Nestler epigenetic

Depression and anxiety risk are highly influenced by both genetic and environmental factors. Recently, it has been proposed that epigenetic mechanisms may also contribute to the transmission of both depression- and anxiety-related behaviors across multiple generations. This review highlights long-lasting epigenetic alterations observed in offspring of fathers, including some distinct effects on male and female offspring, in animal models. Available evidence emphasizes how both the developmental time point and the type of paternal stress (social vs...

Opioid use kills tens of thousands of Americans each year, devastates families and entire communities, and cripples the health care system. Exposure to opioids causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug seeking and drug taking that can remain a lifelong struggle. The persistence of these neuroadaptations is mediated in part by epigenetic remodeling of gene expression programs in discrete brain regions...

As an individual becomes addicted to a drug of abuse, nerve cells within the brain's reward circuitry adapt at the epigenetic level during the course of repeated drug exposure. These drug-induced epigenetic adaptations mediate enduring changes in brain function which contribute to life-long, drug-related behavioral abnormalities that define addiction. Targeting these epigenetic alterations will enhance our understanding of the biological basis of addiction and might even yield more effective anti-addiction therapies...

We aimed to investigate the effects of aging and different exercise modalities on aversive memory and epigenetic landscapes at brain-derived neurotrophic factor, cFos, and DNA methyltransferase 3 alpha (Bdnf, cFos, and Dnmt3a, respectively) gene promoters in hippocampus of rats. Specifically, active epigenetic histone markers (H3K9ac, H3K4me3, and H4K8ac) and a repressive mark (H3K9me2) were evaluated. Adult and aged male Wistar rats (2 and 22 months old) were subjected to aerobic, acrobatic, resistance, or combined exercise modalities for 20 min, 3 times a week, during 12 weeks...

The transcription factor ΔFosB has been proposed as a molecular switch for the transition from casual, volitional drug use into a chronically addicted state, but the upstream regulatory mechanisms governing ΔFosB expression are incompletely understood. In this study, we find a novel regulatory role for the transcription factor E2F3, recently implicated in transcriptional regulation by cocaine, in controlling ΔFosB induction in the mouse nucleus accumbens (NAc) following cocaine administration. We find that an E2F consensus sequence 500 bp upstream of the Fosb transcription start site is enriched for E2F3 specifically over other E2F isoforms...

Studies have reported the significant economic impact of smoking cannabis and drinking alcohol In the USA. It was estimated that the costs of cannabis-related treatment, hospitalization and loss of work-related pay have amounted to $200 billion. (Andersen AM, Dogan MV, Beach SRH, Philibert RA. 2015 Genes 6, 991-1022. ( doi:10.3390/genes6040991 )). Data from the National Epidemiologic Survey on Alcohol and Related Conditions showed that individuals with general anxiety disorder and substance use disorder (GAD-SUD) have higher psychiatric comorbidity rates than those without substance use disorder (Alegría AA, Hasin DS, Nunes EV, Liu SM, Davies C, Grant BF, Blanco C...

Addiction is a disease in which, after a period of recreational use, a subset of individuals develops compulsive use that does not stop even in light of major negative consequences. Here, we review the evidence for underlying epigenetic remodeling in brain in two settings. First, excessive dopamine signaling during drug use may modulate gene expression, altering synaptic function and circuit activity and leading over time to maladaptive behaviors in vulnerable individuals. Second, on a longer timescale, life experience can shape the epigenetic landscape in brain and thereby may contribute to an individual's vulnerability by amplifying drug-induced changes in gene expression that drive the transition to addiction...

Drug addiction is a chronic relapsing brain disorder that is characterized by compulsive drug seeking and continued use despite negative outcomes. Current pharmacological therapies target neuronal receptors or transporters upon which drugs of abuse act initially, yet these treatments remain ineffective for most individuals and do not prevent disease relapse after abstinence. Drugs of abuse, in addition to their acute effects, cause persistent plasticity after repeated use, involving dysregulated gene expression in the brain's reward regions, which are thought to mediate the persistent behavioral abnormalities that characterize addiction...

Comorbid neuropsychiatric disorders such as addiction and anxiety could involve common underlying mechanisms. One potential mechanism involves epigenetic regulation of histone 3 dimethylation at lysine 9 residues (H3K9me2) by the histone dimethyltransferase G9a. Here we provide evidence that local AAV-RNAi-mediated knockdown of G9a expression in nucleus accumbens shell (NAcSh) of male rats reduces both addictive-related and anxiety-related behaviors. Specifically, G9a knockdown reduces sensitivity to low dose cocaine reinforcement when cocaine is freely available (fixed ratio schedule)...

In part <Emphasis Type="Bold">c</Emphasis> of Figure 1 in this article, the orientation of the tail of histone 3 with respect to the core region of this molecule was incorrect, and the amino acid residue K79 should not have been depicted in the tail. The corrected figure is shown below. The authors and editors thank T. Brown, R. Lober and C. Waker for bringing this error to our attention. Note that the present affiliation of the corresponding author and their current email address have been added to the correction notice...

Delivery of engineered zinc-finger proteins (ZFPs) for targeted epigenetic remodeling in rodent brain can be facilitated by the use of viral vector-mediated gene transfer coupled with stereotaxic surgery techniques. Here we describe the surgical protocol utilized by our group which is optimized for herpes simplex virus (HSV) delivery into mouse brain. The protocol outlined herein could be applied for delivery of adeno-associated viruses (AAV) or lentiviruses in both mice and rats. This method allows for the viral expression of engineered DNA-binding factors, particularly engineered ZFPs, and subsequent epigenome editing in rodent brain with excellent spatiotemporal control...

Depression is a prevalent and complex psychiatric syndrome. Epigenetic mechanisms bridge the genetic and environmental factors that contribute to the pathophysiology of depression. A surge of research over the last decade has identified changes in DNA methylation, histone modifications, histone organization, and noncoding RNAs associated with depression and stress-induced depression-like behavior in animal models. We focus here on associations of epigenetic factors concurrent with depression and depression-like behavior, although risk for depression and some of the associated epigenetic changes are known to have developmental origins...

Studies of the mammalian nervous system have revealed widespread epigenetic regulation underlying gene expression intrinsic to basic neurobiological function as well as neurological disease. Over the past decade, a critical role has emerged for the neural regulation of chromatin-modifying enzymes during both development and adulthood, and in response to external stimuli. These biochemical data are complemented by numerous next generation sequencing (NGS) studies that quantify the extent of chromatin and DNA modifications in neurons...

Drug addiction involves long-term behavioral abnormalities that arise in response to repeated exposure to drugs of abuse in vulnerable individuals. It is a multifactorial syndrome involving a complex interplay between genes and the environment. Evidence suggests that the underlying mechanisms regulating these persistent behavioral abnormalities involve changes in gene expression throughout the brain's reward circuitry, in particular, in the mesolimbic dopamine system. In the past decade, investigations have begun to reveal potential genes involved in the risk for addiction through genomewide association studies...

Repeated exposure to cocaine induces lasting epigenetic changes in neurons that promote the development and persistence of addiction. One epigenetic alteration involves reductions in levels of the histone dimethyltransferase G9a in nucleus accumbens (NAc) after chronic cocaine administration. This reduction in G9a may enhance cocaine reward because overexpressing G9a in the NAc decreases cocaine-conditioned place preference. Therefore, we hypothesized that HSV-mediated G9a overexpression in the NAc shell (NAcSh) would attenuate cocaine self-administration (SA) and cocaine-seeking behavior...

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood...

Childhood malnutrition is a risk factor for mental disorders, such as major depression and anxiety. Evidence shows that similar early life adversities induce sex-dependent epigenetic reprogramming. However, little is known about how genes are specifically affected by early malnutrition and the implications for males and females respectively. One relevant target is neuropeptide Y (NPY), which regulates both stress and food-intake. We studied maternal low protein diet (LPD) during pregnancy/lactation in mice...

BACKGROUND: Exposure to drugs of abuse alters the epigenetic landscape of the brain's reward regions, such as the nucleus accumbens. We investigated how combinations of chromatin modifications affect genes that regulate responses to cocaine. We focused on Auts2, a gene linked to human evolution and cognitive disorders, which displays strong clustering of cocaine-induced chromatin modifications in this brain region. METHODS: We combined chromosome conformation capture, circularized chromosome conformation capture, and related approaches with behavioral paradigms relevant to cocaine phenotypes...

Chronic social defeat stress regulates the expression of Fosb in the nucleus accumbens (NAc) to promote the cell-type-specific accumulation of ΔFosB in the two medium spiny neuron (MSN) subtypes in this region. ΔFosB is selectively induced in D1-MSNs in the NAc of resilient mice, and in D2-MSNs of susceptible mice. However, little is known about the consequences of such selective induction, particularly in D2-MSNs. This study examined how cell-type-specific control of the endogenous Fosb gene in NAc regulates susceptibility to social defeat stress...

There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10-20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress)...