Differential effects of sleep deprivation on behavior and microglia in a brain-region-specific manner in young and aged male mice.

Microglia, resident immune cells in the central nervous system, constantly monitor the state of the surrounding brain activity. The animal model induced by sleep deprivation (SD) is widely used to study the pathophysiological mechanisms of insomnia and bipolar disorder. However, it remains unclear whether SD affects behaviors in young and aged male mice and microglia in various brain regions. In this study, we confirmed brain region-specific changes in microglial density and morphology in the accumbens nucleus (Acb), amygdala (AMY), cerebellum (Cb), corpus callosum (cc), caudate putamen, hippocampus (HIP), hypothalamus (HYP), medial prefrontal cortex (mPFC), and thalamus (TH) of young mice. In addition, the density of microglia in old mice was higher than that in young mice. Compared with young mice, old mice showed a markedly increased microglial size, decreased total length of microglial processes, and decreased maximum length. Importantly, we found that 48-h SD decreased microglial density and morphology in old mice, whereas SD increased microglial density and morphology in most observed brain regions in young mice. SD-induced hyperactivity was observed only in young mice but not in old mice. Moreover, microglial density (HIP, AMY, mPFC, CPu) was significantly positively correlated with behaviors in SD- and vehicle-treated young mice. Contrarily, negative correlations were shown between the microglial density (cc, Cb, TH, HYP, Acb, AMY) and behaviors in vehicle-treated young and old mice. These results suggest that SD dysregulates the homeostatic state of microglia in a region- and age-dependent manner. Microglia may be involved in regulating age-related behavioral responses to SD.

Dynamic changes in microglia in the mouse hippocampus during administration and withdrawal of the CSF1R inhibitor PLX3397.

Pexidartinib (PLX3397), a colony-stimulating factor-1 receptor (CSF1R) inhibitor, is currently in phase 1-3 clinical trials as a treatment for a variety of tumours. CSF1R signalling regulates the development, survival and maintenance of microglia, the resident brain innate immune cells. In this study, we examined the effects of PLX3397 in the drinking water of mice on microglia in the hippocampus using ionized calcium-binding adapter molecule 1 (Iba1, a microglial marker) immunocytochemistry. A high concentration of PLX3397 (1 mg/mL) significantly decreased the density of Iba1-immunoreactive cells after 7 days of exposure, but a low concentration of PLX3397 (0.5 mg/mL) did not. In addition, both low and high concentrations of PLX3397 significantly increased the intersection number, total length and maximum length of microglial processes in male mice. PLX3397 administered for 21 days eliminated microglia with 78% efficiency in males and 84% efficiency in females. Significant increases in microglial processes were found after both seven and 21 days of PLX3397 exposure in males, whereas decreases in microglial processes were observed after both 14 and 21 days of exposure in females. After PLX3397 withdrawal following its administration for 14 days in males, the soma size quickly returned to normal levels within a week. However, the microglial density, intersection number and total length of microglial processes after 3 days of recovery stabilized to untreated levels. In summary, these findings provide detailed insight into the dynamic changes in microglial number and morphology in the hippocampus in a dose- and time-dependent manner after PLX3397 treatment and withdrawal.

Sexual dimorphism in the bed nucleus of the stria terminalis, medial preoptic area and suprachiasmatic nucleus in male and female tree shrews.

Sex differences in behaviour partly arise from the sexual dimorphism of brain anatomy between males and females. However, the sexual dimorphism of the tree shrew brain is unclear. In the present study, we examined the detailed distribution of vasoactive intestinal polypeptide-immunoreactive (VIP-ir) neurons and fibres in the suprachiasmatic nucleus (SCN) and VIP-ir fibres in the bed nucleus of the stria terminalis (BST) of male and female tree shrews. The overall volume of the SCN in male tree shrews was comparable with that in females. However, males showed a significantly higher density of VIP-ir cells and fibres in the SCN than females. The shape of the VIP-stained area in coronal sections was arched, elongated or oval in the lateral division (STL) and the anterior part of the medial division (STMA) of the BST and oval or round in the posterior part of the medial division of the BST (STMP). The volume of the VIP-stained BST in male tree shrews was similar to that in females. The overall distribution of VIP-ir fibres was similar between the sexes throughout the BST except within the STMA, where darkly stained fibres were observed in males, whereas lightly stained fibres were observed in females. Furthermore, male tree shrews showed a significantly higher intensity of Nissl staining in the medial preoptic area (MPA) and the ventral part of the medial division of the BST than females. These findings are the first to reveal sexual dimorphism in the SCN, BST and MPA of the tree shrew brain, providing neuroanatomical evidence of sexual dimorphism in these regions related to their roles in sex differences in physiology and behaviour.

[Correlation between altered levels of neurotransmitters in the frontal lobe and hippocampus and behavioral abnormalities in a Clockdelta19 mutant mice modeling bipolar manic disorder].

OBJECTIVE: To explore the correlation between altered levels of neurotransmitters in the frontal lobe and hippocampus and behavioral abnormalities in a Clockdelta19 variant mice modeling bipolar disorder manic disorder. METHODS: Open field test and Elevated plus-maze test were carried out on the Clockdelta19 mutant and wild-type control groups. The frontal lobe and hippocampus of Clockdelta19 mutant mice and controls were dissected, and neurotransmitters in tissue extracts were analyzed by high-performance liquid chromatography and mass spectrometry. The concentration of neurotransmitters and behavioral indicators were assessed by t test and Pearson correlation analysis using SPSS 22.0. RESULTS: The Clockdelta19 mutant mice showed a significant increase in activity, albeit with no difference in the level of anxiety from the wild-type controls, which suggested that the Clockdelta19 mutant mice can be used as a model for manic attack of bipolar disorder. Altered neurotransmitter levels were detected in the frontal and hippocampal regions, including elevated histamine in the left hippocampus, reduced histamine in the right hippocampus, reduced gamma-aminobutyric acid (GABA) in bilateral hippocampus, elevated dihydroxyphenylalanine (DOPA) in the left frontal lobe and reduced DOPA in the right hippocampus, and decreased glutamine in bilateral frontal lobes. The reduced glutamine in the left frontal lobe and GABA in the right hippocampus correlated with the increased activity of Clockdelta19 mutant mice. CONCLUSION: Clockdelta19 mutant mice showed abnormal behavior with increased activity. Reduced glutamine in the left frontal lobe and GABA in the right hippocampus were correlated with increased activity.

Beneficial effects of enriched environment on behaviors were correlated with decreased estrogen and increased BDNF in the hippocampus of male mice.

OBJECTIVE: Previous studies reported that environmental enrichment might induce various beneficial effects in the central nervous system. However, the effect of environmental factors on endogenous estrogen level was not investigated. The present study was designed to examine the effect of enriched environment on endogenous estrogen in hippocampus and behavioral outcomes. METHODS: Behavioural measurements, including open field, elevated plus maze and Morris water maze, were used to evaluate anxiety and learning and memory of the male C57BL/6J mice that were housed in enriched environment for five months. In addition, the estrogen and brain-derived neurotrophic factor (BDNF) expression in the hippocampus were measured. RESULTS: We found that environmental enrichment decreased anxiety-like behaviors and facilitated spatial learning and memory in male C57BL/6J mice. In addition, the mice raised in enriched environment showed decreased endogenous estrogen levels both in the hippocampus and plasma compared to controls. Furthermore, our results indicated that environmental enrichment up-regulated BDNF mRNA expression level in the hippocampus. CONCLUSION: In conclusion, environmental enrichment decreased anxiety-like behaviors and facilitated spatial learning and memory in male C57BL/6J mice. Lastly, environmental enrichment up-regulated BDNF mRNA expression level in the hippocampus and decreased plasma estrogen level. The possible mechanism remained to be determined.

Dysconnectivity of the brain functional network and abnormally expressed peripheral transcriptional profiles in patients with anxious depression.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous mental disorder, and accompanying anxiety symptoms, known as anxious depression (AD), are the most common subtype. However, the pathophysiology of AD may be distinct in depressed patients without anxiety (NAD) and remains unknown. This study aimed to investigate the relationship between functional connectivity and peripheral transcriptional profiles in patients with AD and NAD. METHODS: Functional imaging data were collected to identify differences in functional networks among patients with AD (n = 66), patients with NAD (n = 115), and healthy controls (HC, n = 200). The peripheral transcriptional data were clustered as co-expression modules, and their associations with AD, AND, and HC were analyzed. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of the genes in the significant module were performed. Correlation analysis was performed to identify functional network-associated gene co-expression modules. RESULTS: A network was identified which consisted of 23 nodes and 28 edges that were significantly different among three sample groups. The regions of the network were located in temporal and occipital lobe. Two gene co-expression modules were shown to be associated with NAD, and one of which was correlated with the disrupted network in the AD group. The biological function of this module was enriched in immune regulation pathways. CONCLUSION: The results suggested that immune-related mechanisms were associated with functional networks in AD.

Abnormal functional connectivity within the prefrontal cortex is associated with multiple plasma lipid species in major depressive disorder.

BACKGROUND: Abnormalities in functional connectivity (FC) in major depressive disorder (MDD) have been widely reported. Analysis of the relationship between FC and plasma lipid profiles would be meaningful in the exploration of pathophysiological mechanisms and helpful for the identification of biomarkers for MDD. METHODS: Patients with MDD (n = 49) and healthy controls (HC, n = 87) were recruited. Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected for FC construction. The plasma lipid profiles were acquired using ultra-performance liquid chromatography (UPLC) and mass spectrometry (MS) analysis and clustered as co-expression modules. The differential FC and lipid modules between HCs and patients with MDD were identified, and then the association between FC and lipid co-expression modules was analyzed using correlation analysis. The modules associated molecular function was explored using metabolite set enrichment analysis (MSEA). RESULTS: MDD-associated FC and lipid co-expression modules were identified. One module was associated with FC values between the right orbital part of the middle frontal gyrus and the opercular part of the left inferior frontal gyrus, which was enriched in lipid sets of diacylglycerols and fatty alcohols; another module was associated with FC values between the right middle frontal gyrus and the right anterior cingulate and paracingulate gyri, which was enriched in lipid sets of glycerophosphocholines and glycerophosphoethanolamines. CONCLUSION: Our results indicated that abnormal FC in the prefrontal cortex is associated with multiple plasma lipid species, which may provide novel clues for exploring the pathophysiology of MDD.

The impact of childhood trauma on emotional distress and the moderating role of sense of coherence among college students in China.

Childhood trauma is strongly linked to emotional distress. However, few studies have explored the impact of sense of coherence (SOC) on the relationship between childhood trauma and emotional distress in college students. This study aimed to explore its impact on the relationship between childhood trauma and emotional distress. Analyzing data from 2307 Chinese college students, we found that SOC moderated the association between childhood trauma and anxiety/depression levels. Females showed higher SOC and lower anxiety/depression despite experiencing more childhood trauma. Multiple linear regression revealed that anxiety was negatively associated with SOC(P < 0.001) and grade(P = 0.027), and positively with childhood trauma(P < 0.001) and male gender(P = 0.004). Similarly, the depression exhibited similar associations. SOC moderated negatively the relationship between CTQ and anxiety, as well as between CTQ and depression. Childhood trauma is associated with increased emotional distress risk among college students, but a strong SOC can reduce this risk.

Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain.

Acute administration of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor (NMDAR) antagonist, can establish animal models of psychiatric disorders. However, the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown. Here, we found rapid elimination of microglia in the prefrontal cortex (PFC) and hippocampus (HPC) of mice following administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 (pexidartinib) in drinking water. Single administration of MK-801 induced hyperactivity in the open-field test (OFT). Importantly, PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801. However, neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity. Importantly, microglial density in the PFC and HPC was significantly correlated with behavioral changes. In addition, common and distinct glutamate-, GABA-, and inflammation-related gene (116 genes) expression patterns were observed in the brains of PLX3397- and/or MK-801-treated mice. Moreover, 10 common inflammation-related genes ( CD68, CD163, CD206, TMEM119, CSF3R, CX3CR1, TREM2, CD11b, CSF1R, and F4/80) with very strong correlations were identified in the brain using hierarchical clustering analysis. Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes ( NLRP3, CD163, CD206, F4/80, TMEM119, and TMEM176a), but not glutamate- or GABA-related genes in PLX3397- and MK-801-treated mice. Thus, our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist, which is associated with modulation of immune-related genes in the brain.

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia.

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ.

A Whole Transcriptome Analysis in Peripheral Blood Suggests That Energy Metabolism and Inflammation Are Involved in Major Depressive Disorder.

Introduction: Previous studies on transcriptional profiles suggested dysregulation of multiple RNA species in major depressive disorder (MDD). However, the interaction between different types of RNA was neglected. Therefore, integration of different RNA species in transcriptome analysis would be helpful for interpreting the functional readout of the transcriptome in MDD. Methods: A whole transcriptome sequencing were performed on the peripheral blood of 15 patients with MDD and 15 matched healthy controls (HCs). The differential expression of miRNAs, lncRNAs, circRNAs, and mRNAs was examined between MDD and HCs using empirical analysis of digital gene expression data in R (edgeR). Weighted correlation network analysis (WGCNA) was used to identify RNA co-expression modules associated with MDD. A ceRNA network was constructed for interpretation of interactions between different RNA species. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to explore potential biological mechanisms associated with MDD. Results: Multiple RNAs and co-expression modules were identified to be significantly dysregulated in MDD compared to HCs. Based on the differential RNAs, a ceRNA network that were dysregulated in MDD were constructed. The pathway networks that related to oxidative phosphorylation and the chemokine signaling were found to be associated with MDD. Conclusion: Our results suggested that the processes of energy metabolism and inflammation may be involved in the pathophysiology of MDD.

A combination of neuroimaging and plasma metabolomic analysis suggests inflammation is associated with white matter structural connectivity in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common mental disorder with unknown pathophysiology. The abnormality of white matter structural connectivity and dysregulation of metabolome in MDD had been widely reported previously. Exploration of the relationship between white matter structural connectivity and plasma metabolites would be helpful for explanation of molecular mechanism for the findings from neuroimaging researches in MDD. METHODS: The diffusion spectrum imaging data were collected for identification of difference of white matter structural connectivity between MDD (n = 49) and HC (n = 68). The plasma metabolite profiles were acquired by liquid chromatography-mass spectrometry analysis and clustered as co-expression modules. The correlation analysis was performed to identify structural connectivity associated metabolite. RESULTS: We identified two structural connectivity related metabolite modules. One module was correlated with fractional anisotropy (FA) value between left middle temporal gyrus and left inferior temporal gyrus, which were enriched in tryptophan metabolism pathway; another module was correlated with fiber numbers (FN) between right fusiform gyrus and right inferior temporal gyrus, which was enriched in lysophosphatidylcholine (LPC), lysophosphatidylinositol (LPI) and lysophosphatidylglycerol (LPG) lipid sets. l-Kynurenine in tryptophan metabolism pathway was negatively correlated with FN between right fusiform gyrus and right inferior temporal gyrus, and LPC was positively correlated with FA value between left middle temporal gyrus and left inferior temporal gyrus in MDD. LIMITATIONS: First, the sample size was relatively small. Second, the long-term effects of antidepressants were not excluded. CONCLUSION: The results suggested inflammation-related mechanism was associated with white matter structural connectivity in MDD.

Generation and characterization of human-derived iPSC lines from two cousins with schizophrenia and bipolar disorder and their unaffected cousin.

Schizophrenia (SCZ) and bipolar disorder (BD) are debilitating neurodevelopmental disorders with high heritability. In this study, peripheral blood mononuclear cells (PBMCs) were donated by three females. An adolescent female was clinically diagnosed as first-episode SCZ. One of her cousins was clinically diagnosed as BD and another one was unaffected control. Induced pluripotent stem cells (iPSCs) were established with reprograming factors Oct4, Sox2, Nanog, Lin28, c-myc, Klf4, and SV40LT. All lines presented normal karyotype and highly expressed pluripotency markers in vitro. All iPSCs were capable to differentiate into derivatives of three germ layers in vivo.

Generation and characterization of human-derived iPSC lines from one pair of dizygotic twins discordant for schizophrenia.

Schizophrenia (SCZ) is a debilitating neurodevelopmental disorder with a high heritability. In this study, peripheral blood mononuclear cells (PBMCs) were donated by a pair of dizygotic twins. The female was clinically diagnosed as SCZ by Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria, and her unaffected male sibling was healthy control. Induced pluripotent stem cells (iPSCs) were established using Episomal vectors carrying reprograming factors OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT. These lines with normal karyotype highly expressed pluripotency markers and are capable to differentiate into derivatives of three germ layers. Both lines are negative of mycoplasma.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway.

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Whole-Brain Afferent Inputs to the Caudate Nucleus, Putamen, and Accumbens Nucleus in the Tree Shrew Striatum.

Day-active tree shrews have a well-developed internal capsule (ic) that clearly separates the caudate nucleus (Cd) and putamen (Pu). The striatum consists of the Cd, ic, Pu, and accumbens nucleus (Acb). Here, we characterized the cytoarchitecture of the striatum and the whole-brain inputs to the Cd, Pu, and Acb in tree shrews by using immunohistochemistry and the retrograde tracer Fluoro-Gold (FG). Our data show the distribution patterns of parvalbumin (PV), nitric oxide synthase (NOS), calretinin (CR), and tyrosine hydroxylase (TH) immunoreactivity in the striatum of tree shrews, which were different from those observed in rats. The Cd and Pu mainly received inputs from the thalamus, motor cortex, somatosensory cortex, subthalamic nucleus, substantia nigra, and other cortical and subcortical regions, whereas the Acb primarily received inputs from the anterior olfactory nucleus, claustrum, infralimbic cortex, thalamus, raphe nucleus, parabrachial nucleus, ventral tegmental area, and so on. The Cd, Pu, and Acb received inputs from different neuronal populations in the ipsilateral (60, 67, and 63 brain regions, respectively) and contralateral (23, 20, and 36 brain regions, respectively) brain hemispheres. Overall, we demonstrate that there are species differences between tree shrews and rats in the density of PV, NOS, CR, and TH immunoreactivity in the striatum. Additionally, we mapped for the first time the distribution of whole-brain input neurons projecting to the striatum of tree shrews with FG injected into the Cd, Pu, and Acb. The similarities and differences in their brain-wide input patterns may provide new insights into the diverse functions of the striatal subregions.

Whole-brain mapping of afferent projections to the suprachiasmatic nucleus of the tree shrew.

The suprachiasmatic nucleus (SCN) is essential for the neural control of mammalian circadian timing system. The circadian activity of the SCN is modulated by its afferent projections. In the present study, we examine neuroanatomical characteristics and afferent projections of the SCN in the tree shrew (Tupaia belangeri chinensis) using immunocytochemistry and retrograde tracer Fluoro-Gold (FG). Distribution of the vasoactive intestinal peptide was present in the SCN from rostral to caudal, especially concentrated in its ventral part. FG-labeled neurons were observed in the lateral septal nucleus, septofimbrial nucleus, paraventricular thalamic nucleus, posterior hypothalamic nucleus, posterior complex of the thalamus, ventral subiculum, rostral linear nucleus of the raphe, periaqueductal gray, mesencephalic reticular formation, dorsal raphe nucleus, pedunculopontine tegmental nucleus, medial parabrachial nucleus, locus coeruleus, parvicellular reticular nucleus, intermediate reticular nucleus, and ventrolateral reticular nucleus. In summary, the morphology of the SCN in tree shrews is described from rostral to caudal. In addition, our data demonstrate for the first time that the SCN in tree shrews receives inputs from numerous brain regions in the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. This comprehensive knowledge of the afferent projections of the SCN in tree shrews provides further insights into the neural organization and physiological processes of circadian rhythms.

Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice.

Ketamine, a dissociative anaesthetic, has been used in the treatment of major depressive disorder (MDD) as a rapid acting antidepressant drug. Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in MDD patients. Lithium is a well-known mood stabilizer and has been widely used for the treatment of mania. It is not fully understood which forebrain regions are involved in ketamine- and lithium-induced expression of c-Fos. Therefore, our aim was to investigate the effect of chronic lithium treatment on mania-like behavior and c-Fos expression in the mouse forebrain activated by a single administration of ketamine. In the open field test, our results showed that ketamine significantly increased the total distance and total cumulative duration of movement in mice, while chronic lithium could attenuate these effects of ketamine. In addition, acute ketamine induced higher c-Fos expression in the lateral septal nucleus, hypothalamus, amygdala, and hippocampus of mice in the treatment group compared to those in the control group. However, chronic lithium inhibited the significant increase in c-Fos-immunoreactive neurons following acute ketamine administration in the dentate gyrus of the hippocampus, field CA1 of the hippocampus, dorsal subiculum, ventral subiculum, ventral subiculum, central amygdaloid nucleus and basolateral amygdaloid nucleus. In summary, our research shows that pretreatment with lithium moderates the effects of acute ketamine administration on mania-like behavior and c-Fos expression in the forebrain. These findings could be helpful in better understanding the episodes of mania related to ketamine treatment for MDD and bipolar disorder.

A plasma metabolomics study suggests alteration of multiple metabolic pathways in patients with bipolar disorder.

Previous omics studies have greatly contributed to our knowledge of bipolar disorder. Metabolomics is a relatively new field of omics science that can provide complementary insight into data obtained from genomics, transcriptomics or proteomics analyses. In this study, we aimed to identify metabolic pathways associated with bipolar disorder. We performed a liquid chromatography-mass spectrometry-based study to identify plasma metabolic profiles in patients with bipolar disorder (N = 91) and healthy controls (N = 92). Multivariate features selection by sparse partial least square-discriminant analysis combined with metabolite set enrichment analysis were used to identify metabolites and biological pathways that discriminate patients with bipolar disorder from healthy controls. The results showed that eighty metabolites in the plasma were identified to discriminate patients with bipolar disorder from healthy controls, and nine metabolic pathways, i.e., (1) glycine and serine metabolism, (2) glutamate metabolism, (3) arginine and proline metabolism, (4) tyrosine metabolism, (5) catecholamine biosynthesis, (6) purine metabolism, (7) amino sugar metabolism, (8) ammonia recycling, and (9) carnitine synthesis, were identified to be altered in bipolar disorder compared to healthy controls. We conclude that the 80 metabolites and nine metabolic pathways identified might serve as biomarkers to distinguish bipolar disorder patients from healthy controls.

Valproate Reverses Mania-Like Behavior of Clock delta19 Mouse and Alters Monoamine Neurotransmitters Metabolism in the Hippocampus.

BACKGROUND: Mice with a deletion at exon 19 of the circadian locomotor output cycles Kaput gene (Clock delta19) exhibit mania-like behavior and have been one of the most common animal models for bipolar disorder (BD). The predictive validity of the Clock delta19 was investigated via studies using lithium previously. Determination of effects of other mood stabilizers on Clock delta19 mouse would be helpful for better understanding of the mechanism underlined. METHODS: Wildtype (WT) and Clock delta19 mice were treated with saline (n = 10 for WT and n=10 for Clock delta19) or valproate (VPA) (n = 10 for WT and n=10 for Clock delta19) for 10 days. The hyperactivity, anxiety-like behaviors and depression-like behaviors were tested. The concentration of monoamine neurotransmitters and their metabolites in the hippocampus of saline or VPA treated WT and Clock delta19 mouse (n = 8 for each) were also determined. RESULTS: VPA can reverse hyperactivity, lower level of anxiety-like and depression-like behaviors of the Clock delta19 mouse. Clock delta19 mouse exhibited lower levels of serotonin (5-HT) and dopamine (DA) in right hippocampus compared to WT mouse. Chronic VPA treatment did not affect the levels of 5-HT and DA, but can reduce the level of levodopa (L-DOPA) in the right hippocampus of Clock delta19 mouse. CONCLUSION: Our results indicated that chronic VPA treatment can reverse the mania-like behaviors of the Clock delta19 mouse and further consolidate the validity of the Clock delta19 mouse as a model of BD. Monoamine neurotransmitters and their metabolites in the hippocampus are partly regulated by mutation of the Clock gene or VPA treatment.