Theresa Jones - US grants

Research in the last three decades has made enormous progress in demonstrating and elucidating plasticity in the central nervous system of ~adult animals~. Two important types of proof of this plasticity arise from studies of damage to the brain and from studies using manipulations of behavioral experience. Studies of the effects of brain damage have shown that regions connected to the site of damage undergo reactive neuronal growth and reorganization. Studies manipulating behavioral experience have shown that regions involved in those behaviors also undergo neuronal changes. The emphasis of the present proposal is that these two types of plasticity may be interactive following brain damage. It is obvious that brain damage can produce behavioral changes. Based on abundant evidence that changes in behavioral experience can lead to central neuronal structural changes, it seems reasonable that these behavioral changes may influence and interact with plastic neuronal responses that occur after brain damage. Recent research has revealed a novel examples of neural plasticity following brain damage which seems o be mediated by behavioral changes. Unilateral lesions to the forelimb representation area of the sensorimotor cortex (Flsmc) in adult rats leads to impairments in the use of the forelimb contrlateral to the damage. Animals appear to compensate for these impairments, in part, by developing an over-reliance on the forelimb ipsilateral to the damage (the non-impaired forelimb). Examination of neurons and synapses within the forelimb motor cortex opposite the damage and the non-impaired forelimb revealed a marked dendritic growth and synaptogenesis. This neural plasticity appears to be mediated by the post lesion changes in the use of forelimbs and to be facilitated by the presence of a lesion in the opposite cortex. The processes underlying this behaviorally mediated neural plasticity are not understood and are potentially very important for ongoing attempts to understand brain adaptation to brain injury and to identify processes which can be manipulated to facilitate functional recovery. The proposed studies will (1) characterize structural (neuronal and glial) and connectional plasticity of the motor cortex and cerebellum following unilateral Flsmc lesions using quantitative electron microscopy, immunocytochemistry and anatomical tract tracing methods (2) relate these changes to behavioral changes using sensitive behavioral measures and behavioral manipulations, and (3) manipulate, and perhaps facilitate, adaptive neuronal and behavioral changes using complex motor skills training as "therapy" after the lesions. These studies may be of relevance to post-injury rehabilitation and neurolgical disorders in humans.

DESCRIPTION (provided by applicant): After unilateral cerebral damage, a major contributor to overall functional outcome is the development of compensatory behavioral changes involving the ipsilesional, less-affected, body side. While it is often assumed that behavioral compensation is merely an example of learning, this learning may be among the most significant behavioral changes of an animal's adult life and must be accomplished in the presence of major lesion-induced brain changes. Understanding the neural basis for this behavioral change and how it interacts with lesion-induced degenerative events was the focus of the last project period. We determined that skill acquisition in the ipsilesional forelimb in rats is enhanced by unilateral damage to the sensorimotor cortex (SMC), at least in part as a result of a denervation-induced enhancement of learning-induced neuronal structural changes in the motor cortex contralateral to the lesion. We have also recently discovered that behavioral experiences with the less affected forelimb can worsen performance in the impaired forelimb in a manner that cannot be duplicated in intact animals. The focus of the present project is the nature and neural basis of this experience-dependent worsening of function of the impaired limb after unilateral ischemic SMC lesions in adult rats. The central hypothesis of the proposal is that excessive behavioral experience with the less- affected forelimb suppresses neuroplastic processes in remaining regions of infarcted cortex that could otherwise be used to mediate recovery of function in the impaired forelimb. This will be tested using a combination of sensitive behavioral measures and manipulations and rigorous assays of neuronal structural changes and plasticity of movement representations in the peri-infarct cortex. The aims are to test: (1) the contribution of asymmetry and modality of behavioral experience with the less-affected forelimb on function of the impaired limb, (2) the hypothesis that experiences with the less affected forelimb suppress the ability to drive functionally relevant neuronal plasticity in peri-lesion cortex, (3) the dependency of these effects on activity of the contralesional cortex and transcallosal connections, (4) the post-lesion time- dependency of behavioral experiences with the less-affected forelimb and (5) the possibility that these effects can be overcome by a period of early rehabilitative training focused on the impaired limb. The translational relevance of these studies is that asymmetries in behavioral function and interhemispheric interactions are a prominent result of unilateral brain damage. Understanding how they contribute to functional recovery may guide rehabilitation efforts and interventions after unilateral cerebral stroke and other lateralized brain damage.

Social insects are among the most ecologically dominant terrestrial animals. Their success is largely attributed to division of labor among the workers that make up their colonies. Individual differences in worker behavior are governed by physiological and anatomical changes in the nervous system, particularly in the brain. However, the dynamic properties of brain neurons that influence worker behavior are poorly understood. The goal of this project is to study how changes in brain neurons are associated with division of labor among social insect workers, focusing on neural plasticity in the mushroom bodies (MB). MB are structures in insect forebrains that are involved in learning and sensory integration, and the MB may play an important role in regulating division of labor.
As a first step toward understanding the evolution of MB effects on behavior, the relationships of MB neuroanatomy and worker behavior will be compared between a wasp species with small, simple societies (Mischocyttarus mastigophorus) and a species with larger, more complex colonies (Polybia aequatorialis). Three main approaches will be used. In the first study, MB neurons that are associated with individual differences in task performance will be identified. In the second study the effects of age on MB neuron plasticity and worker behavior will be measured. In the third study, colonies will be manipulated to induce changes in worker behavior, and associated neural changes will be measured.
The proposed projects include graduate and undergraduate training opportunities, and will provide inter-institutional training experiences. They will also promote education for Americans and local residents in Costa Rica, including biology guides (Monteverde Cloud Forest Reserve), and students on graduate and undergraduate field courses. Ongoing investigations in Monteverde will enhance the visibility of basic investigation at this important tropical research and conservation site. The research findings may also have relevance to the control/management of social insect pests and beneficial insects.

stroke therapy; experience; neural plasticity; rehabilitation; human therapy evaluation; patient oriented research; human subject; medical rehabilitation related tag; behavioral /social science research tag; clinical research;

Motor rehabilitation capitalizes upon mechanisms of motor learning and it is now very well-established that motor learning induces major changes in neural connectivity and activity patterns in the brains of adult animals, including humans. This makes motor rehabilitation extremely well suited to promote the formation of functionally appropriate neural connectivity after motor cortical strokes, but it is likely to be most effective when used in combination with other treatment approaches. Converging evidence from the research teams of this program indicate that focal cortical electrical stimulation (CS) enhances the potency of rehabilitative training (RT). The type of RT used is likely to be a critical variable in the efficacy of CS/RT and, to date, only one type of RT has been examined. Project 2 will use a rat model of focal ischemic damage to the sensorimotor cortex to optimize the motor rehabilitation that is combined with epidural CS. The specific aims are to (1) assess the efficacy of combining the optimized CS/RT with a rodent version of constraint-induced movement therapy (2) determine the optimal motor rehabilitative training regime to combine with CS, and (3) determine whether enhanced performance produced by CS/RT is long-lasting after the cessation of the treatment.

DESCRIPTION (provided by applicant): Adaptive brain plasticity after stroke is critically dependent upon behavioral experience. Manipulations of experience, including rehabilitative training, are emerging as a core strategy for driving functionally appropriate brain reorganization after brain damage. However, learning-induced brain changes can be laborious to achieve, perhaps especially when the circuits being driven to reorganize are dysfunctional due to denervation and other injury-induced degenerative changes. There is much room for further improvement. This proposal focuses on a new direction in facilitating "re-learning" after stroke, that of combining rehabilitative training with electrical stimulation of remaining cortex of a stroke-affected hemisphere. In animal models of focal cortical infarcts, this approach improves and prolongs the functional benefits of a period of motor rehabilitative focused on the impaired upper extremity. However, we have practically no understanding of how and why this works. We propose a series of initial experiments to improve our understanding of the neural basis of the behavioral improvements resulting from combining motor cortical stimulation (CS) with motor training. The central hypothesis is that CS improves behavioral outcome by facilitating learning-induced neural plasticity in the motor cortex and connected regions. This will be investigated in rats with unilateral ischemic infarcts of the sensorimotor cortex and rehabilitative training in skilled reaching to improve forelimb function. There are three specific aims. Aim 1 is test the hypothesis that facilitation of training-induced neural plasticity in remaining motor cortex mediates the functional efficacy of CS. Aim 2 is to test the hypothesis that CS+motor training results in persistent synaptic structural plasticity within motor cortex in comparison to motor training alone. Aim 3 is to test the hypotheses that CS+motor training promotes plasticity and lessens long-term deterioration in motor cortical efferent regions compared with motor training alone. These hypotheses will be tested with a combination of sensitive behavioral measures, quantitative light and electron microscopy to assay changes in neuronal activity and synaptic structure as well as intracortical microstimulation (ICMS) mapping to reveal the functional integrity and organization of motor cortex. The immediate goal is to obtain data on the characteristics of CS-induced plasticity that are useful both for guiding more detailed future studies and for its clinical applications. The more general goal is to obtain a sufficient understanding of CS mechanisms to improve the ability to use it and related therapies to improve function after stroke. PUBLIC HEALTH RELEVANCE: Physical therapy and rehabilitation can be used to improve function after stroke but, even with extreme effort, such treatments can be limited in efficacy. Cortical stimulation (CS) has recently been found to enhance motor rehabilitative training effects in rats and monkeys. By gaining knowledge of the neural mechanisms underlying the beneficial effects of CS, we hope to better understand how to use this and related therapies to optimize functional outcome after stroke.

DESCRIPTION (provided by applicant): Timing is likely to be critical in attempts to promote restorative brain plasticity after stroke. Animal studies of stroke have revealed that ischemic injury triggers cascades of growth promoting and inhibiting cellular reactions and prolonged periods of neuroanatomical reorganization. Many ischemia-triggered remodeling events are activity-dependent and sensitive to behavioral manipulations. There is a growing awareness that rehabilitation strategies might capitalize on this sensitivity to optimize stroke outcome, and that this is likely to require that interventions be timed to coincide with more dynamic stages of remodeling, a timing likely to vary with stroke and patient characteristics, including age. However, the specific cellular events underlying time- dependencies in post-stroke rehabilitation continue to be poorly understood, making it impossible to clearly target them to optimize and tailor rehabilitation strategies. This project is focused on understanding how behavioral experiences differentially impact, depending on timing, post-ischemic neural and vascular remodeling events and their coordination, and the relevance of these time-dependencies for long-term outcome. This will be studied in a mouse model of chronic upper extremity (forelimb) impairments resulting from unilateral ischemic motor cortical damage in which functional impairments are improved by motor rehabilitative training of the paretic limb or exacerbated by compensatory skill learning with the nonparetic limb. Repeated in vivo imaging of synaptic elements, vascular microstructure and blood flow will be used together with sensitive behavioral measures, high resolution mapping of motor cortical organization and quantitative light and electron microscopy to reveal time- and age-dependencies in the effects of functionally beneficial and detrimental experiences on neural and vascular remodeling in peri-infarct cortex, and the consequences of these effects for cortical reorganization and behavioral outcome. The central hypothesis of this project is that behavioral experience- and injury-induced neural and vascular plasticity interact in a time- and age-dependent manner to remodel neural connections and vasculature in remaining motor cortex and to influence behavioral outcome. The specific aims are to test the hypotheses that motor rehabilitative training (1) interacts with post-ischemic neural and vascular plasticity to promote functionally beneficial remodeling of peri-infarct cortex but that this interaction is dependent upon (2) angiogenesis, (3) on its specific timing and duration relative to the onset of ischemic injury, (4) on its timing relative to the development of compensatory skill learning with the nonparetic limb and (5) on the age during which ischemic damage is incurred. The long-term goal of this project is to identify neural and vascular events that create time-dependencies in motor rehabilitative training efficacy so that these events can be targeted to tailor and facilitate the effects of rehabilitative training and to improve long-ter outcome after stroke.

PROJECT SUMMARY Women comprise more than half of the population of stroke survivors. Upper extremity motor impairments are an especially prevalent and disabling consequence of stroke. Improvements in the functional capacity of the paretic upper limb can be driven with motor rehabilitative training, an effect that is linked with its promotion of new synapse formation and the resurrection and reorganization of upper limb motor maps in the motor cortex of the injured hemisphere. There are currently many investigational treatments focused on facilitating motor cortical plasticity to improve post-stroke function. However, the mechanistic understanding that is guiding these directions is based largely on studies in young adult males. We have recently uncovered a striking difference in the effect of age on motor cortical organization in female, compared with male, rodents. Aging in males is characterized by shifts in the relative areas of distal and proximal forelimb movement representations, without reductions in the overall size of motor maps. Our preliminary data in females indicate that, beginning around middle age, there are reductions in the cortical territory devoted to forelimb movement, an effect that is not easily explained by declines in ovarian estradiol release. This includes a drastic reduction in distal forelimb (hand) movement representations in the rostral motor cortex, a region related to premotor cortex in humans. These data and related findings lead us to suspect that just as stroke incidence begins to rise dramatically, there could be substantial alterations in the cortical substrates of motor skill learning and of post-stroke functional improvements in females that are not present in males. We will begin to test this possibility using an established mouse model of post-stroke chronic upper extremity impairments and motor rehabilitative training. We will investigate in females and males with matched infarct severities the effects of chronological aging, but do so in a manner that is sensitive to influences of reproductive aging in females. Repeated in vivo cranial window imaging of synaptic elements motor cortex will be used in combination with sensitive behavioral measures and high resolution mapping of motor cortical organization to detect age-dependencies in the structural and functional reorganization of cortex linked with motor skill learning (Aim 1), motor recovery (Aim2) and motor rehabilitative training efficacy (Aim 3) and differences in the patterns of these age-related effects across sexes. The studies are intended to support and guide the mechanistic direction of future studies to understand age by sex interactions in the neural mechanisms of recovery and rehabilitation efficacy. At minimum, the results will begin to fill a huge knowledge gap surrounding aging effects on neural events in the chronic post-stroke period in the female brain. The results also have the potential to be of major importance for post-stroke treatment tailoring efforts.