Martin T. Woodlee

The Vermicelli Handling Test: A Simple Quantitative Measure of Dexterous Forepaw Function in Rats

Loss of function in the hands occurs with many brain disorders, but there are few measures of skillful forepaw use in rats available to model these impairments that are both sensitive and simple to administer. Whishaw and Coles previously described the dexterous manner in which rats manipulate food items with their paws, including thin pieces of pasta [Whishaw IQ, Coles BL. Varieties of paw and digit movement during spontaneous food handling in rats: postures, bimanual coordination, preferences, and the effect of forelimb cortex lesions. Behav Brain Res 1996;77:135-48]. We set out to develop a measure of this food handling behavior that would be quantitative, easy to administer, sensitive to the effects of damage to sensory and motor systems of the CNS and useful for identifying the side of lateralized impairments. When rats handle 7 cm lengths of vermicelli, they manipulate the pasta by repeatedly adjusting the forepaw hold on the pasta piece. As operationally defined, these adjustments can be easily identified and counted by an experimenter without specialized equipment. After unilateral sensorimotor cortex (SMC) lesions, transient middle cerebral artery occlusion (MCAO) and striatal dopamine depleting (6-hydroxydopamine, 6-OHDA) lesions in adult rats, there were enduring reductions in adjustments made with the contralateral forepaw. Additional pasta handling characteristics distinguished between the lesion types. MCAO and 6-OHDA lesions increased the frequency of several identified atypical handling patterns. Severe dopamine depletion increased eating time and adjustments made with the ipsilateral forepaw. However, contralateral forepaw adjustment number most sensitively detected enduring impairments across lesion types. Because of its ease of administration and sensitivity to lateralized impairments in skilled forepaw use, this measure may be useful in rat models of upper extremity impairment.

Reduction of dopamine synaptic activity: Degradation of 50-kHz ultrasonic vocalization in rats

Vocal deficits are prevalent and debilitating in Parkinsons disease. These deficits may be related to the initial pathology of the nigrostriatal dopamine neurons and resulting dopamine depletion, which contributes to dysfunction of fine motor control in multiple functions. Although vocalization in animals and humans may differ in many respects, we evaluated complex (50-kHz) ultrasonic mate calls in 2 rat models of Parkinsons disease, including unilateral infusions of 6-hydroxydopamine to the medial forebrain bundle and peripheral administration of a nonakinesia dose of the dopamine antagonist haloperidol. We examined the effects of these treatments on multiple aspects of the acoustic signal. The number of trill-like (frequency modulated) 50-kHz calls was significantly reduced, and appeared to be replaced by simpler (flat) calls. The bandwidth and maximum intensity of simple and frequency-modulated calls were significantly decreased, but call duration was not. Our findings suggest that the nigrostriatal dopamine pathway is involved to some extent in fine sensorimotor function that includes USV production and complexity.

A simple modification of the water maze test to enhance daily detection of spatial memory in rats and mice.

The water maze is one of the most frequently used tools in behavioral neuroscience. Many variations of the water maze task have been used; however, established water maze protocols have several disadvantages. Notably, these protocols demand considerable time to perform reference and probe tests separately. Here, we suggest a modified protocol, which is rapidly performed, is sensitive to cognitive deficits, and can assay reference as well as strategy-switching ability. The platform is relocated randomly within the target quadrant with each training trial. Because the rodents must spend more time searching within the target quadrant, every trial effectively becomes a probe trial. The rodents are then run in the switching strategy test, where the platform is randomly placed along the wall of the pool. The best new strategy would thus be to search along the walls of the pool systematically. The percent distance traveled and time spent near the wall is evaluated across trials, as is the distance traveled and time spent in the previously correct quadrant. In this way one can assess whether the rodent is continuing to search in the older platform location (i.e., displaying a strategy-switching problem) or whether it has successfully adopted a new search strategy.

Should the injured and intact hemispheres be treated differently during the early phases of physical restorative therapy in experimental stroke or parkinsonism

Over a century ago the intact cortex was proposed to contribute to recovery from unilateral brain injury, but its possible role in functional outcome has become more appreciated in recent years as a result of anatomic, metabolic and behavioral studies. Although use of the contralesional limb is naturally impaired after sensorimotor cortex injury, neural and astrocytic events in the intact hemisphere may give rise to, and may be influenced by, an enhanced ability to compensate for lost motor function. The debate is still open as to whether the neural changes are generally compensatory in nature, with activity in the homotopic cortex leading to greater capability in the nonimpaired limb, or whether they are actually a matter of reorganization in the homotopic cortex leading to connections to denervated targets in the opposite hemisphere, thus allowing the homotopic cortex to control motor programs there. Although both phenomena may occur to some degree, there is mounting evidence in support of the former view. Careful behavioral techniques have been developed that can expose compensatory tricks, and the time course of these behaviors correlates well with anatomic data. Moreover, if the intact cortex sustains a second lesion after recovery from the first, forelimb sensorimotor function specific to the first-impaired side of the body is not worsened. Partial denervation of callosal fibers coming from the injured hemisphere, plus preferential use of the good forelimb caused by a cortical injury, may increase trophic factors in the intact hemisphere. These and related events seem to provide a growth-favorable environment there that permits motor learning in the intact forelimb at a level of skill exceeding that which a normal animal can attain in the same period of time. There are anecdotal cases in human neurologic patients that are consistent with these findings. For example, a colleague of the authors who sustained a unilateral infarction that rendered his dominant right hand severely impaired noticed that soon after the stroke he was able to use his left hand for writing and computers as well as he had ever used his right hand. Cross-midline placing tests also indicate that the structural events observed in the intact cortex may potentiate projections to the damaged hemisphere. These changes may help restore the capacity of tactile information projecting to the intact hemisphere to control limb placing in the impaired forelimb. Neural events in the injured hemisphere can be affected by behavior differently than the neural events in the intact hemisphere. Different therapeutic strategies might well be used on opposing limbs at different times after unilateral sensorimotor cortex injury to optimize recovery (and, indeed, to avoid exaggerating the insult). Finally, the details of reorganization in both hemispheres differ greatly depending on the type of brain injury sustained (eg, in stroke versus Parkinsons disease), suggesting that an approach that considers the role of both hemispheres is likely to be beneficial in research on a broad variety of brain pathologies.

Repetitive vibrissae-elicited forelimb placing before and immediately after unilateral 6-hydroxydopamine improves outcome in a model of Parkinson's disease.

In rodent models of Parkinsons disease (PD), exercise or complex living environments introduced immediately before or during early stages of degeneration can provide beneficial effects on functional and/or neurochemical outcome. The goal of this study was to determine whether or not exposure to repetitive vibrissae-elicited forelimb placing, a dopamine-dependent sensorimotor movement, improves functional outcome in rats infused unilaterally with 6-OHDA. Prior to unilateral 6-OHDA infusions into the medial forebrain bundle, male Sprague-Dawley rats were randomly divided into groups exposed to one of five placing schedules: (1) two consecutive days pre-6-OHDA (PRE), (2) PRE+day 1 post-6-OHDA, (3) PRE+days 1, 2, 3 post-6-OHDA, (4) HANDLE, and (5) Sham infusion+handle. A session consisted of 180 total trials (90 left forelimb and 90 right forelimb trials) including 60 consecutive trials where vibrissae stimulation evoked ipsilateral forelimb movement and 30 consecutive trials where the ipsilateral forelimb was restrained so that vibrissae evoked contralateral forelimb movement (cross-midline placing). All groups were exposed to forelimb placing sessions on post-infusion days 7 and 14. The ability of vibrissae stimulation to elicit an ipsilateral response of the 6-OHDA affected forelimb was assessed on all days. Animals were sacrificed on post-lesion day 15 and substantia nigra tyrosine hydroxylase immunoreactivity (TH-ir) quantified. Repetitive forelimb placing had a significant effect on behavioral performance for all groups compared to the HANDLE group, but only the PRE+123 group was not significantly different from SHAM controls. Only the PRE+123 group showed significant sparing of TH-ir compared to the HANDLE group. These data suggest that extensive repetitive exposure to a sensorimotor task may provide therapeutic effects in an animal model of PD.

Brain-dependent movements and cerebral-spinal connections: key targets of cellular and behavioral enrichment in CNS injury models.

One of the most difficult problems in experimental and clinical neurology is how to facilitate recovery of the ability to walk voluntarily. Local spinal mechanisms, descending input from the brain, and ascending sensory feedback to the brain are required for non-treadmill, self-initiated stepping. In evaluating the integrity of axons connecting the brain and spinal cord in neural injury models, the selection of behavioral tests may be at least as important as the histological procedures, if not more so. A comprehensive and clinically meaningful test battery should include assessments of brain-dependent movement capacity. Behavioral enrichment procedures that prominently encourage self-initiation of stepping have been used to facilitate plasticity and motor function after brain or spinal cord injury. Progressive degeneration characteristic of parkinsonian models can be slowed or halted altogether by forced exercise and limb use. Behavioral interventions may work partly because the animal adopts alternative behavioral strategies to compensate for impaired performance. However, mounting evidence suggests that motor rehabilitation can also promote restoration of function or prevent slow degeneration of tissue by engaging constitutively available mechanisms that protect, repair, rewire, or reactivate cells.

The Impact of Motor Activity and Inactivity on the Brain Implications for the Prevention and Treatment of Nervous-System Disorders

Since Donald Hebbs pioneering observations in the 1940s, much research has focused on the effects of variations in physical activity and environmental complexity on behavioral performance and brain structure. Beneficial effects on brain health have been linked to physical fitness, skilled training, and exposure to complex environments, though in rodents these effects may be negated by sudden changes in social structure. Such manipulations can alleviate the deficits associated with several nervous-system disorders and aging. But how increased activity produces its beneficial effects is still not fully understood. How does unskilled physical activity (e.g., repetitive exercise) compare to training in skilled activities or exposure to complex environments? In injury states, is task-specific training a better rehabilitative strategy than general exercise? How do changes in motor activity affect specific brain regions, and can the intensity and timing of therapeutic movement be adjusted to produce optimal outcomes? Are the beneficial effects of motor enrichment banked over periods of inactivity and can they be called upon with booster training to treat a later neurological disorder? Are there circumstances in which increased activity is harmful? Enrichment of physical activity shows promise as an easy and healthful means for improving or restoring brain function, and questions like these are now being investigated so that the full potential of increased activity may be harnessed.