Activation of androgen receptor-expressing neurons in the posterior medial amygdala is associated with stress resistance in dominant male hamsters.

Social stress is a negative emotional experience that can increase fear and anxiety. Dominance status can alter the way individuals react to and cope with stressful events. The underlying neurobiology of how social dominance produces stress resistance remains elusive, although experience-dependent changes in androgen receptor (AR) expression is thought to play an essential role. Using a Syrian hamster (Mesocricetus auratus) model, we investigated whether dominant individuals activate more AR-expressing neurons in the posterior dorsal and posterior ventral regions of the medial amygdala (MePD, MePV), and display less social anxiety-like behavior following social defeat stress compared to subordinate counterparts. We allowed male hamsters to form and maintain a dyadic dominance relationship for 12 days, exposed them to social defeat stress, and then tested their approach-avoidance behavior using a social avoidance test. During social defeat stress, dominant subjects showed a longer latency to submit and greater c-Fos expression in AR+ cells in the MePD/MePV compared to subordinates. We found that social defeat exposure reduced the amount of time animals spent interacting with a novel conspecific 24 h later, although there was no effect of dominance status. The amount of social vigilance shown by dominants during social avoidance testing was positively correlated with c-Fos expression in AR+ cells in the MePV. These findings indicate that dominant hamsters show greater neural activity in AR+ cells in the MePV during social defeat compared to their subordinate counterparts, and this pattern of neural activity correlates with their proactive coping response. Consistent with the central role of androgens in experience-dependent changes in aggression, activation of AR+ cells in the MePD/MePV contributes to experience-dependent changes in stress-related behavior.

Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.

Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

Higher dominance rank is associated with lower glucocorticoids in wild female baboons: A rank metric comparison.

In vertebrates, glucocorticoid secretion occurs in response to energetic and psychosocial stressors that trigger the hypothalamic-pituitary-adrenal (HPA) axis. Measuring glucocorticoid concentrations can therefore shed light on the stressors associated with different social and environmental variables, including dominance rank. Using 14,172 fecal samples from 237 wild female baboons, we test the hypothesis that high-ranking females experience fewer psychosocial and/or energetic stressors than lower-ranking females. We predicted that high-ranking females would have lower fecal glucocorticoid (fGC) concentrations than low-ranking females. Because dominance rank can be measured in multiple ways, we employ an information theoretic approach to compare 5 different measures of rank as predictors of fGC concentrations: ordinal rank; proportional rank; Elo rating; and two approaches to categorical ranking (alpha vs non-alpha and high-middle-low). Our hypothesis was supported, but it was also too simplistic. We found that alpha females exhibited substantially lower fGCs than other females (typical reduction = 8.2%). If we used proportional rank instead of alpha versus non-alpha status in the model, we observed a weak effect of rank such that fGCs rose 4.2% from the highest- to lowest-ranking female in the hierarchy. Models using ordinal rank, Elo rating, or high-middle-low categories alone failed to explain variation in female fGCs. Our findings shed new light on the association between dominance rank and the stress response, the competitive landscape of female baboons as compared to males, and the assumptions inherent in a researcher's choice of rank metric.

Dynamics and determinants of glucocorticoid metabolite concentrations in wild Verreaux's sifakas.

Glucocorticoids have wide-ranging effects on animals' behaviour, but many of these effects remain poorly understood because numerous confounding factors have often been neglected in previous studies. Here, we present data from a 2-year study of 7 groups of wild Verreaux's sifakas (Propithecus verreauxi), in which we examined concentrations of faecal glucocorticoid metabolites (fGCMs, n = 2350 samples) simultaneously in relation to ambient temperatures, food intake, rank, reproduction, adult sex ratios, social interactions, vigilance and self-scratching. Multi-variate analyses revealed that fGCM concentrations were positively correlated with increases in daily temperature fluctuations and tended to decrease with increasing fruit intake. fGCM concentrations increased when males were sexually mature and began to disperse, and dominant males had higher fGCM concentrations than subordinate males. In contrast to males, older females showed a non-significant trend to have lower fGCM levels, potentially reflecting differences in male and female life-history strategies. Reproducing females had the highest fGCM concentrations during late gestation and had higher fGCM levels than non-reproducing females, except during early lactation. Variation in fGCM concentrations was not associated with variation in social interactions, adult sex ratios, vigilance and self-scratching. Altogether, we show that measures of glucocorticoid output constitute appropriate tools for studying energetic burdens of ecological and reproductive challenges. However, they seem to be insufficient indicators for immediate endocrinological responses to social and nonsocial behaviours that are not directly linked to energy metabolism.

Rising to the challenge? Inter-individual variation of the androgen response to social interactions in cichlid fish.

The Challenge Hypothesis (Wingfield et al. Am. Nat. 136, 829-846) aims to explain the complex relationship between androgens and social interactions. Despite its well acceptance in the behavioral endocrinology literature, several studies have failed to found an androgen response to staged social interactions. Possible reasons for these inconsistencies are the use of single sampling points that may miss the response peak, and the occurrence of inter-individual variability in the androgen response to social interactions. In this study we addressed these two possible confounding factors by characterizing the temporal pattern of the androgen response to social interactions in the African cichlid, Oreochromis mossambicus, and relating it to inter-individual variation in terms of the individual scope for androgen response (i.e. the difference between baseline and maximum physiological levels for each fish) and behavioral types. We found that the androgen response to territorial intrusions varies between individuals and is related to their scope for response. Individuals that have a lower scope for androgen response did not increase androgens after a territorial intrusion but were more aggressive and exploratory. In contrast males with a higher scope for response had fewer aggressive and exploratory behaviors and exhibited two peaks of KT, an early response 2-15 min after the interaction and a late response at 60-90 min post-interaction. Given that the pharmacological challenge of the Hypothalamic-Pituitary-Gonad axis only elicits the late response, we suggest that these two peaks may be regulated by different physiological mechanisms, with the early response being mediated by direct brain-gonad neural pathways. In summary, we suggest that determining the temporal pattern of the androgen response to social interactions and considering inter-individual variation may be the key to understanding the contradictory results of the Challenge Hypothesis.

Social stress and glucocorticoids alter PERIOD2 rhythmicity in the liver, but not in the suprachiasmatic nucleus.

Circadian (~24 h) rhythms in behavior and physiological functions are under control of an endogenous circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN directly drives some of these rhythms or serves as a coordinator of peripheral oscillators residing in other tissues and organs. Disruption of the circadian organization may contribute to disease, including stress-related disorders. Previous research indicates that the master clock in the SCN is resistant to stress, although it is unclear whether stress affects rhythmicity in other tissues, possibly mediated by glucocorticoids, released in stressful situations. In the present study, we examined the effect of uncontrollable social defeat stress and glucocorticoid hormones on the central and peripheral clocks, respectively in the SCN and liver. Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 (PER2) in SCN slices and liver tissue collected after 10 consecutive days of social defeat stress. The rhythmicity of PER2 expression in the SCN was not affected by stress exposure, whereas in the liver the expression showed a delayed phase in defeated compared to non-defeated control mice. In a second experiment, brain slices and liver samples were collected from transgenic mice and exposed to different doses of corticosterone. Corticosterone did not affect PER2 rhythm of the SCN samples, but caused a phase shift in PER2 expression in liver samples. This study confirms earlier findings that the SCN is resistant to stress and shows that clocks in the liver are affected by social stress, which might be due to the direct influence of glucocorticoids released from the adrenal gland.

Explaining negative kin discrimination in a cooperative mammal society.

Kin selection theory predicts that, where kin discrimination is possible, animals should typically act more favorably toward closer genetic relatives and direct aggression toward less closely related individuals. Contrary to this prediction, we present data from an 18-y study of wild banded mongooses, Mungos mungo, showing that females that are more closely related to dominant individuals are specifically targeted for forcible eviction from the group, often suffering severe injury, and sometimes death, as a result. This pattern cannot be explained by inbreeding avoidance or as a response to more intense local competition among kin. Instead, we use game theory to show that such negative kin discrimination can be explained by selection for unrelated targets to invest more effort in resisting eviction. Consistent with our model, negative kin discrimination is restricted to eviction attempts of older females capable of resistance; dominants exhibit no kin discrimination when attempting to evict younger females, nor do they discriminate between more closely or less closely related young when carrying out infanticidal attacks on vulnerable infants who cannot defend themselves. We suggest that in contexts where recipients of selfish acts are capable of resistance, the usual prediction of positive kin discrimination can be reversed. Kin selection theory, as an explanation for social behavior, can benefit from much greater exploration of sequential social interactions.

Actives, passives and power: heteronormative gender norms and their implications for intimate partner violence among men who have sex with men in Tajikistan.

Global research reveals that gender-role norms have a profound effect on socio- and psycho-sexual expression (e.g. sexual positioning) among gay and bisexual men, which in turn may affect mental health and sexual risks. However, little is known about these factors among gay and bisexual men in Muslim-majority countries such as Tajikistan. Using a combination of in-depth individual interviews and focus-group assessments, this exploratory, qualitative study examined how gender roles might function as a social determinant for the practice of sexual positioning, which in turn may influence intimate partner violence (IPV), sexual risk and relational power. Results suggest that being the 'active' partner in sexual relationships closely aligns with the construct of hegemonic masculinity, affording actives more power in male-male relationships which may in some cases result in IPV directed against 'passives'. Despite this imbalance, passives also hold power in some cases, such as easier access to public resources such as the police and gay and bisexual focused services. Further research should examine gender norms and sexual positioning relative to IPV and sexual risks among Muslim men in Tajikistan.

The Role of Consent in the Context of BDSM.

Consent represents a central focus in the controversial realm of BDSM-an overlapping acronym referring to the practices of Bondage and Discipline, Dominance and Submission, and Sadism and Masochism. Many authors have argued that the hallmark feature that distinguishes BDSM activity from abuse and psychopathology is the presence of mutual informed consent of all those involved. This review examines the relevant literature on consent in BDSM, including discussions on safety precautions, consent violations, North American laws pertaining to BDSM practice, and the role of the BDSM community with respect to education and etiquette surrounding consent. Practical information relevant to professionals who work toward the prevention of sexual exploitation and abuse is provided. The explicit approach to consent practiced by those in the BDSM community is proposed as a model for discussions around consent in clinical and educational contexts. Criteria for distinguishing abuse from BDSM and identifying abuse within BDSM relationships are outlined. It is our hope to demystify the consent process and add to the growing body of literature that destigmatizes consensual BDSM practices.

About the inconvenience of handling mixed-breed herds; aspects of social behavior as a potential source of stress and economic losses.

The objective of this study was to assess aspects of the social behavior of a mixed-breed herd of beef cows as a potential source for stress and economic losses. Angus (AN; N = 10), Brahman (BR; N = 10), and Senepol (SE; N = 10) cows were assigned to two groups (N = 15 each containing equal breed numbers) on separate pastures. Agonistic interactions (win/loss) during feeding were recorded daily for 45 days. Dominance values were estimated as the proportion of individuals dominated to total herdmates. From this, individuals were placed into social categories based upon linear ranking as follows: dominants (D), intermediate (I), and subordinates (S). Breed influenced (P < 0.01) social category, with SE cows being dominants (P < 0.05) over AN and BR cows. Interactions between AN and BR cows were less (P < 0.0005) than interactions between AN and SE (53 vs 140, respectively). Within breeds, BR (152) and SE (182) cows had more (P < 0.0005) agonistic interactions than AN (107) cows. Although apparently influenced by breed, agonistic interactions occurred more frequently (P < 0.005) between social categories than within social categories (814 vs 310, respectively). Dominant cows were involved in more agonistic interactions with cows from different social categories than were intermediate and subordinate cows (P < 0.0005). However, intermediate (100) and subordinate (157) cows generated more (P < 0.0005) agonistic interactions within their own social category than dominant cows (53). It was concluded that, in mixed-breed herds, breed influences both social organization and agonistic interactions which could be considered as potential sources of stress and economic losses.

Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice.

Dopamine in prefrontal cortices is implicated in cognitive and emotional functions, and the dysfunction of prefrontal dopamine has been associated with cognitive and emotional deficits in mental illnesses. These findings have led to clinical trials of dopamine-targeting drugs and brain imaging of dopamine receptors in patients with mental illnesses. Rodent studies have suggested that dopaminergic pathway projecting to the medial prefrontal cortex (mPFC) suppresses stress susceptibility. Although various types of mPFC neurons express several dopamine receptor subtypes, previous studies neither isolated a role of dopamine receptor subtype nor identified the site of its action in mPFC. Using social defeat stress (SDS) in mice, here we identified a role of dopamine D1 receptor subtype in mPFC excitatory neurons in suppressing stress susceptibility. Repeated social defeat stress (R-SDS) reduces the expression of D1 receptor subtype in mPFC of mice susceptible to R-SDS. Knockdown of D1 receptor subtype in whole neuronal populations or excitatory neurons in mPFC facilitates the induction of social avoidance by SDS. Single social defeat stress (S-SDS) induces D1 receptor-mediated extracellular signal-regulated kinase phosphorylation and c-Fos expression in mPFC neurons. Whereas R-SDS reduces dendritic lengths of mPFC layer II/III pyramidal neurons, S-SDS increases arborization and spines of apical dendrites of these neurons in a D1 receptor-dependent manner. Collectively, our findings show that D1 receptor subtype and related signaling in mPFC excitatory neurons mediate acute stress-induced dendritic growth of these neurons and contribute to suppression of stress susceptibility. Therefore, we propose that D1 receptor-mediated dendritic growth in mPFC excitatory neurons suppresses stress susceptibility.

Social stress increases plasma cortisol and reduces forebrain cell proliferation in subordinate male zebrafish (Danio rerio).

Many animals, including zebrafish (Danio rerio), form social hierarchies through competition for limited resources. Socially subordinate fish may experience chronic stress, leading to prolonged elevation of the glucocorticoid stress hormone cortisol. As elevated cortisol levels can impair neurogenesis, the present study tested the hypothesis that social stress suppresses cell proliferation in the telencephalon of subordinate zebrafish via a cortisol-mediated mechanism. Cell proliferation was assessed using incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU). After 48 and 96 h of social interaction, subordinate male zebrafish exhibited elevated plasma cortisol concentrations and significantly lower numbers of BrdU+ cells in the dorsal but not ventral regions of the telencephalon compared with dominant or group-housed control male fish. After a 2 week recovery in a familiar group of conspecifics, the number of BrdU+ cells that co-labelled with a neuronal marker (NeuN) was modestly reduced in previously subordinate male fish, suggesting that the reduction of cell proliferation during social stress may result in fewer cells recruited into the neuronal population. In contrast to male social hierarchies, subordinate female zebrafish did not experience elevated plasma cortisol, and the number of BrdU+ cells in the dorsal telencephalic area was comparable among dominant, subordinate and group-housed control female fish. Treating male zebrafish with metyrapone, a cortisol synthesis inhibitor, blocked the cortisol response to social subordination and attenuated the suppression of brain cell proliferation in the dorsal telencephalic area of subordinate fish. Collectively, these data support a role for cortisol in regulating adult neurogenesis in the telencephalon of male zebrafish during social stress.

The association between involuntary subordination and common mental disorders among men who have sex with men (MSM) in Shanghai, China.

BACKGROUND: Involuntary subordination is a mechanism that switches off fighting behaviors when a losing organism is unable to continue in a struggle. The study aim was to investigate the association between involuntary subordination and the common mental disorders of anxiety and depression among men who have sex with men (MSM) in Shanghai, China. METHODS: A cross-sectional study was conducted of 547 MSM in four Shanghai districts. Sociodemographic and psychosocial participant data were collected. Logistic regression was used to assess the association between anxiety, depression, and involuntary subordination. RESULTS: 12.2 and 30.9% Of the MSM demonstrated high levels of anxiety and depression respectively. Univariate analysis showed that involuntary subordination and the involuntary subordination constructs of defeat, social comparison, submissive behavior, and entrapment were associated with anxiety and depression. Multivariate analysis indicated that defeat (ORm = 1.091, 95% CI = 1.004-1.185) and entrapment (ORm = 1.174, 95% CI = 1.079-1.278) were significantly associated with anxiety. Defeat (ORm = 1.265, 95% CI = 1.166-1.372), social comparison (ORm = 1.119, 95% CI = 1.061-1.181), entrapment (ORm = 1.132, 95% CI = 1.047-1.224), and submissive behavior (ORm = 0.897, 95% CI = 0.825-0.975) were significantly associated with depression. CONCLUSIONS: The findings confirmed an association between anxiety, depression, and involuntary subordination among MSM. These findings could form the basis of a new, integrated, and holistic approach to the identification of high-risk groups and the development of interventions for anxiety and depression among MSM.

Social status predicts response to dietary cycling in female rhesus monkeys.

With the prevalence of obesity among women the United States surpassing 40%, it is critical to understand how environmental factors influence appetite, body fat accumulation, and the ability to lose weight and maintain weight loss. Psychosocial stress exposure is a risk factor for increased consumption of calorically dense diets (CDD), which are high in fat and sugars and promote both increased food intake and weight gain. However, it remains unclear how appetite is affected by psychosocial factors when people striving to lose weight restrict intake of unhealthy, calorically dense foods. Using a translational non-human primate model of chronic psychosocial stressor exposure in females (n = 16), mediated by social subordination, we examined ad libitum food intake, weight change, and social behavior during three consecutive, 15-week dietary conditions: 1) obesogenic, dietary choice; 2) chow-only; and 3) a switch back to dietary choice. Data showed that a choice dietary environment that includes both chow and CDD promotes increased calorie consumption of CDD in subordinate female rhesus monkeys during the baseline choice and back-to-choice phases (p = 0.016). Removal of the CDD during the chow-only phase resulted in mild inappetence (p = 0.005) and a loss in body weight (p < 0.001) in subordinate females. Reintroduction of the CDD to subordinate, but not dominant, females was associated with increased calorie intake that surpassed baseline intake (p < 0.001), and greater body weight gain (p = 0.026). There were no effects of diet cycling on total food intake and body weight change in dominant females (p's > 0.05). Overall, our results suggest that adverse psychosocial experience is associated with increased preference for highly palatable, calorically dense food in a choice dietary environment.

Taking the fight out of people: Exploring how defeat modulates the automatic aggressive response to facial anger.

Past studies indicate that angry facial expressions automatically activate an aggressive response, seeming to support the view that humans possess an inborn, automatic tendencies to aggress. However, the current authors drew on influential models from evolutionary game theory to suggest that experiences of defeat may modulate this tendency. To examine this, four experiments were conducted to explore how defeat may modulate this aggressive response. In each study, participants executed simulated fight or flight responses based a computerized opponent's facial expression. Across studies, participants were typically faster to initiate fight (than flight) responses against an angry opponent. Simply losing simulated fights (Experiment 1) or experiencing aversive, white noise following simulated losses (Experiment 2) did not eliminate this tendency. However, when aversive noise was specifically experienced after losing to an angry opponent, the automatic aggressive response was eliminated (Experiment 3). This result was directly replicated (Experiment 4). Thus, these studies isolate the cues which automatize submissive behavior and show that fighting experience can modulate even our automatic aggressive responses to others' anger displays.

Interpersonal Style and Posttraumatic Stress Disorder Symptoms in Female Victims of Dating Violence.

Symptoms of posttraumatic stress disorder (PTSD) are some of the most common mental health symptoms women experience following exposure to dating violence (DV). However, not all women who experience DV exhibit PTSD symptoms. One factor that may influence whether or not women exhibit PTSD symptoms in the aftermath of DV exposure is interpersonal style, often operationalized in terms of two orthogonal dimensions, warmth and dominance. In this study, we examined the main and moderating effects of warmth and dominance on the association between DV and PTSD symptoms using latent moderating structural equation modeling in a sample of 303 female college students who reported DV exposure in the past year. Results indicated that warmth exerted a main effect predicting fewer PTSD symptoms. In addition, dominance moderated the association between DV and PTSD symptoms such that at high levels of DV, women who were high on dominance reported fewer PTSD symptoms than did women who were low on dominance. These findings suggest that aspects of interpersonal style may promote resilience to symptoms of posttraumatic stress following DV exposure. Directions for future research are also discussed.

Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility.

Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility.SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces susceptibility to a subthreshold stress, while genetic overexpression in D2-neurons prevents social avoidance after chronic social defeat stress.

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress.

Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction. Control and previously defeated rats did not differ in either DOPA accumulation following amino acid decarboxylase inhibition (NSD-1015 100 mg/kg ip.) or total/phosphorylated tyrosine hydroxylase protein expression, suggesting dopamine synthesis in the adult mPFC is not altered by adolescent defeat. However, exposure to adolescent defeat caused greater decreases in extracellular dopamine release (measured using in vivo chronoamperometry) in the adult mPFC upon local infusion of the D2 receptor agonist quinpirole (3 nM), implying greater D2 autoreceptor function. Equally enhanced D2 autoreceptor-mediated inhibition of dopamine release is seen in the adolescent (P40 or P49) mPFC, which declines in control rats by adulthood. However, this developmental decrease in autoreceptor function is absent following adolescent defeat, suggesting retention of an adolescent-like phenotype into adulthood. Current and previous findings indicate adolescent defeat decreases extracellular dopamine availability in the adult mPFC via both enhanced inhibition of dopamine release and increased dopamine clearance, which may be viable targets for improving treatment of cognitive deficits seen in neuropsychiatric disorders promoted by adolescent stress.

Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder.

BACKGROUND: Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica ( http://genoanalytica.ru/ , Moscow, Russia). RESULTS: Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. CONCLUSION: Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.

Social defeat stress before pregnancy induces depressive-like behaviours and cognitive deficits in adult male offspring: correlation with neurobiological changes.

BACKGROUND: Epidemiological surveys and studies with animal models have established a relationship between maternal stress and affective disorders in their offspring. However, whether maternal depression before pregnancy influences behaviour and related neurobiological mechanisms in the offspring has not been studied. RESULTS: A social defeat stress (SDS) maternal rat model was established using the resident-intruder paradigm with female specific pathogen-free Wistar rats and evaluated with behavioural tests. SDS maternal rats showed a significant reduction in sucrose preference and locomotor and exploratory activities after 4 weeks of stress. In the third week of the experiment, a reduction in body weight gain was observed in SDS animals. Sucrose preference, open field, the elevated-plus maze, light-dark box, object recognition, the Morris water maze, and forced swimming tests were performed using the 2-month-old male offspring of the female SDS rats. Offspring subjected to pre-gestational SDS displayed enhanced anxiety-like behaviours, reduced exploratory behaviours, reduced sucrose preference, and atypical despair behaviours. With regard to cognition, the offspring showed significant impairments in the retention phase of the object recognition test, but no effect was observed in the acquisition phase. These animals also showed impairments in recognition memory, as the discrimination index in the Morris water maze test in this group was significantly lower for both 1 h and 24 h memory retention compared to controls. Corticosterone, adrenocorticotropic hormone, and monoamine neurotransmitters levels were determined using enzyme immunoassays or radioimmunoassays in plasma, hypothalamus, left hippocampus, and left prefrontal cortex samples from the offspring of the SDS rats. These markers of hypothalamic-pituitary-adrenal axis responsiveness and the monoaminergic system were significantly altered in pre-gestationally stressed offspring. Brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), phosphorylated CREB (pCREB), and serotonin transporter (SERT) protein levels were evaluated using western blotting with right hippocampus and right prefrontal cortex samples. Expression levels of BDNF, pCREB, and SERT in the offspring were also altered in the hippocampus and in the prefrontal cortex; however, there was no effect on CREB. CONCLUSION: We conclude that SDS before pregnancy might induce depressive-like behaviours, cognitive deficits, and neurobiological alterations in the offspring.