Brain Environment Interactions: Stress, Posttraumatic Stress Disorder, and the Need for a Postmortem Brain Collection.

Stress, especially the extreme stress of traumatic events, can alter both neurobiology and behavior. Such extreme environmental situations provide a useful model for understanding environmental influences on human biology and behavior. This paper will review some of the evidence of brain alterations that occur with exposure to environmental stress. This will include recent studies using neuroimaging and will address the need for histological confirmation of imaging study results. We will review the current scientific approaches to understanding brain environment interactions, and then make the case for the collection and study of postmortem brain tissue for the advancement of our understanding of the effects of environment on the brain.Creating a brain tissue collection specifically for the investigation of the effects of extreme environmental stressors fills a gap in the current research; it will provide another of the important pieces to the puzzle that constitutes the scientific investigation of negative effects of environmental exposures. Such a resource will facilitate new discoveries related to the psychiatric illnesses of acute stress disorder and posttraumatic stress disorder, and can enable scientists to correlate structural and functional imaging findings with tissue abnormalities, which is essential to validate the results of recent imaging studies.

Tgf-beta induced Erk phosphorylation of smad linker region regulates smad signaling.

The Transforming Growth Factor-Beta (TGF-ß) family is involved in regulating a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-ß binding to a Serine/Threonine kinase receptor complex causes the recruitment and subsequent activation of transcription factors known as smad2 and smad3. These proteins subsequently translocate into the nucleus to negatively or positively regulate gene expression. In this study, we define a second signaling pathway leading to TGF-ß receptor activation of Extracellular Signal Regulated Kinase (Erk) in a cell-type dependent manner. TGF-ß induced Erk activation was found in phenotypically normal mesenchymal cells, but not normal epithelial cells. By activating phosphotidylinositol 3-kinase (PI3K), TGF-ß stimulates p21-activated kinase2 (Pak2) to phosphorylate c-Raf, ultimately resulting in Erk activation. Activation of Erk was necessary for TGF-ß induced fibroblast replication. In addition, Erk phosphorylated the linker region of nuclear localized smads, resulting in increased half-life of C-terminal phospho-smad 2 and 3 and increased duration of smad target gene transcription. Together, these data show that in mesenchymal cell types the TGF-ß/PI3K/Pak2/Raf/MEK/Erk pathway regulates smad signaling, is critical for TGF-ß-induced growth and is part of an integrated signaling web containing multiple interacting pathways rather than discrete smad/non-smad pathways.

Activated Ras/MEK inhibits the antiviral response of alpha interferon by reducing STAT2 levels.

The ability of interferon (IFN) to induce the expression of antiviral genes, and therefore suppress viral infection, is dependent on the activity of cellular suppressors. The Ras/MEK pathway is one of these cellular suppressors, since the activation of Ras/MEK permits viral replication in the presence of alpha IFN (IFN-alpha). Here, we have investigated the mechanism by which activated Ras/MEK inhibits the IFN-alpha response. We found that the induction of antiviral proteins in response to IFN-alpha was impaired in Ras-transformed NIH 3T3 (RasV12) cells. The inhibition of the Ras/MEK pathway restored the IFN-mediated induction of antiviral genes, indicating that activated Ras interrupts the IFN pathway upstream of antiviral gene transcription. Indeed, the IFN-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 was inhibited in RasV12 cells compared to that of vector control cells. In addition, we found that the total amount of STAT2 was reduced in RasV12 cells. To determine if the impaired IFN-alpha response can be rescued by restoring the overall level of STAT2, we overexpressed STAT2 in RasV12 cells. The IFN-alpha-induced phosphorylation of STAT1 and STAT2, as well as the expression of antiviral protein, were restored, and IFN-induced antiviral protection was partially restored. Moreover, we demonstrated that the downregulation of STAT2 levels by Ras/MEK was mediated at the transcriptional level. Thus, the activation of the Ras/MEK pathway reduces the amount of STAT2 available for propagating the IFN signal, resulting in the impairment of the IFN-alpha-induced antiviral response.

Addressing arsenic bioaccessibility in ecological risk assessment: a novel approach to avoid overestimating risk.

The risk of arsenic exposure to deer mice (Peromyscus maniculatus) living in areas of naturally and anthropogenically elevated arsenic levels was determined using three separate calculations of arsenic daily intake: Estimated daily intake (EDI), bioaccessible EDI (BEDI), and actual daily intake (ADI). The present work is of particular interest, because the risk assessments were determined for animals naturally exposed to arsenic. Gastric fluid extraction was used to obtain bioaccessibility data for soil and plant samples collected from three study sites (background, mine forest, and tailings) in Yellowknife (NT, Canada). Calculations using the EDI indicated that deer mice living in tailings habitat (average soil arsenic concentration, 1,740 +/- 2,240 microg/g) should have been experiencing serious health effects as a result of their exposure to arsenic. Using BEDI and ADI in the risk assessment calculation, however, resulted in an order-of-magnitude decrease in calculated risk. In addition, results calculated using the BEDI and ADI were not significantly different, suggesting that using bioaccessibility provides a more realistic estimate of potential risk. The present results provide evidence that the use of EDI in traditional risk assessments may seriously overestimate the actual risk, which in some instances may result in expensive and unnecessary clean-up measures.

Models of PTSD and traumatic stress: the importance of research "from bedside to bench to bedside".

The epidemiology and psychology of PTSD noted above is not often considered in neurobiological models of PTSD. Neurobiological models tend to focus on symptoms. This is an important perspective but it does not capture the brains total response to traumatic events. Similarly, neurobiologists have rarely used the extensive knowledge of animal behavioral responses to stress as a means to define the human stress phenomenology, looking for the human equivalent (rather than the other way around). The development of animal models for PTSD and other traumatic stress-related brain changes is an important part of advancing our neurobiological understanding of the disease process as well as recovery, resilience, and possible therapeutic targets. Animal models should address symptoms but also other aspects of PTSD that are seen in clinical care including the waxing and waning of symptoms, Understanding "forgetting", toxic exposure, failure to recover and how the neural systems fail rather than function are important perspectives on developing animal models. The cognitive process of identification is another important animal model to develop. Using these perspectives recent work has shown new avenues for understanding the trauma response in animal models and human brain tissue of individuals with PTSD. The 5-HT2A receptor and p11 protein and associated regulators are avenues of new investigation that warrant study and consideration in models of PTSD.

Brain environment interactions: stress, posttraumatic stress disorder, and the need for a postmortem brain collection.

Stress, especially the extreme stress of traumatic events, can alter both neurobiology and behavior. Such extreme environmental situations provide a useful model for understanding environmental influences on human biology and behavior. This paper will review some of the evidence of brain alterations that occur with exposure to environmental stress. This will include recent studies using neuroimaging and will address the need for histological confirmation of imaging study results. We will review the current scientific approaches to understanding brain environment interactions, and then make the case for the collection and study of postmortem brain tissue for the advancement of our understanding of the effects of environment on the brain. Creating a brain tissue collection specifically for the investigation of the effects of extreme environmental stressors fills a gap in the current research; it will provide another of the important pieces to the puzzle that constitutes the scientific investigation of negative effects of environmental exposures. Such a resource will facilitate new discoveries related to the psychiatric illnesses of acute stress disorder and posttraumatic stress disorder, and can enable scientists to correlate structural and functional imaging findings with tissue abnormalities, which is essential to validate the results of recent imaging studies.