Background This study aimed to determine whether patients with post-traumatic stress disorder (PTSD) show difficulty in recruitment of the regions of the frontal and parietal cortex implicated in top-down attentional control in the presence and absence of emotional distracters. Method Unmedicated individuals with PTSD (n=14), and age-, IQ- and gender-matched individuals exposed to trauma (n=15) and healthy controls (n=19) were tested on the affective number Stroop task. In addition, blood oxygen level-dependent responses, as measured via functional magnetic resonance imaging, were recorded. Results Patients with PTSD showed disrupted recruitment of lateral regions of the superior and inferior frontal cortex as well as the parietal cortex in the presence of negative distracters. Trauma-comparison individuals showed indications of a heightened ability to recruit fronto-parietal regions implicated in top-down attentional control across distracter conditions. Conclusions These results are consistent with suggestions that emotional responsiveness can interfere with the recruitment of regions implicated in top-down attentional control ; the heightened emotional responding of patients with PTSD may lead to the heightened interference in the recruitment of these regions.

The recent development of low-risk imaging technologies, such as functional magnetic resonance imaging (fMRI), have had a significant impact on the investigation of psychopathologies in children and adolescents. This review considers what we can infer from fMRI work regarding the development of conduct disorder (CD) and oppositional defiant disorder (ODD). We make two central assumptions that are grounded in the empirical literature. First, the diagnoses of CD and ODD identify individuals with heterogeneous pathologies; that is, different developmental pathologies can receive a CDD or ODD diagnosis. This is indicated by the comorbidities associated with CD/ODD, some of which appear to be mutually exclusive at the biological level (e.g., posttraumatic stress disorder [PTSD] and psychopathic tendencies). Second, two populations of antisocial individuals can be identified: those that show an increased risk for only reactive aggression and those that show an increased risk for both reactive and instrumental aggression. We review the fMRI data indicating that particular comorbidities of CD/ODD (i.e., mood and anxiety conditions such as childhood bipolar disorder and PTSD) are associated with either increased responsiveness of neural regions implicated in the basic response to threat (e.g., the amygdala) or decreased responsiveness in regions of frontal cortex (e.g., ventromedial frontal cortex) that are implicated in the regulation of the basic threat response. We suggest why such pathology would increase the risk for reactive aggression and, in turn, lead to the association with a CD/ODD diagnosis. We also review the literature on psychopathic tendencies, a condition where the individual is at significantly elevated risk for both reactive and instrumental aggression. We show that in individuals with psychopathic tendencies, the functioning of the amygdala in stimulus-reinforcement learning and of the ventromedial frontal cortex in the representation of reinforcement expectancies is impaired. We suggest why such pathology would increase the risk for reactive and instrumental aggression and thus also lead to the association with a CD/ODD diagnosis.

Excessive activation of ionotropic glutamate receptors increases oxidative stress, contributing to the neuronal death observed following neurological insults such as ischemia and seizures. Posttranslational histone modifications may be key mediators in the detection and repair of damage resulting from oxidative stress, including DNA damage, and may thus affect neuronal survival in the aftermath of insults characterized by excessive glutamate release. In non-neuronal cells, phosphorylation of histone variant H2A.X (termed γ-H2AX) occurs rapidly following DNA doublestrand breaks. We investigated γ-H2AX formation in rat cortical neurons (day in vitro 14) following activation of NMDA or AMPA/Kainate glutamate receptors using fluorescent immunohistochemical techniques. Moreover, we evaluated the co-localization of γ-H2AX "foci" with Mre11, a doublestrand break repair protein, to provide further evidence for the activation of this DNA damage response pathway. Here we show that minimally cytotoxic stimulation of ionotropic glutamate receptors is sufficient to evoke γ-H2AX in neurons and that NMDA-induced γ-H2AX foci formation was attenuated by pretreatment with the antioxidant, Vitamin E, and the intracellular calcium chelator, BAPTA-AM. Moreover, a subset of γ-H2AX foci co-localized with Mre11, indicating that Corresponding Author: Alexei Kondratyev, Ph.D., Assistant Professor, Department of Pediatrics, 3970 Reservoir Rd, NW, The Research Building, W217, Washington, D.C. 20057, Phone: 202-687-0204; Fax: 801-469-5580, e-mail: kondrata@georgetown.edu. We would like to thank Dr. Karen Gale for her valuable feedback and helpful comments in the preparation of this manuscript. We would also like to thank Irina Kats for technical assistance. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptat least a portion of γ-H2AX foci is damage-dependent. The extent of γ-H2AX induction following glutamate receptor activation corresponded to the increases we observed following conventional DNA damaging agents (i.e., non-lethal doses of gamma-radiation (1 Gy) and hydrogen peroxide (10 μM)). These data suggest that insults not necessarily resulting in neuronal death induce the DNA damage-evoked chromatin modification, γ-H2AX, and implicate a role for histone alterations in determining neuronal vulnerability following neurological insults.Keywords histone modification; rat; cortical neurons; gamma-H2AX; glutamate receptorsIn addition to DNA repair protein regulation, post-translational histone modifications can mediate the cellular response to DNA damage (Hassa & Hottiger, 2005). Although the importance of functional DNA-repair pathways is underscored by the abnormal neuronal development and vulnerability to injury observed in DNA repair-deficient mice (Vemuri et al., 2001;Culmsee et al., 2001;Meira et al., 2001;Laposa & Cleaver, 2001) and humans (Rolig & McKinnon, 2000;Brooks, 2002), DNA damage-related histone alterations remain relatively unexamined in neurons.It is well documented in non-neuronal cells ...

The peptide neurotransmitter N-acetylaspartylglutamate is inactivated by extracellular peptidase activity following synaptic release. It is speculated that the enzyme, glutamate carboxypeptidase II (GCPII, EC 3.14.17.21), participates in this inactivation. However, CGCPII knockout mice appear normal in standard neurological tests. We report here the cloning and characterization of a mouse enzyme (tentatively identified as glutamate carboxypeptidase III or GCPIII) that is homologous to an enzyme identified in a human lung carcinoma. The mouse peptidase was cloned from two non-overlapping EST clones and mouse brain cDNA using PCR. The sequence (GenBank, AY243507) is 85% identical to the human carcinoma enzyme and 70% homologous to mouse GCPII. GCPIII sequence analysis suggests that it too is a zinc metallopeptidase. Northern blots revealed message in mouse ovary, testes and lung, but not brain. Mouse cortical and cerebellar neurons in culture expressed GCPIII message in contrast to the glial specific expression of GCPII. Message levels of GCPIII were similar in brains obtained from wild-type mice and mice that are null mutants for GCPII. Chinese hamster ovary (CHO) cells transfected with rat GCPII or mouse GCPIII expressed membrane bound peptidase activity with similar V max and K m values (1.4 lM and 54 pmol/min/mg; 3.5 lM and 71 pmol/min/mg, respectively). Both enzymes are activated by a similar profile of metal ions and their activities are blocked by EDTA. GCPIII message was detected in brain and spinal cord by RT-PCR with highest levels in the cerebellum and hippocampus. These data are consistent with the hypothesis that nervous system cells express at least two differentially distributed homologous enzymes with similar pharmacological properties and affinity for NAAG.

BackgroundThe psychological and neurobiological processes underlying moral judgment have been the focus of extensive recent research. Here we show that serotonin transporter (5-HTTLPR) genotype predicts responses to moral dilemmas featuring foreseen harm to an innocent.Methodology/Principal FindingsParticipants in this study judged the acceptability of actions that would unintentionally or intentionally harm an innocent victim in order to save others' lives. An analysis of variance revealed a genotype × scenario interaction, F(2, 63) = 4.52, p = .02. Results showed that, relative to long allele homozygotes (LL), carriers of the short (S) allele showed particular reluctance to endorse utilitarian actions resulting in foreseen harm to an innocent individual. LL genotype participants rated perpetrating unintentional harm as more acceptable (M = 4.98, SEM = 0.20) than did SL genotype participants (M = 4.65, SEM = 0.20) or SS genotype participants (M = 4.29, SEM = 0.30). No group differences in moral judgments were observed in response to scenarios featuring intentional harm.Conclusions/SignificanceThe results indicate that inherited variants in a genetic polymorphism that influences serotonin neurotransmission influence utilitarian moral judgments as well. This finding is interpreted in light of evidence that the S allele is associated with elevated emotional responsiveness.

The phosphorylated form of histone H2A.X (γ-H2AX) is a well-documented early, sensitive and selective marker of DNA double-strand breaks (DSBs). Previously we found that excessive glutamatergic activity increased γ-H2AX in neurons in vitro. Here we evaluated γ-H2AX formation in the adult rat brain following neuronal excitation evoked by seizure activity in vivo. We found that brief, repeated electroconvulsive shock (ECS)-induced seizures (three individual seizures within 60 min) did not trigger an increase γ-H2AX immunostaining. In contrast, a cluster of 5–7 individual seizures evoked by kainic acid (KA) rapidly (within 30 min) induced γ-H2AX in multiple neuronal populations in hippocampus and entorhinal cortex. This duration of seizure activity is well below threshold for induction of neuronal cell death, indicating that the γ-H2AX increase occurs in response to sublethal insults. Moreover, an increase in γ-H2AX was seen in dentate granule cells which are resistant to cell death caused by KA-evoked seizures. With as little as a 5 min duration of status epilepticus (SE), γ-H2AX increased in CA1, CA3 and entorhinal cortex, to a greater extent than observed after the clusters of individual seizures, with still greater increases after 120 min of SE. Our findings provide the first direct demonstration that DNA DSB damage occurs in vivo in the brain following seizures. Furthermore, we found that the γ-H2AX increase caused by 120 min of SE was prevented by neuroprotective preconditioning with ECS-evoked seizures. This demonstrates that DNA DSB damage is an especially sensitive indicator of neuronal endangerment, and that it is responsive to neuroprotective intervention.

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