Cognitive deficits, particularly memory impairments, are the most common persistent disability after TBI, resulting from disruptions in the striatum, limbic system, and frontal cortex. Experimental and clinical evidence from our group and others implicates altered dopamine (DA) systems in contributing such deficits. Furthermore, in experimental models and in Phase I human studies, DA-enhancing agents can attenuate functional deficits. However, little is known about the cellular signaling mechanisms underlying DA-mediated deficits and the mechanisms by which DA-enhancing agents confer their beneficial effects after TBI. The striatum is a location of significant DA signaling. Long considered a modulator of motor function, the striatum more recently was found to be vital to learning and memory function through connections with the limbic system and cortex. Disturbances in DA signaling in the striatum have not been investigated in any experimental model of TBI. The DA- and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein, Mr 32 kDA (DARPP-32), is a key convergence point in striatal medium spiny neurons for the activity of multiple neurotransmitter systems, including DA. The convergent properties of DARPP-32 are related to the two distinct phosphorylation sites, threonine 34 (Thr34) and threonine 75 (Thr75), which act antagonistically to regulate intracellular signaling molecules. In particular, DARPP-32 phosphorylation at Thr34 is an important mediator of the cAMP-extracellular regulated kinase (ERK1/2) pathway, acting as an inhibitor of protein phosphatase 1 (PP1). This project represents the first examination of the DARPP-32 signaling pathway as a mechanism for TBI-induced functional deficits. Our study will test the hypothesis that TBI causes dysfunction of DARPP-32 phosphorylation in striato-cortical neurons, which may contribute to alterations in ERK1/2 cascades and working-memory deficits. We will measure the effects of TBI on this important intracellular signaling convergence point. In the revised project, we will first examine the effects of TBI on DARRP-32 and key downstream effectors. Second, we propose to determine if increasing phosphorylation of DARPP-32 at the Thr34 phosphorylation site can attenuate TBI-induced changes in the same key downstream signaling changes, and functional deficits. Third, we will evaluate the role of DARPP-32 in mediating the positive effects of a clinically relevant DA enhancer that is frequently given during rehabilitation. Lastly, to better determine causal relationships between DARPP-32 changes, treatments, and subsequent outcome variables, we propose complementary experiments that utilize a DARPP-32 knockout (KO) model. The results of these studies will clarify striato-cortical function after TBI and provide initial preclinical evidence to support clinical studies targeting downstream biochemical pathways associated with DA agonist therapies for TBI.
In the United States traumatic brain injury (TBI) accounts for over one third of all injury related deaths. In survivors, TBI results in the persistent disturbance of cognitive functioning. This project seeks to examine key neurochemical mechanisms underlying cognitive deficits and to evaluate novel therapies to maximize recovery of function.
|Carlson, Shaun W; Yan, Hong; Dixon, C Edward (2017) Lithium increases hippocampal SNARE protein abundance after traumatic brain injury. Exp Neurol 289:55-63|
|Bondi, Corina O; Semple, Bridgette D; Noble-Haeusslein, Linda J et al. (2015) Found in translation: Understanding the biology and behavior of experimental traumatic brain injury. Neurosci Biobehav Rev 58:123-46|
|Yan, Hong Q; Shin, Samuel S; Ma, Xiecheng et al. (2014) Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus. Brain Res 1548:63-72|
|Shin, Samuel S; Bales, James W; Yan, Hong Q et al. (2013) The effect of environmental enrichment on substantia nigra gene expression after traumatic brain injury in rats. J Neurotrauma 30:259-70|
|Shin, Samuel S; Bray, Eric R; Dixon, C Edward (2012) Effects of nicotine administration on striatal dopamine signaling after traumatic brain injury in rats. J Neurotrauma 29:843-50|
|Shin, Samuel S; Bray, Eric R; Zhang, Cathy Q et al. (2011) Traumatic brain injury reduces striatal tyrosine hydroxylase activity and potassium-evoked dopamine release in rats. Brain Res 1369:208-15|
|Shin, Samuel S; Dixon, C Edward (2011) Oral fish oil restores striatal dopamine release after traumatic brain injury. Neurosci Lett 496:168-71|
|Bales, James W; Yan, Hong Q; Ma, Xiecheng et al. (2011) The dopamine and cAMP regulated phosphoprotein, 32 kDa (DARPP-32) signaling pathway: a novel therapeutic target in traumatic brain injury. Exp Neurol 229:300-7|
|Bales, James W; Ma, Xiecheng; Yan, Hong Q et al. (2010) Expression of protein phosphatase 2B (calcineurin) subunit A isoforms in rat hippocampus after traumatic brain injury. J Neurotrauma 27:109-20|
|Bales, James W; Ma, Xiecheng; Yan, Hong Q et al. (2010) Regional calcineurin subunit B isoform expression in rat hippocampus following a traumatic brain injury. Brain Res 1358:211-20|
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