Social stress-induced serotonin dysfunction activates spexin in male Nile tilapia (Oreochromis Niloticus).

Social disturbance in interpersonal relationships is the primary source of stress in humans. Spexin (SPX, SPX1a in cichlid), an evolutionarily conserved neuropeptide with diverse physiological functions, is up-regulated in the brain during chronic social defeat stress in teleost. On the other hand, repeated exposure to social stress can lead to dysregulation of the monoaminergic system and increase the vulnerability of developing depression. Since dysfunction of the serotonin (5-hydroxytryptamine, 5-HT) system is associated with social stress and the pathophysiology of depression, the present study investigated the regulatory relationship between the central 5-HT system and SPX1a in the male teleost, Nile tilapia (Oreochromis niloticus). To identify stress factors that regulate SPX1a gene expression, cortisol, dexamethasone (DEX), and 5-HT were used to treat tilapia brain primary cultures. Our study shows cortisol and DEX treatment had no effect on SPX1a gene expression, but SPX1a gene expression was down-regulated following 5-HT treatment. Anatomical localization showed a close association between 5-HT immunoreactive projections and SPX1a neurons in the semicircular torus. In addition, 5-HT receptors (5-HT2B) were expressed in SPX1a neurons. SPX1a immunoreactive neurons and SPX1a gene expression were significantly increased in socially defeated tilapia. On the other hand, citalopram (antidepressant, 5-HT antagonist) treatment to socially defeated tilapia normalized SPX1a gene expression to control levels. Taken together, the present study shows that 5-HT is an upstream regulator of SPX1a and that the inhibited 5-HT activates SPX1a during social defeat.

Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner.

The hypothalamic neurohormone kisspeptin-10 (KP-10) was inherently implicated in cholinergic pathologies when aberrant fluctuations of expression patterns and receptor densities were discerned in neurodegenerative micromilieus. That said, despite variable degrees of functional redundancy, KP-10, which is biologically governed by its cognate G-protein-coupled receptor, GPR54, attenuated the progressive demise of α-synuclein (α-syn)-rich cholinergic-like neurons. Under explicitly modeled environments, in silico algorithms further rationalized the surface complementarities between KP-10 and α-syn when KP-10 was unambiguously accommodated in the C-terminal binding pockets of α-syn. Indeed, the neuroprotective relevance of KP-10's binding mechanisms can be insinuated in the amelioration of α-syn-mediated neurotoxicity; yet it is obscure whether these extenuative circumstances are contingent upon prior GPR54 activation. Herein, choline acetyltransferase (ChAT)-positive SH-SY5Y neurons were engineered ad hoc to transiently overexpress human wild-type or E46K mutant α-syn while the mitigation of α-syn-induced neuronal death was ascertained via flow cytometric and immunocytochemical quantification. Recapitulating the specificity observed on cell viability, exogenously administered KP-10 (0.1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated apoptosis and mitochondrial depolarization in cholinergic differentiated neurons. In particular, co-administrations with a GPR54 antagonist, kisspeptin-234 (KP-234), failed to abrogate the robust neuroprotection elicited by KP-10, thereby signifying a GPR54 dispensable mechanism of action. Consistent with these observations, KP-10 treatment further diminished α-syn and ChAT immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn. Overall, these findings lend additional credence to the previous notion that KP-10's binding zone may harness efficacious moieties of neuroprotective intent.

Gender Differences in Cortisol and Cortisol Receptors in Depression: A Narrative Review.

Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies on the neuronal mechanisms of gender differences in mental health. Here, we discuss gender and cortisol in depression as presented by recent clinical studies, as well as gender differences in the role of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in stress-associated mental disorders. When examining clinical studies drawn from PubMed/MEDLINE (National Library of Medicine) and EMBASE, salivary cortisol generally showed no gender correlation. However, young males were reported to show heightened cortisol reactivity compared to females of similar age in depression. Pubertal hormones, age, early life stressors, and types of bio-samples for cortisol measurement affected the recorded cortisol levels. The role of GRs and MRs in the HPA axis could be different between males and females during depression, with increased HPA activity and upregulated MR expression in male mice, while the inverse happened in female mice. The functional heterogeneity and imbalance of GRs and MRs in the brain may explain gender differences in mental disorders. This knowledge and understanding will support the development of gender-specific diagnostic markers involving GRs and MRs in depression.

Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro.

The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-ß (Aß) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aß toxicity via an extracellular binding mechanism may provide a new horizon for innovative drug design endeavors. Considering the sequence similarities between α-syn's non-amyloid-ß component (NAC) and Aß's C-terminus, we hypothesized that KP-10 would enhance cholinergic neuronal resistance against α-syn's deleterious consequences through preferential binding. Here, human cholinergic SH-SY5Y cells were transiently transformed to upsurge the mRNA expression of α-syn while α-syn-mediated cholinergic toxicity was quantified utilizing a standardized viability-based assay. Remarkably, the E46K mutant α-syn displayed elevated α-syn mRNA levels, which subsequently induced more cellular toxicity compared with the wild-type α-syn in choline acetyltransferase (ChAT)-positive cholinergic neurons. Treatment with a high concentration of KP-10 (10 µM) further decreased cholinergic cell viability, while low concentrations of KP-10 (0.01-1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated toxicity. Correlating with the in vitro observations are approximations from in silico algorithms, which inferred that KP-10 binds favorably to the C-terminal residues of wild-type and E46K mutant α-syn with CDOCKER energy scores of -118.049 kcal/mol and -114.869 kcal/mol, respectively. Over the course of 50 ns simulation time, explicit-solvent molecular dynamics conjointly revealed that the docked complexes were relatively stable despite small-scale fluctuations upon assembly. Taken together, our findings insinuate that KP-10 may serve as a novel therapeutic scaffold with far-reaching implications for the conceptualization of α-syn-based treatments.

Brain Beta-Catenin Signalling During Stress and Depression.

Beta-catenin is a protein with dual functions in the cell, playing a role in both adhesion between cells as well as gene transcription via the canonical Wnt signalling pathway. In the canonical Wnt signalling pathway, beta-catenin again plays multiple roles. In the embryonic stage, the regulation of beta-catenin levels activates genes that govern cell proliferation and differentiation. In an adult organism, beta-catenin continues to regulate the cell cycle - as a result over-expression of beta-catenin may lead to cancer. In the brain, dysfunctions in Wnt signalling related to beta-catenin levels may also cause various pathological conditions like Alzheimer's disease, Parkinson's disease, and depression. Beta-catenin can be influenced by stressful conditions and increases in glucocorticoid levels. In addition, beta-catenin can be regulated by neurotransmitters such as serotonin and dopamine. Fluctuations in beta-catenin in brain regions under duress have been associated with depressive-like behaviours. It is theorized that the change in behaviour can be attributed to the regulation of Dicer by beta-catenin. Dicer, a protein that produces micro-RNAs in the cell, is a target gene for beta-catenin. Amongst the micro-RNA that it produces are those involved in stress resilience. In this way, beta-catenin has taken its place in the well-studied biochemistry of stress and depression, and future research into this interesting protein may yet yield fruitful results in that field.

Early-life exposure to Tris(1,3-dichloroisopropyl) phosphate induces dose-dependent suppression of sexual behavior in male rats.

Exposure to endocrine-disrupting chemicals may adversely affect animals, particularly during development. Tris(1,3-dichloroisopropyl) phosphate (TDCIPP) is an organophosphate with anti-androgen function in vitro that is present in indoor dust at relatively high concentrations. In male rats, androgens are necessary for the development of reproductive organs, as well as the endocrine and central nervous systems. However, we currently do not know the exact effects of TDCIPP exposure through suckling on subsequent reproductive behavior in males. Here, we show that TDCIPP exposure (25-250 mg kg-1 via oral administration over 28 consecutive days post-birth) suppressed male sexual behavior and reduced testes size. These changes were dose-dependent and appeared first in adults rather than in juveniles. These results demonstrate that TDCIPP exposure led to normal body growth and appearance in juveniles, but disrupted the endocrine system and physiology in adults. Therefore, assays should be performed using adult animals to ensure accuracy, and to confirm the influence of chemical substances given during early mammalian life.

Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7.

Gonadotropin-inhibitory hormone (GnIH) acts as a negative regulator of reproduction by acting on gonadotropes and gonadotropin-releasing hormone (GnRH) neurons. Despite its functional significance, the molecular mechanism of GnIH action in the target cells has not been fully elucidated. To expand our previous study on GnIH actions in gonadotropes, we investigated the potential signal transduction pathway that conveys the inhibitory action of GnIH in GnRH neurons by using the GnRH neuronal cell line, GT1-7. We examined whether GnIH inhibits the action of kisspeptin and vasoactive intestinal polypeptide (VIP), positive regulators of GnRH neurons. Although GnIH significantly suppressed the stimulatory effect of kisspeptin on GnRH release in hypothalamic culture, GnIH had no inhibitory effect on kisspeptin stimulation of serum response element and nuclear factor of activated T-cell response element activities and ERK phosphorylation, indicating that GnIH may not directly inhibit kisspeptin signaling in GnRH neurons. On the contrary, GnIH effectively eliminated the stimulatory effect of VIP on p38 and ERK phosphorylation, c-Fos mRNA expression, and GnRH release. The use of pharmacological modulators strongly demonstrated the specific inhibitory action of GnIH on the adenylate cyclase/cAMP/protein kinase A pathway, suggesting a common inhibitory mechanism of GnIH action in GnRH neurons and gonadotropes.-Son, Y. L., Ubuka, T., Soga, T., Yamamoto, K., Bentley, G. E., Tsutsui, K. Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7.

MicroRNA expression signature of methamphetamine use and addiction in the rat nucleus accumbens.

Methamphetamine (METH) is a highly addictive psycho-stimulant that induces behavioral changes due to high level of METH-induced dopamine in the brain. Nucleus accumbens (NAc) plays an important role in these changes, especially in drug addiction. However, little is known about the underlying molecular mechanisms of METH-induced addiction. The objective of this study was to establish a behavioral model of METH use and addiction using escalating doses of METH over 15 days and to determine the global miRNA expression profiling in NAc of METH-addicted rats. In the behavioral study, the experimental rats were divided into 3 groups of 9 each: a control group, a single dose METH (5 mg/kg) treatment group and a continuous 15 alternate days METH (0.25, 0.5, 1, 2, 3, 4, 5 mg/kg) treatment group. Following that, six rats in each group were randomly selected for global miRNA profiling. Addiction behavior in rats was established using Conditioned Place Preference task. The analysis of the miRNA profiling in the NAc was performed using Affymetric microarray GeneChip® System. The findings indicated that a continuous 15 alternate days METH treatment rats showed a preference for the drug-paired compartment of the CPP. However, a one-time acute treatment with 5 mg/kg METH did not show any significant difference in preference when compared with controls. Differential profiling of miRNAs indicated that 166 miRNAs were up-regulated and 4 down-regulated in the chronic METH-treatment group when compared to controls. In comparing the chronic treatment group with the acute treatment group, 52 miRNAs were shown to be up-regulated and 7 were down-regulated. MiRNAs including miR-496-3p, miR-194-5p, miR-200b-3p and miR-181a-5p, were found to be significantly associated with METH addiction. Canonical pathway analysis revealed that a high number of METH addiction-related miRNAs play important roles in the MAPK, CREB, G-Protein Couple Receptor and GnRH Signaling pathways. Our results suggest that dynamic changes occur in the expression of miRNAs following METH exposure and addiction.

Early-life stress changes expression of GnRH and kisspeptin genes and DNA methylation of GnRH3 promoter in the adult zebrafish brain.

Early-life stress can cause long-term effects in the adulthood such as alterations in behaviour, brain functions and reproduction. DNA methylation is a mechanism of epigenetic change caused by early-life stress. Dexamethasone (DEX) was administered to zebrafish larvae to study its effect on reproductive dysfunction. The level of GnRH2, GnRH3, Kiss1 and Kiss2 mRNAs were measured between different doses of DEX treatment groups in adult zebrafish. Kiss1 and GnRH2 expression were increased in the 200mg/L DEX treated while Kiss2 and GnRH3 mRNA levels were up-regulated in the 2mg/L DEX-treated zebrafish. The up-regulation may be related to programming effect of DEX in the zebrafish larvae, causing overcompensation mechanism to increase the mRNA levels. Furthermore, DEX treatment caused negative impact on the development and maturation of the testes, in particular spermatogenesis. Therefore, immature gonadal development may cause positive feedback by increasing GnRH and Kiss. This indicates that DEX can alter the regulation of GnRH2, GnRH3, Kiss1 and Kiss2 in adult zebrafish, which affects maturation of gonads. Computer analysis of 1.5 kb region upstream of the 5' UTR of Kiss1, Kiss2, GnRH2 and GnRH3 promoter showed that there are putative binding sites of glucocorticoid response element and transcription factors involved in stress response. GnRH3 promoter analysed from pre-optic area, ventral telencephalon and ventral olfactory bulb showed higher methylation at CpG residues located on -1410, -1377 and -1355 between control and 2mg/L DEX-treated groups. Hence, early-life DEX treatment can alter methylation of GnRH3 gene promoter, which subsequently affects gene regulation and reproductive functions.

[Association between Service Utilization Patterns and Frailty in the Elderly Certified at the Support Level in the Long-term Care Insurance System].

OBJECTIVES: This cross-sectional study clarified the association between service utilization patterns and frailty in the elderly certified at the support level in Japan's long-term care insurance (LTCI) system. METHODS: We analyzed 710 subjects who completed in-home assessments and interviews from 1,033 elderly aged 65 and over living in Izumiotsu who had been certified at the LTCI support level in August 2014. The long-term service utilization data were collected from the local governmental office. Frailty was examined by the in-home structured assessment conducted by local health and welfare professionals. As frailty indicators, we measured subjects' frailty using the Kaigo-Yobo-Checklist (CL frailty), handgrip strength, body mass index, depression, and cognitive function. Long-term service utilization patterns were classified into five patterns: (1) home helper service only, (2) day care service only, (3) home helper and day care service, (4) one or more other services (using at least one other service regardless of home helper or day care), and (5) no service utilization. Odds ratios (ORs) of each frailty indicator were estimated by service utilization patterns by using logistic regression analyses adjusted for demographic characteristics, with the other services group as the reference category. RESULTS: Out of 710 subjects (100%), the proportions of the service utilization patterns were as follows: home helper service only, 17.9%; day care service only, 15.6%; home helper and day care service, 13.1%; one or more other services, 27.0%; and no service utilization, 26.3%. The logistic regression analyses showed that compared with the one or more other services group, the day care service only group had lower odds of CL frailty (OR=0.57, 95% confidence interval (CI)=0.34 to 0.95) and lower odds of low handgrip strength (OR=0.59, 95% CI=0.35 to 1.00). The no service utilization group had lower odds of CL frailty (OR=0.50, 95% CI=0.32 to 0.79) and lower odds of low handgrip strength (OR=0.58, 95% CI=0.37 to 0.91). The home helper service only group had higher odds of low handgrip strength (OR=1.91, 95% CI=1.11 to 3.29). CONCLUSION: Long-term service utilization patterns of the elderly certified at the support level in the LTCI system were associated with frailty. Classifying frailty characteristics by long-term service utilization patterns may be considered as a method to provide community-based resources and support for older adults in the community.

Maternal dexamethasone exposure inhibits the gonadotropin-releasing hormone neuronal movement in the preoptic area of rat offspring.

Migration and final positioning of gonadotropin-releasing hormone (GnRH) neurons in the preoptic area (POA) is critical for reproduction. It is known that maternal dexamethasone (DEX) exposure impairs reproductive function and behaviour in the offspring. However, it is still not known whether maternal DEX exposure affects the postnatal GnRH neurons in the offspring. This study determined the neuronal movement of enhanced green fluorescent protein (EGFP)-tagged GnRH neurons in slice culture of postnatal day 0 (P0), P5 and P50-60 transgenic male rats. Effect of maternal DEX treatment on EGFP-GnRH neuronal movement and F-actin distribution on GnRH neurons at P0 stage were studied. Time-lapse analysis of P0 and P5 EGFP-GnRH neurons displayed active cellular movement within the POA compared to young adult P50-60 stages, suggesting possible fine-tuning movement for positioning of early postnatal GnRH neurons. The DEX-treated EGFP-GnRH neurons demonstrated decreased motility in the POA and reduced F-actin distribution in the GnRH neurons at 60 h culture compared to the vehicle-treated. These results suggest that the P0 GnRH neuronal movement in the POA is altered by maternal DEX exposure, which possibly disrupts the fine-tuning process for positioning and development of early postnatal GnRH neurons in the brain, potentially linked to reproductive dysfunction in adulthood.

Maternal dexamethasone exposure during pregnancy in rats disrupts gonadotropin-releasing hormone neuronal development in the offspring.

The migration of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode to the preoptic area (POA) from embryonic day 13 is important for successful reproduction during adulthood. Whether maternal glucocorticoid exposure alters GnRH neuronal morphology and number in the offspring is unknown. This study determines the effect of maternal dexamethasone (DEX) exposure on enhanced green fluorescent protein (EGFP) driven by GnRH promoter neurons (TG-GnRH) in transgenic rats dual-labelled with GnRH immunofluorescence (IF-GnRH). The TG-GnRH neurons were examined in intact male and female rats at different postnatal ages, as a marker for GnRH promoter activity. Pregnant females were subcutaneously injected with DEX (0.1 mg/kg) or vehicle daily during gestation days 13-20 to examine the number of GnRH neurons in P0 male offspring. The total number of TG-GnRH neurons and TG-GnRH/IF-GnRH neuronal ratio increased from P0 and P5 stages to P47-52 stages, suggesting temporal regulation of GnRH promoter activity during postnatal development in intact rats. In DEX-treated P0 males, the number of IF-GnRH neurons decreased within the medial septum, organum vasculosom of the lamina terminalis (OVLT) and anterior hypothalamus. The percentage of TG-GnRH neurons with branched dendritic structures decreased in the OVLT of DEX-P0 males. These results suggest that maternal DEX exposure affects the number and dendritic development of early postnatal GnRH neurons in the OVLT/POA, which may lead to altered reproductive functions in adults.

Comparative Side-Effects of Neurosurgical Treatment of Treatment-Resistant Depression.

INTRODUCTION: Treatment-resistant depression (TRD) is a condition in which patients suffering from depression no longer respond to common methods of treatment, such as anti-depressant medication. Neurosurgical procedures such as ablative surgery, deep brain stimulation, and vagus nerve stimulation have been used in efforts to overcome TRD. OBJECTIVES: This review aims to provide an overview of the side effects of neurosurgery performed in clinical studies related to depression. METHODS: A literature search was conducted through PubMed, MEDLINE, EMBASE, Ovid, and ClinicalTrials.gov databases. RESULTS: This review selected 10 studies for ablative surgery, 12 for deep brain stimulation, and 10 for vagus nerve stimulation, analyzing their side effect profiles of neurosurgery for TRD. The major side effects of each type of neurosurgery were identified, such as incontinence and confusion for ablative surgery, headaches and increased suicide ideation for deep brain stimulation, and voice hoarseness and dyspnea for vagus nerve stimulation. CONCLUSION: The review discusses the merits and demerits of neurosurgery as a treatment option for TRD. It also suggests new insights into decreasing the burden of these neurosurgical side effects so that they can be a viable, high-efficacy treatment method for TRD.

Accelerated biological brain aging in major depressive disorder.

Major depressive disorder (MDD) patients commonly encounter multiple types of functional disabilities, such as social, physical, and role functioning. MDD is related to an accreted risk of brain atrophy, aging-associated brain diseases, and mortality. Based on recently available studies, there are correlations between notable biological brain aging and MDD in adulthood. Despite several clinical and epidemiological studies that associate MDD with aging phenotypes, the underlying mechanisms in the brain remain unknown. The key areas in the study of biological brain aging in MDD are structural brain aging, impairment in functional connectivity, and the impact on cognitive function and age-related disorders. Various measurements have been used to determine the severity of brain aging, such as the brain age gap estimate (BrainAGE) or brain-predicted age difference (BrainPAD). This review summarized the current results of brain imaging data on the similarities between the manifestation of brain structural changes and the age-associated processes in MDD. This review also provided recent evidence of BrainPAD or BrainAGE scores in MDD, brain structural abnormalities, and functional connectivity, which are commonly observed between MDD and age-associated processes. It serves as a basis of current reference for future research on the potential areas of investigation for diagnostic, preventive, and potentially therapeutic purposes for brain aging in MDD.

Caffeine neuroprotects against dexamethasone-induced anxiety-like behaviour in the Zebrafish (Danio rerio).

The early-life stress has critical impact on brain development which can lead to long-term effects on brain functions during adulthood. It has been reported that caffeine possesses a protective effect in neurodegenerative diseases. Thus, this study investigates the potential of caffeine to protect brain functions from adverse effects due to stress exposure during early-life development in the male zebrafish. In the first part of this study, synthetic glucocorticoid, dexamethasone (DEX) (2-200 mg/L for 24 h) was used to induce stress effects in the zebrafish larvae from 4 to 5 days post-fertilisation (dpf) and the effect of DEX administration on zebrafish larvae on anxiety-like behaviour during adulthood in novel tank test was investigated. Next, the possible protective effect of caffeine pre-treatment (5-50 mg/L for 24 h from 3 to 4dpf) before DEX administration was studied. DEX-treated adult male zebrafish showed higher anxiety levels in behavioural tests, as seen in longer latency to enter the top part of the tank, lower transition numbers between the top and bottom parts with more time spent at the bottom and lesser time spent at the top and lower distance travelled at top part. The effect of DEX on anxiety-like behaviour was dose-dependent. Importantly, adult male zebrafish pre-treated with caffeine before DEX treatment did not show any anxiety-like behaviour. These results show that exposure to stress during early-life leads to anxiety-like behaviour in the adult male zebrafish but pre-treatment with caffeine protects from stress-induced anxiety.

Estrogenic regulation of Kiss1 mRNA variants in Hatano rats.

Differences in reproductive endocrinology distinguish Hatano high-avoidance animals (HAA) from low-avoidance animals (LAA). Compared to HAA rats, female LAA rats secrete low levels of basal luteinizing hormone (LH) and a reduced LH surge. To investigate the underlying cause of the differences between the two strains, levels of the following mRNAs were measured in the hypothalamus of intact and ovariectomized (OVX) females treated with vehicle control or estradiol-17ß (E2): gonadotropin-releasing hormone (Gnrh), newly isolated rat kisspeptin (Kiss)1 mRNA variant-1 (Kiss1V1) and variant-2 (Kiss1V2) and estrogen receptor (Er) α. In OVX-HAA rats, the levels of Gnrh mRNA in the preoptic area (POA) 30 h after E2 treatment were significantly higher than in OVX-LAA rats. For HAA rats, the levels of Kiss1V1 and Kiss1V2 mRNA in the anteroventral periventricular nucleus (AVPV) were significantly higher in the E2-treated group than in the vehicle-treated group. In the arcuate nucleus (Arc) of HAA rats, Kiss1V1 and Kiss1V2 expression was significantly lower in E2-treated females compared to vehicle-treated females. Kiss1V2 expression was significantly higher than Kiss1V1 expression in intact HAA rats. In E2-treated OVX-LAA rats, there were no changes in the expression levels of Gnrh, Kiss1V1 or Kiss1V2. In intact LAA rats, no differences were observed in the expression levels of Kiss1V1 or Kiss1V2 in the AVPV, but the expression levels of these mRNAs in the Arc were significantly lower in E2-treated OVX-LAA rats. Additionally, no strain differences were observed for Erα mRNA expression in either the AVPV or Arc. These results indicate that the failure of estrogenic regulation of GnRH neurons in the POA and of kisspeptin neurons in the AVPV of LAA rats causes low LH secretion and reduced reproductive function.

Cannabinoids: Emerging sleep modulator.

Sleep is an essential biological phase of our daily life cycle and is necessary for maintaining homeostasis, alertness, metabolism, cognition, and other key functions across the animal kingdom. Dysfunctional sleep leads to deleterious effects on health, mood, and cognition, including memory deficits and an increased risk of diabetes, stroke, and neurological disorders. Sleep is regulated by several brain neuronal circuits, neuromodulators, and neurotransmitters, where cannabinoids have been increasingly found to play a part in its modulation. Cannabinoids, a group of lipid metabolites, are regulatory molecules that bind mainly to cannabinoid receptors (CB1 and CB2). Much evidence supports the role of cannabinoid receptors in the modulation of sleep, where their alteration exhibits sleep-promoting effects, including an increase in non-rapid-eye movement sleep and a reduction in sleep latency. However, the pharmacological alteration of CB1 receptors is associated with adverse psychotropic effects, which are not exhibited in CB2 receptor alteration. Hence, selective alteration of CB2 receptors is also of clinical importance, where it could potentially be used in treating sleep disorders. Thus, it is crucial to understand the neurobiological basis of cannabinoids in sleep physiology. In this review article, the alteration of the endocannabinoid system by various cannabinoids and their respective effects on the sleep-wake cycle are discussed based on recent findings. The mechanisms of the cannabinoid receptors on sleep and wakefulness are also explored for their clinical implications and potential therapeutic use on sleep disorders.

Teleosts as behaviour test models for social stress.

Stress is an important aspect of our everyday life and exposure to it is an unavoidable occurrence. In humans, this can come in the form of social stress or physical stress from an injury. Studies in animal models have helped researchers to understand the body's adaptive response to stress in human. Notably, the use of behavioural tests in animal models plays a pivotal role in understanding the neural, endocrine and behavioural changes induced by social stress. Under socially stressed conditions, behavioural parameters are often measured physiological and molecular parameters as changes in behaviour are direct responses to stress and are easily assessed by behavioural tests. Throughout the past few decades, the rodent model has been used as a well-established animal model for stress and behavioural changes. Recently, more attention has been drawn towards using fish as an animal model. Common fish models such as zebrafish, medaka, and African cichlids have the advantage of a higher rate of reproduction, easier handling techniques, sociability and most importantly, share evolutionary conserved genetic make-up, neural circuitry, neuropeptide molecular structure and function with mammalian species. In fact, some fish species exhibit a clear diurnal or seasonal rhythmicity in their stress response, similar to humans, as opposed to rodents. Various social stress models have been established in fish including but not limited to chronic social defeat stress, social stress avoidance, and social stress-related decision-making. The huge variety of behavioural patterns in teleost also aids in the study of more behavioural phenotypes than the mammalian species. In this review, we focus on the use of fish models as alternative models to study the effects of stress on different types of behaviours. Finally, fish behavioural tests against the typical mammalian model-based behavioural test are compared and discussed for their viability.

The Molecular Effects of Environmental Enrichment on Alzheimer's Disease.

Environmental enrichment (EE) is an environmental paradigm encompassing sensory, cognitive, and physical stimulation at a heightened level. Previous studies have reported the beneficial effects of EE in the brain, particularly in the hippocampus. EE improves cognitive function as well as ameliorates depressive and anxiety-like behaviors, making it a potentially effective neuroprotective strategy against neurodegenerative diseases such as Alzheimer's disease (AD). Here, we summarize the current evidence for EE as a neuroprotective strategy as well as the potential molecular pathways that can explain the effects of EE from a biochemical perspective using animal models. The effectiveness of EE in enhancing brain activity against neurodegeneration is explored with a view to differences present in early and late life EE exposure, with its potential application in human being discussed. We discuss EE as one of the non pharmacological approaches in preventing or delaying the onset of AD for future research.