Over-activation of the innate immune system constitutes a risk factor for the development of nervous system disorders but may reduce the severity of these disorders by inducing tolerance effect. Here, we studied the tolerance-inducing effect and properties of innate immune stimulation on chronic social defeat stress (CSDS)-induced behavioral abnormalities in mice. A single injection of the innate immune enhancer lipopolysaccharide (LPS) one day before stress exposure prevented CSDS-induced impairment in social interaction and increased immobility time in the tail suspension test and forced swimming test. This effect was observed at varying doses (100, 500, and 1000 μg/kg) and peaked at 100 μg/kg. A single LPS injection (100 μg/kg) either one or five but not ten days before stress exposure prevented CSDS-induced behavioral abnormalities. A second LPS injection ten days after the first LPS injection, or a 2 × or 4 × LPS injections ten days before stress exposure also induced tolerance against stress-induced behavioral abnormalities. Our results furthermore showed that a single LPS injection one day before stress exposure skewed the neuroinflammatory response in the hippocampus and prefrontal cortex of CSDS-exposed mice toward an anti-inflammatory phenotype. Inhibiting the central innate immune response by pretreatment with minocycline or PLX3397 abrogated the tolerance-inducing effect of LPS preconditioning on CSDS-induced behavioral abnormalities and neuroinflammatory responses in the brain. These results provide evidence for a prophylactic effect of innate immune stimulation on stress-induced behavioral abnormalities via changes in microglial activation, which may help develop novel strategies for the prevention of stress-induced psychological disorders.

Tolerance-inducing effect and properties of innate immune stimulation on chronic stress-induced behavioral abnormalities in mice.

Dementia occurs mainly in the elderly and is associated with cognitive decline and impairment of activities of daily living. The most common forms of dementia are Alzheimer's disease (AD), vascular dementia (VD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). To date, there are no causal options for therapy, but drug and non-drug treatments can positively modulate the course of the disease. Valid biomarkers are needed for the earliest possible and reliable diagnosis, but so far, such biomarkers have only been established for AD and require invasive and expensive procedures. In this context, proton magnetic resonance spectroscopy (1H-MRS) provides a non-invasive and widely available technique for investigating the biochemical milieu of brain tissue in vivo. Numerous studies have been conducted for AD, but for VD, DLB, and FTD the number of studies is limited. Nevertheless, MRS can detect measurable metabolic alterations in common dementias. However, most of the studies conducted are too heterogeneous to assess the potential use of MRS technology in clinical applications. In the future, technological advances may increase the value of MRS in dementia diagnosis and treatment. This review summarizes the results of MRS studies conducted in common dementias and discusses the reasons for the lack of transfer into clinical routine.

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Proton Magnetic Resonance Spectroscopy in Common Dementias-Current Status and Perspectives.

Background: Metabolomics-the novel science that evaluates the multitude of low-molecular-weight metabolites in a biological system, provides new data on pathogenic mechanisms of diseases, including endocrine tumors. Although development of metabolomic profiling in pituitary disorders is at an early stage, it seems to be a promising approach in the near future in identifying specific disease biomarkers and understanding cellular signaling networks. Objectives: To review the metabolomic profile and the contributions of metabolomics in pituitary adenomas (PA). Methods: A systematic review was conducted via PubMed, Web of Science Core Collection and Scopus databases, summarizing studies that have described metabolomic aspects of PA. Results: Liquid chromatography tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) spectrometry, which are traditional techniques employed in metabolomics, suggest amino acids metabolism appears to be primarily altered in PA. N-acetyl aspartate, choline-containing compounds and creatine appear as highly effective in differentiating PA from healthy tissue. Deoxycholic and 4-pyridoxic acids, 3-methyladipate, short chain fatty acids and glucose-6-phosphate unveil metabolite biomarkers in patients with Cushing's disease. Phosphoethanolamine, N-acetyl aspartate and myo-inositol are down regulated in prolactinoma, whereas aspartate, glutamate and glutamine are up regulated. Phosphoethanolamine, taurine, alanine, choline-containing compounds, homocysteine, and methionine were up regulated in unclassified PA across studies. Intraoperative use of ultra high mass resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which allows localization and delineation between functional PA and healthy pituitary tissue, may contribute to achievement of complete tumor resection in addition to preservation of pituitary cell lines and vasopressin secretory cells, thus avoiding postoperative diabetes insipidus. Conclusion: Implementation of ultra high performance metabolomics analysis techniques in the study of PA will significantly improve diagnosis and, potentially, the therapeutic approach, by identifying highly specific disease biomarkers in addition to novel molecular pathogenic mechanisms. Ultra high mass resolution MALDI-MSI emerges as a helpful clinical tool in the neurosurgical treatment of pituitary tumors. Therefore, metabolomics appears to be a science with a promising prospect in the sphere of PA, and a starting point in pituitary care.

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Metabolomics-A Promising Approach to Pituitary Adenomas.

Striatal Shati/Nat8l-BDNF pathways determine the sensitivity to social defeat stress in mice through epigenetic regulation.

Depression is one of the most common mental diseases, with increasing numbers of patients globally each year. In addition, approximately 30% of patients with depression are resistant to any treatment and do not show an expected response to first-line antidepressant drugs. Therefore, novel antidepressant agents and strategies are required. Although depression is triggered by post-birth stress, while some individuals show the pathology of depression, others remain resilient. The molecular mechanisms underlying stress sensitivity remain unknown. Brain-derived neurotrophic factor (BDNF) has both pro- and anti-depressant effects, dependent on brain region. Considering the strong region-specific contribution of BDNF to depression pathogenesis, the regulation of BDNF in the whole brain is not a beneficial strategy for the treatment of depression. We reviewed a novel finding of BDNF function in the dorsal striatum, which induces vulnerability to social stress, in addition to recent research progress regarding the brain regional functions of BDNF, including the prefrontal cortex, hippocampus, and nucleus accumbens. Striatal BDNF is regulated by Shati/Nat8l, an N-acetyltransferase through epigenetic regulation. Targeting of Shati/Nat8l would allow BDNF to be striatum-specifically regulated, and the striatal Shati/Nat8l-BDNF pathway could be a promising novel therapeutic agent for the treatment of depression by modulating sensitivity to stress.

A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity "Shati/Nat8l-BDNF System" in the Dorsal Striatum.

Vulnerability to depressive behavior induced by overexpression of striatal Shati/Nat8l via the serotonergic neuronal pathway in mice.

Shati/Nat8l was originally isolated as a methamphetamine-related-molecule from the nucleus accumbens of mice. Since then, Shati/Nat8l has been characterized as an N-acetyltransferase-8-like protein (Nat8l) that catalyzes N-acetylaspartate (NAA) synthesis from aspartate and acetyl-coenzyme A. It has been shown that elevated NAA levels detected by proton magnetic resonance spectroscopy (1H-MRS) brain imaging indicates increased neuronal activity. Our group produced Shati/Nat8l knock out mice (Shati/Nat8l KO mice), which exhibit hyper locomotion, anxiety behaviors, and social dysfunction. These mice have a high sensitivity to methamphetamine, as evidenced by their results in assessments of locomotor activity and conditioned place preference, as well as their elevated dopamine levels. We used an adeno-associated virus (AAV) vector containing Shati/Nat8l (AAV-Shati/Nat8l) to overexpress the protein in different brain regions such as the striatum and the nucleus accumbens, in order to investigate their involvement in methamphetamine-induced behavioral and pharmacological changes. We showed that overexpression of accumbal Shati/Nat8l attenuates methamphetamine-induced behaviors.

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Shati/Nat8l and N-acetylaspartate (NAA) Have Important Roles in Regulating Nicotinic Acetylcholine Receptors in Neuronal and Psychiatric Diseases in Animal Models and Humans

Hajime Miyanishi

Papers

Striatal Shati/Nat8l-BDNF pathways determine the sensitivity to social defeat stress in mice through epigenetic regulation.

A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity "Shati/Nat8l-BDNF System" in the Dorsal Striatum.

Vulnerability to depressive behavior induced by overexpression of striatal Shati/Nat8l via the serotonergic neuronal pathway in mice.

Shati/Nat8l and N-acetylaspartate (NAA) Have Important Roles in Regulating Nicotinic Acetylcholine Receptors in Neuronal and Psychiatric Diseases in Animal Models and Humans

Cannabinoid Type 1 Receptors in the Basolateral Amygdala Regulate ACPA-Induced Place Preference and Anxiolytic-Like Behaviors