This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ability of an organism to adapt to changes in its environment to maintain homeostasis is critical for survival. A threat to this homeostasis results in stress and successful adaptation to counter the effects of stress confers a survival advantage. The stress response is mediated, in part, by the hypothalamic-pituitary-adrenal (HPA) axis. Stimulation of the HPA axis by a stressful event results in the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids affect a variety of tissues to enable the organism to adapt to the stress. Hippocampal neurons contain glucocorticoid receptors and respond to elevated glucocorticoid levels by downregulating the HPA axis. Chronically stress, however, is deleterious to hippocampal neurons. Chronically elevated levels of glucocorticoids result in a decrease in the number of dendritic spines, reduced axonal growth and synaptogenesis and decreased neurogenesis in the hippocampus. These changes may be the basis for diseases and disorders attributed to chronic stress, such as Post Traumatic Stress Disorder, Borderline Personality Disorder and Schizophrenia. Mammalian Tolloid-like 1 (mTll-1) is a metalloprotease that potentiates the activity of the Bone Morphogenetic Proteins (BMPs). BMPs are required for neurogenesis in the hippocampus of both developing and adult mammals. In the promoter of mTll-1 there are 2 putative glucocorticoid response element indicating that mTll-1 may be regulated by glucocorticoids. mTll-1 is expressed by a small subset of cells that increase in animals with enhanced neurogenesis. This proposal seeks to determine if mTll-1 expression is responsive to the levels of circulating glucocorticoids.
The first aim will be to determine the cell type that expresses mTll-1. Secondly, does stressful stimuli result in changes in mTll-1 mRNA expression. Third, does the administration of exogenous glucocorticoids (corticosterone) result in changes in mTll-1 mRNA expression in a fashion similar to that of stressful stimuli. Finally, does the ablation of mTll-1 gene expression change the rate of neurogenesis within the dentate gyrus of the hippocampus? The results of these studies will provide a possible mechanism for the effect of chronic stress and elevated glucocorticoid levels on hippocampal function.
|Burrell, Brian D (2017) Comparative biology of pain: What invertebrates can tell us about how nociception works. J Neurophysiol 117:1461-1473|
|Robertson, James M; Achua, Justin K; Smith, Justin P et al. (2017) Anxious behavior induces elevated hippocampal Cb2 receptor gene expression. Neuroscience 352:273-284|
|Novick, Andrew M; Mears, Mackenzie; Forster, Gina L et al. (2016) Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood. Behav Brain Res 304:51-9|
|Smith, Justin P; Prince, Melissa A; Achua, Justin K et al. (2016) Intensity of anxiety is modified via complex integrative stress circuitries. Psychoneuroendocrinology 63:351-61|
|Robertson, James M; Prince, Melissa A; Achua, Justin K et al. (2015) Nuance and behavioral cogency: How the Visible Burrow System inspired the Stress-Alternatives Model and conceptualization of the continuum of anxiety. Physiol Behav 146:86-97|
|Ranek, Mark J; Zheng, Hanqiao; Huang, Wei et al. (2015) Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload. J Mol Cell Cardiol 85:273-81|
|Hahn, Elizabeth; Burrell, Brian (2015) Pentylenetetrazol-induced seizure-like behavior and neural hyperactivity in the medicinal leech. Invert Neurosci 15:177|
|Novick, Andrew M; Forster, Gina L; Hassell, James E et al. (2015) Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress. Neuropharmacology 97:194-200|
|Ranek, Mark J; Kost Jr, Curtis K; Hu, Chengjun et al. (2014) Muscarinic 2 receptors modulate cardiac proteasome function in a protein kinase G-dependent manner. J Mol Cell Cardiol 69:43-51|
|Watt, Michael J; Roberts, Christina L; Scholl, Jamie L et al. (2014) Decreased prefrontal cortex dopamine activity following adolescent social defeat in male rats: role of dopamine D2 receptors. Psychopharmacology (Berl) 231:1627-36|
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