Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels.

Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. KEY MESSAGES : Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes.

Longitudinal CSF proteome profiling in mice to uncover the acute and sustained mechanisms of action of rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK).

Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as an animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNK's rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GR in vitro. In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNK's rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future.

Early life adversity targets the transcriptional signature of hippocampal NG2+ glia and affects voltage gated sodium (Nav) channels properties.

The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice.

Chronic social stress lessens the metabolic effects induced by a high-fat diet.

Stress has a major impact on the modulation of metabolism, as previously evidenced by hyperglycemia following chronic social defeat (CSD) stress in mice. Although CSD-triggered metabolic dysregulation might predispose to pre-diabetic conditions, insulin sensitivity remained intact, and obesity did not develop, when animals were fed with a standard diet (SD). Here, we investigated whether a nutritional challenge, a high-fat diet (HFD), aggravates the metabolic phenotype and whether there are particularly sensitive time windows for the negative consequences of HFD exposure. Chronically stressed male mice and controls (CTRL) were kept under (i) SD-conditions, (ii) with HFD commencing post-CSD, or (iii) provided with HFD lasting throughout and after CSD. Under SD conditions, stress increased glucose levels early post-CSD. Both HFD regimens increased glucose levels in non-stressed mice but not in stressed mice. Nonetheless, when HFD was provided after CSD, stressed mice did not differ from controls in long-term body weight gain, fat tissue mass and plasma insulin, and leptin levels. In contrast, when HFD was continuously available, stressed mice displayed reduced body weight gain, lowered plasma levels of insulin and leptin, and reduced white adipose tissue weights as compared to their HFD-treated non-stressed controls. Interestingly, stress-induced adrenal hyperplasia and hypercortisolemia were observed in mice treated with SD and with HFD after CSD but not in stressed mice exposed to a continuous HFD treatment. The present work demonstrates that CSD can reduce HFD-induced metabolic dysregulation. Hence, HFD during stress may act beneficially, as comfort food, by decreasing stress-induced metabolic demands.

A distinct transcriptional signature of antidepressant response in hippocampal dentate gyrus granule cells.

Major depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future.

The impact of chronic stress on energy metabolism.

The brain is exceptionally demanding in terms of energy metabolism. Approximately 20% of the calories consumed are devoted to our cerebral faculties, with the lion's share provided in the form of glucose. The brain's stringent energy dependency requires a high degree of harmonization between the elements responsible for supplying- and metabolizing energetic substrates. However, chronic stress may jeopardize this homeostatic energy balance by disruption of critical metabolic processes. In agreement, stress-related mental disorders have been linked with perturbations in energy metabolism. Prominent stress-induced metabolic alterations include the actions of hormones, glucose uptake and mitochondrial adjustments. Importantly, fundamental stress-responsive metabolic adjustments in humans and animal models bear a striking resemblance. Here, an overview is provided of key findings, demonstrating the pervasive impact of chronic stress on energy metabolism. Furthermore, I argue that medications, aimed primarily at restoring metabolic homeostasis, may constitute a novel approach to treat mental disorders.

Elevated Testosterone Level and Urine Scent Marking in Male 5xFAD Alzheimer Model Mice.

BACKGROUND: Function of the Amyloid Precursor Protein (AßPP) and its various cleavage products still is not unraveled down to the last detail. While its role as a source of the neurotoxic Amyloid beta (Aß) peptides in Alzheimer's Disease (AD) is undisputed and its property as a cell attachment protein is intriguing, while functions outside the neuronal context are scarcely investigated. This is particularly noteworthy because AßPP has a ubiquitous expression profile and its longer isoforms, AßPP750 and 770, are found in various tissues outside the brain and in non-neuronal cells. OBJECTIVE: Here, we aimed at analyzing the 5xFAD Alzheimer's disease mouse model in regard to male sexual function. The transgenes of this mouse model are regulated by Thy1 promoter activity and Thy1 is expressed in testes, e.g. by Sertoli cells. This allows speculation about an influence on sexual behavior. METHODS: We analyzed morphological as well as biochemical properties of testicular tissue from 5xFAD mice and wild type littermates and testosterone levels in serum, testes and the brain. Sexual behavior was assessed by a urine scent marking test at different ages for both groups. RESULTS: While sperm number, testes weight and morphological phenotypes of sperms were nearly indistinguishable from those of wild type littermates, testicular testosterone levels were significantly increased in the AD model mice. This was accompanied by elevated and prolonged sexual interest as displayed within the urine scent marking test. CONCLUSION: We suggest that overexpression of AßPP, which mostly is used to mimic AD in model mice, also affects male sexual behavior as assessed additional by the Urine Scent Marking (USM) test. The elevated testosterone levels might have an additional impact on central nervous system androgen receptors and also have to be considered when assessing learning and memory capabilities.

Current understanding of fear learning and memory in humans and animal models and the value of a linguistic approach for analyzing fear learning and memory in humans.

Fear is an emotion that serves as a driving factor in how organisms move through the world. In this review, we discuss the current understandings of the subjective experience of fear and the related biological processes involved in fear learning and memory. We first provide an overview of fear learning and memory in humans and animal models, encompassing the neurocircuitry and molecular mechanisms, the influence of genetic and environmental factors, and how fear learning paradigms have contributed to treatments for fear-related disorders, such as posttraumatic stress disorder. Current treatments as well as novel strategies, such as targeting the perisynaptic environment and use of virtual reality, are addressed. We review research on the subjective experience of fear and the role of autobiographical memory in fear-related disorders. We also discuss the gaps in our understanding of fear learning and memory, and the degree of consensus in the field. Lastly, the development of linguistic tools for assessments and treatment of fear learning and memory disorders is discussed.

Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory.

Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, ∼40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.

GABAA receptors in the ventral tegmental area control the outcome of a social competition in rats.

Social dominance can be attained through social competitions. Recent work in both humans and rodents has identified trait anxiety as a crucial predictor of social competitiveness. In addition, the anxiolytic GABAA positive modulator, diazepam, injected either systemically or into the ventral tegmental area (VTA) was shown to increase social dominance. Here, we investigated the impact of pharmacologically targeting GABAA receptors in the VTA for the outcome of a social competition between two unfamiliar male rats, one of them infused with vehicle and the other one with the drug under study. We show that infusion of the GABAA receptor agonist, muscimol, reduced anxiety-like behaviors and enhanced social competition, the GABAA receptor antagonist, bicuculline had the opposite effects. Importantly, intra-VTA muscimol administration also counteracted the disadvantage of high anxious rats to win a social competition against low anxious rats. Furthermore, we assessed the effectiveness of targeting specific GABAA receptor subunits by infusing zolpidem (α1-subunit agonist) or TCS1105 (a benzodiazepine ligand with α2-subunit agonistic and α1-subunit antagonistic effects) into the VTA. While zolpidem infusion did not affect the outcome of the social competition, TCS1105 enhanced social dominance. Our data highlight GABAergic mechanisms involving the engagement of α2-subunit containing GABAA receptors in the VTA in the attainment of dominance rank. The involvement of α2-subunit containing GABAA receptors in the VTA in the regulation of social competitiveness supports the potential therapeutic relevance of targeting these receptors to ameliorate anxiety-related social dysfunctions.

Temporal profiling of an acute stress-induced behavioral phenotype in mice and role of hippocampal DRR1.

Understanding the neurobiological mechanisms underlying the response to an acute stressor may provide novel insights into successful stress-coping strategies. Acute behavioral stress-effects may be restricted to a specific time window early after stress-induction. However, existing behavioral test batteries typically span multiple days or even weeks, limiting the feasibility for a broad behavioral analysis following acute stress. Here, we designed a novel comprehensive behavioral test battery in male mice that assesses multiple behavioral dimensions within a sufficiently brief time window to capture acute stress-effects and its temporal profile. Using this battery, we investigated the behavioral impact of acute social defeat stress (ASD) early thereafter (ASD-early, ∼4 h), when circulating corticosterone levels were elevated, and late after stress-induction (ASD-late, ∼8 h), when corticosterone were returned to timed control levels. ASD-early, but not ASD-late, displayed hippocampal-dependent cognitive impairments in the Y-maze and in the spatial object recognition test. The actin-binding protein (ABP) Tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1) has been described as resilience-promoting factor but the potential of DRR1 to curb stress-effects has not been investigated. Hippocampal DRR1 mRNA-expression was increased in ASD-early and ASD-late whereas DRR1-protein levels were increased only in ASD-late. We hypothesized that the absence of hippocampal DRR1 protein-upregulation in ASD-early caused the associated cognitive impairments. Hence, virus-mediated hippocampal DRR1-overexpression was induced as putative treatment, but cognitive deficits in ASD-early were not improved. We conclude that hippocampal DRR1-overexpression is insufficient to protect from the detrimental cognitive effects following acute social stress where perhaps a more global response in local actin dynamics, involving multiple stress-responsive ABPs that act synergistically, was warranted.

The stressed cytoskeleton: How actin dynamics can shape stress-related consequences on synaptic plasticity and complex behavior.

Stress alters synaptic plasticity but the molecular and cellular mechanisms through which environmental stimuli modulate synaptic function remain to be elucidated. Actin filaments are the major structural component of synapses and their rearrangements by actin-binding proteins (ABPs) are critical for fine-tuning synaptic plasticity. Accumulating evidence suggests that some ABPs are specifically regulated by stress and stress-related effectors such as glucocorticoids and corticotropin releasing hormone. ABPs may thus be central in stress-induced perturbations at the level of synaptic plasticity, leading to impairments in behavioral domains including cognitive performance and social behavior. Identified stress-responsive ABPs include: tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1), ADF/cofilin, LIMK1, caldesmon and myosin VI. Here we discuss how stress may impact synaptic plasticity through specific effects on these ABPs and how these adaptations might modulate complex behavior, predisposing individuals at genetic risk for the development of mental dysfunctions. We argue that a precise understanding of the mechanisms underlying stress-associated changes in synaptic function could stimulate the development of innovative treatment strategies against stress-related mental disorders.

Mitochondrial function in the brain links anxiety with social subordination.

Dominance hierarchies are integral aspects of social groups, yet whether personality traits may predispose individuals to a particular rank remains unclear. Here we show that trait anxiety directly influences social dominance in male outbred rats and identify an important mediating role for mitochondrial function in the nucleus accumbens. High-anxious animals that are prone to become subordinate during a social encounter with a low-anxious rat exhibit reduced mitochondrial complex I and II proteins and respiratory capacity as well as decreased ATP and increased ROS production in the nucleus accumbens. A causal link for these findings is indicated by pharmacological approaches. In a dyadic contest between anxiety-matched animals, microinfusion of specific mitochondrial complex I or II inhibitors into the nucleus accumbens reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in high-anxious individuals. We conclude that mitochondrial function in the nucleus accumbens is crucial for social hierarchy establishment and is critically involved in the low social competitiveness associated with high anxiety. Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.

The effects of extrinsic stress on somatic markers and behavior are dependent on animal housing conditions.

Properties of the environment play an important role in animal wellbeing and may modulate the effects of external threats. Whereas stressors can affect emotion and impair cognition, environmental enrichment may prevent the occurrence of such negative sequelae. Animals exposed to semi-natural group-housing experience a complex environment; whereas environmental enrichment might protect against stressors, a socially-enriched environment(SEE) could entail aggressive inter-male encounters with additive stress effects. In the present study, we investigated the effects of exposure to external stressors, footshocks and forced swimming, on adrenal gland and body weights as well as on behavior in rats housed under SEE or standard, non-enriched environment (NEE), conditions. We found that SEEs reduced the anxiogenic effects of stress. Moreover, SEEs improved the performance in an operant task and prevented the increase in impulsive behavior produced by external stressors on NEE animals. Whereas these findings are indicative of stress-buffering effects of SEEs, adrenal gland weights were increased while total body weights were decreased in SEE rats, suggesting that SEEs may simultaneously exacerbate physiological measurements of stress. Finally, in the SEE, total aggressive behaviors and body wounds were paradoxically reduced in animals that received external stressors in comparison to non-stressed controls. The consequences of the external stressors applied here are not uniform, varying according to the housing condition and the outcome considered.

Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations.

Chronic stress is a risk factor for the development of psychopathologies characterized by cognitive dysfunction and deregulated social behaviours. Emerging evidence suggests a role for cell adhesion molecules, including nectin-3, in the mechanisms that underlie the behavioural effects of stress. We tested the hypothesis that proteolytic processing of nectins by matrix metalloproteinases (MMPs), an enzyme family that degrades numerous substrates, including cell adhesion molecules, is involved in hippocampal effects induced by chronic restraint stress. A reduction in nectin-3 in the perisynaptic CA1, but not in the CA3, compartment is observed following chronic stress and is implicated in the effects of stress in social exploration, social recognition and a CA1-dependent cognitive task. Increased MMP-9-related gelatinase activity, involving N-methyl-D-aspartate receptor, is specifically found in the CA1 and involved in nectin-3 cleavage and chronic stress-induced social and cognitive alterations. Thus, MMP-9 proteolytic processing emerges as an important mediator of stress effects in brain function and behaviour.

Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression.

Neuroligins (NLGNs) are cell adhesion molecules that are important for proper synaptic formation and functioning, and are critical regulators of the balance between neural excitation/inhibition (E/I). Mutations in NLGNs have been linked to psychiatric disorders in humans involving social dysfunction and are related to similar abnormalities in animal models. Chronic stress increases the likelihood for affective disorders and has been shown to induce changes in neural structure and function in different brain regions, with the hippocampus being highly vulnerable to stress. Previous studies have shown evidence of chronic stress-induced changes in the neural E/I balance in the hippocampus. Therefore, we hypothesized that chronic restraint stress would lead to reduced hippocampal NLGN-2 levels, in association with alterations in social behavior. We found that rats submitted to chronic restraint stress in adulthood display reduced sociability and increased aggression. This occurs along with a reduction of NLGN-2, but not NLGN-1 expression (as shown with western blot, immunohistochemistry, and electron microscopy analyses), throughout the hippocampus and detectable in different layers of the CA1, CA3, and DG subfields. Furthermore, using synthetic peptides that comprise sequences in either NLGN-1 (neurolide-1) or NLGN-2 (neurolide-2) involved in the interaction with their presynaptic partner neurexin (NRXN)-1, intra-hippocampal administration of neurolide-2 led also to reduced sociability and increased aggression. These results highlight hippocampal NLGN-2 as a key molecular substrate regulating social behaviors and underscore NLGNs as promising targets for the development of novel drugs for the treatment of dysfunctional social behaviors.

A key role for nectin-1 in the ventral hippocampus in contextual fear memory.

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1-but not nectin-3-protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions.

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage.

BACKGROUND: Both hypothermia and erythropoietin (EPO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (HI). We investigated a possible additive effect of the use of a combination of hypothermia-EPO in a rat model of neonatal HI. METHODS: At postnatal day 7, rats were subjected to HI and then randomized to 3 h of hypothermia, EPO, or both. Sensorimotor function was assessed by the cylinder-rearing test (CRT) at 2 and 5 wk after HI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. RESULTS: Multivariable analysis using general linear modeling showed that hypothermia, EPO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after HI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the CRT. Maximal improvement in males was 26% after combined treatment with hypothermia and EPO. Histological outcome was improved by hypothermia only with no additional effect of EPO or gender. CONCLUSION: Hypothermia after HI improved sensorimotor function in females more than in males. There was a borderline additive effect of EPO when combined with hypothermia. Histology of brain lesion volume and white matter damage was improved only by hypothermia.

Social memories in rodents: methods, mechanisms and modulation by stress.

Intact social memory forms the basis of meaningful interactions between individuals. Many factors can modulate the quality of social memory, and these have been studied in detail in rodents. Social memory, however, cannot be considered a single entity. The term social memory reflects different processes, such as social recognition of a novel conspecific individual and social learning (or 'learning from others'). This review summarizes the findings obtained with behavioral paradigms that were developed for the study of memory formation by social recognition and social learning. In particular, we focus on studies that include tests for social habituation/discrimination paradigms, tests for memory of a previously established social hierarchy and the social transmission of the food preference test. The role of individual differences and the main neurobiological mechanisms (i.e., the brain regions and neurochemical systems involved) that have been implicated in each of these types of social-related memories are reviewed. In addition, we address the key modulatory influence of stress on the formation of these types of memories; discussing the contribution of central (corticotropin-releasing factor, CRF) and peripheral (glucocorticoids) stress systems and their interactions with the social neuropeptide systems. Overall, we present here a general overview of the current state of a thriving research area within the field of social neuroscience.

Targeting the p53 pathway to protect the neonatal ischemic brain.

OBJECTIVE: To investigate whether inhibition of mitochondrial p53 association using pifithrin-µ (PFT-µ) represents a potential novel neuroprotective strategy to combat perinatal hypoxic-ischemic (HI) brain damage. METHODS: Seven-day-old rats were subjected to unilateral carotid artery occlusion and hypoxia followed by intraperitoneal treatment with PFT-µ, an inhibitor of p53 mitochondrial association or PFT-α an inhibitor of p53 transcriptional activity. Cerebral damage, sensorimotor and cognitive function, apoptotic pathways (cytosolic cytochrome c, Smac/DIABLO, active caspase 3), and oxidative stress (lipid peroxidation and PARP-1 cleavage) were investigated. RESULTS: PFT-µ treatment completely prevented the HI-induced increase in mitochondrial p53 association at 3 hours and reduced neuronal damage at 48 hours post-HI. PFT-µ had long-term (6-10 weeks post-HI) beneficial effects as sensorimotor and cognitive outcome improved and infarct size was reduced by ~79%. Neuroprotection by PFT-µ treatment was associated with strong inhibition of apoptotic pathways and reduced oxidative stress. Unexpectedly, PFT-µ also inhibited HI-induced upregulation of p53 target genes. However, the neuroprotective effect of inhibiting only p53 transcriptional activity by PFT-α was significantly smaller and did not involve reduced oxidative stress. INTERPRETATION: We are the first to show that prevention of mitochondrial p53 association by PFT-µ strongly improves functional outcome and decreases lesion size after neonatal HI. PFT-µ not only inhibits mitochondrial release of cytochrome c, but also inhibits oxidative stress. We propose that as a consequence nuclear accumulation of p53 and transcription of proapoptotic target genes are prevented. In conclusion, targeting p53 mitochondrial association by PFT-µ may develop into a novel and powerful neuroprotective strategy.