Fiona Hollis

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

Social Defeat as an Animal Model for Depression

Depression is one of the most disabling medical conditions in the world today, yet its etiologies remain unclear and current treatments are not wholly effective. Animal models are a powerful tool to investigate possible causes and treatments for human diseases. We describe an animal model of social defeat as a possible model for human depression. We discuss the paradigm, behavioral correlates to depression, and potential underlying neurobiological mechanisms with an eye toward possible future therapies.

Sex Differences in Social Interaction in Rats: Role of the Immediate-Early Gene zif268

Given both the high prevalence of anxiety disorders in women and the fact that little is known about the mechanisms of gender differences in anxiety, our primary aim in this study was to investigate the neurobiological mechanisms underlying sex differences in social anxiety-like behavior in rats. Through the use of zif268 antisense oligodeoxynucleotides (zif ASO), we induced a temporary downregulation of zif268 expression in the medial prefrontal cortex of male and female rats and found that zif268 ASO male rats show more social anxiety-like behaviors when compared with control male rats in the social interaction test. In fact, zif268 ASO males displayed social anxiety-like behaviors, which were similar to control females, thus downregulation of zif268 expression in the mPFC of male rats eliminated sex differences previously found in the social anxiety-like behavior tests. Interestingly, zif268 ASO in female rats had no effect on their social interaction. Our novel findings have led us to ascertain that sexually dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety-like behavior in the social interaction test.

Mitochondrial function in the brain links anxiety with social subordination

Significance Within a dominance hierarchy, low social status strongly reduces individual well-being. In socially living species, rank in a hierarchy is determined through competitive encounters. Despite the numerous health consequences, the ability of personality traits to predispose individuals to a particular social rank remains largely unclear. Our work identifies trait anxiety as a predisposing factor to a subordinate rank. We demonstrate that mitochondrial function in the nucleus accumbens, a brain region relevant for motivation and depression, is a critical mediating factor in the subordinate status displayed by high-anxious rats. These findings highlight a role for cerebral energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for mood disorders. 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.

Methyl Supplementation Attenuates Cocaine-Seeking Behaviors and Cocaine-Induced c-Fos Activation in a DNA Methylation-Dependent Manner

Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway.

Individual Differences in Novelty-Seeking Behavior in Rats as a Model for Psychosocial Stress-Related Mood Disorders

Most neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Diagnoses are therefore hard to establish and current therapeutic strategies suffer from significant variability in effectiveness, making the understanding of inter-individual variations crucial to unveiling effective new treatments. In rats, such individual differences are observed during exposure to a novel environment, where individuals will exhibit either high or low locomotor activity and can thus be separated into high (HR) and low (LR) responders, respectively. In rodents, a long-lasting, psychosocial, stress-induced depressive state can be triggered by exposure to a social defeat procedure. We therefore analyzed the respective vulnerabilities of HR and LR animals to long-lasting, social defeat-induced behavioral alterations relevant to mood disorders. Two weeks after four daily consecutive social defeat exposures, HR animals exhibit higher anxiety levels, reduced body weight gain, sucrose preference, and a marked social avoidance. LR animals, however, remain unaffected. Moreover, while repeated social defeat exposure induces long-lasting contextual fear memory in both HR and LR animals, only HR individuals exhibit marked freezing behavior four weeks after a single social defeat. Combined, these findings highlight the critical involvement of inter-individual variations in novelty-seeking behavior in the vulnerability to stress-related mood disorders, and uncover a promising model for posttraumatic stress disorder.

The consequences of adolescent chronic unpredictable stress exposure on brain and behavior

There is increasing evidence for adolescence as a time period vulnerable to environmental perturbations such as stress. What is unclear is the persistent nature of the effects of stress and how specific these effects are to the type of stressor. In this review, we describe the effects of chronic, unpredictable stress (CUS) exposure during adolescence on adult behavior and brain morphology and function in animal models. We provide evidence for adolescence as a critical window for the effects of physical CUS that persist into adulthood, with ramifications for morphological development, associated hippocampal-dependent tasks, and anxiety- and depressive-like behaviors. The results of this investigation are contrasted against those of social CUS stress exposure from the same time period that show reversible and, in the case of responses to drugs of abuse, potentially protective effects in adulthood. Finally, we discuss potential underlying mechanisms for these morphological and behavioral findings. It is our aim that the research highlighted in this review will aid in our understanding of the role of stress in adolescent mental health and development. This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors

Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines’ effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.

Acute stress alters individual risk taking in a time-dependent manner and leads to anti-social risk.

Decision‐making processes can be modulated by stress, and the time elapsed from stress induction seems to be a crucial factor in determining the direction of the effects. Although current approaches consider the first post‐stress hour a uniform period, the dynamic pattern of activation of the physiological stress systems (i.e., the sympathetic nervous system and hypothalamic‐pituitary‐adrenal axis) suggests that its neurobehavioural impact might be heterogeneous. Here, we evaluate economic risk preferences on the gain domain (i.e., risk aversion) at three time points following exposure to psychosocial stress (immediately after, and 20 and 45 min from onset). Using lottery games, we examine decisions at both the individual and social levels. We find that risk aversion shows a time‐dependent change across the first post‐stress hour, evolving from less risk aversion shortly after stress to more risk averse behaviour at the last testing time. When risk implied an antisocial outcome to a third party, stressed individuals showed less regard for this person in their decisions. Participants’ cortisol levels explained their behaviour in the risk, but not the antisocial, game. Our findings reveal differential stress effects in self‐ and other‐regarding decision‐making and highlight the multidimensional nature of the immediate aftermath of stress for cognition.

Mitochondrial dysfunction in Autism Spectrum Disorder: clinical features and perspectives

Autism Spectrum Disorder (ASD) is a prototypic pervasive developmental disorder characterized by social interaction, and communication deficits, repetitive, stereotypic patterns of behavior, and impairments in language and development. Clinical studies have identified mitochondrial disturbances at the levels of DNA, activity, complexes, oxidative stress, and metabolites in blood and urine of ASD patients. However, these observations from postmortem brains or peripheral tissues do not provide a direct link between autism and mitochondria. The synaptic abnormality of autistic patients has not been investigated yet. Here we review the findings of clinical studies investigating mitochondrial involvement in ASD patients, focusing particularly on the brain and the limitations and future directions needed in order to fully understand the role of mitochondria in ASD pathology.