Genomic Signatures of Positive Selection in Human Populations of the , , , and Gene Variants Related to the Regulation of Psychoemotional Response.

The neurobiological systems of maintenance and control of behavioral responses result from natural selection. We have analyzed the selection signatures for single nucleotide variants (SNV) of the genes of oxytocin (, ) and vasopressin (, , ) systems, which are associated with the regulation of social and emotional behavior in distinct populations. The analysis was performed using original WGS (whole genome sequencing) data on Eastern Slavs (SlEast), as well as publicly available data from the 1000 Genomes Project on GBR, FIN, IBR, PUR, BEB, CHB, and ACB populations (the latter were taken as reference).

Epidrugs in the Therapy of Central Nervous System Disorders: A Way to Drive on?

The polygenic nature of neurological and psychiatric syndromes and the significant impact of environmental factors on the underlying developmental, homeostatic, and neuroplastic mechanisms suggest that an efficient therapy for these disorders should be a complex one. Pharmacological interventions with drugs selectively influencing the epigenetic landscape (epidrugs) allow one to hit multiple targets, therefore, assumably addressing a wide spectrum of genetic and environmental mechanisms of central nervous system (CNS) disorders. The aim of this review is to understand what fundamental pathological mechanisms would be optimal to target with epidrugs in the treatment of neurological or psychiatric complications.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function.

Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD.

Adaptive neuroplasticity is a pivotal mechanism for healthy brain development and maintenance, as well as its restoration in disease- and age-associated decline. Management of mental disorders such as attention deficit hyperactivity disorder (ADHD) needs interventions stimulating adaptive neuroplasticity, beyond conventional psychopharmacological treatments. Physical exercises are proposed for the management of ADHD, and also depression and aging because of evoked brain neuroplasticity.

Brain Expression, Physiological Regulation and Role in Motivation and Associative Learning of Peroxisome Proliferator-activated Receptor γ.

Like other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARγ in the CNS, many reports suggest direct PPARγ-mediated actions in the brain. This study aimed to (i) map PPARγ expression in rodent brain areas, involved in the regulation of cognitive, motivational, and emotional functions, (ii) examine the regulation of central PPARγ by physiological variables (age, sex, obesity); (iii) chemotypically identify PPARγ-expressing cells in the frontal cortex (FC) and hippocampus (HP); (iv) study whether activation of PPARγ by pioglitazone (Pio) in FC and HP cells can induce target gene expression; and (v) demonstrate the impact of activated PPARγ on learning behavior and motivation.

Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion.

The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes.

The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice.

We report here the involvement of the stress-responsive glucocorticoid receptor co-chaperone FKBP51 in the mechanism of secretion of mature BDNF (mBDNF). We used a novel method combining brain microdialysis with a capillary electrophoresis-based immunoassay, to examine mBDNF secretion in the medial prefrontal cortex (mPFC) in freely moving mice. By combining optogenetic, neurochemical (KCl-evoked depolarization), and transgenic (conditional BDNF knockout mice) means, we have shown that the increase in extracellular mBDNF is determined by neuronal activity.

ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus.

Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits.

Hippo Signaling: Emerging Pathway in Stress-Related Psychiatric Disorders?

Discovery of the Hippo pathway and its core components has made a significant impact on our progress in the understanding of organ development, tissue homeostasis, and regeneration. Upon diverse extracellular and intracellular stimuli, Hippo signaling regulates stemness, cell proliferation and apoptosis by a well-conserved signaling cascade, and disruption of these systems has been implicated in cancer as well as metabolic and neurodegenerative diseases. The central role of Hippo signaling in cell biology also results in prominent links to stress-regulated pathways.

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity.

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality.

Animal models in psychiatric research: The RDoC system as a new framework for endophenotype-oriented translational neuroscience.

The recently proposed Research Domain Criteria (RDoC) system defines psychopathologies as phenomena of multilevel neurobiological existence and assigns them to 5 behavioural domains characterizing a brain in action. We performed an analysis on this contemporary concept of psychopathologies in respect to a brain phylogeny and biological substrates of psychiatric diseases. We found that the RDoC system uses biological determinism to explain the pathogenesis of distinct psychiatric symptoms and emphasises exploration of endophenotypes but not of complex diseases.

The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior.

Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter.

NextGen Brain Microdialysis: Applying Modern Metabolomics Technology to the Analysis of Extracellular Fluid in the Central Nervous System.

Microdialysis is a powerful method for in vivo neurochemical analyses. It allows fluid sampling in a dynamic manner in specific brain regions over an extended period of time. A particular focus has been the neurochemical analysis of extracellular fluids to explore central nervous system functions.

Glycogen synthase kinase-3β inhibition in the medial prefrontal cortex mediates paradoxical amphetamine action in a mouse model of ADHD.

Psychostimulants show therapeutic efficacy in the treatment of attention-deficit hyperactivity disorder (ADHD). It is generally assumed that they ameliorate ADHD symptoms via interfering with monoaminergic signaling. We combined behavioral pharmacology, neurochemistry and molecular analyses to identify mechanisms underlying the paradoxical calming effect of amphetamine in low trait anxiety behavior (LAB) mice, a novel multigenetic animal model of ADHD.

Brain microdialysis and its applications in experimental neurochemistry.

Abstract Microdialysis is one of the most powerful neurochemistry techniques, which allows the monitoring of changes in the extracellular content of endogenous and exogenous substances in the brain of living animals. The strength as well as wide applicability of this experimental approach are based on the bulk theory of brain neurotransmission. This methodological review introduces basic principles of chemical neurotransmission and emphasizes the difference in neurotransmission types.

Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety.

We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze.

Strain differences in profiles of dopaminergic neurotransmission in the prefrontal cortex of the BALB/C vs. C57Bl/6 mice: consequences of stress and afobazole.

We found that in mice the basal activity of monoamine oxidase B (MAO-B) in the medial prefrontal cortex (mPFC) is lower in BALB/C than in C57Bl/6J mice, whereas activity of MAO-A is similar between strains. BALB/C mice, in comparison to C57Bl/6N mice, have higher basal content of dopamine in the mPFC, in both microdialysates and tissue content. Novelty stress (open field test) elicits a further increase in the microdialysate levels of dopamine in BALB/C, but not in C57Bl/6N mice; a subsequent accumulation of extracellular 3,4-dioxyphenylacetic acid (DOPAC) reaffirms the difference in catabolic capacity of monoaminergic systems between the strains.

Experimental evidence for sildenafil's action in the central nervous system: dopamine and serotonin changes in the medial preoptic area and nucleus accumbens during sexual arousal.

Introduction: Sildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc).

Altered basal and stimulated accumbens dopamine release in obese OLETF rats as a function of age and diabetic status.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking the CCK-1 receptor is hyperphagic, prefers palatable and high-calorie meals, and gradually develops obesity and type 2 diabetes. To determine dopamine levels in this strain, we used in vivo quantitative (no net flux) microdialysis at three different ages representing nondiabetic (8 wk), prediabetic (18 wk), and diabetic (56 wk) stages in OLETF and age-matched lean Long-Evans Tokushima Otsuka (LETO) controls. Results showed significantly elevated basal dopamine levels in the caudomedial nucleus accumbens of OLETF rats compared with LETO at younger ages (8 wk: 20.

Changes in the striatal extracellular levels of dopamine and dihydroxyphenylacetic acid evoked by ammonia and N-methyl-D-aspartate: modulation by taurine.

Acute hyperammonemia is associated with motor disturbances that are thought to involve striatal dopaminergic dysfunction. Discharge of striatal dopaminergic neurons is controlled by N-methyl-D-aspartate (NMDA) receptors, the excessive activation of which contributes to ammonia neurotoxicity. Here we show that ammonium chloride ("ammonia", extracellular concentration 5 mM) or NMDA (1 mM), when directly administered to the rat striatum via a microdialysis probe, evoke a prompt accumulation of dopamine (DA) in the microdialysates.

Effect of sulpiride on the amphetamine-induced changes in extracellular dopamine, DOPAC, and hydroxyl radical generation in the rat striatum.

The neurotoxic effects of psychostimulants are mediated by several mechanisms, which together lead to neuronal damage. These mechanisms include an increase in the extracellular content of dopamine, stimulation of dopamine oxidation, accumulation of extracellular glutamate, and an increase in body temperature. In the present study, the dopamine receptor antagonist sulpiride proved able to prevent the delayed loss of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and depressed the gradual generation of hydroxyl radicals induced in the rat striatum by D-amphetamine.

Taurine reduces ammonia- and N-methyl-D-aspartate-induced accumulation of cyclic GMP and hydroxyl radicals in microdialysates of the rat striatum.

Acute ammonia neurotoxicity caused by intraperitoneal administration of ammonium salts is mediated by overactivation of N-methyl-D-aspartate (NMDA) receptors, with ensuing generation of free radicals and extracellular accumulation of cyclic GMP (cGMP) arising from stimulation of nitric oxide (NO) synthesis. In this study, infusion of ammonium chloride or NMDA into the striata of rats via microdialysis probes increased the contents of cyclic GMP and hydroxyl radicals in the microdialysates. Co-infusion of taurine virtually abolished both the ammonia- and NMDA-induced accumulation of cGMP.