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Adult zebrafish have the ability to regenerate cells of the central nervous system. However, few neuronal regeneration studies in adult zebrafish addressed their ability to regenerate specific types of neurons following cell specific ablation. We show here that treatment of transgenic Tg(dat:CFP-NTR) adult zebrafish with the prodrug metronidazole (Mtz) according to our administration regimen predominantly ablates dopamine (DA) neurons within the olfactory bulb (OB) of adult fish. Loss of DA neurons was accompanied by an impaired olfaction phenotype, as early as 1-week post-treatment, in which fish were unable to sense the presence of the repulsive stimulus cadaverine. The olfactory impairment was reversed within 45 days and coincided with the recovery of DA neuron counts in the OB. A multi-label pulse-chase analysis with BrdU and EdU over the first seventeen days-post Mtz exposure showed that newly formed DA neurons were recruited within the first nine days following exposure and led to functional and morphological recovery of the OB.

Because the underdog in a conflict typically gains the support of observers, nations will often adopt a narrative that persuades both their domestic following and international allies that they are the true victim in the conflict. Three survey studies were conducted to assess the perceptions of citizens of a third-party observer nation (Canada) in relation to two nations in conflict that differ in their historical persecution, namely the U.S. and Israel. Perceptions of the vulnerability of their safety and survival, and their strength to protect themselves against their opponents were hypothesized to mediate differences in the perceived justification for each nation's conflict actions. Study 1 (N = 91) supported this mediational model, with the U.S. seen as less vulnerable and more powerful than Israel, and perceptions of vulnerability accounting for differences in the justifiability of their respective conflict actions. Study 2 (N = 315) further demonstrated a moderating effect of Canadians' shared identity with the nations i

Perceived discrimination has consistently been shown to be associated with diminished mental health, but the psychological processes underlying this link are less well understood. The present series of four studies assessed the role of a history traumatic events in generating a proliferation of discrimination stressors and threat appraisals, which in turn predict psychological distress (depressive and posttraumatic stress symptoms) (mediation model), or whether prior traumatic events sensitize group members, such that when they encounter discrimination, the link to stress-rel

Environmental enrichment is typically associated with enhanced well-being, improved cognitive function and stress resilience. However, in some instances grouping adult male mice in enriched conditions promoted a stressful environment, which resulted in elevated endocrine, monoamine and inflammatory outcomes in response to subsequent stressor exposure. The current investigation examined whether raising male mice in an enriched environment (EE) would modulate social and anxiety-like behaviors in early adulthood and in

Cognitive control and (cognitive) flexibility play an important role in an individual's ability to adapt to continuously changing environments. In addition to facilitating goal-directed behaviors, cognitive control and flexibility have been implicated in emotion regulation, and disturbances of these abilities are present in mood and anxiety disorders. In the context of stressful experiences, the reported studies examined processes related to cognitive control and flexibility, emotional regulation and depressive symptoms. To this end, a brief (18-item) self-report measure - the Cognitive Control and Flexibility Questionnaire (CCFQ) - was developed. This questionnaire measures an individual's perceived ability to exert control over intrusive, unwanted (negative) thoughts and emotions, and their ability to flexibly cope with a stressful situation. In Study 1, the CCFQ was assessed among both university students (N = 300) and a community sample (N = 302). Preliminary analyses suggested a stable and reliable two-factor structure, that of cognitive control over emotion, and appraisal and coping flexibility. Scores on the CCFQ were strongly associated wi

The present research explored whether components of social identity, namely ingroup ties, affect, and centrality, were differentially linked to mental health and inflammatory immune responses, and whether rumination mediated those relations. Study 1 (N = 138) indicated that stronger ingroup ties were associated with fewer mental health (depressive and post-traumatic stress) symptoms; those relations were mediated by the tendency for individuals with strong ties to rely less on ruminative coping to deal with a stressful life event. Study 2 (N = 54) demonstrated that ingroup ties were negatively associated with depressive symptoms, dispositional rumination, as well as stress-linked inflammatory elements at the physiological level. Consistent associations for centrality and ingroup affect were absent, sugg

Disturbances of brain derived neurotrophic factor (BDNF) signaling, which may occur among those with a polymorphism of the Val66Met gene, comprising a Met substitution for the Val allele, may be associated with depressive cognitions. However, presumed elevated BDNF levels among individuals with the Val/Val genotype, might confer increased responsivity to contextual challenges, thus fostering vulnerability to depression. In Study 1, among undergraduate students (N = 252), increased loneliness perceptions were accompanied with depressive symptoms. This relationship was moderated by self-efficacy and BDNF genotype, such that when individuals appraised high self-efficacy, those with the Val/Val genotype, compared to Met carriers, reported greater depression scores when they perceived feeling lonely. Study 2 revealed that among undergraduate students (N = 178), lower depressive scores were associated with increased problem-focused coping among Val/Val individuals, but not Met carriers. Moreover, with increased perceived loneliness, Val/Val carriers endorsed lower problem-focused coping. Findings suggest that Val/Val individuals may have adverse neurocognitive vulnerability to loneliness experiences.

Cognitive flexibility plays an important role in an individual’s ability to adapt to a continuously changing environment and is considered central to goal-oriented behavior. Accordingly, increasing attention has been devoted to understanding the factors, including genetic and early life experiences, which might contribute to individual differences in this ability. In the present investigation, we examined the contribution of the BDNF Val66Met polymorphism to cognitive flexibility, as assessed by set-shifting ability on the Wisconsin Card Sorting Task (WCST), and whether this polymorphism moderated the relation between trauma experiences (including type and timing of trauma occurrence) and cognitive flexibility. Among undergraduate students (N = 239), greater frequency of total traumas experienced prior to the age 5 was associated with greater difficulties in set-shifting (as indexed by more frequent perseverative errors on the WCST) among individuals carrying the Met allele of the BDNF polymorphism, but not those who were Val homozygotes. By contrast, total traumas experienced between the age of 6 to 12 and 13 to 18 were not related to set-shifting ability, and these relations were not moderated by BDNF genotype. Moreover, greater frequency of general traumas and emotional abuse was associated with set-shifting difficulties for both male and female Met allele carriers, but not Val homozygotes. In contrast, physical punishment was related to difficulties in set-shifting, but only among male Met carriers, an effect that was likely attributed to greater frequency of this form of trauma among males. The present findings suggest that the relationship between early life trauma and later-life cognitive flexibility might depend on the presence of the BDNF Val66Met polymorphism as well as the development stage at which the trauma has occurred. Moreover, the present investi

Although the neuropeptide oxytocin has been associated with enhanced prosocial behaviors, it has also been linked to aggression and mental health disorders. Thus, it was suggested that oxytocin might act by increasing the salience of social stimuli, irrespective of whether these are positive or negative, thus increasing vulnerability to negative mental health outcomes. The current study (N = 243), conducted among white university students, examined the relation of trauma, depressive symptoms including suicidal ideation in relation to a single nucleotide polymorphism (SNP) within the oxytocin receptor gene (OXTR), rs53576, and a SNP on the CD38 gene that controls oxytocin release, rs3796863. Individuals with the polymorphism on both alleles (AA genotype) of the CD38 SNP had previously been linked to elevated plasma oxytocin levels. Consistent with the social sensitivity perspective, however, in the current study, individuals carrying the AA genotype displayed elevated feelings of alienation from parents and peers as well as increased levels of suicidal ideation. Moreover, they tended to report elevated depressive symptoms compared to CC homozygotes. It was also observed that the CD38 genotype moderated the relation between trauma and suicidal ideation scores, such that high levels of trauma were associated with elevated suicidal ideation among all CD38 genotypes, but this relationship was stronger among individuals with the AA genotype. In contrast, there was no relationship between the OXTR SNP, rs53576, depression or suicidal ideation. These findings support a social sensitivity hypothesis of oxytocin, wherein the AA genotype of the CD38 SNP, which has been considered the “protective allele” was associated with increased sensitivity and susceptibility to disturbed social relations and suicidal ideation.

Stress responses in humans can be attenuated by exogenous oxytocin administration, and these stress-buffering properties may be moderated by social factors. Yet, the influence of acute stressors on circulating endogenous oxytocin levels have been inconsistent, and limited information is available concerning the influence of social support in moderating this relationship. In the current investigation, undergraduate women (N = 67) were assessed in the Trier Social Stress Test (TSST) with either social support available from a close female friend or no social support being available. An additional set of women served as controls. The TSST elicited marked elevations of state anxiety and negative emotions, which were largely attenuated among women who received social support. Furthermore, baseline oxytocin levels were inversely related to women's general feelings of distrust, as well as basal plasma cortisol levels. Despite thes

Stressor experiences during the juvenile period may increase vulnerability to anxiety and depressive-like symptoms in adulthood. Stressors may also promote pala

A single-nucleotide polymorphism on the oxytocin receptor gene (OXTR), rs53576, involving a guanine (G) to adenine (A) substitution has been associated with altered prosocial features. Specifically, individuals with the GG genotype (i.e. the absence of the polymorphism) display beneficial traits including enhanced trust, empathy and self-esteem. However, because G carriers might also be more socially sensitive, this may render them more vulnerable to the adverse effects of a negative social stressor. The current investigation, conducted among 128 white female undergraduate students, demonstrated that relative to individuals with AA genotype, G carriers were more emotionally sensitive (lower self-esteem) in response to social ostracism promoted through an on-line ball tossing game (Cyberball). Furthermore, GG individuals also exhibited altered blood pressure and cortisol levels following rejection, effects not apparent among A carriers. The data support the view that the presence of the G allele not only promotes prosocial behaviors but also favors sensitivity to a negative social stressor.

Combined cell and gene-based therapeutic strategies offer potential in the treatment of neurodegenerative and psychiatric conditions that have been associated with structural brain disturbances. In the present investigation, we used a novel virus-free re-programming method to generate induced pluripotent stem cells (iPSCs), and then subsequently transformed these cells into neural cells which over-expressed brain derived neurotrophic factor (BDNF). Importantly, the infusion of iPSC derived neural cells (a

Social identity threats, depending on the content of the identity targeted, may evoke varying socio-political responses. In this regard, religious discrimination may be especially threatening, challenging both the social group and its belief system, thereby promoting more active collective responses. This research examined how religious and ethnic identification differentially evoked engagement with support resources (ingroup and spiritual), civic involvement (including individual and collective action-taking), and political participation (voting or political consciousness) following group-based threats. Study 1 drew from the Canadian Ethnic Diversity Survey (N = 1806). Participants who reported religious discrimination demonstrated greater religious identification, ingroup social engagement, and civic involvement—comparable associations were absent for ethnic discrimination. Study 2 (N = 287) experimentally primed participants to make salient a specific incident of religious or ethnic discrimination. Although ethnic discrimination elicited greater ingroup support-seeking and political consciousness, religious discrimination was perceived as especially harmful and evoked more individual and collective action-taking. Further

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.

Stressful events promote several neuroendocrine and neurotransmitter changes that might contribute to the provocation of psychological and physical pathologies. Perhaps, because of its apparent ecological validity and its simple application, there has been increasing use of social defeat (resident-intruder) paradigms as a stressor. The frequency of stress-related psychopathology is much greater in females than in males, but the typical resident-intruder paradigm is less useful in assessing stressor effects in females. An alternative, but infrequently used procedure in females involves exposing a mouse to a lactating dam, resulting in threatening gestures being expressed by the resident. In the present investigation we demonstrated the utility of this paradigm, showing that the standard resident-intruder paradigm in males and the modified version in females promoted elevated anxiety in a plus-maze test. The behavioral effects that reflected anxiety were more pronounced 2 weeks after the stressor treatment than they were 2 hr afterward, possibly reflecting the abatement of the stress-related of hyper-arousal. These treatments, like a stressor comprising physical restraint, increased plasma corticosterone and elicited variations of norepinephrine and serotonin levels and turnover within the prefrontal cortex, hippocampus and central amygdala. Moreover, the stressor effects were exaggerated among mice that had been exposed to a chronic or subchronic-intermittent regimen of unpredictable stressors. Indeed, some of the monoamine changes were more pronounced in females than in males, although it is less certain whether this represented compensatory changes to deal with chronic stressors that could result in excessive strain on biological systems (allostatic overload).

Depression is a chronic and debilitating condition with a significant degree of relapse and treatment resistance that could stem, at least in part, from disturbances of neuroplasticity. This has led to an increased focus on treatment strategies that target brain derived neurotrophic factor (BDNF), synaptic plasticity and adult neurogenesis. In the current study we aimed to assess whether erythropoietin (EPO) would have antidepressant-like effects given its already established pro-trophic actions. In particular, we assessed whether EPO would diminish the deleterious effects of a social stressor in mice. Indeed, EPO induced anxiolytic and antidepressant-like responses in a forced swim test, open field, elevated-plus maze, and a novelty test, and appeared to blunt some of the negative behavioural effects of a social stressor. Furthermore, EPO promoted adult hippocampal neurogenesis, an important feature of effective antidepressants. Finally, a separate study using the mTOR inhibitor rapamycin revealed that antagonizing this pathway prevented the impact of EPO upon forced swim performance. These data are consistent with previous findings showing that the mTOR pathway and its neurogenic and synaptogenic effects might mediate the behavioral consequences of antidepressant agents. Our findings further highlight EPO as a possible adjunct treatment for affective disorders, as well as other stressor associated disorders of impaired neuroplasticity.

Disturbances of brain derived neurotrophic factor (BDNF) signalling have been implicated in the evolution of depression, which likely arises, in part, as a result of diminished synaptic plasticity. Predictably, given stressor involvement in depression, BDNF is affected by recent stressors as well as stressors such as neglect experienced in early life. The effects of early lif

Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Herewedemonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [D-Lys3]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, oldGHSRKOmice did notshowthese alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress-induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions. Copyright

The LIM domain only 4 (LMO4) protein is expressed in the hypothalamus, but its function there is not known. Using mice with LMO4 ablated in postnatal glutamatergic neurons, including most neurons of the paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei where LMO4 is expressed, we asked whether LMO4 is required for metabolic homeostasis. LMO4 mutant mice exhibited early onset adiposity. These mice had reduced energy expenditure and impaired thermogenesis together with reduced sympathetic outflow to adipose tissues. The peptide hormone leptin, produced from adipocytes, activates Jak/Stat3 signaling at the hypothalamus to control food intake, energy expenditure, and fat metabolism. Intracerebroventricular infusion of leptin suppressed feeding similarly in LMO4 mutant and control mice. However, leptin-induced fat loss was impaired and activation of Stat3 in the VMH was blunted in these mice. Thus, our study identifies LMO4 as a novel modulator of leptin function in selective hypothalamic nuclei to regulate fat metabolism.

Social conflicts may engender stress-related behavioural and physiological disturbances in the victims of aggression. In addition, stress-like neurochemical changes and ensuing depressive and anxiety symptoms might also be evident in the perpetrators of aggressive acts. The present investigation assessed basal levels of circulating corticosterone and of brain serotonin (5-HT) and norepinephrine (NE) in pre-identified submissive and dominant mice. In addition, brain neurochemical changes were determined following a single or three 15-min aggressive episodes both in submissive mice and in those that dominated the aggressive interplay. Three minutes after single and repeated confrontations, plasma corticosterone levels and 5-HT utilization within the prefrontal cortex (PFC) and hippocampus were increased to a comparable extent in submissive and dominant animals. Interestingly, however, NE utilization within the PFC and hippocampus was augmented to a greater level in submissive mice. These results suggest that 5-HT neuronal functioning was generally responsive to aggressive events, irrespective of social rank, whereas NE neuronal activity within the PFC and hippocampus was more sensitive to the submissive/dominance attributes of the social situation. It is possible that NE and 5-HT variations associated with an aggressive experience contribute to depressive- and anxiety-like manifestations typically observed after such psychosocial stressors, particularly in submissive mice. However, given that 5-HT changes occur irrespective of social rank, these data suggest that a toll is taken on both submissive and dominant mice, leaving them vulnerable to stress-related pathology.

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminerg

Expression of the transcription factor c-Jun is induced in neurons of the central nervous system (CNS) in response to injury. Mechanical transection of the nigrostriatal pathway at the medial forebrain bundle (MFB) results in the delayed retrograde degeneration of the dopamine neurons i