Effects of centrally administered etanercept on behaviour, histology and TNF-α expression in mice following a peripheral immune challenge

Background: Peripheral cytokines affect central nervous system (CNS) function, triggering anxiety and cognitive decline. Although peripheral blockade of tumor necrosis factor (TNF-α) by etanercept, has been effective in alleviating rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated effects of central etanercept administration post-peripheral immune challenge, on behaviour and histology. Methods: 12-week-old C57BL/6 mice (n=40) were challenged with either LPS or saline, administered peripherally 24hr before being treated with etanercept or artificial CSF (aCSF), via intracerebroventricular injection. Mice underwent behavioural analyses for locomotion (open field test: OFT), memory (Y maze) and anxiety (elevated zero maze: EZM) 24hr post etanercept/aCSF treatment. Brain tissue was then collected to estimate number of hippocampal microglia and expression of Tnfa. Results: Acute systemic challenge with LPS decreased weight in mice at 24hr, and impaired locomotor activity. LPS significantly increased anxiety-like behaviour (2-way ANOVA: Interaction: P=0.096; Saline/LPS challenge: P=0.0006, aCSF/etanercept treatment: P=0.0008), which was reversed by etanercept and significantly reduced cognition in the Y Maze (Interaction: P=0.037, Saline/LPS challenge: P=0.31, aCSF/etanercept treatment: P=0.80), which was not reversed by etanercept. LPS challenge also increased Tnfa expression in the hippocampus (Interaction: F(1,13)=28.04, P=0.0001, Saline/LPS challenge: P=0.0003, aCSF/etanercept treatment: P=0.021) and etanercept treatment was effective in reducing this Tnfa expression (P=0.001). Etanercept also significantly reduced microglial numbers within the hippocampus, which were increased following LPS administration (2-way ANOVA: Interaction: P= 0.0041; Saline/LPS challenge: P<0.0001, etanercept/aCSF: P=0.08,). Conclusion: A single dose of etanercept was found to be effective in significantly decreasing anxiety, Tnfa expression and microglia numbers 48hr post-peripheral immune challenge. The present study suggests that there is effective cross-talk between peripheral and central immune systems. Additionally behavioural and biological changes caused by LPS challenge which may be mediated by TNF-α related central inflammation, were reversed by etanercept treatment

Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment

Recent studies on environmental enrichment (EE) have shown cytokines, cellular immune components [e.g., T lymphocytes, natural killer (NK) cells], and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise (PE), a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including interleukin (IL)-6 secretion from muscle fibers, reduced expression of Toll-like receptors on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia, and upregulation of mitogen-activated protein kinase phosphatase-1 in central nervous system. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1β and tumor necrosis factor-α in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning, and EE has paved a way toward formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immunomodulatory role of PE has been evaluated extensively, more research is required to investigate neuroimmune changes associated with other enrichment methods.Gaurav Singhal, Emily J. Jaehne, Frances Corrigan and Bernhard T. Baun

Interaction of Brain-Derived Neurotrophic Factor Val66Met genotype and history of stress in regulation of prepulse inhibition in mice

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism results in reduced activity-dependent BDNF release and has been implicated in schizophrenia. However, effects of the polymorphism on functional dopaminergic and N-methyl-D-aspartate (NMDA) receptor-associated activity remain unclear. We used prepulse inhibition, a measure of sensorimotor gating which is disrupted in schizophrenia, and assessed the effects of acute treatment with the dopamine receptor agonist, apomorphine (APO). and the NMDA receptor antagonist, MK-801. We used adult humanized hBDNF(Val66Met) 'knockin' mice which express either the Val/Val, Val/Met or Met/Met genotype. An interaction of BDNF with stress was modelled by chronic young-adult treatment with corticosterone (CORT). At 1 or 3 mg/kg, APO had no effect in ValNal mice but significantly reduced PPI at the 100 ms inter-stimulus interval (ISI) in Val/Met and Met/Met mice. However, after CORT pretreatment, APO significantly reduced PPI in all genotypes similarly. At 0.1 or 0.25 mg/kg, MK-801 significantly disrupted PPI at the 100 ms ISI independent of genotype or CORY pretreatment. There were differential effects of APO and MK-801 on PPI at the 30 ms ISI and startle between the genotypes, irrespective of CORT pretreatment. These results show that the BDNF Val66Met Val/Met and Met/Met genotypes are more sensitive than the Val/Val genotype to the effect of APO on PPI. A history of stress, here modelled by chronic CORT administration, increases effects of APO in Val/Val mice

Brain-Derived neurotrophic factor Va166Met induces female-specific changes in impulsive behaviour and alcohol self-administration in mice

Substance use disorders are a debilitating neuropsychiatric condition, however it remains unclear why some individuals are at greater risk of substance use disorders than others and what genetic factors determine such individual differences. Impulsivity appears a promising candidate endophenotype to bridge the gap between genetic risk and addiction. Brain-derived neurotrophic factor (BDNF), and in particular the BDNFVal66Met polymorphism, has been suggested to be involved in both impulsivity and substance use disorders, however results so far have been inconsistent. To investigate the role of BDNF, and more specifically the BDNFVal66Met polymorphism, in both impulsivity and operant alcohol self-administration using the same animal model. Separate cohorts of humanized Val66Met transgenic mice were assessed for either trait impulsivity in the 5-choice serial reaction time (5-CSRT) touchscreen task, or propensity towards obtaining ethanol in an operant paradigm. It was found that female hBDNFVal/Val mice exhibited both greater impulsivity compared to hBDNFMet/Met mice of the same sex as shown by a higher number of premature responses at one of three increased inter-trial intervals tested in the 5-CSRT task, and a greater propensity toward stable ethanol self-administration relative to male mice of the same genotype in the operant paradigm. By contrast, male mice showed no difference between genotypes in impulsivity or stable ethanol self-administration. The hBDNFMet/Met genotype appears to sex-specifically alter aspects of both impulsive behaviour and addiction propensity. These results suggest that impulse behaviour may be a possible predictor of addiction risk

Maternal separation modifies behavioural and neuroendocrine responses to stress in CCR7 deficient mice

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−/− naïve 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

A Rat Model of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Shows Attenuated Motivation for Alcohol Self-Administration and Diminished Propensity for Cue-Induced Relapse in Females

Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol use disorder. The Val66Met polymorphism is a common variant of the BDNF gene (rs6265) which reduces activity-dependent BDNF release, and has been suggested as a risk factor for psychiatric disorders and substance use. Using an operant self-administration paradigm, this study aimed to investigate ethanol preference and ethanol seeking in a novel rat model of the BDNF Val66Met polymorphism, Val68Met rats. Male and female BDNF Val68Met rats of three genotypes (Val/Val, Val/Met and Met/Met) were trained to lever press for a 10% ethanol solution. There was no effect of Val68Met genotype on acquisition of stable response to ethanol or its extinction. Met/Met rats of both sexes had a slight, but significantly lower breakpoint during progressive ratio sessions while female rats with the Met/Met genotype demonstrated a lower propensity for reinstatement of responding to cues. There were no effects of Val68Met genotype on anxiety-like behaviour or locomotor activity. In conclusion, Met/Met rats showed lower motivation to continue to press for a reward, and also a decreased propensity to relapse, suggesting a possible protective effect of the Met/Met genotype against alcohol use disorder, at least in females

Differential effects of chronic adolescent glucocorticoid or methamphetamine on drug-induced locomotor hyperactivity and disruption of prepulse inhibition in adulthood in mice

Sensitization of dopaminergic activity has been suggested as an underlying mechanism in the psychotic symptoms of schizophrenia. Adolescent stress and chronic abuse of methamphetamine (Meth) are well-known risk factors for psychosis and schizophrenia; however it remains unknown how these factors compare in terms of dopaminergic behavioural sensitization in adulthood. In addition, while Brain-Derived Neurotrophic Factor (BDNF) has been implicated in dopaminergic activity and schizophrenia, its role in behavioural sensitization remains unclear. In this study we therefore compared the effect of chronic adolescent treatment with the stress hormone, corticosterone (Cort), or with Meth, on drug-induced locomotor hyperactivity and disruption of prepulse inhibition in adulthood in BDNF heterozygous mice and their wild-type controls, as well as on dopamine receptor gene expression. Between 6 and 9 weeks of age, the animals either received Cort in the drinking water or were treated with an escalating Meth dose protocol. In adulthood, Cort-pretreated mice showed significantly reduced Meth-induced locomotor hyperactivity compared to vehicle-pretreated mice. In contrast, Meth hyperlocomotion was significantly enhanced in animals pretreated with the drug in adolescence. There were no effects of either pretreatment on prepulse inhibition. BDNF Het mice showed greater Meth-induced hyperlocomotion and lower prepulse inhibition than WT mice. There were no effects of either pretreatment on D1 or D2 gene expression in either the dorsal or ventral striatum, while D3 mRNA was shown to be reduced in male mice only irrespective of genotype. These results suggest that in adolescence, chronically elevated glucocorticoid levels, a component of chronic stress, do not cause dopaminergic sensitization adulthood, in contrast to the effect of chronic Meth treatment in the same age period. BDNF does not appear to be involved in the effects of chronic Cort or chronic Meth