Grace Griesbach - US grants

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is one of the leading causes of disability in our society. Unfortunately, there is no specific treatment for TBI. Brain derived neurotrohic factor (BDNF) is a key player in neuronal survival, growth and plasticity. These qualities provide it with therapeutic capabilities. However, BDNF-based treatments have been limited by delivery problems. I propose to endogenously upregulate BDNF and associated molecular systems with exercise following TBI. The concept of endogenously upregulating molecules important in synaptic plasticity after TBI is an uncharted area of research that could have an impact on rehabilitative startegies. However, during the first days to weeks following TBI, the brain is in a state of energy crisis that may compromise the reactivity of molecular systems to physiological stimulation as a result of exercise. I would like to determine to what degree BDNF and associated molecular systems respond to TBI and subsequent voluntary exercise. In order to address this topic the following specific aims are proposed to: Specific Aim 1: Determine if injury-induced changes in BDNF and associated proteins involved with synaptic plasticity are time and severity dependent. Within this aim I will determine the effects of a lateral fluid percussion injury (FPI) on hipppocampal and cortical BDNF (and associated molecules) at postinjury times that are pertinent to the recovery and rehabilitative period. Specific Aim 2: Determine the post-traumatic time window in which exercise can produce an endogenous up-regulation of BDNF (and its associated molecular systems). Within this aim I will determine the period of time following injury when voluntary exercise does not result in an up-regulation of BDNF and determine if this time window is injury-severity dependent. Specific Aim 3: Determine the short and long-term effects of exercise on cognitive outcome and determine if any exercise-induced improvement is dependent on BDNF. The Morris Water Maze (MWM) will be used to assess learning acquisition and memory performance. In order to address these specific aims, I will utilize the lateral fluid-percussion injury model in rats and voluntary running wheel exposure. Protein, gene, histological and behavioral studies will be conducted.

[unreadable] DESCRIPTION (provided by applicant): Physical therapy is widely used during traumatic brain injury (TBI) rehabilitation. However most of the knowledge concerning the effects of exercise on recovery from TBI has been based on observation, and scientifically based research regarding the effects of exercise on recovery from TBI is scant. Previous studies have indicated that voluntary exercise promotes recovery from concussive brain injury. In particular, post-TBI voluntary exercise increases levels of brain derived neurotrophic factor (BDNF) and other key molecules involved in neuroplasticity. However, when exercise is provided acutely after injury there is no increase in BDNF and behavioral outcome worsens. This proposal will continue this line of research by testing the hypothesis that early post-traumatic stress response-induced elevation in glucocorticoids blunts the effects of exercise-induced BDNF upregulation. The effects of stress on BDNF will be investigated in rats through utilizing different exercise regimens during the first week (acute) and later-weeks after TBI. Because sustained stress is likely to decrease BDNF and downstream molecules, some forms of exercise may encumber recovery of function after TBI. The first experiments within this proposal will determine if injury induced alterations in levels of corticosterone (CORT) play a key role in the disruption of BDNF mediated neuroplasticity during different post-TBI time periods. CORT is the main circulating glucocorticoid in rats. These experiments will provide the framework to determine if some exercise regimens can prolong or foment injury-induced disruptions in glucocorticoids. The effects of non-self-regulated (forced) and self-regulated (voluntary) exercise will be compared during the acute and later-weeks after TBI. These forms of exercise are likely to produce different stress responses that will consequentially influence BDNF upregulation and ultimately have an effect on recovery or outcome. Forced exercise is more intensive in that it is administered in relatively short sessions, making it more akin to current physical therapy. In contrast voluntary exercise is spaced throughout the active period of the day. Finally this proposal will determine if stress alleviation through the use of antidepressant treatment can reverse stress-induced changes in BDNF. A substantial number of TBI patients are diagnosed and treated for disorders that are associated with glucocorticoid disregulation, such as depression and post- traumatic stress disorder (PTSD). Antidepressants, which are widely administered in the rehabilitative period, are associated with upregulating BDNF and decreasing levels of glucocorticoids. The effects of a selective norepinephrine and serootonergic uptake inhibitors will be studied. It is expected that antidepressant treatment will decrease levels of CORT and enhance exercise-dependent BDNF increases. Ultimately these studies will aid in developing adequate exercise regimens that endogenously increase levels of BDNF and associated molecules at a time that is pertinent to the rehabilitative time-period. PUBLIC HEALTH RELEVANCE: Those affected with brain injury endure long-lasting impairments that have a strong impact on life quality. We will investigate the effects of different post-injury exercise regimens on recovery and how these can be influenced by stress. This proposal will provide mechanistically based information that will aid in developing an optimal exercise regimen after TBI. [unreadable] [unreadable] [unreadable]