Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action
TL;DR: An important role for histone remodeling in the pathophysiology and treatment of depression is underscored and the therapeutic potential for hist one methylation and deacetylation inhibitors in depression is highlighted.
Abstract: To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.
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TL;DR: Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits and show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.
Abstract: Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.
2,535 citations
Cites background from "Sustained hippocampal chromatin reg..."
...Increased histone acetylation at the Bdnf promoter in the hippocampus was shown to be required for the ability of chronically administered imipramine to reverse certain deleterious effects of social defea...
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TL;DR: It is shown that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior and validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance.
1,863 citations
Cites background or methods from "Sustained hippocampal chromatin reg..."
...…mice subjected to chronic social defeat (10 such defeats over 10 days) display a long-lasting reduction in social interaction (Berton et al., 2006; Tsankova et al., 2006), which is measured by comparing the time a mouse spends in an interaction zone with a social target to the time in that zone…...
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...All PCR experiments were conducted in triplicate, and the data were analyzed by using the DDCt method (Tsankova et al., 2006) and were normalized to measures of Gapdh mRNA....
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...We have previously shown that c57bl/6 mice subjected to chronic social defeat (10 such defeats over 10 days) display a long-lasting reduction in social interaction (Berton et al., 2006; Tsankova et al., 2006), which is measured by comparing the time a mouse spends in an interaction zone with a social target to the time in that zone in the absence of a social target....
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...While these modifications play an important role in an organism’s stress responses (Tsankova et al., 2006), future work is needed to delineate the relative contribution of epigenetic, genetic, and environmental factors that may together explain variations in susceptibility....
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...Social Defeat and Behavioral Testing Social defeat and avoidance testing were performed according to published protocols (Berton et al., 2006; Tsankova et al., 2006)....
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TL;DR: This review presents the major current approaches to understanding the biologic mechanisms of major depression and defines depression as a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism.
Abstract: Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.
1,841 citations
Cites background from "Sustained hippocampal chromatin reg..."
...some BDNF splice variants, in the hippocampus [28]....
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...cial because chronic antidepressant treatment downregulates HDAC5, and overexpression of HDAC5 in the hippocampus prevents its antidepressant effect [28]....
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...depressant medication and electro-convulsive shocks increase the levels in the hippocampus [28,46]....
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...This downregulation appears to be due to induction of H3-K27 dimethylation, a histone code for transcriptional repression [28,48]....
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...hippocampus by increasing neurogenesis [27,28]....
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TL;DR: Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Abstract: The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...
1,775 citations
Book•
01 Aug 2009
TL;DR: Mental, emotional, and behavioral (MEB) disorders—which include depression, conduct disorder, and substance abuse—affect large numbers of young people.
Abstract: This report builds on a highly valued predecessor, the 1994 Institute of Medicine (IOM) report entitled Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research. That report provided the basis for understanding prevention science, elucidating its then-existing research base, and contemplating where it should go in the future. This report documents that an increasing number of mental, emotional, and behavioral problems in young people are in fact preventable. The proverbial ounce of prevention will indeed be worth a pound of cure: effectively applying the evidence-based prevention interventions at hand could potentially save billions of dollars in associated costs by avoiding or tempering these disorders in many individuals. Furthermore, devoting significantly greater resources to research on even more effective prevention and promotion efforts, and then reliably implementing the findings of such research, could substantially diminish the human and economic toll.
1,744 citations
References
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TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Abstract: Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
9,309 citations
"Sustained hippocampal chromatin reg..." refers background in this paper
...In general, histone acetylation (H3 and H4 acetylation) loosens DNA-histone interactions and allows the transcriptional machinery to bind and increase transcriptio...
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TL;DR: It is shown that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible, suggesting a causal relation among epigenomicState, GR expression and the maternal effect on stress responses in the offspring.
Abstract: Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
5,514 citations
"Sustained hippocampal chromatin reg..." refers methods in this paper
...DNA methylation analysis was performed according to published methods and Chemicon's DNA methylation Kit protocols, with a few modification...
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TL;DR: A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome, and advances will fundamentally improve the treatment and prevention of depression.
2,768 citations
TL;DR: The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
Abstract: The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
2,077 citations
TL;DR: A genomic sequencing technique which is capable of detecting every methylated cytosine on both strands of any target sequence, using DNA isolated from fewer than 100 cells is developed.
Abstract: An understanding of DNA methylation and its potential role in gene control during development, aging and cancer has been hampered by a lack of sensitive methods which can resolve exact methylation patterns from only small quantities of DNA. We have now developed a genomic sequencing technique which is capable of detecting every methylated cytosine on both strands of any target sequence, using DNA isolated from fewer than 100 cells. In this method, sodium bisulphite is used to convert cytosine residues to uracil residues in single-stranded DNA, under conditions whereby 5-methylcytosine remains non-reactive. The converted DNA is amplified with specific primers and sequenced. All the cytosine residues remaining in the sequence represent previously methylated cytosines in the genome. The work described has defined procedures that maximise the efficiency of denaturation, bisulphite conversion and amplification, to permit methylation mapping of single genes from small amounts of genomic DNA, readily available from germ cells and early developmental stages.
1,954 citations
"Sustained hippocampal chromatin reg..." refers methods in this paper
...DNA methylation analysis was performed according to published methods and Chemicon's DNA methylation Kit protocols, with a few modification...
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