Whole-Brain Wiring Diagram of Oxytocin System in Adult Mice.

Oxytocin (Oxt) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of Oxt neurons and their quantitative relationship with Oxt receptor (Oxtr) expression presents challenges to understanding circuit-specific Oxt functions. Here, we establish a whole-brain distribution and anatomic connectivity map of Oxt neurons, and their relationship with Oxtr expression using high-resolution 3D mapping methods in adult male and female mice. We use a flatmap to describe Oxt neuronal expression in four hypothalamic domains including under-characterized Oxt neurons in the tuberal nucleus (TU). Oxt neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, Oxt neurons in the supraoptic (SO) and accessory (AN) nuclei have limited central projection to a small subset of the nine circuits. Surprisingly, quantitative comparison between Oxt output and Oxtr expression showed no significant correlation across the whole brain, suggesting abundant indirect Oxt signaling in Oxtr-expressing areas. Unlike output, Oxt neurons in both the PVH and SO receive similar monosynaptic inputs from a subset of the nine circuits mainly in the thalamic, hypothalamic, and cerebral nuclei areas. Our results suggest that PVH-Oxt neurons serve as a central modulator to integrate external and internal information via largely reciprocal connection with the nine circuits while the SO-Oxt neurons act mainly as unidirectional Oxt hormonal output. In summary, our Oxt wiring diagram provides anatomic insights about distinct behavioral functions of Oxt signaling in the brain.SIGNIFICANCE STATEMENT Oxytocin (Oxt) neurons regulate diverse physiological functions from prosocial behavior to pain sensation via central projection in the brain. Thus, understanding detailed anatomic connectivity of Oxt neurons can provide insight on circuit-specific roles of Oxt signaling in regulating different physiological functions. Here, we use high-resolution mapping methods to describe the 3D distribution, monosynaptic input and long-range output of Oxt neurons, and their relationship with Oxt receptor (Oxtr) expression across the entire mouse brain. We found Oxt connections with nine functional circuits controlling cognition, brain state, and somatic visceral response. Furthermore, we identified a quantitatively unmatched Oxt-Oxtr relationship, suggesting broad indirect Oxt signaling. Together, our comprehensive Oxt wiring diagram advances our understanding of circuit-specific roles of Oxt neurons.

Rates and risk factors for suicidal ideation, suicide attempts and suicide deaths in persons with HIV: a protocol for a systematic review and meta-analysis.

INTRODUCTION: The prevalence of HIV/AIDS is high and is associated with psychiatric morbidity and suicide risk. The objective of this study will be to assess the rates of suicidal ideation, suicide attempts and suicide deaths in people living with HIV/AIDS (PLWHA). METHODS AND ANALYSIS: We present a study protocol for a systematic review and meta-analysis of studies reporting the suicidality outcomes (suicidal ideation, suicide attempts and suicide deaths) in PLWHA. PubMed (MEDLINE), Scopus, EMBASE, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE), Joanna Briggs Institute EBP Database, Web of Science and PsychINFO databases will be searched from their inception until 1 January 2020. The primary outcome of interest will be the incidence of suicidality in PLWHA. In addition, we will delineate risk factors associated with suicidality in PLWHA. Citations, full-text articles and abstracts will be screened by four reviewers independently. Disagreements will be resolved through discussion. The study methodological quality (or bias) will be appraised using an appropriate tool. Random-effects meta-analysis will be conducted if we find that the studies are very heterogenous. For the suicidality outcome, probability of suicide risk will be reported. Relative risk ratios (with 95% CIs) will be reported for the effects of the risk factors. Potential publication bias will be assessed by conducting Egger's test and creating funnel plots. We will conduct additional analyses to explore the potential sources of heterogeneity (eg, age, sex and geographical location). ETHICS AND DISSEMINATION: No ethics clearance is required as no primary data will be collected. The results of this systematic review and meta-analysis will be presented at scientific conferences and published in a peer-reviewed journal. The results may inform clinical management of PLWHA and may guide future population-specific interventions.We will search PubMed (MEDLINE), Scopus, EMBASE, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE), Joanna Briggs Institute EBP Database, Web of Science and PsychINFO from their inception until 1 January 2020. PROSPERO REGISTRATION NUMBER: CRD42020161501.

Rates and risk factors for suicidal ideation, suicide attempts and suicide deaths in persons with HIV: a systematic review and meta-analysis.

BACKGROUND: People living with HIV/AIDS (PLWHA) must contend with a significant burden of disease. However, current studies of this demographic have yielded wide variations in the incidence of suicidality (defined as suicidal ideation, suicide attempt and suicide deaths). AIMS: This systematic review and meta-analysis aimed to assess the lifetime incidence and prevalence of suicidality in PLWHA. METHODS: Publications were identified from PubMed (MEDLINE), SCOPUS, OVID (MEDLINE), Joanna Briggs Institute EBP and Cochrane Library databases (from inception to before 1 February 2020). The search strategy included a combination of Medical Subject Headings associated with suicide and HIV. Researchers independently screened records, extracted outcome measures and assessed study quality. Data were pooled using a random-effects model. Subgroup and meta-regression analyses were conducted to explore the associated risk factors and to identify the sources of heterogeneity. Main outcomes were lifetime incidence of suicide completion and lifetime incidence and prevalence of suicidal ideation and suicide attempt. RESULTS: A total of 185 199 PLWHA were identified from 40 studies (12 cohorts, 27 cross-sectional and 1 nested case-control). The overall incidence of suicide completion in PLWHA was 10.2/1000 persons (95%CI: 4.5 to 23.1), translating to 100-fold higher suicide deaths than the global general population rate of 0.11/1000 persons. The lifetime prevalence of suicide attempts was 158.3/1000 persons (95%CI: 106.9 to 228.2) and of suicidal ideation was 228.3/1000 persons (95%CI: 150.8 to 330.1). Meta-regression revealed that for every 10-percentage point increase in the proportion of people living with HIV with advanced disease (AIDS), the risk of suicide completion increased by 34 per 1000 persons. The quality of evidence by Grading of Recommendations, Assessment, Development and Evaluations for the suicide deaths was graded as 'moderate' quality. CONCLUSIONS: The risk of suicide death is 100-fold higher in people living with HIV than in the general population. Lifetime incidence of suicidal ideation and attempts are substantially high. Suicide risk assessments should be a priority in PLWHA, especially for those with more advanced disease.

Risk of suicidal ideation, suicide attempts, and suicide deaths in persons with sleep apnea: Protocol for a systematic review and meta-analysis.

AIM: To estimate the pooled prevalence and incidence of suicidal ideation, attempts, and deaths in people with sleep apnea. METHOD: We will identify epidemiological studies reporting the prevalence or incidence rate of suicide in people with sleep apnea. We will search the following databases: PubMed (MEDLINE), Scopus, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE) and Joana Briggs Institute EBF Database. No age, geographical location, study-design or language limits will be applied. This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. Two reviewers (YY and YP) will independently screen citations, abstracts and will identify full-text articles for inclusion, extract data, and appraise the quality and bias of included studies. Discrepancies will be resolved by consulting with a third researcher (MC). Study quality will be assessed by the Newcastle-Ottawa Scale. The primary outcomes will be the overall prevalence or incidence of suicidal ideation, attempts and completion and the risk of suicide in people with sleep apnea. For pooling of the studies, we will use a random-effects model with a logit transformation. The DerSimonian and Laird (DL) random-effects method will be used to estimate the pooled inter-study variance. We will assess the between-study heterogeneity using I2 statistics, and Cochrane's Q statistic (significance level < 0.05). If the I2 is high (>75%), we will perform subgroup meta-analyses and conduct a meta-regression analysis to explore sources of study heterogeneity using study level median age, study-level proportions of race, gender, depression and quality scores. We will report effect estimates as suicide risk per 1000 individuals. Egger's test and funnel plots will be used to assess publication bias, and adjusted estimates using trim and fill methods will be reported if publication bias is suspected. ETHICS AND DISSEMINATION: No ethics clearance is required as no primary data will be collected. The results of this systematic review and meta-analysis will be presented at scientific conferences and published in a peer-review journal. The results may shed more light on the burden of suicide risk among individuals with sleep apnea and may guide future population-specific interventions. TRIAL REGISTRATION: PROSPERO registration number: CRD42020165404.