Functional connectivity of the default mode network predicts subsequent polysomnographically measured sleep in people with symptoms of insomnia.

Insomnia is often accompanied by excessive pre-sleep rumination. Such ruminative thinking is also associated with increased connectivity of the default mode network (DMN). It is likely that DMN connectivity and associated rumination contribute to the pathogenesis of insomnia. We hypothesized that resting state functional connectivity (rsFC) between the DMN and other brain regions prior to bedtime would predict objectively measured sleep among individuals with insomnia. Twenty participants (12 female; M age = 26.9, SD = 6.6 years) with symptoms of insomnia underwent an rsFC scan in the early evening followed by a night of polysomographically (PSG) measured sleep. Connectivity of the DMN with other brain regions was regressed against several PSG sleep metrics, including time in wake, N1, N2, N3, REM, total sleep time (TST), and sleep efficiency (SE) at a cluster corrected false discovery rate (FDR) correction P < 0.05. The connectivity between DMN and cortical regions was negatively correlated with PSG indices of poorer sleep including time in wake (right angular gyrus) and N1 (precuneus) but positively correlated with time in REM (orbitofrontal cortex), TST (insula, orbitofrontal cortex, superior frontal gyrus, paracingulate gyrus), SE (orbitofrontal cortex). Connectivity between DMN and the pons was negatively correlated with SE. Among individuals with symptoms of insomnia, better sleep was predicted by rsFC between the DMN and cortical regions involved in executive functioning, consciousness, and complex cognition. Findings raise the possibility that future interventions aimed at suppressing pre-sleep DMN activation may weaken synergy between pre-sleep ruminative worry and complex cognitions, potentially ameliorating problems falling asleep.

Alcohol dependence during COVID-19 lockdowns.

To determine whether the past half-year of COVID-19-related lockdowns, stay-at-home orders, and social isolation were associated with changes in high-risk alcohol use, a total of 5,931 individuals completed the Alcohol Use Disorders Identification Test (AUDIT) at one of six time points from April through September 2020. Over the 6-month period, hazardous alcohol use and likely dependence increased month-by-month for those under lockdowns compared to those not under restrictions. This increase in harmful alcohol use and related behaviors is likely to have prolonged adverse psychosocial, interpersonal, occupational, and health impacts as the world attempts to recover from the pandemic crisis.

Loneliness during the first half-year of COVID-19 Lockdowns.

During the first 6-months of the COVID-19 pandemic, the primary weapons against the spread of the virus have included local government orders for restriction of movement and broad implementation of face masks and social distancing policies. While some early reports suggested increases in loneliness during the pandemic restrictions, others reported no changes. Here, we provide an update on self-reported loneliness over the first 6-months of community lockdown restrictions from a nationwide sample of 6,186 U.S. adults who completed the UCLA Loneliness Scale-3 and Public Health Questionnaire-9 during the pandemic. Loneliness scores increased significantly from April through September 2020 and were significantly higher for those reporting they were under stay-at-home, shelter-in-place, or lockdown orders compared to those reporting no restrictions. Greater loneliness was positively correlated with depression and suicidal ideation. Loneliness has increased over the first half-year of the pandemic, particularly for those under lockdown restrictions, and remains a significant mental health concern.

Pomegranate derivative urolithin A enhances vitamin D receptor signaling to amplify serotonin-related gene induction by 1,25-dihydroxyvitamin D.

Mediated by the nuclear vitamin D receptor (VDR), the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D), is known to regulate expression of genes impacting calcium and phosphorus metabolism, the immune system, and behavior. Urolithin A, a nutrient metabolite derived from pomegranate, possibly acting through AMP kinase (AMPK) signaling, supports respiratory muscle health in rodents and longevity in C. elegans by inducing oxidative damage-reversing genes and mitophagy. We show herein that urolithin A enhances transcriptional actions of 1,25D driven by co-transfected vitamin D responsive elements (VDREs), and dissection of this genomic effect in cell culture reveals: 1) urolithin A concentration-dependency, 2) occurrence with isolated natural VDREs, 3) nuclear receptor selectivity for VDR over ER, LXR and RXR, and 4) significant 3- to 13-fold urolithin A-augmentation of 1,25D-dependent mRNA encoding the widely expressed 1,25D-detoxification enzyme, CYP24A1, a benchmark vitamin D target gene. Relevant to potential behavioral effects of vitamin D, urolithin A elicits enhancement of 1,25D-dependent mRNA encoding tryptophan hydroxylase-2 (TPH2), the serotonergic neuron-expressed initial enzyme in tryptophan metabolism to serotonin. Employing quantitative real time-PCR, we demonstrate that TPH2 mRNA is induced 1.9-fold by 10 nM 1,25D treatment in culture of differentiated rat serotonergic raphe (RN46A-B14) cells, an effect magnified 2.5-fold via supplementation with 10 µM urolithin A. This potentiation of 1,25D-induced TPH2 mRNA by urolithin A is followed by a 3.1- to 3.7-fold increase in serotonin concentration in culture medium from the pertinent neuronal cell line, RN46A-B14. These results are consistent with the concept that two natural nutrient metabolites, urolithin A from pomegranate and 1,25D from sunlight/vitamin D, likely acting via AMPK and VDR, respectively, cooperate mechanistically to effect VDRE-mediated regulation of gene expression in neuroendocrine cells. Finally, gedunin, a neuroprotective natural product from Indian neem tree that impacts the brain derived neurotropic factor pathway, similarly potentiates 1,25D/VDR-action.

Optimal vitamin D spurs serotonin: 1,25-dihydroxyvitamin D represses serotonin reuptake transport (SERT) and degradation (MAO-A) gene expression in cultured rat serotonergic neuronal cell lines.

BACKGROUND: Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5-HT; serotonin) and 1,25-dihydroxyvitamin D3 (1,25D; active vitamin D metabolite), are proposed to play a role in the atypical social behaviors associated with psychological conditions including autism spectrum disorders and depression. We reported previously that 1,25D induces expression of tryptophan hydroxylase-2 (TPH2), the initial and rate-limiting enzyme in the biosynthetic pathway to 5-HT, in cultured rat serotonergic neuronal cells. However, other enzymes and transporters in the pathway of tryptophan metabolism had yet to be examined with respect to the actions of vitamin D. Herein, we probed the response of neuronal cells to 1,25D by quantifying mRNA expression of serotonin synthesis isozymes, TPH1 and TPH2, as well as expression of the serotonin reuptake transporter (SERT), and the enzyme responsible for serotonin catabolism, monoamine oxidase-A (MAO-A). We also assessed the direct production of serotonin in cell culture in response to 1,25D. RESULTS: Employing quantitative real-time PCR, we demonstrate that TPH-1/-2 mRNAs are 28- to 33-fold induced by 10 nM 1,25D treatment of cultured rat serotonergic neuronal cells (RN46A-B14), and the enhancement of TPH2 mRNA by 1,25D is dependent on the degree of neuron-like character of the cells. In contrast, examination of SERT, the gene product of which is a target for the SSRI-class of antidepressants, and MAO-A, which encodes the predominant catabolic enzyme in the serotonin pathway, reveals that their mRNAs are 51-59% repressed by 10 nM 1,25D treatment of RN46A-B14 cells. Finally, serotonin concentrations are significantly enhanced (2.9-fold) by 10 nM 1,25D in this system. CONCLUSIONS: These results are consistent with the concept that vitamin D maintains extracellular fluid serotonin concentrations in the brain, thereby offering an explanation for how vitamin D could influence the trajectory and development of neuropsychiatric disorders. Given the profile of gene regulation in cultured RN46A-B14 serotonergic neurons, we conclude that 1,25D acts not only to induce serotonin synthesis, but also functions at an indirect, molecular-genomic stage to mimic SSRIs and MAO inhibitors, likely elevating serotonin in the CNS. These data suggest that optimal vitamin D status may contribute to improving behavioral pathophysiologies resulting from dysregulation of serotonergic neurotransmission.