Daily changes in ambient air pollution concentrations and temperature and suicide mortality in Canada: Findings from a national time-stratified case-crossover study.

INTRODUCTION: Worldwide, approximately 1900 people die by suicide daily. Daily elevations in air pollution and temperature have previously been linked to a higher risk of death from suicide. To date, there have been relatively few studies of air pollution and suicide, particularly at a national level. National analyses play an important role in shaping health policy to mitigate against adverse health outcomes. METHODS: We used a time-stratified case-crossover study design to investigate the influence of short-term (i.e., day to day) interquartile range (IQR) increases in air pollutants (nitrogen dioxide [NO2], ozone [O3], and fine particulate matter [PM2.5]) and temperature on suicide mortality in Canada between 2002 and 2015. For air pollution models, odds ratios (ORs) derived from conditional logistic regression models were adjusted for average daily temperature, and holidays. For temperature models, ORs were adjusted for holidays. Stratified analyses were undertaken by suicide type (non-violent and violent), sex, age, and season. RESULTS: Analyses are based on 50,800 suicide deaths. Overall, temperature effects were stronger than those for air pollution. A same day IQR increase in temperature (9.6 °C) was associated with a 10.1% increase (95% confidence interval (CI): 9.0%-11.2%) of death from suicide. For 3-day average increase of O3 (IQR = 14.1 ppb), PM2.5 (IQR = 5.6 µg/m3) and NO2 (IQR = 9.7 ppb) the corresponding risks were 4.7% (95% CI: 3.9, 5.6), 3.4% (95% CI: 3.0, 3.8), and 2.0% (95% CI: 1.1, 2.8), respectively. All pollutants showed stronger associations with suicide during the warmer season (April-September). Stratified analyses revealed stronger associations for both temperature and air pollution in women. CONCLUSIONS: Daily increases in air pollution and temperature were found to increase the risk of death from suicide. Females, particularly during warmer season, were most vulnerable to these exposures. Policy decisions related to air pollution and climate change should consider effects on mental health.

Short-term changes in meteorological conditions and suicide: A systematic review and meta-analysis.

BACKGROUND: Suicide is a leading cause of death, particularly for young adults. Suicidal behaviours are influenced by a wide-range of personal, social, and cultural factors. Emerging evidence suggests that daily changes in meteorological conditions, including temperature, increases the risk of suicide. METHODS: We conducted a systematic review and meta-analysis of studies that examined associations between either daily, or weekly, variations for eight meteorological variables and suicide outcomes (attempts, or deaths). Meta-analytic methods were applied to derive summary measures of association using random effect models. We assessed the heterogeneity in these associations by region and biological sex. RESULTS: We identified 29 studies of suicide. Of these, 26 reported associations between temperature, while fewer studies reported on rain (n = 4), solar radiation (n = 4), humidity (n = 3), sunshine (n = 3), atmospheric pressure (n = 2), wind (n = 2) and cloud cover (n = 2). The overall relative risk for suicide deaths/attempts per 1 °C increase in ambient temperature was 1.016 (95% CI: 1.013-1.019). Subgroup analysis of temperature found stronger associations with suicide when using the maximum rather than the mean daily temperature, among men, and for completed suicides relative to attempts. Regionally, the strongest associations were found in the East Asia and Pacific region. While associations were found for solar radiation and cloud coverage and suicide, we did not undertake a meta-analysis for these exposures as it was not possible to standardize measures of association across studies. Statistically significant associations were not observed for other identified meteorological variables. CONCLUSIONS: Our findings suggest that daily increases in temperature increase the risk of suicide, particularly, among men and in the East Asia and Pacific region.

Acute stressor effects on cognitive flexibility: mediating role of stressor appraisals and cortisol.

Acute stressor experiences may influence cognition, possibly through actions of cognitive flexibility, which comprises the ability to modify cognitive and behavioral strategies in response to changing environmental demands. In the present investigation, we examined the effects of an acute psychosocial stressor (the Trier Social Stress Test) on a specific form of cognitive flexibility, namely that of set-shifting, which was assessed by the Berg's Card Sorting Task (BCST). Among undergraduate students, the stressor promoted better performance on the BSCT relative to that evident among nonstressed individuals, including a reduction of perseverative (an index of enhanced set-shifting) and non-perseverative errors. They also required fewer trials to learn the first sorting category, reflecting augmented acquisition of an attentional set, but did not differ in the ability to maintain a set. Moreover, increased cortisol levels specifically mediated the enhancing effects of the acute stressor on set-shifting, but not the ability to acquire and maintain an attentional set. However, this enhancing effect was minimized among individuals who appraised the stressor as being uncontrollable. These data indicate that an acute, social-evaluative stressor can facilitate certain forms of cognitive flexibility, such as set-shifting. The present investigation also highlights the value of focusing on psychological and physiological mediators in determining the impact of stressful experiences on cognitive functioning. Lay summary A brief social stressor (public speaking) can have an enhancing effect on mental flexibility, and this seems to be related to the stress hormone, cortisol. This cognitive enhancing effect, however, might be minimized if a stressful situation is perceived as beyond a person's control.

Self-Reported Mild Traumatic Brain Injuries in Relation to Rumination and Depressive Symptoms: Moderating Role of Sex Differences and a Brain-Derived Neurotrophic Factor Gene Polymorphism.

OBJECTIVE: Mild traumatic brain injuries (mTBIs) have frequently been associated with the emergence and persistence of depressive symptoms. However, the factors which contribute to the increased risk for depression after these head injuries remain unclear. Accordingly, we examined the relationship between frequency of self-reported mTBIs and current symptoms of depression and the mediating role of rumination and cognitive flexibility. We also examined whether these relations were moderated by sex differences and the presence of the Val66Met polymorphism in a gene coding for brain-derived neurotrophic factor (BDNF). DESIGN: Retrospective, cross-sectional. SETTING: Carleton University. PARTICIPANTS: Two hundred nineteen Carleton University undergraduate students. MAIN OUTCOME MEASURES: Cognitive flexibility as assessed by the Wisconsin Card Sorting Task (WCST); subtypes of rumination (Ruminative Response Scale; Treynor, Gonzalez, and Nolen-Hoeksema, 2003); depressive symptoms (Beck Depression Inventory; Beck, Ward, and Mendelson, 1961). RESULTS: Greater frequency of self-reported mTBIs was associated with more frequent depressive rumination among women, but not men, which was accompanied by elevated current depressive symptoms. In addition, among Met allele carriers of the BDNF polymorphism, but not those who were Val homozygotes, greater frequency of mTBIs was related to higher levels of brooding, which was accompanied by heightened depressive symptoms. Brain-derived neurotrophic factor genotype also moderated the relationship between self-reported mTBIs and cognitive flexibility in that more frequent mTBIs were associated with more perseverative errors on the WCST among Met carriers, but not Val homozygotes. CONCLUSIONS: The present findings raise the possibility that the evolution of depression after mTBIs may be dependant on a BDNF polymorphism and sex differences.

Implications of the gut microbiota in vulnerability to the social avoidance effects of chronic social defeat in male mice.

Appreciable evidence suggests that perturbations within the gut microbiome and the immune system may play a key role in the pathogenesis of depression stemming from earlier stressful experiences. In the present investigation we examined whether microbial changes in cecum contents were associated with social avoidance behaviors, a feature of depression, and pro-inflammatory variations among socially stressed mice. Male C57BL/6 mice experienced social defeat or a control condition once a day for 10 consecutive days. Social avoidance behaviors were examined three weeks after the last defeat or control episode and blood, brain, and cecum contents were collected 24h afterward for the determination of corticosterone, pro-inflammatory cytokines, and microbial populations. Mice that were most susceptible to the behavioral effects of chronic social defeat (reflected by severe social avoidance behaviors) displayed the greatest changes within particular sets of bacteria at the phylum and genus taxonomic ranks. Although plasma and brain cytokines were not significantly altered in socially defeated mice, changes in the mRNA expression of interleukin (IL)-1ß and IL-6 within the prefrontal cortex were associated with elevated abundance of Flavobacterium spp. and reduced abundance of Turicibacter spp., which were also strongly correlated to social avoidance severity. Although at this time a causal connection cannot be inferred, these results point to the possibility that specific clusters of bacterial communities in cecum contents may be linked to vulnerability to social deficits stemming from prolonged social stressor experiences.

Unsupportive social interactions and affective states: examining associations of two oxytocin-related polymorphisms.

Two single-nucleotide polymorphisms (SNPs) on oxytocin-related genes, specifically the oxytocin receptor (OXTR) rs53576 and the CD38 rs3796863 variants, have been associated with alterations in prosocial behaviors. A cross-sectional study was conducted among undergraduate students (N = 476) to examine associations between the OXTR and CD38 polymorphisms and unsupportive social interactions and mood states. Results revealed no association between perceived levels of unsupportive social interactions and the OXTR polymorphism. However, A carriers of the CD38 polymorphism, a variant previously associated with elevated oxytocin, reported greater perceived peer unsupportive interactions compared to CC carriers. As expected, perceived unsupportive interactions from peers was associated with greater negative affect, which was moderated by the CD38 polymorphism. Specifically, this relation was stronger among CC carriers of the CD38 polymorphism (a variant thought to be linked to lower oxytocin). When examining whether the OXTR polymorphism moderated the relation between unsupportive social interactions from peers and negative affect there was a trend toward significance, however, this did not withstand multiple testing corrections. These findings are consistent with the perspective that a variant on an oxytocin polymorphism that may be tied to lower oxytocin is related to poor mood outcomes in association with negative social interactions. At the same time, having a genetic constitution presumed to be associated with higher oxytocin was related to increased perceptions of unsupportive social interactions. These seemingly paradoxical findings could be related to previous reports in which variants associated with prosocial behaviors were also tied to relatively more effective coping styles to deal with challenges.

Suicide Ideation and Attempts among First Nations Peoples Living On-Reserve in Canada: The Intergenerational and Cumulative Effects of Indian Residential Schools.

OBJECTIVE: Suicide rates among Indigenous peoples in Canada are at least twice that of their non-Indigenous counterparts. Although contemporary stressors contribute to this increased risk, historical experiences such as the Indian Residential School (IRS) system may also have continuing links with the risk for suicidal thoughts and behaviors. The current investigation examined the intergenerational and cumulative links between familial IRS attendance in relation to lifetime suicide ideation and attempts among First Nations adults living on-reserve. METHOD: Data from the 2008-2010 First Nations Regional Health Survey were analyzed, and participants comprised a representative sample of First Nations adults older than 18 years (weighted N = 127,338; IRS attendees were excluded). Of those who knew their familial IRS history, 38.0% had no history of attendance, 19.3% had a grandparent who attended, 16.2% had a parent who attended, and 26.5% had a parent and grandparent who attended. RESULTS: Exposure of one previous familial generation to the IRS experience was associated with increased risk for lifetime suicide ideation (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.16 to 1.84; P = 0.001) and attempts (OR, 1.44; 95% CI, 1.07 to 1.94; P < 0.016) compared with those with no IRS history. Having 2 generations of IRS familial history was associated with greater odds of reporting a suicide attempt compared with having one generation (OR, 1.35; 95% CI, 1.05 to 1.75; P = 0.022), which was reduced when current levels of distress and ideation were accounted for. CONCLUSION: Findings support the existence of linkages between intergenerational exposure to IRS and risk for suicidal ideation and attempts and for a potential cumulative risk in relation to suicide attempts across generations.

Chemogenetic ablation of dopaminergic neurons leads to transient locomotor impairments in zebrafish larvae.

To determine the impact of a controlled loss of dopaminergic neurons on locomotor function, we generated transgenic zebrafish, Tg(dat:CFP-NTR), expressing a cyan fluorescent protein-nitroreductase fusion protein (CFP-NTR) under the control of dopamine transporter (dat) cis-regulatory elements. Embryonic and larval zebrafish express the transgene in several groups of dopaminergic neurons, notably in the olfactory bulb, telencephalon, diencephalon and caudal hypothalamus. Administration of the pro-drug metronidazole (Mtz) resulted in activation of caspase 3 in CFP-positive neurons and in a reduction in dat-positive cells by 5 days post-fertilization (dpf). Loss of neurons coincided with impairments in global locomotor parameters such as swimming distance, percentage of time spent moving, as well as changes in tail bend parameters such as time to maximal bend and angular velocity. Dopamine levels were transiently decreased following Mtz administration. Recovery of some of the locomotor parameters was observed by 7 dpf. However, the total numbers of dat-expressing neurons were still decreased at 7, 12, or 14 dpf, even though there was evidence for production of new dat-expressing cells. Tg(dat:CFP-NTR) zebrafish provide a model to correlate altered dopaminergic neuron numbers with locomotor function and to investigate factors influencing regeneration of dopaminergic neurons.

Finding benefit in stressful uncertain circumstances: relations to social support and stigma among women with unexplained illnesses.

Living with a chronic illness can be challenging, but the ability to derive benefits and grow from this experience may enhance well-being. However, the possibility of obtaining such benefits may be dependent on the levels of stigmatization and lack of social support experienced by an individual as a result of the illness. Chronic fatigue syndrome (CFS) and fibromyalgia are chronic conditions that remain largely unexplained and those with these conditions must often contend with stigma and skepticism from others. Individuals with CFS/fibromyalgia often display stress-related biological alterations and the experience of stressful life events has been associated with illness development. The present study demonstrated that women with CFS/fibromyalgia (n = 40) as well as community participants who were depressed/anxious (n = 37), reported higher stigma levels than healthy women (n = 33). Moreover, women with CFS/fibromyalgia and those with depression/anxiety also reported greater levels of stigma than women with a chronic yet more widely accepted condition (n = 35; rheumatoid arthritis, osteoarthritis and multiple sclerosis). Secrecy related to stigma among those with CFS/fibromyalgia declined with increased social support, but this was not apparent among those with other chronic conditions. In addition, posttraumatic growth was lower among women with CFS/fibromyalgia compared to those with other chronic conditions. Qualitative analysis examining both negative impacts and positive changes stemming from illness experience revealed many similarities between women with CFS/fibromyalgia and those with other chronic conditions, including elevated appreciation for life, personal growth and compassion for others. However, women with CFS/fibromyalgia tended to report less positive change regarding interpersonal relationships compared to women with other chronic conditions. In general, unexplained illnesses were also accompanied by stigmatization which might ultimately contribute to women's lower ability to derive positive growth from their illness experience.

Childhood adversity, perceived discrimination, and coping strategies in relation to depressive symptoms among First Nations adults in Canada: The moderating role of unsupportive social interactions from ingroup and outgroup members.

Aboriginal peoples are at greater risk of experiencing early life adversity relative to non-Aboriginal peoples in Canada, and as adults frequently experience high levels of discrimination that act as a further stressor. Although these factors appear to contribute to high rates of depressive disorders and suicidality in Aboriginal peoples, the psychosocial factors that contribute to the relationship between childhood adversity and the development of depressive symptoms have hardly been assessed in this group. The present investigation explored potential mediators to help explain the relation between childhood trauma and depressive symptoms among a sample of First Nations adults from across Canada. These mediated relationships were further examined in the context of unsupportive social interactions from ingroup and outgroup members. In Study 1, (N = 225), the relationship between childhood trauma and depression scores was mediated by perceived discrimination, and this was particularly notable in the presence of unsupportive relations with outgroup members. In Study 2, (N = 134) the relationship between childhood trauma and depressive symptoms was mediated by emotion-focused coping that was specific to coping with experiences of ethnic discrimination, and this mediated effect was moderated by both outgroup and ingroup unsupportive social interactions. Thus, it seems that experiences of discrimination and unsupport might contribute to depressive symptoms among First Nations adults who had experienced early life adverse events.

The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling.

Protein tyrosine phosphatase 1B (PTP1B) counteracts leptin signaling and is a therapeutic target for obesity and diabetes. Here we found that LIM domain only 4 (LMO4) inhibits PTP1B activity by increasing the oxidized inactive form of PTP1B. Mice with neuronal ablation of LMO4 have elevated PTP1B activity and impaired hypothalamic leptin signaling, and a PTP1B inhibitor normalized PTP1B activity and restored leptin control of circulating insulin levels. LMO4 is palmitoylated at its C-terminal cysteine, and deletion of this residue prevented palmitoylation and retention of LMO4 at the endoplasmic reticulum and abolished its inhibitory effect on PTP1B. Importantly, LMO4 palmitoylation is sensitive to metabolic stress; mice challenged with a brief high-fat diet or acute intracerebroventricular infusion of saturated fatty acid had less palmitoylated LMO4, less oxidized PTP1B, and increased PTP1B activity in the hypothalamus. Thus, unleashed PTP1B activity attributable to loss of LMO4 palmitoylation may account for rapid loss of central leptin signaling after acute exposure to saturated fat.

Perturbation of transcription factor Nur77 expression mediated by myocyte enhancer factor 2D (MEF2D) regulates dopaminergic neuron loss in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

We have earlier reported the critical nature of calpain-CDK5-MEF2 signaling in governing dopaminergic neuronal loss in vivo. CDK5 mediates phosphorylation of the neuronal survival factor myocyte enhancer factor 2 (MEF2) leading to its inactivation and loss. However, the downstream factors that mediate MEF2-regulated survival are unknown. Presently, we define Nur77 as one such critical downstream survival effector. Following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo, Nur77 expression in the nigrostriatal region is dramatically reduced. This loss is attenuated by expression of MEF2. Importantly, MEF2 constitutively binds to the Nur77 promoter in neurons under basal conditions. This binding is lost following 1-methyl-4-phenylpyridinium treatment. Nur77 deficiency results in significant sensitization to dopaminergic loss following 1-methyl-4-phenylpyridinium/MPTP treatment, in vitro and in vivo. Furthermore, Nur77-deficient MPTP-treated mice displayed significantly reduced levels of dopamine and 3,4-Dihydroxyphenylacetic acid in the striatum as well as elevated post synaptic FosB activity, indicative of increased nigrostriatal damage when compared with WT MPTP-treated controls. Importantly, this sensitization in Nur77-deficient mice was rescued with ectopic Nur77 expression in the nigrostriatal system. These results indicate that the inactivation of Nur77, induced by loss of MEF2 activity, plays a critical role in nigrostriatal degeneration in vivo.

Anticipation of a psychosocial stressor differentially influences ghrelin, cortisol and food intake among emotional and non-emotional eaters.

Negative emotions trigger eating in some individuals (emotional eaters) possibly by influencing stress hormones that contribute to eating regulation (e.g., cortisol), or eating-related peptides (e.g., ghrelin) signaling food initiation. The present study assessed whether stressor-elicited cortisol and ghrelin changes would differ between emotional and non-emotional eaters, and whether eating would influence these neuroendocrine responses. Undergraduate women (N=103) who completed measures of emotional eating, were assigned to anticipate either a stressful (public speaking) or non-stressful event. During this period, participants were or were not offered food. Blood samples were taken continuously over a 40-min period to assess changes of cortisol and ghrelin levels, and mood was assessed after the anticipation period. Baseline ghrelin levels were lower in emotional than non-emotional eaters, and this relation was mediated by percent body fat. Ghrelin levels were elevated among women anticipating a stressor, compared to those in the control condition. Additionally, the normal decline of ghrelin following food consumption was not apparent among emotional eaters. Although food intake was not tied to hormone responses, reported hunger was associated with greater food intake for women in the stressor condition. It was suggested that emotional eating coupled with subjective feelings of hunger, might contribute to eating in response to an acute stressor. Additionally, feedback mechanisms controlling the normalization of ghrelin levels might be disturbed in emotional eaters. The similarity of the ghrelin profile of emotional eaters to that of binge eaters and obese individuals, raises the possibility that disturbed ghrelin response might be a risk factor for such conditions.

Appraisals of discriminatory events among adult offspring of Indian residential school survivors: the influences of identity centrality and past perceptions of discrimination.

As part of a government policy of assimilation beginning in the mid-1800s, a large proportion of Aboriginal children in Canada were forcibly removed from their homes to attend Indian Residential Schools (IRSs), a practice which continued into the 1990s. This traumatic experience had lasting negative effects not only on those who attended but also on their offspring, who were previously found to report higher levels of perceived discrimination and depressive symptoms compared with Aboriginal adults whose families were not directly affected by IRSs. In attempt to elucidate the processes involved in these previous findings, the current study (N = 399) revealed that greater levels of past perceptions of discrimination among IRS offspring, together with their greater likelihood of considering their Aboriginal heritage to be a central component of their self-concept (i.e., high identity centrality), were associated with an increased likelihood of appraising subsequent negative intergroup scenarios to be a result of discrimination and as threatening to their well-being. In turn, these altered appraisals of threat in response to the scenarios were associated with higher levels of depressive symptoms relative to non-IRS adults. The apparent reinforcing relationships between past discrimination, identity centrality, and appraisals of discrimination and threat in intergroup interactions highlight the need for interventions targeting this cycle that appears to contribute to heightened psychological distress among offspring of those who were directly victimized by collective race-based traumas.

Medicine for the soul: (Non)religious identity, coping, and mental health during the COVID-19 pandemic.

Although the threat and uncertainty of the COVID-19 pandemic has become a significant source of distress, using religion to cope may be associated with more positive health. Given the severity and chronicity of the pandemic, religious individuals may also have relied on a variety of non-religious coping methods. Much of the existing COVID-19 research overlooks the role of religious group membership and beliefs in relation to coping responses and associated mental health, with an additional lack of such research within the Canadian context. Thus, this cross-sectional study investigated relations among religiosity, stressor appraisals, (both religious and non-religious) coping strategies, mental and physical health in a religiously-diverse Canadian community sample (N = 280) during the pandemic's 2nd wave from March to June 2021. Numerous differences were apparent in appraisal-coping methods and health across five (non)religious groups (i.e., Atheists, Agnostics, "Spiritual but not religious", Christians, and those considered to be religious "Minorities" in Canada). Religiosity was also associated with better mental health, appraisals of the pandemic as a challenge from which one might learn or grow, and a greater reliance on problem-focused, emotional-engagement, and religious coping. Moreover, both problem-focused and emotional-engagement coping mediated the relations between religiosity and health. Taken together, this research has implications for individual-level coping as well as informing culturally-sensitive public health messages promoting targeted self-care recommendations with integrated religious or spiritual elements during times of threat and uncertainty, such as the COVID-19 pandemic.

Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice.

Altered regulation of the serotonin-1A (5-HT1A) receptor gene is implicated in major depression and mood disorders. The functional human 5-HT1A C(-1019)G promoter polymorphism (rs6295), which prevents the binding of Deaf-1/NUDR leading to dysregulation of the receptor, has been associated with major depression. In cell models Deaf-1 displays dual activity, repressing 5-HT1A autoreceptor expression in serotonergic raphe cells while enhancing postsynaptic 5-HT1A heteroreceptor expression in nonserotonergic neurons. A functional Deaf-1 binding site on the mouse 5-HT1A promoter was recognized by Deaf-1 in vitro and in vivo and mediated dual activity of Deaf-1 on 5-HT1A gene transcription. To address regulation by Deaf-1 in vivo, Deaf-1 knock-out mice bred to a C57BL/6 background were compared with wild-type siblings for changes in 5-HT1A RNA and protein by quantitative RT-PCR, in situ hybridization, and immunofluorescence. In the dorsal raphe, Deaf-1 knock-out mice displayed increased 5-HT1A mRNA, protein, and 5-HT1A-positive cell counts but reduced 5-HT levels, whereas other serotonergic markers, such as tryptophan hydroxylase (TPH)- or 5-HT-positive cells and TPH2 RNA levels, were unchanged. By contrast, 5-HT1A mRNA and 5-HT1A-positive cells were reduced in the frontal cortex of Deaf-1-null mice, with no significant change in hippocampal 5-HT1A RNA, protein, or cell counts. The region-specific alterations of brain 5-HT1A gene expression and reduced raphe 5-HT content in Deaf-1(-/-) mice indicate the importance of Deaf-1 in regulation of 5-HT1A gene expression and provide insight into the role of the 5-HT1A G(-1019) allele in reducing serotonergic neurotransmission by derepression of 5-HT1A autoreceptors.

Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1.

Mutations in the mitochondrial PTEN-induced kinase 1 (Pink1) gene have been linked to Parkinson disease (PD). Recent reports including our own indicated that ectopic Pink1 expression is protective against toxic insult in vitro, suggesting a potential role for endogenous Pink1 in mediating survival. However, the role of endogenous Pink1 in survival, particularly in vivo, is unclear. To address this critical question, we examined whether down-regulation of Pink1 affects dopaminergic neuron loss following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the adult mouse. Two model systems were utilized: virally delivered shRNA-mediated knockdown of Pink1 and germ line-deficient mice. In both instances, loss of Pink1 generated significant sensitivity to damage induced by systemic MPTP treatment. This sensitivity was associated with greater loss of dopaminergic neurons in the Substantia Nigra pars compacta and terminal dopamine fiber density in the striatum region. Importantly, we also show that viral mediated expression of two other recessive PD-linked familial genes, DJ-1 and Parkin, can protect dopaminergic neurons even in the absence of Pink1. This evidence not only provides strong evidence for the role of endogenous Pink1 in neuronal survival, but also supports a role of DJ-1 and Parkin acting parallel or downstream of endogenous Pink1 to mediate survival in a mammalian in vivo context.

The differential impact of social defeat on mice living in isolation or groups in an enriched environment: plasma corticosterone and monoamine variations.

Social defeat in mice is a potent stressor that promotes the development of depressive- and anxiety-like behaviours, as well as variations of neuroendocrine and brain neurotransmitter activity. Although environmental enrichment may protect against some of the adverse behavioural and biological effects of social defeat, it seems that, among male group-housed mice maintained in an enriched environment (EE), aggressive behaviours may be more readily instigated, thus promoting distress and exacerbating psychopathological features. Thus, although an EE can potentially have numerous beneficial effects, these may depend on the general conditions in which mice were raised. It was observed in the current investigations that EE group-housed BALB/cByJ mice displayed increased anxiety-like behaviours compared to their counterparts maintained in a standard environment (SE). Furthermore, in response to social defeat, EE group-housed male mice exhibited decreased weight gain, exaggerated corticosterone elevations and altered hippocampal norepinephrine utilization compared to their SE counterparts. These effects were not apparent in the individually housed EE mice and, in fact, enrichment among these mice appeared to buffer against serotonin changes induced by social defeat. It is possible that some potentially beneficial effects of enrichment were precluded among group-housed mice, possibly owing to social disturbances that might occur in these conditions. In fact, even if social interaction is an essential feature of enrichment, it seems that some of the positive effects of this housing condition might be optimal when mice are housed individually, particularly with regard to buffering the effects of social defeat.

Central administration of murine interferon-α induces depressive-like behavioral, brain cytokine and neurochemical alterations in mice: a mini-review and original experiments.

A role for pro-inflammatory cytokines and their neuroinflammatory signaling cascades in depressive pathology has increasingly gained acceptance. In this regard, several lines of evidence suggested that interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) can provoke neurochemical and hormonal changes akin to those associated with psychological stressors, and that these cytokines also induce sickness behaviors that resemble some of the neurovegetative features of depression. Similarly, human depressed patients often display marked changes of pro-inflammatory cytokine levels and immune cell activity. Perhaps more germane in the analysis of the cytokine-depression connection, reports of humans undergoing interferon-α (IFN-α) treatment for certain cancers or viral infections have indicated that the pro-inflammatory cytokine caused signs of major depression in a substantial subset of those treated. In the present investigation, we demonstrated that acute or repeated infusion of IFN-α into the lateral ventricles provoked depressive-like behavior and concomitant changes in serotonin (5-HT) and mRNA expression of particular 5-HT receptors and pro-inflammatory cytokines. These actions were less evident following administration directly into the prefrontal cortex and not apparent at all when administered to the dorsal raphe nucleus. The data are discussed in relation to the induction of depression elicited by IFN-α, and are presented in the context of a mini-review that highlights potential mechanisms through which the cytokine might act to promote psychomotor and affective disturbances and interact with stressors.