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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    054—Ischemia: Recovery

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    54.09: Activity-dependent mechanisms of circuit reorganization during limb-overuse after stroke

    Location: Halls B-H

    ">*E. H. NIE1, S. T. CARMICHAEL2;
    1UCLA, Los Angeles, CA; 2Neurol., UCLA Sch. of Med., Los Angeles, CA

    Abstract Body: Stroke is the most prevalent cause of adult disability in the United States, and has no current medical treatment. Recently published work in the lab has identified a molecular growth program that is triggered in the peri-infarct cortex after stroke, a process that promotes axonal sprouting in the surviving brain. Current studies in this project indicate that new connections may form by axonal sprouting after stroke in an activity-dependent manner. This finding is especially germane in light of the 2006 EXCITE clinical trial, which found that stroke patients who engage in constraint-induced movement therapy, a behavioral paradigm for focused limb overuse, demonstrate significant and lasting motor improvements. The goal of this project is to identify activity-dependent mechanisms of circuit reorganization in a mouse model of cortical stroke. We have additionally developed a novel limb-overuse paradigm that is analogous to human constraint-induced movement therapy. Using this model, we hypothesize that a specific ensemble of genes drives circuit rewiring during post-stroke limb overuse, a clinically relevant rehabilitative therapy that converges injury and activity-dependent molecular processes.
    In current cortical circuit mapping studies, the specific brain circuits that rewire during post-stroke limb overuse are quantitatively mapped using fluorescent neuronal tracers. Preliminary data suggest that recovery from forelimb motor stroke involves the formation of new circuits between the premotor areas and cortical areas located posterior and medial to the caudal forelimb region, including trunk motor areas and retrosplenial cortex (RSC). Spinal C5 and T10 retrograde tracing of cortical layer V motor neurons indicate this unique activity-induced connectivity is distinct from forelimb and hindlimb motor areas (n=7 for each hindlimb and forelimb studies). The cells that comprise these circuits are labeled with neuronal tracer and have been isolated by FACS (Fluorescence-Activated Cell Sorting) for deep sequencing of the RNA to generate the activity-dependent transcriptome of this repair circuit. Current FACS and RNA isolation have yielded high quality RNA (RNA Integrity Number = 7) for cDNA library construction. In ongoing parallel studies, a small number of candidate gene systems that are known to be induced by stroke and regulated by activity, are being screened for enhanced axonal sprouting using an in-vitro neuronal sprouting assay. Selected candidates that increase neuronal sprouting will advance to in-vivo genetic manipulation within the specific premotor circuits mapped upon post-stroke limb-overuse.

    Lay Language Summary: Our latest research findings show that arm-overuse rehabilitation after stroke causes a “plastic” area of the brain to form a unique neural circuit to the premotor cortex, an area of the brain that facilitates motor function. This finding is the first to illuminate how increasing the activity of a stroke-affected limb can direct the brain to rewire its motor circuitry after a stroke.
    One of the most common functional losses after stroke is voluntary movement of the arm or leg, a condition that renders many patients dependent on others for daily care. Studies in our lab and others have demonstrated that surviving parts of the adult brain are indeed capable of significant restructuring and repair. Furthermore, clinical trials have also shown that preferential overuse of the stroke-affected arm through constraint of the unaffected arm results in significant and lasting improvements in limb function.1 Such a rehabilitation approach is termed “constraint-induced movement therapy.”
    This current project, conducted in Dr. S. Thomas Carmichael’s lab at UCLA, aims to specifically identify how this clinically relevant therapy may help shape the surviving brain to rewire and regain lost function, and which biological molecules are activated and control this critical aspect of brain repair. These studies are conducted using novel methods to identify the new connections in the brain stimulated by overuse of the stroke-affected limb, and then to characterize the genetic systems that induce these new connections to form.
    Using anatomical brain mapping studies in a mouse model of stroke, we have identified that overuse of the stroke-affected limb elicits new patterns of brain connections when compared to stroke with no limb overuse. These new connections establish a significant new link between brain areas that is not seen in the normal brain, or in the post-stroke brain that has not received this training: from the retrosplenial cortex to the premotor cortex. The retrosplenial cortex is a relatively understudied area of the brain, but typically thought to be involved in spatial navigation and memory. Our latest studies suggest that retrosplenial cortex may also be a highly plastic area engaged in brain reorganization after stroke, and that it is uniquely pulled into a new connectivity pattern by clinically relevant neurorehabilitative activity. Our opening data show that activity-based rehabilitation after stroke can enhance specific brain connections to areas previously shown to be functionally involved in motor recovery after stroke. Via cutting-edge technology, we have fluorescently labeled and isolated these retrosplenial “recovery circuits” and are now using high-throughput sequencing methods to genetically profile their relevant biological pathways to identify targets to enhance recovery.
    Stroke afflicts more than 800,000 Americans per year, and leaves the majority of these patients with lifelong limb paralysis, speech deficits, and cognitive disabilities.2 Currently, the only available drug treatment for stroke is limited to the minority of patients who are seen in the emergency room in less than 4.5 hours after the stroke occurs. We hope to develop therapies to help rehabilitate stroke survivors in the weeks to months after the initial event. Ultimately, the results of this project will identify the molecules and pathways in the brain that underlie how constraint-induced therapy can shape brain connectivity after stroke, and further point toward pharmacological targets to reduce the public health burden of this disease.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    054—Ischemia: Recovery

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    54.09: Activity-dependent mechanisms of circuit reorganization during limb-overuse after stroke

    Location: Halls B-H

    ">*E. H. NIE1, S. T. CARMICHAEL2;
    1UCLA, Los Angeles, CA; 2Neurol., UCLA Sch. of Med., Los Angeles, CA

    Abstract Body: Stroke is the most prevalent cause of adult disability in the United States, and has no current medical treatment. Recently published work in the lab has identified a molecular growth program that is triggered in the peri-infarct cortex after stroke, a process that promotes axonal sprouting in the surviving brain. Current studies in this project indicate that new connections may form by axonal sprouting after stroke in an activity-dependent manner. This finding is especially germane in light of the 2006 EXCITE clinical trial, which found that stroke patients who engage in constraint-induced movement therapy, a behavioral paradigm for focused limb overuse, demonstrate significant and lasting motor improvements. The goal of this project is to identify activity-dependent mechanisms of circuit reorganization in a mouse model of cortical stroke. We have additionally developed a novel limb-overuse paradigm that is analogous to human constraint-induced movement therapy. Using this model, we hypothesize that a specific ensemble of genes drives circuit rewiring during post-stroke limb overuse, a clinically relevant rehabilitative therapy that converges injury and activity-dependent molecular processes.
    In current cortical circuit mapping studies, the specific brain circuits that rewire during post-stroke limb overuse are quantitatively mapped using fluorescent neuronal tracers. Preliminary data suggest that recovery from forelimb motor stroke involves the formation of new circuits between the premotor areas and cortical areas located posterior and medial to the caudal forelimb region, including trunk motor areas and retrosplenial cortex (RSC). Spinal C5 and T10 retrograde tracing of cortical layer V motor neurons indicate this unique activity-induced connectivity is distinct from forelimb and hindlimb motor areas (n=7 for each hindlimb and forelimb studies). The cells that comprise these circuits are labeled with neuronal tracer and have been isolated by FACS (Fluorescence-Activated Cell Sorting) for deep sequencing of the RNA to generate the activity-dependent transcriptome of this repair circuit. Current FACS and RNA isolation have yielded high quality RNA (RNA Integrity Number = 7) for cDNA library construction. In ongoing parallel studies, a small number of candidate gene systems that are known to be induced by stroke and regulated by activity, are being screened for enhanced axonal sprouting using an in-vitro neuronal sprouting assay. Selected candidates that increase neuronal sprouting will advance to in-vivo genetic manipulation within the specific premotor circuits mapped upon post-stroke limb-overuse.

    Lay Language Summary: Our latest research findings show that arm-overuse rehabilitation after stroke causes a “plastic” area of the brain to form a unique neural circuit to the premotor cortex, an area of the brain that facilitates motor function. This finding is the first to illuminate how increasing the activity of a stroke-affected limb can direct the brain to rewire its motor circuitry after a stroke.
    One of the most common functional losses after stroke is voluntary movement of the arm or leg, a condition that renders many patients dependent on others for daily care. Studies in our lab and others have demonstrated that surviving parts of the adult brain are indeed capable of significant restructuring and repair. Furthermore, clinical trials have also shown that preferential overuse of the stroke-affected arm through constraint of the unaffected arm results in significant and lasting improvements in limb function.1 Such a rehabilitation approach is termed “constraint-induced movement therapy.”
    This current project, conducted in Dr. S. Thomas Carmichael’s lab at UCLA, aims to specifically identify how this clinically relevant therapy may help shape the surviving brain to rewire and regain lost function, and which biological molecules are activated and control this critical aspect of brain repair. These studies are conducted using novel methods to identify the new connections in the brain stimulated by overuse of the stroke-affected limb, and then to characterize the genetic systems that induce these new connections to form.
    Using anatomical brain mapping studies in a mouse model of stroke, we have identified that overuse of the stroke-affected limb elicits new patterns of brain connections when compared to stroke with no limb overuse. These new connections establish a significant new link between brain areas that is not seen in the normal brain, or in the post-stroke brain that has not received this training: from the retrosplenial cortex to the premotor cortex. The retrosplenial cortex is a relatively understudied area of the brain, but typically thought to be involved in spatial navigation and memory. Our latest studies suggest that retrosplenial cortex may also be a highly plastic area engaged in brain reorganization after stroke, and that it is uniquely pulled into a new connectivity pattern by clinically relevant neurorehabilitative activity. Our opening data show that activity-based rehabilitation after stroke can enhance specific brain connections to areas previously shown to be functionally involved in motor recovery after stroke. Via cutting-edge technology, we have fluorescently labeled and isolated these retrosplenial “recovery circuits” and are now using high-throughput sequencing methods to genetically profile their relevant biological pathways to identify targets to enhance recovery.
    Stroke afflicts more than 800,000 Americans per year, and leaves the majority of these patients with lifelong limb paralysis, speech deficits, and cognitive disabilities.2 Currently, the only available drug treatment for stroke is limited to the minority of patients who are seen in the emergency room in less than 4.5 hours after the stroke occurs. We hope to develop therapies to help rehabilitate stroke survivors in the weeks to months after the initial event. Ultimately, the results of this project will identify the molecules and pathways in the brain that underlie how constraint-induced therapy can shape brain connectivity after stroke, and further point toward pharmacological targets to reduce the public health burden of this disease.