Abigail L. Kerr

Angiogenesis but not neurogenesis is critical for normal learning and memory acquisition.

Aerobic exercise has been well established to promote enhanced learning and memory in both human and non-human animals. Exercise regimens enhance blood perfusion, neo-vascularization, and neurogenesis in nervous system structures associated with learning and memory. The impact of specific plastic changes to learning and memory performance in exercising animals are not well understood. The current experiment was designed to investigate the contributions of angiogenesis and neurogenesis to learning and memory performance by pharmacologically blocking each process in separate groups of exercising animals prior to visual spatial memory assessment. Results from our experiment indicate that angiogenesis is an important component of learning as animals receiving an angiogenesis inhibitor exhibit retarded Morris water maze (MWM) acquisition. Interestingly, our results also revealed that neurogenesis inhibition improves learning and memory performance in the MWM. Animals that received the neurogenesis inhibitor displayed the best overall MWM performance. These results point to the importance of vascular plasticity in learning and memory function and provide empirical evidence to support the use of manipulations that enhance vascular plasticity to improve cognitive function and protect against natural cognitive decline.

The cerebellum: a neural system for the study of reinforcement learning.

In its strictest application, the term “reinforcement learning” refers to a computational approach to learning in which an agent (often a machine) interacts with a mutable environment to maximize reward through trial and error. The approach borrows essentials from several fields, most notably Computer Science, Behavioral Neuroscience, and Psychology. At the most basic level, a neural system capable of mediating reinforcement learning must be able to acquire sensory information about the external environment and internal milieu (either directly or through connectivities with other brain regions), must be able to select a behavior to be executed, and must be capable of providing evaluative feedback about the success of that behavior. Given that Psychology informs us that reinforcers, both positive and negative, are stimuli or consequences that increase the probability that the immediately antecedent behavior will be repeated and that reinforcer strength or viability is modulated by the organisms past experience with the reinforcer, its affect, and even the state of its muscles (e.g., eyes open or closed); it is the case that any neural system that supports reinforcement learning must also be sensitive to these same considerations. Once learning is established, such a neural system must finally be able to maintain continued response expression and prevent response drift. In this report, we examine both historical and recent evidence that the cerebellum satisfies all of these requirements. While we report evidence from a variety of learning paradigms, the majority of our discussion will focus on classical conditioning of the rabbit eye blink response as an ideal model system for the study of reinforcement and reinforcement learning.

Age-Dependent Reorganization of Peri-Infarct “Premotor” Cortex With Task-Specific Rehabilitative Training in Mice

Background. The incidence of stroke in adulthood increases with advancing age, but there is little understanding of how poststroke treatment should be tailored by age. Objective. The goal of this study was to determine if age and task specificity of rehabilitative training affect behavioral improvement and motor cortical organization after stroke. Methods. Young and aged mice were trained to proficiency on the Pasta Matrix Reaching Task prior to lesion induction in primary motor cortex with endothelin-1. After a short recovery period, mice received 9 weeks of rehabilitative training on either the previously learned task (Pasta Matrix Reaching), a different reaching task (Tray Reaching), or no training. To determine the extent of relearning, mice were tested once weekly on the Pasta Matrix Reaching Task. Mice then underwent intracortical microstimulation mapping to resolve the remaining forelimb movement representations in perilesion motor cortex. Results. Although aged mice had significantly larger lesions compared with young mice, Pasta Matrix Reaching served as effective rehabilitative training for both age-groups. Young animals also showed improvement after Tray Reaching. Behavioral improvement in young mice was associated with an expansion of the rostral forelimb area (“premotor” cortex), but we failed to see reorganization in the aged brain, despite similar behavioral improvements. Conclusions. Our results indicate that reorganization of motor cortex may be limited by either aging or greater tissue damage, but the capacity to improve motor function via task-specific rehabilitative training continues to be well maintained in aged animals.

Training Intensity Affects Motor Rehabilitation Efficacy Following Unilateral Ischemic Insult of the Sensorimotor Cortex in C57BL/6 Mice

Background. Motor rehabilitative training improves behavioral functionality and promotes beneficial neural reorganization following stroke but is often insufficient to normalize function. Rodent studies have relied on skilled reaching tasks to model motor rehabilitation and explore factors contributing to its efficacy. It has been found that greater training intensity (sessions/day) and duration (training days) facilitates motor skill learning in intact animals. Whether rehabilitative training efficacy varies with intensity following stroke is unclear. Methods. Mice were trained preoperatively on a skilled reaching task. Following focal ischemic lesions, mice received rehabilitative training either twice daily (high intensity [HI]), once daily (low intensity [LI]), or not at all (control) to determine the effects of rehabilitative training intensity on skilled motor performance. Results. Within 7 days, the HI-trained mice achieved preischemic levels of performance. Mice receiving LI training eventually reached similar performance levels but required a greater quantity of training. Training intensity did not consistently affect the maintenance of performance gains, which were partially lost over time in both groups. Discussion. These data indicate that increased training intensity increases the rate of functional improvements per time and per training session following ischemic insult. Thus, training intensity is an important variable to consider in efforts to optimize rehabilitation efficacy.

Post-stroke protection from maladaptive effects of learning with the non-paretic forelimb by bimanual home cage experience in C57BL/6 mice.

Behavioral experience, in the form of skilled limb use, has been found to impact the structure and function of the central nervous system, affecting post-stroke behavioral outcome in both adaptive and maladaptive ways. Learning to rely on the less-affected, or non-paretic, body side is common following stroke in both humans and rodent models. In rats, it has been observed that skilled learning with the non-paretic forelimb following ischemic insult leads to impaired or delayed functional recovery of the paretic limb. Here we used a mouse model of focal motor cortical ischemic injury to examine the effects of non-paretic limb training following unilateral stroke. In addition, we exposed some mice to increased bimanual experience in the home cage following stroke to investigate the impact of coordinated dexterous limb use on the non-paretic limb training effect. Our results confirmed that skilled learning with the non-paretic limb impaired functional recovery following stroke in C56BL/6 mice, as it does in rats. Further, this effect was avoided when the skill learning of the non-paretic limb was coupled with increased dexterous use of both forelimbs in the home cage. These findings further establish the mouse as an appropriate model in which to study the neural mechanisms of recovery following stroke and extend previous findings to suggest that the dexterous coordinated use of the paretic and non-paretic limb can promote functional outcome following injury.

Cerebellar dentate nuclei lesions reduce motivation in appetitive operant conditioning and open field exploration

Recently identified pathways from the dentate nuclei of the cerebellum to the rostral cerebral cortex via the thalamus suggest a cerebellar role in frontal and prefrontal non-motor functioning. Disturbance of cerebellar morphology and connectivity, particularly involving these cerebellothalamocortical (CTC) projections, has been implicated in motivational and cognitive deficits. The current study explored the effects of CTC disruption on motivation in male Long Evans rats. The results of two experiments demonstrate that electrolytic lesions of the cerebellar dentate nuclei lower breaking points on an operant conditioning progressive ratio schedule and decrease open field exploration compared to sham controls. Changes occurred in the absence of motor impairment, assessed via lever pressing frequency and rotarod performance. Similar elevated plus maze performances between lesioned and sham animals indicated that anxiety did not influence task performance. Our results demonstrate hedonic and purposive motivational reduction and suggest a CTC role in global motivational processes. These implications are discussed in terms of psychiatric disorders such as schizophrenia and autism, in which cerebellar damage and motivational deficits often present concomitantly.

Rapid cellular genesis and apoptosis: effects of exercise in the adult rat.

Long-term aerobic exercise improves cognition in both human and nonhuman animals and induces plastic changes in the central nervous system (CNS), including neurogenesis and angiogenesis. However, the early and immediate effects of exercise on the CNS have not been adequately explored. There is some evidence to suggest that exercise is initially challenging to the nervous system and that the plastic changes commonly associated with chronic exercise may result as adaptations to this challenge. The current experiment assessed levels of apoptosis, angiogenesis, and neurogenesis during the first week of an exercise regimen in the adult rat. The results indicate that exercise rapidly induces these processes in the hippocampus and cerebellum. The temporal pattern of these events suggests that voluntary exercise in the adult rat rapidly and transiently induces apoptosis, followed by angiogenesis. Neurogenesis is an immediate and independent consequence of exercise in the hippocampus that may require the additional metabolic support supplied by angiogenesis. This is the first report of CNS neuronal apoptosis as a consequence of exercise in the adult rat and suggests that this process is a potential mediator of rapid exercise-induced plasticity.

On Aerobic Exercise and Behavioral and Neural Plasticity

Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging.

Motor System Plasticity in Stroke Models: Intrinsically Use-dependent, Unreliably Useful

Functional impairment is a powerful incentive for behavioral change. The natural response to disability in one limb is to learn new ways of using the other limb. Animals, including humans, with upper extremity impairments spontaneously learn to use the less-affected (nonparetic) hand in novel ways to perform daily activities.1–3 In intact brains, the acquisition of manual skills depends on practice-dependent synaptic structural and functional reorganization of motor cortex (MC).4,5 After stroke, this skill acquisition overlaps with ongoing degenerative and regenerative responses to the injury, many of which are also neural activity dependent6,7 and sensitive to behavioral manipulations.8–10 When they converge on the same circuits, ischemia-induced and experience-driven remodeling responses interact.3 Learning to rely on the nonparetic hand is a particularly prevalent and profound form of poststroke behavioral compensation, but compensatory strategies can be found across different impairment modalities, body sides, and injury loci.11–13 Their development is among the most reliable consequences of brain injury survival. The implication is that understanding the brain’s typical adaptation to stroke will require understanding its interactions with compensatory behavioral changes. The compensatory reliance on the better functioning limb after stroke has long been thought to contribute to persistent dysfunction in the affected (paretic) limb by encouraging its disuse (ie, learned nonuse).14 Our recent findings suggest that it can go well beyond this to directly disrupt the neural substrates paretic limb functional improvements. Here we overview these findings, as revealed in rodent models of chronic upper extremity impairments using precise control and manipulation of forelimb experiences to understand bilateral and interhemispheric contributions to motor functional outcome. After unilateral ischemic MC damage in rats, a relatively subtle variation in behavioral experience—learning a single new motor skill with the nonparetic limb—reduces …

Compensatory limb use and behavioral assessment of motor skill learning following sensorimotor cortex injury in a mouse model of ischemic stroke.

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. The present protocol describes a skilled motor task for use in mouse models of stroke. The Pasta Matrix Reaching Task functions as a versatile and sensitive behavioral assay that permits experimenters to collect accurate outcome data and manipulate limb use to mimic human clinical phenomena including compensatory strategies (i.e., learned non-use) and focused rehabilitative training. When combined with neuroanatomical tools, this task also permits researchers to explore the mechanisms that support behavioral recovery of function (or lack thereof) following stroke. The task is both simple and affordable to set up and conduct, offering a variety of training and testing options for numerous research questions concerning functional outcome following injury. Though the task has been applied to mouse models of stroke, it may also be beneficial in studies of functional outcome in other upper extremity injury models.