B2 SINE RNA as a novel regulator of glucocorticoid receptor transcriptional activity.

Glucocorticoids are a key component to the cellular response to stress. Glucocorticoids act via glucocorticoid receptors found ubiquitously in the brain and body. Glucocorticoid receptors can bind to response elements throughout the genome to elicit changes in transcription, an adaptation observed at the cellular level. Yet, the transcriptional changes as a consequence of glucocorticoid receptor activation are variable across brain regions, stress conditions and recurrent bouts of glucocorticoid exposure. Here we describe a non-coding RNA, B2 SINE, which is regulated by glucocorticoids and can in turn regulate glucocorticoid receptor transcriptional activity. We show that activated glucocorticoid receptors interact directly with B2 SINE RNA via a decoy response element contained within the transcript sequence and alter receptor binding to response elements in the genome and, subsequently, changes in loci expression.

B6D2F1 mice that retain sexual behavior long term after castration outperform those that cease in the radial arm maze.

In rodents, gonadal steroids play a critical yet variable role in behaviors such as social interaction and cognitive performance. Gonadal steroids organize sex differences observed in spatial working memory, while the absence of activational effects induced by castration generally impedes spatial learning and memory. Although male sexual behavior is typically inhibited following castration, a significant proportion of gonadectomized B6D2F1 hybrid males retains the complete repertoire of male reproductive behavior. In a prior study, amyloid precursor protein and tau, proteins involved in cognitive behavior, facilitated steroid-independent male sex behavior in B6D2F1 hybrid male mice. We used this strain to investigate the relationship between gonadal steroid-independent male sexual behavior and cognition. After identifying "maters" (animals retaining steroid-independent male sex behavior) and "non-maters," we tested spatial memory in an 8-arm radial arm maze. Although neither group demonstrated a decrease in errors as a function of time, maters committed fewer errors compared to non-maters overall (p < 0.05). Maters also completed the maze more quickly than non-maters (p < 0.05). We measured mRNA expression of APP and MAPT as well as LEPR and D2R to probe potential roles of metabolism and motivation. Uniquely among maters, increased relative expression of D2R and LEPR in the hippocampus was associated with a longer latency to complete the maze during the last 3 or across all trials, respectively. These data demonstrate that maters outperform non-maters in the radial arm maze, warranting further study of potential differences in acquisition of spatial memory tasks or learning strategy between these groups.

Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses.

Brain kappa-opioid receptors (KORs) are implicated in the pathophysiology of depressive and anxiety disorders, stimulating interest in the therapeutic potential of KOR antagonists. Research on KOR function has tended to focus on KOR-expressing neurons and pathways such as the mesocorticolimbic dopamine system. However, KORs are also expressed on non-neuronal cells including microglia, the resident immune cells in the brain. The effects of KOR antagonists on microglia are not understood despite the potential contributions of these cells to overall responsiveness to this class of drugs. Previous work in vitro suggests that KOR activation suppresses proinflammatory signaling mediated by immune cells including microglia. Here, we examined how KOR antagonism affects microglia function in vivo, together with its effects on physiological and behavioral responses to an immune challenge. Pretreatment with the prototypical KOR antagonist JDTic potentiates levels of proinflammatory cytokines (IL-1ß, IL-6) in blood following administration of lipopolysaccharide (LPS), an immune-activating agent, without triggering effects on its own. Using magnetic-activated cell sorting (MACs), we found that KOR antagonism potentiates LPS-induced cytokine expression within microglia. This effect is accompanied by potentiation of LPS-induced hyperthermia, although reductions in body weight and locomotion were not affected. Histological analyses confirm that LPS produces visible changes in microglia morphology consistent with activation, but this effect is not altered by KOR antagonism. Considering that inflammation is increasingly implicated in depressive and anxiety disorders, these findings raise the possibility that KOR antagonist actions on microglia may detract from actions on neurons that contribute to their therapeutic potential.

Early experience alters developmental trajectory of central oxytocin systems involved in hypothalamic-pituitary-adrenal axis regulation in Long-Evans rats.

Oxytocin is important for postnatal developmental experiences for mothers, infants, and transactions between them. Oxytocin is also implicated in adult affiliative behaviors, including social buffering of stress. There is evidence for connections between early life experience and adult oxytocin system functioning, but effects of early experience on behavioral, endocrine, and neurophysiological outcomes related to adult social buffering are not well explored. We use a limited bedding and nesting (LBN) material paradigm as an environmental disruption of early experiences and assessed central oxytocin systems in brain regions related to hypothalamic-pituitary-adrenal (HPA) axis regulation (paraventricular nucleus of the hypothalamus, amygdala, hippocampus). We also assessed developmentally-appropriate social behaviors and HPA reactivity during social buffering testing in adulthood. LBN litters had larger huddles and more pups visible compared to control litters during the first two weeks of life. LBN also altered the developmental trajectory of oxytocin-expressing cells and oxytocin receptor cells, with increases in oxytocin receptor cells at P15 in LBN pups. By adulthood, LBN females had more and LBN males had fewer oxytocin and oxytocin receptor cells in these areas compared to sex-matched controls. Adult LBN females, but not LBN males, had behavioral changes during social interaction and social buffering testing. The sex-specific effects of early experience on central oxytocin systems and social behavior may contribute to female resilience to early life adversity.

In search of optimal resilience ratios: Differential influences of neurobehavioral factors contributing to stress-resilience spectra.

The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal's position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.

Epigenetic Mechanisms of the Glucocorticoid Receptor.

The glucocorticoid receptor (GR) has been shown to be important for mediating cellular responses to stress and circulating glucocorticoids. Ligand-dependent transcriptional changes induced by GR are observed across numerous tissues. However, the mechanisms by which GR achieves cell and tissue-specific effects are less clear. Epigenetic mechanisms have been proposed to explain some of these differences as well as some of the lasting, even transgenerational, effects of stress and glucocorticoid action. GR functions in tandem with epigenetic cellular machinery to coordinate transcription and shape chromatin structure. Here, we describe GR interactions with these effectors and how GR acts to reshape the epigenetic landscape in response to the environment.

Chromatin Immunoprecipitation Techniques in Neuropsychiatric Research.

Neuropsychiatric disorders are highly prevalent (e.g., affecting children 2-8 years old at a rate of 14%). Many of these disorders are highly heritable such as major depressive disorder and schizophrenia. Despite this, genome-wide association has failed to identify gene(s) significantly associated with diagnostic status suggesting a strong role for environmental factors and the epigenome. From a molecular standpoint, the study of DNA-protein interactions yields fruitful information regarding the regulation of cellular processes above the level of the nucleotide sequence. Understanding chromatin dynamics may continue to explain individual variation to environmental perturbation and subsequent behavioral response. Chromatin immunoprecipitation (ChIP) techniques have allowed for probing of epigenetic effectors at specific regions of the genome. The following article reviews the current techniques and considerations when incorporation ChIP into neuropsychiatric models.

Stress and glucocorticoid receptor regulation of mitochondrial gene expression.

Glucocorticoids have long been recognized for their role in regulating the availability of energetic resources, particularly during stress. Furthermore, bidirectional connections between glucocorticoids and the physiology and function of mitochondria have been discovered over the years. However, the precise mechanisms by which glucocorticoids act on mitochondria have only recently been explored. Glucocorticoids appear to regulate mitochondrial transcription via activation of glucocorticoid receptors (GRs) with elevated circulating glucocorticoid levels following stress. While several mechanistic questions remain, GR and other nuclear transcription factors appear to have the capacity to substantially alter mitochondrial transcript abundance. The regulation of mitochondrial transcripts by stress and glucocorticoids will likely prove functionally relevant in many stress-sensitive tissues including the brain.

Transposons, stress and the functions of the deep genome.

The brain is responsible for both recognition and adaptation to stressful stimuli. Many molecular mechanisms have been implicated in this response including those governing neuronal plasticity, neurogenesis and, changes gene expression. Far less is known regarding effects of stress on the deep genome. In the hippocampus, stress appears to regulate expression of non-coding elements of the genome as well as the chromatin permissive for their transcription. Specifically, hippocampal retrotransposon (RT) elements are regulated by acute stress via the accumulation of the repressive H3K9me3 mark at RT loci. Further, corticosteroids appear to induce changes in heterochromatin status as well as RT expression in both adrenalectomized animal and rat cell culture models. Dysregulation of RT expression is predicted to result in functional deficits in affected brain areas. More broadly, however, transposons may have a variety of adaptive functions. As techniques improve to probe the deep genome, this approach to understanding stress neurobiology has the potential to yield insights into environment and genome interactions that may contribute to the physiology underlying a number of stress-related mental health disorders.

Anxiety and Epigenetics.

Anxiety disorders are highly prevalent psychiatric disorders often comorbid with depression and substance abuse. Twin studies have shown that anxiety disorders are moderately heritable. Yet, genome-wide association studies (GWASs) have failed to identify gene(s) significantly associated with diagnosis suggesting a strong role for environmental factors and the epigenome. A number of anxiety disorder subtypes are considered "stress related." A large focus of research has been on the epigenetic and anxiety-like behavioral consequences of stress. Animal models of anxiety-related disorders have provided strong evidence for the role of stress on the epigenetic control of the hypothalamic-pituitary-adrenal (HPA) axis and of stress-responsive brain regions. Neuroepigenetics may continue to explain individual variation in susceptibility to environmental perturbations and consequently anxious behavior. Behavioral and pharmacological interventions aimed at targeting epigenetic marks associated with anxiety may prove fruitful in developing treatments.