Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.

BACKGROUND: Recent advances in neuroscience tools for single-cell molecular profiling of brain neurons have revealed an enormous spectrum of neuronal subpopulations within the neuroendocrine hypothalamus, highlighting the remarkable molecular and cellular heterogeneity of this brain area. RATIONALE: Neuronal diversity in the hypothalamus reflects the high functional plasticity of this brain area, where multiple neuronal populations flexibly integrate a variety of physiological outputs, including energy balance, stress and fertility, through crosstalk mechanisms with peripheral hormones. Intrinsic functional heterogeneity is also observed within classically 'defined' subpopulations of neuroendocrine neurons, including subtypes with distinct neurochemical signatures, spatial organisation and responsiveness to hormonal cues. AIM: The aim of this review is to critically evaluate past and current research on the functional diversity of hypothalamic neuroendocrine neurons and their plasticity. It focuses on how this neuronal plasticity in this brain area relates to metabolic control, feeding regulation and interactions with stress and fertility-related neural circuits. CONCLUSION: Our analysis provides an original framework for improving our understanding of the hypothalamic regulation of hormone function and the development of neuroendocrine diseases.

Central and cardiac stress resilience consistently linked to integrated immuno-neuroendocrine responses across stress models in male mice.

Stress resilience, and behavioural and cardiovascular impacts of chronic stress, are theorised to involve integrated neuro-endocrine/inflammatory/transmitter/trophin signalling. We tested for this integration, and whether behaviour/emotionality, together with myocardial ischaemic tolerance, are consistently linked to these pathways across diverse conditions in male C57Bl/6 mice. This included Restraint Stress (RS), 1 h restraint/day for 14 days; Chronic Unpredictable Mild Stress (CUMS), seven stressors randomised over 21 days; Social Stress (SS), 35 days social isolation with brief social encounters in final 13 days; and Control conditions (CTRL; un-stressed mice). Behaviour was assessed via open field (OFT) and sucrose preference (SPT) tests, and neurobiology from frontal cortex (FC) and hippocampal transcripts. Endocrine factors, and function and ischaemic tolerance in isolated hearts, were also measured. Model characteristics ranged from no behavioural or myocardial changes with homotypic RS, to increased emotionality and cardiac ischaemic injury (with apparently distinct endocrine/neurobiological profiles) in CUMS and SS models. Highly integrated expression of HPA axis, neuro-inflammatory, BDNF, monoamine, GABA, cannabinoid and opioid signalling genes was confirmed across conditions, and consistent/potentially causal correlations identified for (i) locomotor activity (noradrenaline, ghrelin; FC Crhr1, Tnfrsf1b, Il33, Nfkb1, Maoa, Gabra1; hippocampal Il33); (ii) thigmotaxis (adrenaline, leptin); (iii) anxiety-like behaviour (adrenaline, leptin; FC Tnfrsf1a; hippocampal Il33); (iv) depressive-like behaviour (ghrelin; FC/hippocampal s100a8); and (v) cardiac stress-resistance (noradrenaline, leptin; FC Il33, Tnfrsf1b, Htr1a, Gabra1, Gabrg2; hippocampal Il33, Tnfrsf1a, Maoa, Drd2). Data support highly integrated pathway responses to stress, and consistent adipokine, sympatho-adrenergic, inflammatory and monoamine involvement in mood and myocardial disturbances across diverse conditions.

Sex-specific behavioral, neurobiological, and cardiovascular responses to chronic social stress in mice.

Psychosocial stress promotes and links mood and cardiovascular disorders in a sex-specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippocampal monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippocampal Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females; and repression of hippocampal Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti-inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress-related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex-specific mechanisms and potential approaches to stress-dependent disease.

A novel method for identifying coded tags recorded on aquatic acoustic monitoring systems.

Aquatic biotelemetry increasingly relies on using acoustic transmitters ('tags') that enable passive detection of tagged animals using fixed or mobile receivers. Both tracking methods are resource-limited, restricting the spatial area in which movements of highly mobile animals can be measured using proprietary detection systems. Transmissions from tags are recorded by underwater noise monitoring systems designed for other purposes, such as cetacean monitoring devices, which have been widely deployed in the marine environment; however, no tools currently exist to decode these detections, and thus valuable additional information on animal movements may be missed. Here, we describe simple hybrid methods, with potentially wide application, for obtaining information from otherwise unused data sources. The methods were developed using data from moored, acoustic cetacean detectors (C-PODs) and towed passive receiver arrays, often deployed to monitor the vocalisations of cetaceans, but any similarly formatted data source could be used. The method was applied to decode tag detections that were found to have come from two highly mobile fish species, bass (Dicentrarchus labrax) and Twaite shad (Alosa fallax), that had been tagged in other studies. Decoding results were validated using test tags; range testing data were used to demonstrate the relative efficiency of these receiver methods in detecting tags. This approach broadens the range of equipment from which acoustic tag detections can be decoded. Novel detections derived from the method could add significant value to past and present tracking studies at little additional cost, by providing new insights into the movement of mobile animals at sea.

Efficacy of the Zero Suicide framework in reducing recurrent suicide attempts: cross-sectional and time-to-recurrent-event analyses.

BACKGROUND: The Zero Suicide framework is a system-wide approach to prevent suicides in health services. It has been implemented worldwide but has a poor evidence-base of effectiveness. AIMS: To evaluate the effectiveness of the Zero Suicide framework, implemented in a clinical suicide prevention pathway (SPP) by a large public mental health service in Australia, in reducing repeated suicide attempts after an index attempt. METHOD: A total of 604 persons with 737 suicide attempt presentations were identified between 1 July and 31 December 2017. Relative risk for a subsequent suicide attempt within various time periods was calculated using cross-sectional analysis. Subsequently, a 10-year suicide attempt history (2009-2018) for the cohort was used in time-to-recurrent-event analyses. RESULTS: Placement on the SPP reduced risk for a repeated suicide attempt within 7 days (RR = 0.29; 95% CI 0.11-0.75), 14 days (RR = 0.38; 95% CI 0.18-0.78), 30 days (RR = 0.55; 95% CI 0.33-0.94) and 90 days (RR = 0.62; 95% CI 0.41-0.95). Time-to-recurrent event analysis showed that SPP placement extended time to re-presentation (HR = 0.65; 95% CI 0.57-0.67). A diagnosis of personality disorder (HR = 2.70; 95% CI 2.03-3.58), previous suicide attempt (HR = 1.78; 95% CI 1.46-2.17) and Indigenous status (HR = 1.46; 95% CI 0.98-2.25) increased the hazard for re-presentation, whereas older age decreased it (HR = 0.92; 95% CI 0.86-0.98). The effect of the SPP was similar across all groups, reducing the risk of re-presentation to about 65% of that seen in those not placed on the SPP. CONCLUSIONS: This paper demonstrates a reduction in repeated suicide attempts after an index attempt and a longer time to a subsequent attempt for those receiving multilevel care based on the Zero Suicide framework.

Synergistic effects of low-level stress and a Western diet on metabolic homeostasis, mood, and myocardial ischemic tolerance.

How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies; however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac "death proteins" were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (-20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), P < 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice (P < 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically "benign" stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).

The brain-adipocyte-gut network: Linking obesity and depression subtypes.

Major depressive disorder (MDD) and obesity are dominant and inter-related health burdens. Obesity is a risk factor for MDD, and there is evidence MDD increases risk of obesity. However, description of a bidirectional relationship between obesity and MDD is misleading, as closer examination reveals distinct unidirectional relationships in MDD subtypes. MDD is frequently associated with weight loss, although obesity promotes MDD. In contrast, MDD with atypical features (MDD-AF) is characterised by subsequent weight gain and obesity. The bases of these distinct associations remain to be detailed, with conflicting findings clouding interpretation. These associations can be viewed within a systems biology framework-the psycho-immune neuroendocrine (PINE) network shared between MDD and metabolic disorders. Shared PINE subsystem perturbations may underlie increased MDD in overweight and obese people (obesity-associated depression), while obesity in MDD-AF (depression-associated obesity) involves more complex interactions between behavioural and biomolecular changes. In the former, the chronic PINE dysfunction triggering MDD is augmented by obesity-dependent dysregulation in shared networks, including inflammatory, leptin-ghrelin, neuroendocrine, and gut microbiome systems, influenced by chronic image-associated psychological stress (particularly in younger or female patients). In MDD-AF, behavioural dysregulation, including hypersensitivity to interpersonal rejection, fundamentally underpins energy imbalance (involving hyperphagia, lethargy, hypersomnia), with evolving obesity exaggerating these drivers via positive feedback (and potentially augmenting PINE disruption). In both settings, sex and age are important determinants of outcome, associated with differences in emotional versus cognitive dysregulation. A systems biology approach is recommended for further research into the pathophysiological networks underlying MDD and linking depression and obesity.

The sensitivity of 38 heart rate variability measures to the addition of artifact in human and artificial 24-hr cardiac recordings.

BACKGROUND: Artifact is common in cardiac RR interval data derived from 24-hr recordings and has a significant impact on heart rate variability (HRV) measures. However, the relative impact of progressively added artifact on a large group of commonly used HRV measures has not been assessed. This study compared the relative sensitivity of 38 commonly used HRV measures to artifact to determine which measures show the most change with increasing increments of artifact. A secondary aim was to ascertain whether short-term and long-term HRV measures, as groups, share similarities in their sensitivity to artifact. METHODS: Up to 10% of artifact was added to 20 artificial RR (ARR) files and 20 human cardiac recordings, which had been assessed for artifact by a cardiac technician. The added artifact simulated deletion of RR intervals and insertion of individual short RR intervals. Thirty-eight HRV measures were calculated for each file. Regression analysis was used to rank the HRV measures according to their sensitivity to artifact as determined by the magnitude of slope. RESULTS: RMSSD, SDANN, SDNN, RR triangular index and TINN, normalized power and relative power linear measures, and most nonlinear methods examined are most robust to artifact. CONCLUSION: Short-term time domain HRV measures are more sensitive to added artifact than long-term measures. Absolute power frequency domain measures across all frequency bands are more sensitive than normalized and relative frequency domain measures. Most nonlinear HRV measures assessed were relatively robust to added artifact, with Poincare plot SD1 being most sensitive.

The heartbreak of depression: 'Psycho-cardiac' coupling in myocardial infarction.

Ample evidence identifies strong links between major depressive disorder (MDD) and both risk of ischemic or coronary heart disease (CHD) and resultant morbidity and mortality. The molecular mechanistic bases of these linkages are poorly defined. Systemic factors linked to MDD, including vascular dysfunction, atherosclerosis, obesity and diabetes, together with associated behavioral changes, all elevate CHD risk. Nonetheless, experimental evidence indicates the myocardium is also directly modified in depression, independently of these factors, impairing infarct tolerance and cardioprotection. It may be that MDD effectively breaks the heart's intrinsic defense mechanisms. Four extrinsic processes are implicated in this psycho-cardiac coupling, presenting potential targets for therapeutic intervention if causally involved: sympathetic over-activity vs. vagal under-activity, together with hypothalamic-pituitary-adrenal (HPA) axis and immuno-inflammatory dysfunctions. However, direct evidence of their involvement remains limited, and whether targeting these upstream mediators is effective (or practical) in limiting the cardiac consequences of MDD is unknown. Detailing myocardial phenotype in MDD can also inform approaches to cardioprotection, yet cardiac molecular changes are similarly ill defined. Studies support myocardial sensitization to ischemic insult in models of MDD, including worsened oxidative and nitrosative damage, apoptosis (with altered Bcl-2 family expression) and infarction. Moreover, depression may de-sensitize hearts to protective conditioning stimuli. The mechanistic underpinnings of these changes await delineation. Such information not only advances our fundamental understanding of psychological determinants of health, but also better informs management of the cardiac consequences of MDD and implementing cardioprotection in this cohort.

Adeno-associated virus-mediated expression of ß-hexosaminidase prevents neuronal loss in the Sandhoff mouse brain.

Sandhoff disease, a GM2 gangliosidosis caused by a deficiency in ß-hexosaminidase, is characterized by progressive neurodegeneration. Although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. Using an authentic murine model of GM2 gangliosidosis, we examined the pattern of neuronal loss in the central nervous system and investigated the effects of gene transfer using recombinant adeno-associated viral vectors expressing ß-hexosaminidase subunits (rAAV2/1-Hex). In 4-month-old Sandhoff mice with neurological deficits, cells staining positively for the apoptotic signature in the TUNEL reaction were found in the ventroposterior medial and ventroposterior lateral (VPM/VPL) nuclei of the thalamus. There was progressive loss of neuronal density in this region with age. Comparable loss of neuronal density was identified in the lateral vestibular nucleus of the brainstem and a small but statistically significant loss was present in the ventral spinal cord. Loss of neurons was not detected in other regions that were analysed. Administration of rAAV2/1-Hex into the brain of Sandhoff mice prevented the decline in neuronal density in the VPM/VPL. Preservation of neurons in the VPM/VPL was variable at the humane endpoint in treated animals, but correlated directly with increased lifespan. Loss of neurons was localized to only a few regions in the Sandhoff brain and was prevented by rAAV-mediated transfer of ß-hexosaminidase gene function at considerable distances from the site of vector administration.

The contribution of major depression to the global burden of ischemic heart disease: a comparative risk assessment.

BACKGROUND: Cardiovascular disease and mental health both hold enormous public health importance, both ranking highly in results of the recent Global Burden of Disease Study 2010 (GBD 2010). For the first time, the GBD 2010 has systematically and quantitatively assessed major depression as an independent risk factor for the development of ischemic heart disease (IHD) using comparative risk assessment methodology. METHODS: A pooled relative risk (RR) was calculated from studies identified through a systematic review with strict inclusion criteria designed to provide evidence of independent risk factor status. Accepted case definitions of depression include diagnosis by a clinician or by non-clinician raters adhering to Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) classifications. We therefore refer to the exposure in this paper as major depression as opposed to the DSM-IV category of major depressive disorder (MDD). The population attributable fraction (PAF) was calculated using the pooled RR estimate. Attributable burden was calculated by multiplying the PAF by the underlying burden of IHD estimated as part of GBD 2010. RESULTS: The pooled relative risk of developing IHD in those with major depression was 1.56 (95% CI 1.30 to 1.87). Globally there were almost 4 million estimated IHD disability-adjusted life years (DALYs), which can be attributed to major depression in 2010; 3.5 million years of life lost and 250,000 years of life lived with a disability. These findings highlight a previously underestimated mortality component of the burden of major depression. As a proportion of overall IHD burden, 2.95% (95% CI 1.48 to 4.46%) of IHD DALYs were estimated to be attributable to MDD in 2010. Eastern Europe and North Africa/Middle East demonstrate the highest proportion with Asia Pacific, high income representing the lowest. CONCLUSIONS: The present work comprises the most robust systematic review of its kind to date. The key finding that major depression may be responsible for approximately 3% of global IHD DALYs warrants assessment for depression in patients at high risk of developing IHD or at risk of a repeat IHD event.

The sex-dependent response to psychosocial stress and ischaemic heart disease.

Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome-a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.

Using machine learning to mine mental health diagnostic groups from emergency department presentations before and during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic had a profound negative effect on mental health worldwide. The hospital emergency department plays a pivotal role in responding to mental health crises. Understanding data trends relating to hospital emergency department usage is beneficial for service planning, particularly around preparing for future pandemics. Machine learning has been used to mine large volumes of unstructured data to extract meaningful data in relation to mental health presentations. This study aims to analyse trends in five mental health-related presentations to an emergency department before and during, the COVID-19 pandemic. METHODS: Data from 690,514 presentations to two Australian, public hospital emergency departments between April 2019 to February 2022 were assessed. A machine learning-based framework, Mining Emergency Department Records, Evolutionary Algorithm Data Search (MEDREADS), was used to identify suicidality, psychosis, mania, eating disorder, and substance use. RESULTS: While the mental health-related presentations to the emergency department increased during the COVID-19 pandemic compared to pre-pandemic levels, the proportion of mental health presentations relative to the total emergency department presentations decreased. Several troughs in presentation frequency were identified across the pandemic period, which occurred consistently during the public health lockdown and restriction periods. CONCLUSION: This study implemented novel machine learning techniques to analyse mental health presentations to an emergency department during the COVID-19 pandemic. Results inform understanding of the use of emergency mental health services during the pandemic, and highlight opportunities to further investigate patterns in presentation.

Reply to Obegi, J.H. Distinguishing Prevention from Treatment in Suicide Prevention. Comment on "Turner et al. The Paradox of Suicide Prevention. Int. J. Environ. Res. Public Health 2022, 19, 14983".

One of the aims of our paper "The Paradox of Suicide Prevention" is to promote greater discourse on suicide prevention, with a particular focus on the mental health models used for the identification of, and interventions with, individuals who come into contact with tertiary mental health services [...].

Interventional Response of Hospital and Health Services to the Mental Health Effects of Viral Outbreaks on Health Professionals.

The aim of this integrative review was to examine the impact of past viral epidemics on staff mental health interventional responses, with a specific focus on healthcare provider response in the context of the COVID-19 pandemic. Following PRISMA methodology, databases were searched for relevant articles. A total of 55 articles with a range of methodologies (e.g., commentary papers, cohort studies, qualitative studies) were included to ensure broad coverage of this rapidly emerging research area. The literature showed that many healthcare providers implemented a variety of wellbeing initiatives to support their staff during a viral outbreak. Most of these interventions, however, were not formally evaluated. Interventions included leadership/team support; online psychoeducational resources and updated information on the pandemic; respite spaces; peer support outreach; staff resilience training; telephone hotline support; staff support groups; and individual counseling. Staff were generally supportive of the initiatives offered by hospital and health services, with certain interventions being more appreciated (e.g., staff respite areas). Rapid, locally, and culturally appropriate workplace-based responses may counter the negative mental health impact on staff; but a stepped response is required for a smaller number of staff at risk of mental illness, or those with pre-existing mental illness. Systematic Review Registration: Unique Identifier: CRD42020222761.

Environmental Stressors and the PINE Network: Can Physical Environmental Stressors Drive Long-Term Physical and Mental Health Risks?

Both psychosocial and physical environmental stressors have been linked to chronic mental health and chronic medical conditions. The psycho-immune-neuroendocrine (PINE) network details metabolomic pathways which are responsive to varied stressors and link chronic medical conditions with mental disorders, such as major depressive disorder via a network of pathophysiological pathways. The primary objective of this review is to explore evidence of relationships between airborne particulate matter (PM, as a concrete example of a physical environmental stressor), the PINE network and chronic non-communicable diseases (NCDs), including mental health sequelae, with a view to supporting the assertion that physical environmental stressors (not only psychosocial stressors) disrupt the PINE network, leading to NCDs. Biological links have been established between PM exposure, key sub-networks of the PINE model and mental health sequelae, suggesting that in theory, long-term mental health impacts of PM exposure may exist, driven by the disruption of these biological networks. This disruption could trans-generationally influence health; however, long-term studies and information on chronic outcomes following acute exposure event are still lacking, limiting what is currently known beyond the acute exposure and all-cause mortality. More empirical evidence is needed, especially to link long-term mental health sequelae to PM exposure, arising from PINE pathophysiology. Relationships between physical and psychosocial stressors, and especially the concept of such stressors acting together to impact on PINE network function, leading to linked NCDs, evokes the concept of syndemics, and these are discussed in the context of the PINE network.

Forgetful, sad and old: Do vascular cognitive impairment and depression share a common pre-disease network and how is it impacted by ageing?

Vascular cognitive impairment (VCI) and depression frequently coexist in geriatric populations and reciprocally increase disease risks. We assert that a shared pre-disease state of the psycho-immune-neuroendocrine (PINE) network model mechanistically explains bidirectional associations between VCI and depression. Five pathophysiological sub-networks are identified that are shared by VCI and depression: neuroinflammation, kynurenine pathway imbalance, hypothalamic-pituitary-adrenal (HPA) axis overactivity, impaired neurotrophic support and cerebrovascular dysfunction. These do not act independently, and their complex interactions necessitate a systems biology approach to better define disease pathogenesis. The PINE network is already established in the context of non-communicable diseases (NCDs) such as depression, hypertension, atherosclerosis, coronary heart disease and type 2 diabetes mellitus. We build on previous literature to specifically explore mechanistic links between MDD and VCI in the context of PINE pathways and discuss key mechanistic commonalities linking these comorbid conditions and identify a common pre-disease state which precedes transition to VCI and MDD. We expand the model to incorporate bidirectional interactions with biological ageing. Diathesis factors for both VCI and depression feed into this network and the culmination of shared mechanisms (on an ageing substrate) lead to a critical network transition to one or both disease states. A common pre-disease state underlying VCI and depression can provide clinicians a unique opportunity for early risk assessment and intervention in disease development. Establishing the mechanistic elements and systems biology of this network can reveal early warning or predictive biomarkers together with novel therapeutic targets. Integrative studies are recommended to elucidate the dynamic networked biology of VCI and depression over time.

The Paradox of Suicide Prevention.

The recognition that we cannot use risk stratification (high, medium, low) to predict suicide or to allocate resources has led to a paradigm shift in suicide prevention efforts. There are challenges in adapting to these new paradigms, including reluctance of clinicians and services to move away from traditional risk categorisations; and conversely, the risk of a pendulum swing in which the focus of care swings from one approach to determining service priority and focus (e.g., diagnosis, formulation, risk and clinical care) to a new focus (e.g., suicide specific and non-clinical care), potentially supplanting the previous approach. This paper argues that the Prevention Paradox provides a useful mental model to support a shift in paradigm, whilst maintaining a balanced approach that incorporates new paradigms within the effective aspects of existing ones. The Prevention Paradox highlights the seemingly paradoxical situation where the greatest burden of disease or death is caused by those at low to moderate risk due their larger numbers. Current planning frameworks and resources do not support successful or sustainable adoption of these new approaches, leading to missed opportunities to prevent suicidal behaviours in healthcare. Adopting systems approaches to suicide prevention, such as the Zero Suicide Framework, implemented in a large mental health service in Australia and presented in this paper as a case study, can support a balanced approach of population- and individual-based suicide prevention efforts. Results demonstrate significant reductions in re-presentations with suicide attempts for consumers receiving this model of care; however, the increasing numbers of placements compromise the capacity of clinical teams to complete all components of standardised pathway of care. This highlights the need for review of resource planning frameworks and ongoing evaluations of the critical aspects of the interventions.

The pathophysiology of major depressive disorder through the lens of systems biology: Network analysis of the psycho-immune-neuroendocrine physiome.

BACKGROUND/AIMS: The psycho-immune-neuroendocrine (PINE) network is a predominantly physiological (metabolomic) model constructed from the literature, inter-linking multiple biological processes associated with major depressive disorder (MDD), thereby integrating putative mechanistic pathways for MDD into a single network. MATERIAL AND METHODS: Previously published metabolomic pathways for the PINE network based on literature searches conducted in 1991-2021 were used to construct an edge table summarizing all physiological pathways in pairs of origin nodes and target nodes. The Gephi software program was used to calculate network metrics from the edge table, including total degree and centrality measures, to ascertain key network nodes and construct a directed network graph. RESULTS: An edge table and directional network graph of physiological relationships in the PINE network is presented. The network has properties consistent with complex biological systems, with analysis yielding key network nodes comprising pro-inflammatory cytokines (TNF- α, IL6 and IL1), glucocorticoids and corticotropin releasing hormone (CRH). These may represent central structural and regulatory elements in the context of MDD. CONCLUSION: The identified hubs have a high degree of connection and are known to play roles in the progression from health to MDD. These nodes represent strategic targets for therapeutic intervention or prevention. Future work is required to build a weighted and dynamic simulation of the network PINE.

Behavioural disruption in diabetic mice: Neurobiological correlates and influences of dietary α-linolenic acid.

AIM: Evolving type 2 diabetes (T2D) may influence locomotion and affective state, promoting metabolic dysfunction. We examined behaviour and neurobiology in a model of T2D, testing for benefits with dietary n-3 polyunsaturated fatty acid (PUFA). METHODS: Male C57Bl/6 mice received vehicle or 75 mg/kg streptozotocin (STZ) and 21 wks of control or Western diets (43 % fat, 40 % carbohydrate, 17 % protein). Sub-sets received dietary α-linolenic acid (ALA; 10 % of fat intake) for 6 wks. Behaviour was examined via open field and sucrose preference tests, and hippocampal and frontal cortex (FC) leptin and dopamine levels and inflammatory signalling assessed. KEY FINDINGS: T2D mice exhibited weight gain (+15 %), hyperglycemia (+35 %), hyperinsulinemia (+60 %) and insulin-resistance (+80 % higher HOMA-IR), together with anxiety-like behaviour (without anhedonia) that appeared independent of body weight and glycemic status. Cortical leptin declined whereas receptor mRNA increased. Supplementation with ALA did not influence metabolic state, while enhancing locomotion and reducing anxiety-like behaviours in healthy but not T2D mice. Hippocampal dopamine was selectively increased by ALA in T2D mice, with a trend to reduced circulating leptin in both groups. Across all groups, anxiety-like behaviour was associated with declining cortical and hippocampal leptin levels and increasing receptor mRNA, while declining dopamine levels were accompanied by decreased dopamine/serotonin receptor transcripts. SIGNIFICANCE: Chronic T2D induced anxiogenesis in mice appears to be independent of metabolic homeostasis but linked to central leptin-resistance, together with disturbed dopamine and serotonin signalling. Despite anxiolytic effects of ALA in healthy mice, no metabolic or behavioural benefits were evident in T2D.