A reliable consequence of survivable brain damage is that animals, including humans, learn compensatory behavioral strategies for resuming daily activities in the presence of lost function. An obvious example of this can be found in clinical stroke populations with upper extremity impairments in their reliance on the less- affected (nonparetic) hand and arm. The focus of this project across periods has been on the interactions between such compensatory behavioral changes and injury-induced degenerative and regenerative responses. This is investigated in a rat model of chronic upper extremity impairments and compensatory skill learning after focal ischemic damage to motor cortex. We've previously found that, as a result of its interaction with ischemia-triggered regenerative responses, learning to rely on the nonparetic forelimb promotes a major neuronal growth response in the contralesional motor cortex, a response that has no known benefit for the paretic forelimb, but facilitates compensatory skill learning with the nonparetic limb. In the most recent project period, we discovered that the same skill learning that promotes this contralesional growth response also exacerbates dysfunction in the paretic hand, and blocks the cortical structural and functional reorganization in the injured hemisphere that can mediate its functional improvements. The implication is that, simply by adopting perfectly reasonable strategies for resuming everyday activities, some stroke survivors could inadvertently squelch the paretic hand's potential for functionality. The goal for the proposed studies is to understand the mechanisms of this disruption of the functional potential of the paretic limb. We see in the pattern of our results reflections of "experience-expectant" plasticity, a brain developmental process that relies on experiences to sculpt circuitry patterns using mechanisms of activity-dependent synaptic competition. The purpose of this project is to determine whether the maladaptive effects of learning to rely on the nonparetic forelimb are due to its ability to outcompete with the paretic limb in driving the direction of post-ischemic reorganizational patterns. We will use a hypothesis-driven approach in combination with behavioral- and cortical-level manipulations to test for experience- and activity-dependent competition in circuitry remodeling of the converging projections of the ipsi and contralesional hemispheres to regions denervated by the injury.
The specific aims are to test the hypotheses that skill learning and "re-learning" with the nonparetic and paretic forelimbs drive different reorganizational patterns within peri-infarct MC (Aim 1) and of corticofugal projections (Aim2), that the nonparetic limb's disarray of peri-infarct reorganization can be overcome by balancing motor cortical (Aim 3) and behavioral activity (Aim 4) and that these effects depend on the specific territory of the injuries (Aim 5). These studies are significant for advancing our basic understanding of the mechanisms of brain reorganization after stroke and, ultimately, for informing therapeutic decision on when to promote or discourage behavioral compensation.

Public Health Relevance

Stroke is the leading cause of serious long-term disability in the US. It frequently results in major deficits in upper extremity function, which can be exacerbated by the overreliance on the other hand and arm. This project will advance the understanding of the influence of behavioral experience on promoting both functionally beneficial and functionally detrimental brain plasticity. This is significant for optimizing and tailoring post-stroke behavioral therapies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS056839-13
Application #
8690174
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Bell, Jared A; Wolke, Malerie L; Ortez, Ryan C et al. (2015) Training Intensity Affects Motor Rehabilitation Efficacy Following Unilateral Ischemic Insult of the Sensorimotor Cortex in C57BL/6 Mice. Neurorehabil Neural Repair 29:590-8
Tennant, Kelly A; Kerr, Abigail L; Adkins, DeAnna L et al. (2015) Age-dependent reorganization of peri-infarct "premotor" cortex with task-specific rehabilitative training in mice. Neurorehabil Neural Repair 29:193-202
O'Bryant, Amber J; Adkins, DeAnna L; Sitko, Austen A et al. (2014) Enduring Poststroke Motor Functional Improvements by a Well-Timed Combination of Motor Rehabilitative Training and Cortical Stimulation in Rats. Neurorehabil Neural Repair :
Carrillo, Jennifer; Cheng, Shao-Ying; Ko, Kwang Woo et al. (2013) The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning. J Neurosci 33:8301-7
Kerr, Abigail L; Wolke, Malerie L; Bell, Jared A et al. (2013) Post-stroke protection from maladaptive effects of learning with the non-paretic forelimb by bimanual home cage experience in C57BL/6 mice. Behav Brain Res 252:180-7
Jones, Theresa A; Allred, Rachel P; Jefferson, Stephanie C et al. (2013) Motor system plasticity in stroke models: intrinsically use-dependent, unreliably useful. Stroke 44:S104-6
Kim, Soo Young; Jones, Theresa A (2013) The effects of ceftriaxone on skill learning and motor functional outcome after ischemic cortical damage in rats. Restor Neurol Neurosci 31:87-97
O'Bryant, Amber J; Allred, Rachel P; Maldonado, Monica A et al. (2011) Breeder and batch-dependent variability in the acquisition and performance of a motor skill in adult Long-Evans rats. Behav Brain Res 224:112-20
Jones, Theresa A; Jefferson, Stephanie C (2011) Reflections of experience-expectant development in repair of the adult damaged brain. Dev Psychobiol 53:466-75
Kerr, Abigail L; Cheng, Shao-Ying; Jones, Theresa A (2011) Experience-dependent neural plasticity in the adult damaged brain. J Commun Disord 44:538-48

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