinent animal models, has been proposed. However, it is not clear how IL6 impinges on neurotransmission and thus contributes to depression. Here we tested the hypothesis that IL6-induced modulation of serotonergic neurotransmission through the STAT3 signaling pathway contributes to the role of IL6 in depression. Addition of IL6 to JAR cells, endogenously expressing SERT, reduced SERT activity and downregulated SERT mRNA and protein levels. Similarly, SERT expression was reduced upon IL6 treatment in the mouse hippocampus. Conversely, hippocampal tissue of IL6-KO mice contained elevated levels of SERT and IL6-KO mice displayed a reduction in depression-like behavior and blunted response to acute antidepressant treatment. STAT3 IL6-dependently associated with the SERT promoter and inhibition of STAT3 blocked the effect of IL6 in-vitro and modulated depression-like behavior in-vivo. These observations demonstrate that IL6 directly controls SERT levels and consequently serotonin reuptake and identify STAT3-dependent regulation of SERT as conceivable neurobiological substrate for the involvement of IL6 in depression.

Background:Disturbances in circadian rhythm-related physiological and behavioral processes are frequently observed in depressed patients and several clock genes have been identified as risk factors for the development of mood disorders. However, the particular involvement of the circadian system in the pathophysiology of depression and its molecular regulatory interface is incompletely understood.Methods:A naturalistic animal model of depression based upon exposure to chronic mild stress was used to induce anhedonic behavior in mice. Micro-punch dissection was used to isolate basolateral amygdala tissue from anhedonic mice followed by quantitative real-time PCR–based analysis of gene expression.Results:Here we demonstrate that chronic mild stress-induced anhedonic behavior is associated with disturbed diurnal oscillation of the expression of Clock, Cry2, Per1, Per3, Id2, Rev-erbα, Ror-β and Ror-γ in the mouse basolateral amygdala. Clock gene desynchronization was accompanied by disruption of the diurnal expressional pattern of vascular endothelial growth factor A expression in the basolateral amygdala of anhedonic mice, also reflected in alterations of circulating vascular endothelial growth factor A levels.Conclusion:We propose that aberrant control of diurnal rhythmicity related to depression may indeed directly result from the illness itself and establish an animal model for the further exploration of the molecular mechanisms mediating the involvement of the circadian system in the pathophysiology of mood disorders.

Mood disorders are frequently paralleled by disturbances in circadian rhythm-related physiological and behavioral states and genetic variants of clock genes have been associated with depression. Cryptochrome 2 (Cry2) is one of the core components of the molecular circadian machinery which has been linked to depression, both, in patients suffering from the disease and animal models of the disorder. Despite this circumstantial evidence, a direct causal relationship between Cry2 expression and depression has not been established. Here, a genetic mouse model of Cry2 deficiency (Cry2−/− mice) was employed to test the direct relevance of Cry2 for depression-like behavior. Augmented anhedonic behavior in the sucrose preference test, without alterations in behavioral despair, was observed in Cry2−/− mice. The novelty suppressed feeding paradigm revealed reduced hyponeophagia in Cry2−/− mice compared to wild-type littermates. Given the importance of the amygdala in the regulation of emotion and their relevance for the pathophysiology of depression, potential alterations in diurnal patterns of basolateral amygdala gene expression in Cry2−/− mice were investigated focusing on core clock genes and neurotrophic factor systems implicated in the pathophysiology of depression. Differential expression of the clock gene Bhlhe40 and the neurotrophic factor Vegfb were found in the beginning of the active (dark) phase in Cry2−/− compared to wild-type animals. Furthermore, amygdala tissue of Cry2−/− mice contained lower levels of Bdnf-III. Collectively, these results indicate that Cry2 exerts a critical role in the control of depression-related emotional states and modulates the chronobiological gene expression profile in the mouse amygdala.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-015-1968-3) contains supplementary material, which is available to authorized users.

Object-in-place (OiP) memory is critical for remembering the location in which an object was last encountered and depends conjointly on the medial prefrontal cortex, perirhinal cortex, and hippocampus. Here we examined the role of dopamine D 1 /D 5 receptor neurotransmission within these brain regions for OiP memory. Bilateral infusion of D 1 /D 5 receptor antagonists SCH23390 or SKF83566 into the medial prefrontal cortex, prior to memory acquisition, impaired OiP performance following a 5 min or 1 h delay. Retrieval was unaffected. Intraperirhinal or intrahippocampal infusions of SCH23390 had no effect. These results reveal a selective role for D 1 /D 5 receptors in the mPFC during OiP memory encoding.Object-in-place (OiP) associative recognition memory involves the formation of an association between an object and the location in which it was last encountered (Gaffan and Parker 1996; Dix and Aggleton 1999) and is therefore a key component of event memory (Mecklinger and Meinshausen 1998). The medial prefrontal cortex (mPFC), perirhinal cortex (PRH), and hippocampus (HPC), comprise an associative recognition memory neural circuit (Gaffan 1994;Browning et al. 2005;Barker et al. 2007;Bachevalier and Nemanic 2008;Barker and Warburton 2013;Lee and Park 2013). However, the neural mechanisms, which underlie the formation of OiP memory, are currently underexplored. The mPFC, PRH, and HPC all receive prominent dopaminergic innervation (Berger et al. 1974;Scatton et al. 1980;Swanson 1982;Sobel and Corbett 1984;Fallon and Laughlin 1995;DiChiara 2002) and exposure to novel stimuli and novel environments increases midbrain dopaminergic cell body firing (Feenstra et al. 1995;Beaufour et al. 2001;De Leonibus et al. 2006). Chao et al. (2013) recently reported that a unilateral forebrain dopamine lesion combined with a unilateral mPFC lesion significantly impaired OiP memory. Thus dopamine is a strong candidate for driving novelty processing, critical during recognition memory. Dopamine acts through different receptor subtypes (D 1 -D 5 ) located within the mPFC, HPC, and PRH, and intra-PRH infusion of the D 1 /D 5 receptor antagonist SCH23390 impaired object recognition after 24 h but not 90 min (Balderas et al. 2013). Thus here we examined the importance of D 1 /D 5 receptor neurotransmission, selectively within the mPFC, PRH, and HPC, during recognition memory encoding or retrieval.Rats were implanted with bilateral cannulae aimed at the mPFC, HPC, or PRH to allow direct intracerebral administration of the D 1 /D 5 receptor antagonists SCH23390 or SKF83566. All animal procedures were performed in accordance with the United Kingdom Animals Scientific Procedures Act (1986) and associated guidelines. Details of the surgery, infusion procedures, behavioral testing, and histology have been published previously (Barker and Warburton 2008). Briefly, male Dark Agouti rats (230-250 g; Harlan, UK) housed under a 12-h/12-h light/dark cycle (light phase 18:00-6:00 h), were anesthetized with isoflurane (induction 4%, maintenance 2%-3%) ...

Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesized to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluA2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluA2-dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluA2-independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation.