2012 |
Burman, Michael A |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Assessing the Development of Hippocampus-Amygdala Interactions During Emotional L @ University of New England
DESCRIPTION (provided by applicant): There is growing agreement that many complex cognitive functions (especially learning, memory, and emotional expression) are best understood as requiring an interaction among semi-independent neural circuits focused around a variety of limbic system structures, including the hippocampus, amygdala and limbic-associated regions of cortex. However, the functional development of these systems is only beginning to be understood. Depending on the specific neural substrates involved, even very similar learning, memory and emotional processing tasks appear to have different ontogenetic profiles. For example, it has been well established that the ability to form aversive associations with discrete cues, as demonstrated by auditory or visual classical fear conditioning, emerges prior to the ability to form emotional associations with physical environments, as demonstrated by contextual fear conditioning. Since aversive memories all depend upon the amygdala, but spatial and contextual memories uniquely depend on the hippocampus, such findings had been interpreted as suggesting that the hippocampus was relatively slow to develop. However, recent data from our lab presents two challenges to this idea. First, the ability to form a representation of the environment (dependent upon the hippocampus) is present early than previously believed. Further development is required prior to the ability to integrate these types of experiences with emotional events and to express fear to a particular environment. Moreover, the ability to express fear to an explicit cue (dependent on the amygdala) continues to increase for some time after its initial emergence, longer than previously believed. Thus, the data show that contrary to previous understanding, the hippocampus-dependent memory system is functional as early as day 17 in rats, and the amygdala-dependent system continues to mature. Using contextual and cued fear conditioning protocols, the current project examines the emergence of amygdala and hippocampus functionality and interactions by testing the novel hypothesis that it is slow-developing amygdala- hippocampus interactions that are responsible for the developmental delay. To test this hypothesis, the effects of behavioral manipulations, immediate-early gene expression, and temporary pharmacological inactivation will be examined on various aspects fear conditioning. Overall this project will elucidate the neural structures governing the use of physical environments to regulate aversive emotional expression in developing rats. PUBLIC HEALTH RELEVANCE: This project investigates the development of limbic system function. The focus is to create and examine a paradigm that can be used to assess the connectivity between major limbic system structures including the hippocampus and amygdala. Although relatively little is known about how they functionally interact in intact developing organisms, the connectivity between these structures appears to be altered in several developmental disorders including major psychoses, autism and anxiety disorders. Thus, in addition to advancing our understanding of typical development, these experiments will open the door for future studies that further elucidate the mechanisms underlying these disorders. Therefore, this project will provide data leading to a better understanding of limbic system development and the creation of better animal models of developmental disorders.
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2017 |
Burman, Michael A |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Neonatal Trauma Alters Subsequent Fear and Sensory Function Via Changes in Limbic Crf and Cort @ University of New England
There is now agreement that early life pain and stress are risk factors for subsequent changes in emotional, mood and sensory systems. Nevertheless, painful events continue to occur in the context of neonatal intensive care units (NICU) and other preventable settings. Similarly, a variety of less controllable stressful situations, such as suboptimal parenting conditions, also contribute to subsequent dysfunction. However, the mechanisms by which neonatal adversity leads to later anxiety, depression and sensory hypersensitivity remain unclear. As the consequences of early life trauma tend to emerge during late childhood or early adolescence, in order to design novel treatments and successful interventions, it is critical to examine the effects of neonatal events on behavioral and brain function at various times during development. In order to better understand how early life pain and stress can affect later brain function and behavior, this proposal uses a ?double-hit? model of trauma to test the hypothesis that neonatal trauma alters the developmental trajectory of the amygdala, and subsequently hypothalamic-adrenal-pituitary axis function, including the role of corticotrophin releasing factor (CRF) and corticosterone (CORT). In particular, we believe that neonatal trauma alters CRF signaling in the amygdala and perhaps hypothalamus. When exposed to an ?activating trauma? later in life, the anxiogenic or depressive phenotype is expressed. Furthermore, alterations to the amygdala will alter the descending pain system leading to tactile hypersensitivity and a predisposition towards pain. In the current experiments, neonatal rats will be exposed to invasive heel pricks, inflammatory injury or non-noxious handling over the first week of life. Fear conditioning and somatosensory function will then be assessed at multiple ages including early childhood, adolescence and adulthood. Once the behavioral effects are established, we will examine the role of amygdalar and hypothalamic CRF and CORT in these effects. This will be accomplished by measuring CRF and CORT expression, as well as receptor distribution. This will be followed by experiments that disrupt these signals using local and systemic pharmacology. We anticipate that neonatal pain will lead to alterations in subsequent fear conditioning and sensory function. Moreover, changes in CRF/CORT levels and receptor distribution in the amygdala will account for the observed behavioral changes. Although previous work has demonstrated that early life adversity can affect subsequent HPA axis function, the link between those changes and subsequent behavioral alterations that may lead to behavioral dysfunction is not well established. Overall, these experiments will examine the consequences of early-life trauma and offer insight into potential interventions protecting human well being.
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2017 — 2021 |
Burman, Michael A |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Painful Neonatal Trauma Alters Subsequent Fear and Sensory Function Via Changes in Amygdalar Crf Function @ University of New England
Neonatal injury and trauma, such as occurs in the neonatal intensive care unit (NICU), induces life-long changes in cognitive, sensory and affective function. Although the mechanisms are as-of-yet unknown, we believe that developmental alteration of the Amygdalar CRF is likely to be a common contributing mechanism. Anatomically, CRF+ positive cells in the Central Nucleus of the Amygdala project to the ventrolateral Periaqueductal Grey and the Lateral Hypothalamus, regions involved in a variety of nocifensive behaviors. In addition, Amygdalar CRF has been shown to be critical for the acquisition or expression of both fear and pain, and the amygdala CRF system appears to be particularly sensitive to neonatal trauma. To investigate this, our lab has recently adapted a ?two-hit? paradigm to produce a trauma phenotype. First, modeled after practices in the NICU, neonatal rat pups are exposed to multiple paw punctures daily for the first week of life. Second, at one of four developmental stages (infancy, weaning, adolescence or adulthood) rats are exposed to a traumatic fear conditioning procedure. Our preliminary data show two sets of behavioral changes, which appear to differ in developmental timecourse. First, weanling rats exposed to both neonatal trauma and fear conditioning show a tactile hypersensitivity following fear conditioning, that cannot be explained solely by age, neonatal trauma or fear conditioning alone. Second, a sizeable subpopulation (~25-33%) of neonatal pain subjects show impaired freezing following fear conditioning later in life. This effect is present following weaning and strengthens as a function of age. The current proposal further examines these effects over 3 specific aims. In aim 1, we further examine the behavioral heterogeneity in response to neonatal pain by examining additional painful stimuli (inflammatory paw injections), additional activating stressors (restraint) and additional behavioral outcomes (non-conditioned anxiety tests; non-reflexive pain behaviors). In aim 2, we examine whether changes in amygdalar CRF can explain the observed behavioral changes. For example, CRF expression levels following both neonatal and activating stress will be observed using PCR and unbiased stereology. Newly created CRF-Cre rats crossed with a TD-tomato reporter line will be used to examine changes in circuit anatomy, with additional labeling of FOS used to examine changes in CRF+ cell activation. Tract tracing tools will be used to determine whether distinct projections of this system are differentially affected. In aim 3, we manipulate the Amygdalar CRF system in an attempt to reverse the neonatal trauma- induced phenotype. Systemic and local injections of CRF antagonists and agonists will be used during both the neonatal and activating stress in order to reverse the hypersensitive and affective phenotypes. In addition, chemogenetic approaches can be used with CRF-Cre rats to disrupt or enhance CRF projections to specific targets. Together, these experiments will definitely test the hypothesis that neonatal trauma affects subsequent behavior via alternations in CRF signaling in the Amygdala.
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