| Project Grants |
Resulting Articles |
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Analysis of PKMι/λ, a second memory storage molecule (2014)
Principal Investigator: Todd C. Sacktor, M.D., Distinguished Professor of Physiology,Pharmacology & Neurology at SUNY Downstate Medical Center
Description: To help individuals with PTSD, for whom painful memories are extremely strong and debilitating, we must make drugs that target the specific, core molecules that store long-term memory. This is because when long-term memories are recalled, they can undergo a second process called “reconsolidation,” during which the long-term memory is “destabilized,” converted into short-term memory, and then reconsolidated back into a long-term memory. Therefore, if the process of reconsolidation could be prevented, traumatic memories might be specifically dampened or even erased after their recall, helping people with PTSD, anxiety, and depression. But to design a highly effective reconsolidation therapy, the treatment needs to focus on the essential molecules that store long-term memory. Work has now identified one core molecule of long-term memory storage, called protein kinase Mzeta (PKMζ), which stores memories of traumatic, stressful events. But recent work with knock-out mice has revealed that there is a “back-up” storage molecule from a gene very closely related to PKMζ, termed protein kinase Miota (PKMι). This molecule, together with PKMζ, is found in the brains of humans, and it is highly likely that both are important for memory storage, particularly of very strong memories. To understand PKMι function in memory, however, we must first characterize how it changes in memory — when does it go up, does it increase with weak and strong memories, how long does it last? This project will allow us to characterize the function of PKMι in learning and memory using previously obtained tissue from animals used in earlier experiments on PKMζ. We believe it is essential for developing an effective strategy to block reconsolidation of traumatic memories underlying PTSD.
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Psychobiology of suicidal behavior among military veterans (2012)
Principal Investigator: Leo Sher, M.D., Associate Professor of Psychiatry, Mount Sinai School of Medicine and Associate Director, Inpatient Psychiatry, James J. Peters Veterans' Administration Medical Center
Co-investigators: Rachel Yehuda, Ph.D.; Janine Flory, Ph.D.; Linda Bierer, M.D.
Description: Suicidal behavior in combat veterans is a crucial issue in veterans’ health care, as it has reached epidemic proportions. This places a moral obligation on us to try to understand this epidemic and prevent these tragedies. Efforts at suicide prevention are restricted by the lack of knowledge about the reasons for the increased rate of suicidality among veterans and its underlying neurobiological basis, and more specifically, about the question of whether suicidality in combat veterans represents a unique and distinct problem from other combat related consequences or suicidal behavior as it occurs in civilians. Although combat trauma is often likened to other forms of life-threatening events (i.e., civilian trauma), there are numerous aspects of combat that are not often emphasized in the medical literature, but may be essential for understanding unique psychological and biological characteristics and behaviors of combat veterans. For example, an important distinction between combat and civilian trauma is that combat veterans often seek and prepare for their combat experiences, anticipating that they will encounter significant life threats. Without knowing whether suicidality in combat veterans has distinct determinants, it is not possible to optimize treatment. This project aims to study suicide attempters from a psychological and biological perspective in order to identify what makes combat veterans suicidal. The primary objective of this project is to test the hypothesis that veterans who have made a suicide attempt post-deployment can be distinguished from veterans who have never made a suicide attempt based on differences in several psychological (e.g., impulsivity, aggression, and levels of trauma exposure) and biological (e.g., levels of stress-related hormones and other biomarkers, including cortisol, brain-derived neurotrophic factor and endocannabinoids) variables that have previously been linked to suicide or stress-related psychiatric conditions in civilians.
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Combat PTSD, Inflammation, and Atrophy of the Hippocampus (2011)
Principal Investigator: Thomas C. Neylan, M.D., Professor of Psychiatry at University of California, San Francisco and Director of the PTSD Program
Co-investigators: Brigitte Apfel, M.D.; Aoife O’Donovan, Ph.D.
Description: Accumulating evidence indicates that Post Traumatic Stress Disorder (PTSD) substantially increases risk for age-related diseases, including cardiovascular, autoimmune, neurodegenerative diseases, and early mortality. Although the biological mechanisms mediating these associations remain unclear, PTSD is associated with dysregulation of bodily systems that have been linked with biological aging. Accelerated biological aging is a possible mechanism of increased disease risk in PTSD. The hippocampus is a brain area essential for learning and memory, and known to be responsive to stress. Advanced age is associated with a reduction in the size of the hippocampus. Magnetic resonance imaging (MRI) studies have shown that PTSD is also associated with a reduced size of the hippocampus. However, the nature of the relationship between PTSD and hippocampal size is poorly understood. Two fundamentally different ideas about the relationship are currently considered. According to one, a small hippocampus is considered a sequel of chronic stress reactivity in PTSD and hippocampal damage is attributed to the toxic effects of glucocorticoids and glutamate, or alternatively, related to decreased brain trophic factors such as brain derived neurotrophic factor. This model implies hippocampal plasticity in humans. The second model of hippocampal atrophy in PTSD is that it represents a pre-existing hereditary risk factor that increases the vulnerability to develop PTSD. Telomeres are DNA-protein complexes that cap the ends of chromosomes and protect against DNA damage. Telomeres shorten with each cycle of cell division and with oxidative stress. Leukocyte telomere length (LTL) is a marker of biological age that predicts incidence of age-related diseases as well as mortality. Telomere shortening is not just an index of biological age, but also a mechanism of biological aging because critically short telomere length can lead to DNA damage and cell death. Preliminary data indicates that short LTL is associated with smaller hippocampal volume, a risk factor for neurodegenerative disease. Inflammation is a widely accepted mechanism of biological aging in general, and of telomere shortening in particular. There is accumulating evidence that PTSD is associated with elevated inflammation. However, it is not known if elevated inflammation is a vulnerability factor for PTSD or a consequence of PTSD, and little is known about the association of inflammation with brain abnormalities such as hippocampal abnormalities in PTSD. This project will analyze levels of the inflammatory proteins C-reactive protein, interleukin-6 and tumor necrosis factor-alpha in a large sample of almost 300 veterans who served in the Persian Gulf War and participated in a prior neuroimaging project which obtained detailed measures of both childhood and combat trauma exposure. The project aims to shed light on the nature of inflammatory abnormalities in PTSD and also examine if elevated inflammation is associated with reduced hippocampal volume in PTSD.
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Posttraumatic Stress Disorder, Glucocorticoids and the Endocannabinoid System: A Novel Therapeutic Perspective (2009)
Principal Investigator: Bruce S. McEwen, Ph.D., Alfred E. Mirsky Professor, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University
Co-investigators: Dr. Matthew Hill, Post-doctoral Fellow, Rockefeller University; Prof. Sumantra Chattarji, National Centre for Biological Sciences, Bangalore, India
Description: The mechanism by which glucocorticoids modulate the expression of fear behavior is not yet well characterized. The research project addresses how this phenomenon may be mediated by the endocannabinoid system. Endocannabinoids are known to reduce fear and anxiety behavior and at the cellular level are known to be local regulators of the release of excitatory and inhibitory neurotransmitters. Recent evidence has suggested that glucocorticoids possess the ability to rapidly induce endocannabinoid release.
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Cortisol Augmentation of a Psychological Treatment in Warfighters with PTSD (2009)
Principal Investigator: Rachel Yehuda, Ph.D., Professor of Psychiatry and Neurobiology at the Mount Sinai School of Medicine and Director of the Traumatic Stress Studies Division and the PTSD Clinic at the James J. Peters Veterans Affairs Medical Center Bronx, NY
Co-investigators: Julia Golier M.D., Assistant Professor of Psychiatry, MSSM, and Medical Director for the PTSD Clinic at the JJP VAMC; Linda M. Bierer, M.D., Clinical Associate Professor, MSSM; Melissa Altman, Ph.D., Assistant Clinical Professor of Psychiatry (voluntary) at MSSM and Clinical Psychologist, JJP VAMC
Description: Combat-related posttraumatic stress disorder (PTSD) is a common and often disabling disorder that is prevalent in combat veterans, and has received a great deal of recent attention as this problem afflicts 1/3 of returnees from Operation Iraqi Freedom and Operation Enduring Freedom. Left untreated, or unsuccessfully treated, PTSD is associated with a high burden of illness including associated psychiatric conditions such as depression and substance abuse, physical health problems, marital instability, interpersonal violence and unemployment. Cognitive behavioral psychotherapy has emerged as a first line treatment for PTSD, and the evidence for the efficacy of prolonged exposure (PE) therapy in particular is strong. PE has consistently been shown to significantly reduce symptoms of PTSD in civilian trauma survivors, often leading to sustained remission of the disorder. However, the experience of clinicians treating PTSD at Veterans Affairs (VA) medical centers around the country has been that PE does not appear to be as efficacious or as well tolerated in combat veterans as has been observed in civilian populations. This research project examines whether psychotherapy outcomes can be improved in veterans with PTSD through the use of a pharmacological augmentation strategy using hydrocortisone (Hcort).
