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In this Issue-February 1st
IN THIS ISSUE-FEBRUARY 1ST Special Section: The Influence of Epigenetic Mechanisms There is an emerging appreciation for the role of epigenetic mechanisms in controlling behavioral function and dysfunction. In this review, Sweatt (pages 191–197) provides a summary of the basic molecular processes that underlie epigenetic mechanisms and their traditional roles in development. He also reviews the roles of these mechanisms, i.e. the regulation of chromatin structure and DNA methylation, in long-term synaptic plasticity, memory formation, and long-term behavioral modification. Mutations of genes involved in the regulation of histone lysine methylation, a type of epigenetic modification, are associated with neurodevelopmental diseases, including mental retardation, autism and schizophrenia. Akbarian and Huang (pages 198 – 203) discuss novel approaches to examining histone lysine methylation at specific genomic loci in postmortem brain tissue. Such studies could provide insights into transcriptional mechanisms operating in a normal or diseased human brain. Rett Syndrome is a neurodevelopmental disorder that arises from loss of function mutations in the methyl-CpG-binding protein-2 (MeCP2) gene, which is widely believed to be a transcriptional repressor that silences methylated genes. Recent work has demonstrated that MeCP2 plays an important role in mediating spontaneous neurotransmission and short-term synaptic plasticity. This review by Monteggia and Kavalali (pages 204 –210) discusses the synaptic basis for neurological symptoms associated with Rett Syndrome as well as a potentially important role for MeCP2 and epigenetic processes involved in mediating transcriptional repression in the regulation of neurotransmission. Evaluating Biomarkers of Vulnerability and Resilience to Stress Effects Considerable interest has surrounded early reports of a moderating effect of the serotonin transporter polymorphic region (5-HTTLPR) on the relationship between stressful life events (SLE) and major depression. Munafò et al. (pages 211–219) combined data from previous studies to determine the strength of this association, and found that only a minority of studies report a replication that is qualitatively comparable to that in the original report. These results not only suggest that the positive results for the 5-HTTLPR ⫻ SLE interactions in logistic regression models are compatible with chance findings, but also highlight the importance of large sample sizes to provide sufficient statistical power, and the publication of non-significant findings to avoid distortion of the published literature. Craske et al. (pages 220 –226) evaluated fear-potentiated startle in normal adolescent boys and girls with varying levels of neuroticism, a trait that predicts the development of anxiety. 0006-3223/09/$36.00
They found that neuroticism potentiated startle when subjects were assured that shock could not occur, but not when shock was imminent. These results suggest that adolescents with high levels of neuroticism show greater sensitivity to contexts that are indirectly associated with threat, a state associated with “anxiety,” but not to imminent threat, a state associated with “fear.” Choi et al. (pages 227–234) provide preliminary evidence that chronic exposure to parental verbal abuse can affect brain development. Using diffusion tensor imaging to compare young adults with a history of exposure to verbal abuse to healthy controls, they found significantly reduced fractional anisotropy (FA) in three white matter tract regions. In addition, they found that FA correlated with language development and psychopathology in these same regions. This longitudinal magnetic resonance spectroscopy (MRS) study by Siegmund et al. (pages 258 –262) demonstrates that basal levels of the brain metabolite N-acetylaspartate (NAA) – an indicator of neuronal integrity - in the left dorsal hippocampus of mice, measured before a traumatic incident, predict resilience (high NAA levels) and vulnerability (low NAA levels) to the development and maintenance of posttraumatic stress disorder (PTSD)-like symptoms. Proton MRS studies have found lower gamma-aminobutyric acid (GABA) concentrations in the occipital cortex of subjects with panic disorder. Hasler et al. (pages 273–275) have now discovered that GABA levels in the prefrontal cortex of panic disorder subjects off medication and in age- and sex-matched healthy controls do not differ significantly. There was also no statistically significant difference in glutamate/glutamine, choline or N-acetylaspartate concentrations. There is conflicting evidence about whether exaggerated startle is a pre-existing vulnerability factor for PTSD or a consequence of traumatization. Pole et al. (pages 235–240) measured exaggerated startle under threat of shock prior to police-related trauma and found that startle measures predicted increased PTSD symptoms after one year of police work. This may aid future work to identify individuals at a higher risk of psychopathology for early interventions. Animal Models of Traumatic Stress and Its Treatment The amygdala evaluates the environment for potential dangers and orchestrates other brain areas to facilitate escape when a danger is detected. In rhesus monkeys, Antoniadis et al. (pages 241–248) demonstrated that the amygdala is needed for learning that a neutral stimulus can potentially signal a danger. However, in a follow-up experiment, they found that once fear learning takes place, the amygdala is no longer needed to demonstrate or express the memory of the conditioned fear. These studies imply that the fear BIOL PSYCHIATRY 2009;65:187–188 © 2009 Society of Biological Psychiatry
188 BIOL PSYCHIATRY 2009;65:187–188 memory is stored in regions other than the amygdala, which has important implications for a variety of human conditions including anxiety disorders and phobias. Using an animal model of traumatic memory, Taubenfeld et al. (pages 249 –257) demonstrate that systemic administration of RU38486, a glucocorticoid receptor antagonist, before or after retrieval persistently weakens memory retention and that the efficacy of treatment is a function of the initial trauma intensity. They also found that RU38486 treatment selectively targets the reactivated memory, indicating that it may be a potential treatment for psychiatric disorders linked to traumatic memories, such as PTSD. Stress and Health Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to
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disease in later life. O’Mahony et al. (pages 263–267) found that early life stress results in an altered communication between the brain and the gut, perhaps contributing to stress-related gastrointestinal illnesses in the long run. Beckham et al. (pages 268 –272) evaluated the relationship between hostility and cardiovascular activity in women with and without PTSD. Women with PTSD demonstrated significantly higher ambulatory heart rate readings over time. For heart rate and diastolic blood pressure, there was a significant interaction between hostile beliefs and overt hostility by group. Increases in hostility resulted in higher heart rate and higher diastolic blood pressure only in those women with PTSD. These results suggest that PTSD may influence the relationship between hostility and cardiovascular outcomes.
They found that neuroticism potentiated startle when subjects were assured that shock could not occur, but not when shock was imminent. These results suggest that adolescents with high levels of neuroticism show greater sensitivity to contexts that are indirectly associated with threat, a state associated with “anxiety,” but not to imminent threat, a state associated with “fear.” Choi et al. (pages 227–234) provide preliminary evidence that chronic exposure to parental verbal abuse can affect brain development. Using diffusion tensor imaging to compare young adults with a history of exposure to verbal abuse to healthy controls, they found significantly reduced fractional anisotropy (FA) in three white matter tract regions. In addition, they found that FA correlated with language development and psychopathology in these same regions. This longitudinal magnetic resonance spectroscopy (MRS) study by Siegmund et al. (pages 258 –262) demonstrates that basal levels of the brain metabolite N-acetylaspartate (NAA) – an indicator of neuronal integrity - in the left dorsal hippocampus of mice, measured before a traumatic incident, predict resilience (high NAA levels) and vulnerability (low NAA levels) to the development and maintenance of posttraumatic stress disorder (PTSD)-like symptoms. Proton MRS studies have found lower gamma-aminobutyric acid (GABA) concentrations in the occipital cortex of subjects with panic disorder. Hasler et al. (pages 273–275) have now discovered that GABA levels in the prefrontal cortex of panic disorder subjects off medication and in age- and sex-matched healthy controls do not differ significantly. There was also no statistically significant difference in glutamate/glutamine, choline or N-acetylaspartate concentrations. There is conflicting evidence about whether exaggerated startle is a pre-existing vulnerability factor for PTSD or a consequence of traumatization. Pole et al. (pages 235–240) measured exaggerated startle under threat of shock prior to police-related trauma and found that startle measures predicted increased PTSD symptoms after one year of police work. This may aid future work to identify individuals at a higher risk of psychopathology for early interventions. Animal Models of Traumatic Stress and Its Treatment The amygdala evaluates the environment for potential dangers and orchestrates other brain areas to facilitate escape when a danger is detected. In rhesus monkeys, Antoniadis et al. (pages 241–248) demonstrated that the amygdala is needed for learning that a neutral stimulus can potentially signal a danger. However, in a follow-up experiment, they found that once fear learning takes place, the amygdala is no longer needed to demonstrate or express the memory of the conditioned fear. These studies imply that the fear BIOL PSYCHIATRY 2009;65:187–188 © 2009 Society of Biological Psychiatry
188 BIOL PSYCHIATRY 2009;65:187–188 memory is stored in regions other than the amygdala, which has important implications for a variety of human conditions including anxiety disorders and phobias. Using an animal model of traumatic memory, Taubenfeld et al. (pages 249 –257) demonstrate that systemic administration of RU38486, a glucocorticoid receptor antagonist, before or after retrieval persistently weakens memory retention and that the efficacy of treatment is a function of the initial trauma intensity. They also found that RU38486 treatment selectively targets the reactivated memory, indicating that it may be a potential treatment for psychiatric disorders linked to traumatic memories, such as PTSD. Stress and Health Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to
www.sobp.org/journal
disease in later life. O’Mahony et al. (pages 263–267) found that early life stress results in an altered communication between the brain and the gut, perhaps contributing to stress-related gastrointestinal illnesses in the long run. Beckham et al. (pages 268 –272) evaluated the relationship between hostility and cardiovascular activity in women with and without PTSD. Women with PTSD demonstrated significantly higher ambulatory heart rate readings over time. For heart rate and diastolic blood pressure, there was a significant interaction between hostile beliefs and overt hostility by group. Increases in hostility resulted in higher heart rate and higher diastolic blood pressure only in those women with PTSD. These results suggest that PTSD may influence the relationship between hostility and cardiovascular outcomes.