Missing and Possible Link between Neuroendocrine Factors, Neuropsychiatric Disorders, and Microglia

Abstract

Endocrine systems have long been suggested to be one of the important factors in neuropsychiatric disorders, while the underlying mechanisms have not been well understood. Traditionally, neuropsychiatric disorders have been mainly considered the consequence of abnormal conditions in neural circuitry. Beyond the neuronal doctrine, microglia, one of the glial cells with inflammatory/immunological functions in the central nervous system (CNS), have recently been suggested to play important roles in neuropsychiatric disorders. However, the crosstalk between neuroendocrine factors, neuropsychiatric disorders, and microglia has been unsolved. Therefore, we herein introduce and discuss a missing and possible link between these three factors; especially highlighting the following hormones; (1) Hypothalamic-Pituitary-Adrenal (HPA) axis-related hormones such as corticotropin-releasing hormone (CRH) and glucocorticoids, (2) sex-related hormones such as estrogen and progesterone, and (3) oxytocin. A growing body of evidence has suggested that these hormones have a direct effect on microglia. We hypothesize that hormone-induced microglial activation and the following microglia-derived mediators may lead to maladaptive neuronal networks including synaptic dysfunctions, causing neuropsychiatric disorders. Future investigations to clarify the correlation between neuroendocrine factors and microglia may contribute to a novel understanding of the pathophysiology of neuropsychiatric disorders.

The type of stress matters: repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations

“…As with repeated injection, we believe that these different changes in HPA axis/immune system activity promote the microglial/astrocyte-associated abnormalities observed in socially isolated mice 61 . For example, the reduced levels of corticosterone and the increased levels of pro-inflammatory cytokines promote microglial overactivation 44 , 62 , which can lead to increased microglial apoptosis 63 and hyper-ramification 62 , which we observe in our socially isolated animals, as indicated by a decrease in Iba1 cell density and an increase in the internal complexity of these cells.…”

Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression

“…Prolonged psychosocial stress and the associated HPA axis hyperactivation lead to glucocorticoid receptor desensitization and glucocorticoid resistance, culminating in reduced anti-inflammatory effects [31,32,33]. However, recent evidence shows that glucocorticoids are not exclusively anti-inflammatory, and can, in certain contexts, enhance proinflammatory responses, possibly through microglia activation, which is associated with psychiatric disorders including MDD [34,35]. …”

Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis

“…Psychological and environmental stress conditions induces the release of CRH. CRH also called as corticotropin-releasing factor (CRF), is a 41 amino acid peptide released from hypothalamic neurons as well as from the activated mast cells (Kato et al, 2013 ). VEGF, an angiogenic cytokine that plays an important role in inflammation, is also elevated in PTSD patients (De Kloet et al, 2008 ; Pervanidou and Chrousos, 2012 ).…”

“…Microglia express CRH receptors, and activation of microglia by CRH from brain cells cause the release of neurotoxic inflammatory mediators in mental disorders (Kritas et al, 2014a ). Activation of rat microglia by CRH through CRHR1-induces microglial proliferation and release of TNF-α and activation of mitogen-activated protein kinase (MAPKs) (Kato et al, 2013 ). CRH also increases microglial expression of IL-18 which is implicated in stress, depression, and PTSD conditions (Kato et al, 2013 ).…”