Distinctiveness and continuity in transcriptome and connectivity in the anterior-posterior axis of the paraventricular nucleus of the thalamus.

The paraventricular nucleus of the thalamus (PVT) projects axons to multiple areas, mediates a wide range of behaviors, and exhibits regional heterogeneity in both functions and axonal projections. Still, questions regarding the cell types present in the PVT and the extent of their differences remain inadequately addressed. We applied single-cell RNA sequencing to depict the transcriptomic characteristics of mouse PVT neurons. We found that one of the most significant variances in the PVT transcriptome corresponded to the anterior-posterior axis. While the single-cell transcriptome classified PVT neurons into five types, our transcriptomic and histological analyses showed continuity among the cell types. We discovered that anterior and posterior subpopulations had nearly non-overlapping projection patterns, while another population showed intermediate patterns. In addition, these subpopulations responded differently to appetite-related neuropeptides, with their activation showing opposing effects on food consumption. Our studies unveiled the contrasts and the continuity of PVT neurons that underpin their function.

GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice.

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.

Genetic variation of melatonin productivity in laboratory mice under domestication.

Melatonin is a pineal hormone produced at night; however, many strains of laboratory mice are deficient in melatonin. Strangely enough, the gene encoding HIOMT enzyme (also known as ASMT) that catalyzes the last step of melatonin synthesis is still unidentified in the house mouse (Mus musculus) despite the completion of the genome sequence. Here we report the identification of the mouse Hiomt gene, which was mapped to the pseudoautosomal region (PAR) of sex chromosomes. The gene was highly polymorphic, and nonsynonymous SNPs were found in melatonin-deficient strains. In C57BL/6 strain, there are two mutations, both of which markedly reduce protein expression. Mutability of the Hiomt likely due to a high recombination rate in the PAR could be the genomic basis for the high prevalence of melatonin deficiency. To understand the physiologic basis, we examined a wild-derived strain, MSM/Ms, which produced melatonin more under a short-day condition than a long-day condition, accompanied by increased Hiomt expression. We generated F2 intercrosses between MSM/Ms and C57BL/6 strains and N2 backcrosses to investigate the role of melatonin productivity on the physiology of mice. Although there was no apparent effect of melatonin productivity on the circadian behaviors, testis development was significantly promoted in melatonin-deficient mice. Exogenous melatonin also had the antigonadal action in mice of a melatonin-deficient strain. These findings suggest a favorable impact of melatonin deficiency due to Hiomt mutations on domestic mice in breeding colonies.

Hemodynamic responses of eye movement desensitization and reprocessing in posttraumatic stress disorder.

Eye movement desensitization and reprocessing (EMDR) is an effective psychological intervention for posttraumatic stress disorder (PTSD). Trauma-related recall (Recall) with eye movements (EMs) is thought to reduce distress. However, the neural mechanisms underlying this process remain unknown. Thirteen patients with PTSD received EMDR treatment over the course of 2-10 weeks. We assessed the change in hemoglobin concentration in the lateral prefrontal cortex (PFC) during Recall with and without EM using multi-channel near-infrared spectroscopy (NIRS). Clinical diagnosis and improvement were evaluated using the Clinician-Administered PTSD Scale. Recall with EM was associated with a significant decrease in oxygenated hemoglobin concentration ([oxy-Hb]) in the lateral PFC as compared with Recall without EM. Longitudinally, [oxy-Hb] during Recall significantly decreased and the amount of decrease was significantly correlated with clinical improvement when the post-treatment data was compared with that of the pre-treatment. Our results suggest that performing EM during Recall reduces the over-activity of the lateral PFC, which may be part of the biological basis for the efficacy of EMDR in PTSD. NIRS may be a useful tool for objective assessment of psychological intervention in PTSD.

Attenuated BDNF-induced upregulation of GABAergic markers in neurons lacking Xbp1.

XBP1 is a transcription factor induced by unconventional splicing associated with endoplasmic reticulum stress and plays a role in development. Brain-derived neurotrophic factor (BDNF) causes splicing of Xbp1 mRNA in neurites, and Xbp1 is required for BDNF-induced neurite extension and branching. To search for the molecular mechanisms of how Xbp1 plays a role in neural development, comprehensive gene expression analysis was performed in primary telencephalic neurons obtained from Xbp1 knockout mice at embryonic day 12.5. By searching for the genes induced by BDNF in wild type neurons but not in Xbp1 knockout mice, we found that upregulation of three GABAergic markers, somatostatin (Sst), neuropeptide Y (Npy), and calbindin (Calb1), were compromised in Xbp1 knockout neurons. Attenuated upregulation of Npy and Calb1 in Xbp1 knockout neurons was confirmed by quantitative RT-PCR. This finding may be relevant to impaired BDNF-induced neurite extension in Xbp1 knockout neurons.

Expression of mitochondria-related genes in lymphoblastoid cells from patients with bipolar disorder.

OBJECTIVES: Several studies have suggested mitochondrial abnormality in bipolar disorder. We reported the association of mitochondrial complex I subunit gene, NDUFV2 at 18p11, with bipolar disorder. A decrease in the mRNA expression of this gene was found in patients with bipolar disorder compared with controls. However, it was unclear whether only the NDUFV2 gene exhibited the decreased expression level in bipolar disorder. The aim of this study was to clarify the association of other nuclear-encoded complex I subunit genes and mitochondria-related genes with bipolar disorder. METHODS: We quantified the mRNA expression level of five nuclear-encoded mitochondrial complex I subunit genes located at the chromosomal regions linked with bipolar disorder other than NDUFV2, three complex IV subunit genes, and four mitochondrial transcription-related genes using a real-time quantitative reverse transcription polymerase chain reaction method in the lymphoblastoid cell lines from 21 patients with bipolar disorder and 11 controls. RESULTS: Decreased mRNA expression in patients with bipolar I disorder compared with control subjects was found in most of the complex I subunit genes. In addition, decreased expression levels of these genes correlated with that of NDUFV2. No statistically significant alterations of mRNA expression levels were found between bipolar patients and controls among two of three complex IV subunit genes and all transcription-related genes. CONCLUSIONS: Our study suggests that the decreased expression of NDUFV2 has a considerable effect on other subunit genes in the mitochondrial respiratory chain and presents further evidence of the biological significance of NDUFV2 in bipolar disorder.

Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder.

The authors have previously reported that intracellular pH measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was decreased in the frontal lobes of patients with bipolar disorder. In the present study, phosphorus metabolism in the basal ganglia was examined in 13 patients with bipolar disorder and 10 matched controls by localized 31P-MRS. While no significant alteration of peak area ratios was found for all phosphorus metabolites, intracellular pH was significantly reduced in the basal ganglia in patients with bipolar disorder (7.014 +/- 0.045) compared with control subjects (7.066 +/- 0.047, P < 0.05). Unexpectedly, non-localized 31P-MR spectra also showed significantly lower levels of intracellular pH (6.970 +/- 0.025) than controls (6.986 +/- 0.024, P < 0.05). These results suggest that decreased intracellular pH in the brain of patients with bipolar disorder is not caused by dysfunction of the frontal lobes but reflect altered metabolism at the cellular level.