Neurodevelopmental and Neuropsychiatric Disorders.

This chapter will focus on microglial involvement in neurodevelopmental and neuropsychiatric disorders, particularly autism spectrum disorder (ASD), schizophrenia and major depressive disorder (MDD). We will describe the neuroimmune risk factors that contribute to the etiopathology of these disorders across the lifespan, including both in early life and adulthood. Microglia, being the resident immune cells of the central nervous system, could play a key role in triggering and determining the outcome of these disorders. This chapter will review preclinical and clinical findings where microglial morphology and function were examined in the contexts of ASD, schizophrenia and MDD. Clinical evidence points out to altered microglial morphology and reactivity, as well as increased expression of pro-inflammatory cytokines, supporting the idea that microglial abnormalities are involved in these disorders. Indeed, animal models for these disorders found altered microglial morphology and homeostatic functions which resulted in behaviours related to these disorders. Additionally, as microglia have emerged as promising therapeutic targets, we will also address in this chapter therapies involving microglial mechanisms for the treatment of neurodevelopmental and neuropsychiatric disorders.

Black seed oil reverses chronic antibiotic-mediated depression and social behaviour deficits via modulation of hypothalamic mitochondrial-dependent markers and insulin expression.

Chronic antibiotic use has been reported to impair mitochondrial indices, hypothalamus-mediated metabolic function, and amygdala-regulated emotional processes. Natural substances such as black seed (Nigella sativa) oil could be beneficial in mitigating these impairments. This study aimed to assess the impact of black seed oil (NSO) on depression and sociability indices, redox imbalance, mitochondrial-dependent markers, and insulin expression in mice subjected to chronic ampicillin exposure. Forty adult male BALB/c mice (30 ± 2 g) were divided into five groups: the CTRL group received normal saline, the ABT group received ampicillin, the NSO group received black seed oil, the ABT/NSO group concurrently received ampicillin and black seed oil, and the ABT+NSO group experienced pre-exposure to ampicillin followed by subsequent treatment with black seed oil. The ampicillin-exposed group exhibited depressive-like behaviours, impaired social interactive behaviours, and disruptions in mitochondrial-dependent markers in plasma and hypothalamic tissues, accompanied by an imbalance in antioxidant levels. Moreover, chronic antibiotic exposure downregulated insulin expression in the hypothalamus. However, these impairments were significantly ameliorated in the ABT/NSO, and ABT+NSO groups compared to the untreated antibiotic-exposed group. Overall, findings from this study suggest the beneficial role of NSO as an adjuvant therapy in preventing and abrogating mood behavioural and neural-metabolic impairments of chronic antibiotic exposure.

Prolonged ketamine therapy differentially rescues psychobehavioural deficits via modulation of nitro-oxidative stress and oxytocin receptors in the gut-brain-axis of chronically-stressed mice.

Ketamine is an anaesthetic known to have short but rapid-acting anti-depressant effects; however, the neurobehavioural effects of its prolonged use and its role on the oxytocin system in the gut-brain axis are largely undetermined. Female BALB/c mice were either exposed to the chronic unpredictable mild stress (CUMS) paradigm for 21 days and then treated with ketamine in four doses for 14 days or exposed to CUMS and treated simultaneously in four doses of ketamine during the last two weeks of CUMS exposure. After each dose, the forced swim test was conducted to assess depressive-like behaviour. Before sacrifice, all the mice were subjected to behavioural tests to assess anxiety, memory, and social interaction. Prolonged treatment of depression with ketamine did not rescue depressive-like behaviour. It did, however, improve depression-associated anxiety-like behaviours, short-term memory and social interaction deficits when compared to the stressed untreated mice. Furthermore, ketamine treatment enhanced plasma oxytocin levels, expression of oxytocin receptors; as well as abrogated nitro-oxidative stress biomarkers in the intestinal and hippocampal tissues. Taken together, our findings indicate that while short-term use of ketamine has anti-depressant benefits, its prolonged therapeutic use does not seem to adequately resolve depressive-like behaviour in mice.

Sex differences of microglia in the healthy brain from embryonic development to adulthood and across lifestyle influences.

Microglia, the central nervous system innate immune cells, play a critical role in maintaining a homeostatic environment in the brain throughout life. These cells exhibit an impressive range of functions and characteristics that help to ensure proper functioning of the brain. Notably, microglia can present differences in their genetic and physical traits, which can be influenced by a range of factors, including age, environmental exposures, disease, and sex. Remarkably, microglia have been found to express receptors for sex hormones, suggesting that these hormones may play a role in modulating microglial behavior and potentially contribute to sex differences. Additionally, sex-chromosomal factors were shown to impact microglial genetics and functioning. In this review, we will examine how microglial responses in homeostasis are impacted by their interaction with sex hormones and sex chromosomes. Specifically, our investigation will focus on examining this interaction from embryonic development to adulthood, and the influence of lifestyle elements on various microglial features, including density and distribution, morphology, transcriptome, and proteome.

Quercetin abrogates lipopolysaccharide-induced depressive-like symptoms by inhibiting neuroinflammation via microglial NLRP3/NFκB/iNOS signaling pathway.

BACKGROUND: Major depressive disorder is a serious psychiatric illness having serious damaging effect on the quality of life of suffers. Quercetin is a plant flavonoid, mostly used as a constituent in dietary products. This study evaluated antidepressant effect of quercetin on lipopolysaccharide (LPS)-induced depression in rats. MATERIALS AND METHODS: Twenty-one male rats were randomly assigned into three groups (n = 7): group 1 (vehicle only), group 2 (quercetin), group 3 (LPS). Rats were treated with vehicle (10 mL/kg, p.o.) or quercetin (50 mg/kg, p.o.) for seven days. Sixty minutes after treatment on day seven, all animals were injected with LPS (0.83 mg/kg, i.p.) except group 1 (vehicle only). Twenty-four hours after LPS injection, animals were assessed for depressive symptoms using forced swim, sucrose splash and open field tests. Animals were sacrificed; brain samples collected for bioassay of pro-inflammatory mediators, TNF-α, IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA) while expressions of NF-κB, inflammasomes, microglia and iNOS were quantified by immunohistochemistry. RESULTS: The LPS significantly (p < 0.05) decreased mobility of rats in FST and decreased sucrose preference, which is indicative of depressive-like behaviours. These behaviours were significantly (p < 0.05) attenuated by quercetin compared to control (vehicle only). Following LPS exposure, the expressions of inflammasomes, NF-κB, iNOS, proinflammatory cytokines and microglia positive cells in the hippocampus and prefrontal cortex were significantly (p < 0.05) elevated. All these were attenuated by pretreating animals with quercetin. CONCLUSION: Quercetin exhibit antidepressant-like property, which may be related to inhibition of neuroinflammatory signaling pathways.

Combined Exposure to Chronic Sleep Deprivation and Caffeine Potentiates Behavioural Deficits by Altering Neurochemical Profile and Synaptophysin Expression in Long-Evans Rats.

Using the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm we developed, the combined effects of chronic sleep deprivation and high caffeine intake on prefrontal cortical synaptophysin expression, neurochemical profiles, and behavioural outcomes in Long-Evans rats were evaluated. The combination of chronic sleep deprivation and high-dose caffeine treatment produced varying degrees of behavioural impairments, depletion of antioxidants, serotonin, and an upregulation of acetylcholinesterase (AChE) activity in the prefrontal cortex. An immunohistochemical assessment revealed a reduction in synaptophysin protein expression in the prefrontal cortex following exposure to high-dose caffeine and chronic sleep deprivation. Overall, our findings support the advocacy for adequate sleep for optimal mental performance as a high intake of caffeine to attenuate the effects of sleep deprivation that may alter the neurochemical profile and synaptic plasticity in the prefrontal cortex, significantly increasing the risk of neuropsychiatric/degenerative disorders.

Ketamine abrogates sensorimotor deficits and cytokine dysregulation in a chronic unpredictable mild stress model of depression.

Major depressive disorder (MDD) is a serious mental disorder with influence across the functional systems of the body. The pathogenesis of MDD has been known to involve the alteration of normal body functions responsible for the normal inflammation processes within the CNS; this along with other effects results in the depreciation of the sensorimotor performance of the body. Ketamine hydrochloride, a novel antidepressant agent, has been used as a therapeutic agent to treat MDD with its efficacy stretching as far as enhancing sensorimotor performance and restoring normal cytokine levels of the CNS. While these therapeutic actions of ketamine may or may not be related, this study made use of chronic unpredictable mild stress (CUMS) to generate the mouse model of depression. The efficacy of ketamine as an antidepressant following sequential exposure and co-administrative treatment protocols of administration was evaluated using behavioural tests for sensorimotor performance and depressive-like behaviours. Its effect in managing CNS inflammation was assessed via the biochemical analysis of inflammatory cytokine levels in the cerebrum, spinal cord and cerebellum; and immunohistochemical demonstration of microglial activity in the corpus striatum and cerebellum. The sensorimotor performance which had been diminished by CUMS showed greater improvement under the sequential exposure regimen of ketamine. Ketamine was also efficacious in decreasing the level of inflammation with an evident reduction in microglial activation and pro-inflammatory cytokines in the studied regions, following CUMS exposure. Taken together, our study indicates that ketamine therapy can improve sensorimotor deficits co-morbid with a depressive disorder in parallel with modulation of the inflammatory system.

Virgin coconut oil abrogates depression-associated cognitive deficits by modulating hippocampal antioxidant balance, GABAergic and glutamatergic receptors in mice.

OBJECTIVES: GABA and glutamate neurotransmission play critical roles in both the neurobiology of depression and cognition; and Virgin coconut oil (VCO) is reported to support brain health. The present study investigated the effect of VCO on depression-associated cognitive deficits in mice. METHODS: Thirty male mice divided into five groups were either exposed to chronic unpredicted mild stress (CUMS) protocol for 28 days or pre-treated with 3 mL/kg b. wt. of VCO for 21 days or post-treated with 3 mL/kg b. wt. of VCO for 21 days following 28 days of CUMS exposure. Mice were subjected to behavioural assessments for depressive-like behaviours and short-term memory, and thereafter euthanised. Hippocampal tissue was dissected from the harvested whole brain for biochemical and immunohistochemical evaluations. RESULTS: Our results showed that CUMS exposure produced depressive-like behaviours, cognitive deficits and altered hippocampal redox balance. However, treatment with VCO abrogated depression-associated cognitive impairment, and enhanced hippocampal antioxidant concentration. Furthermore, immunohistochemical evaluation revealed significant improvement in GABAA and mGluR1a immunoreactivity following treatment with VCO in the depressed mice. CONCLUSIONS: Therefore, findings from this study support the dietary application of VCO to enhance neural resilience in patients with depression and related disorders.

Lactobacillus plantarum mitigates sexual-reproductive deficits by modulating insulin receptor expression in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice.

OBJECTIVES: Hyperinsulinemia increases the risk factor of diabetes and infertility at a manifold. Lactobacillus plantarum has several medical significances with limited reports. Hence, this study assessed the effect of L. plantarum on sexual-reproductive functions and distribution of insulin receptors in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice. METHODS: Forty male adult mice were divided into five groups as follows: control, high-fat diet (HFD) + streptozotocin (STZ), therapeutic, co-administration group type 1 (CO-AD) and probiotics. They were either simultaneously exposed to an HFD and L. plantarum treatment for 28 days with a dose of STZ injection to induce hyperinsulinemia on day 28 or treated with L. plantarum for 14 days, and following induction of hyperinsulinemia. Mice were subjected to a sexual behavioural test and thereafter sacrificed under euthanasia condition. Blood, brain and testes were collected for biochemical and immunohistochemical assays. RESULTS: Treatment with L. plantarum ameliorated reproductive hormones activity disruption, sexual behavioural defects, antioxidant imbalance, insulin dysregulation and lipid metabolism dysfunction following exposure to HFD + STZ when compared to the hyperinsulinemic untreated mice. CONCLUSIONS: Taken together, data from this study reveal that L. plantarum abrogated hyperinsulinemia-induced male sexual and reproductive deficits by modulating antioxidant status, lipid metabolism and insulin signalling in the hypothalamic-pituitary-testicular axis of mice.