2009 — 2011 |
Kaufer, Daniela |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Identification &Prevention of Developmental Myelin Misregulation in Ptsd @ University of California Berkeley
DESCRIPTION (provided by applicant): Changes in white matter have been reported in depression, schizophrenia, and post- traumatic stress disorder (PTSD) and suicide, suggesting that altered myelination may be a new mechanism by which psychopathologies emerge. We found that stress and the adrenal stress hormones, glucocorticoids (GC), induce Neural Precursor Cells in the adult hippocampus to an oligodendrogenic fate, thereby increasing myelin production capacity. We have also demonstrated increased myelination capacity in the hippocampus of pups subjected to adverse parental care. Here, we hypothesize that early adverse experiences increase myelination across the lifespan, altering development of the brain environment and increasing susceptibility to mental illness including PTSD and depression. We propose to examine the effects that neonatal stress and adverse parental care have on long-lasting changes on white matter patterning across the lifespan, using an integrated approach that correlates molecular/cellular analysis with behavioral outputs. In specific aims 1-2, we will document, at the cellular level, changes in myelination and oligodendrogenesis after early life maternal separation or low maternal care, and analyze the underpinnings of myelination at the molecular level by qPCR of the transcription factors involved in cell fate choice, and myelin-related genes. Furthermore, we will correlate developmental white matter patterning with vulnerability to PTSD in response to acute stress in adulthood. In specific aim 3, we will use anti-GC gene intervention vectors to try to prevent misdevelopment of the white matter when delivered in early life, or mitigate persistent white matter dysregulation when delivered in adulthood. In specific aim 4, we will expand these cellular-level analyses to the behavioral level by testing for depression/anxiety behavior and hippocampus-dependent cognitive performance in each experimental group. Together, these aims will give us a comprehensive picture of the development of altered white matter patterning after early adverse experience, ranging from quantification of myelin and oligodendrogenesis at different developmental time points to ultimate effects in impaired behavior and cognitive function. This application is innovative in (1) focusing on white matter support cells, rather than neurons, as a developmental basis for mental illness and (2) using interdisciplinary, integrative approaches to explore the developmental basis of mental illness. This project aims to examine whether adverse early experiences exert long-lasting changes on oligodendrogenesis and myelination across the lifespan, and render vulnerability to development of mental illness such as post-traumatic stress disorder and depression. Anti-glucocorticoids genetic therapies are employed as tools to prevent or reverse these effects. This application is innovative, as it sheds light on a generally unexplored issue-the persistent dysregulation of white matter by early adverse experience, and how this contributes to the development of brain malfunction in adulthood, specifically in the context of mental illness.
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1 |
2009 — 2014 |
Kaufer, Daniela |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Tgf-Beta Mediated Inflammatory Signaling: a Critical Role in Epileptogenesis @ University of California Berkeley
DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders. It has long been known that brain injury or ischemia often result in epileptic activity. Post-traumatic epilepsy (PTE) is a recurrent seizure disorder secondary to brain injury following head trauma. PTE accounts for 20% of symptomatic epilepsy in the general population, and up to 50% in the military population due to higher incidence of penetrating head injuries. Mechanisms by which brain injury leads to epileptogenesis are mostly unknown. Traumatic, ischemic, or infectious brain injuries are often associated with vascular injuries, specifically with opening of the blood-brain barrier (BBB). We have identified a novel mechanism for the development of epilepsy following BBB compromise: in the rat neocortex, we have shown that opening of the BBB leads to the development of focal epileptiform activity, similar to that observed following injury, and that serum albumin is a critical factor in subsequent epileptogenesis. Specifically, we have found that albumin interacts with transforming growth factor-beta (TGF-b) receptors in astrocytes, leading to albumin uptake, and that albumin uptake causes induction of the TGF-b signaling pathway. We propose to perform a detailed analysis of the molecular and physiological changes that are induced by albumin activation of the TGF-b pathway. We will then target this pathway to assess the efficacy of TGF-b pathway blockers to therapeutically prevent albumin signal transduction and epileptogenesis in living rats. The following specific aims will be carried out: (1) To characterize albumin uptake into specific cell types and albumin interactions with TGF-bRs;(2) To determine the downstream signaling cascade activated by albumin interaction with TGF-bRs;(3) To characterize the downstream effects of TGF-b signaling on the morphology and biophysical properties of astrocytes;and (4) To demonstrate the potential efficacy of epilepsy prevention using TGF-bR antagonists. In this proposal we combine genomic, molecular, biochemical and electrophysiological techniques to unravel a novel epileptogenic cascade, and demonstrate profound clinical implications of blocking this process. PUBLIC HEALTH RELEVANCE: This project will impact public health in two major ways. Firstly, the project will elucidate the pathways that lead to epileptogenesis following traumatic head injury. Secondly, the project will assess the efficacy of targeting these pathways for therapeutic intervention and prevention of epileptogenesis. Since brain insults are one of the primary causes of disability with no means of prevention as of yet, this proposal represents an important advancement toward resolving this unmet medical need.
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1 |
2012 — 2013 |
Kaufer, Daniela |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Identification & Prevention of Developmental Myelin Misregulation in Ptsd @ University of California Berkeley
DESCRIPTION (provided by applicant): Changes in white matter have been reported in depression, schizophrenia, and post- traumatic stress disorder (PTSD) and suicide, suggesting that altered myelination may be a new mechanism by which psychopathologies emerge. We found that stress and the adrenal stress hormones, glucocorticoids (GC), induce Neural Precursor Cells in the adult hippocampus to an oligodendrogenic fate, thereby increasing myelin production capacity. We have also demonstrated increased myelination capacity in the hippocampus of pups subjected to adverse parental care. Here, we hypothesize that early adverse experiences increase myelination across the lifespan, altering development of the brain environment and increasing susceptibility to mental illness including PTSD and depression. We propose to examine the effects that neonatal stress and adverse parental care have on long-lasting changes on white matter patterning across the lifespan, using an integrated approach that correlates molecular/cellular analysis with behavioral outputs. In specific aims 1-2, we will document, at the cellular level, changes in myelination and oligodendrogenesis after early life maternal separation or low maternal care, and analyze the underpinnings of myelination at the molecular level by qPCR of the transcription factors involved in cell fate choice, and myelin-related genes. Furthermore, we will correlate developmental white matter patterning with vulnerability to PTSD in response to acute stress in adulthood. In specific aim 3, we will use anti-GC gene intervention vectors to try to prevent misdevelopment of the white matter when delivered in early life, or mitigate persistent white matter dysregulation when delivered in adulthood. In specific aim 4, we will expand these cellular-level analyses to the behavioral level by testing for depression/anxiety behavior and hippocampus-dependent cognitive performance in each experimental group. Together, these aims will give us a comprehensive picture of the development of altered white matter patterning after early adverse experience, ranging from quantification of myelin and oligodendrogenesis at different developmental time points to ultimate effects in impaired behavior and cognitive function. This application is innovative in (1) focusing on white matter support cells, rather than neurons, as a developmental basis for mental illness and (2) using interdisciplinary, integrative approaches to explore the developmental basis of mental illness. This project aims to examine whether adverse early experiences exert long-lasting changes on oligodendrogenesis and myelination across the lifespan, and render vulnerability to development of mental illness such as post-traumatic stress disorder and depression. Anti-glucocorticoids genetic therapies are employed as tools to prevent or reverse these effects. This application is innovative, as it sheds light on a generally unexplored issue-the persistent dysregulation of white matter by early adverse experience, and how this contributes to the development of brain malfunction in adulthood, specifically in the context of mental illness.
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1 |
2019 — 2021 |
Kaufer, Daniela Neylan, Thomas C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Individual Variation in Effects of Traumatic Stress On Gray Matter Myelin @ Northern California Institute/Res/Edu
PROJECT SUMMARY/ABSTRACT This research will examine maladaptive myelination as a potential mechanism underpinning the structural and functional brain abnormalities associated with exposure to traumatic stress. Specifically, we will explore the mechanisms behind persistent sensitivity to acute threat (?fear?: RDoC domain) arising from traumatic stress during early adulthood. Myelination most likely evolved to improve conduction velocity but in gray matter (GM), it reduces axonal sprouting, synaptic density, and neuroplasticity. Exciting recent findings have shown that myelin development in both cortical and subcortical gray matter is highly plastic and strongly influenced by new experiences and learning, even during adult life. Importantly, myelin-forming oligodendrocytes are sensitive to environmental stressors and therefore may provide a novel mechanism by which aberrant structural and functional changes arise in the brain. Human brain imaging data from our labs show that subjects with a range of PTSD symptoms secondary to adult trauma exposure have increased myelin content in the hippocampal (HP), frontal, and temporal GM. Importantly, myelin content predicted symptom severity over and above potential confounding variables. Furthermore, we found that adult traumatic stress exposure in rodents produces an increase in oligodendrocytes (OGs) and myelin content in the dentate gyrus (DG), a GM structure13. Similar to human subjects, our preliminary data show that symptom severity (fear score) in rats is significantly correlated with DG OGs and myelin content. Overall, these findings provide a translational model to better understand the mechanisms of oligodendrocyte and myelin plasticity in the human. In this proposal, we will test the hypothesis that traumatic stress exposure during adulthood leads to increased myelination in cortical and subcortical GM in regions critical for fear memory. Specifically, we expect to see this increased myelination only in those that subsequently become sensitive to acute threat following stress exposure. Additionally, we hypothesize that increased myelination will constrain the proper functioning of the major intrinsic functional connectivity (IFC) networks. This integrated animal-human design enables an innovative multilevel and causal exploration. Additionally, we focus on a novel role for myelin plasticity in the adult brain as a mediator of trauma-induced acute threat symptoms. Aim 1 is focused on the question of whether hippocampal gray matter myelination predict post-trauma sensitivity to acute threat. Aim 2 is focused on the question of whether the effects of trauma exposure on cortical and subcortical GM myelination predict network connectivity and fear memory.
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0.927 |