336 research outputs found
The Striatal Balancing Act in Drug Addiction: Distinct Roles of Direct and Indirect Pathway Medium Spiny Neurons
The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum’s two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction
Toxics source reduction and sewage upgrades eliminated winter flounder liver neoplasia (1984-2017) from Boston Harbor, MA, USA
© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Diseases of Aquatic Organisms 131 (2018) 239-243, doi:10.3354/dao03299.Chemical carcinogen biomarkers can validate public investment in environmental remediation. A major factor driving the clean-up of Boston Harbor, MA, USA, induced by the federal Clean Water Act legislation of 1972, was the high prevalence of petroleum and halogenated aromatic hydrocarbon contaminant-associated liver neoplasia in winter flounder Pseudopleuronectes americanus in the harbor in the 1980s. In the present study, we examined the spatial and temporal relationships between the suspended solids and contaminants in the municipal sewage discharge, and liver neoplasia and histopathology in flounder, from 1987 to 2017. Toxics source reduction, sewage treatment, and sludge removal in the 1990s and outfall relocation offshore in 2000 enabled a decreasing prevalence of persistent toxic chemicals in flounder, effluent, and sediment, and consequent disappearance of liver neoplasia and reduction of neoplasm-associated, hydropically vacuolated biliary epithelial cells to background levels. This supports long-term investment in elimination and treatment of anthropogenic waste streams and the value of federal regulatory mandates to maintain and improve regional environmental quality.This work was supported by the
Massachusetts Water Resources Authority, Woods Hole
Oceanographic Institution, and US Public Health Service
(USPHS) grant CA/ES44306
Targeted Epigenetic Remodeling of the \u3cem\u3eCdk5\u3c/em\u3e Gene in Nucleus Accumbens Regulates Cocain- and Stress-Evoked Behavior
Recent studies have implicated epigenetic remodeling in brain reward regions following psychostimulant or stress exposure. It has only recently become possible to target a given type of epigenetic remodeling to a single gene of interest, and to probe the functional relevance of such regulation to neuropsychiatric disease. We sought to examine the role of histone modifications at the murine Cdk5 (cyclin-dependent kinase 5) locus, given growing evidence of Cdk5 expression in nucleus accumbens (NAc) influencing reward-related behaviors. Viral-mediated delivery of engineered zinc finger proteins (ZFP) targeted histone H3 lysine 9/14 acetylation (H3K9/14ac), a transcriptionally active mark, or histone H3 lysine 9 dimethylation (H3K9me2), which is associated with transcriptional repression, specifically to the Cdk5 locus in NAc in vivo. We gound that Cdk5-ZFP transcription factors are sufficient to bidirectionally regulate Cdk5 gene expression via enrichment of their respective histone modifications. We examined the behavioral consequences of this epigenetic remodeling and found that Cdk5-targeted H3K9/14ac increased cocaine-induced locomotor behavior, as well as resilience to social stress. Conversely, Cdk5-targeted H3K9me2 attenuated both cocaine-induced locomotor behavior and conditioned place preference, but had no effect on stress-induced social avoidance behavior. The current study provides evidence for the causal role of Cdk5 epigenetic remodeling in NAc in Cdk5 gene expression and in the control of reward and stress responses. Moreover, these data are especially compelling given that previous work demonstrated opposite behavioral phenotypes compared with those reported here upon Cdk5 overexpression or knockdown, demonstrating the importance of targeted epigenetic remodeling tools for studying more subtle molecular changes that contribute to neuropsychiatric disease
Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.
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\u27s 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. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures
Environmental Programming of Susceptibility and Resilience to Stress in Adulthood in Male Mice
Epidemiological evidence identifies early life adversity as a significant risk factor for the development of mood disorders. Much evidence points to the role of early life experience in susceptibility and, to a lesser extent, resilience, to stress in adulthood. While many models of these phenomena exist in the literature, results are often conflicting and a systematic comparison of multiple models is lacking. Here, we compare effects of nine manipulations spanning the early postnatal through peri-adolescent periods, both at baseline and following exposure to chronic social defeat stress in adulthood, in male mice. By applying rigorous criteria across three commonly used measures of depression- and anxiety-like behavior, we identify manipulations that increase susceptibility to subsequent stress in adulthood and other pro-resilient manipulations that mitigate the deleterious consequences of adult stress. Our findings point to the importance of timing of early life stress and provide the foundation for future studies to probe the neurobiological mechanisms of risk and resilience conferred by variation in the early life environment
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Class I HDAC Inhibition Blocks Cocaine-Induced Plasticity Through Targeted Changes in Histone Methylation
Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and prior studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here, we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part via a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons. Our findings suggest a novel mechanism by which prolonged and selective HDAC inhibition can alter behavioral and molecular adaptations to cocaine and inform the development of novel therapeutics for cocaine addiction
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