Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice

Accumulation of the transactive response DNA-binding protein 43 (TDP-43) is a major hallmark of several neurodegenerative disorders, collectively known as TDP-43 proteinopathies. The most common TDP-43 proteinopathies, frontotemporal lobar degeneration with TDP–43-positive inclusions, and amyotrophic lateral sclerosis, share overlapping neuropathological and clinical phenotypes. The development and detailed analysis of animal models of TDP-43 proteinopathies are critical for understanding the pathogenesis of these disorders. Transgenic mice overexpressing mutant human TDP-43 (herein referred to as hTDP-43) are characterized by neurodegeneration and reduced life span. However, little is known about the behavioral phenotype of these mice. Here we report the novel finding that hTDP-43 mice develop deficits in cognition, motor performance, and coordination. We show that these behavioral deficits are associated with the accumulation of nuclear and cytosolic TDP-43 C-terminal fragments, a decrease in endogenous TDP-43 levels, and synaptic loss. Our findings provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents on the onset and progression of TDP-43 proteinopathies.     

Effects of sensorimotor restriction and anoxia on gait and motor cortex organization: implications for a rodent model of cerebral palsy

Chronic or acute perinatal asphyxia (PA) has been correlated with the subsequent development of cerebral palsy (CP), a developmental neurological disorder characterized by spasticity and motor abnormalities often associated with cognitive deficits. Despite the prevalence of CP, an animal model that mimics the lifetime hypertonic motor deficits is still not available. In the present study, the consequences of PA on motor behavior, gait and organization of the primary motor cortex were examined in rats, and compared with the behavioral and neurological consequences of early postnatal movement-restriction with or without oxygen deprivation. Rats subjected to PA had mild increases in muscular tone accompanied by subtle differences in walking patterns, paralleled by significantly altered but relatively modest disorganization of their primary motor cortices. Movement-restricted rats, suffering PA or not, had reduced body growth rate, markedly increased muscular tone at rest and with active flexion and extension around movement-restricted joints that resulted in abnormal walking patterns and in a profoundly distorted representation of the hind limbs in the primary motor cortex. Within the sensorimotor-restricted groups, non-anoxic rats presented the most abnormal pattern and the greatest cortical representational degradation. This outcome further supports the argument that PA per se may represent a substrate for subtle altered motor behaviors, and that PA alone is sufficient to alter the organization of the primary motor cortex. At the same time, they also show that early experience-dependent movements play a crucial role in shaping normal behavioral motor abilities, and can make a powerful contribution to the genesis of aberrant movement abilities.     

Spatial hemineglect in humans

The paper reviews the main findings of studies of hemispatial neglect after acquired brain lesions in people. The behavioral consequences of experimentally induced lesions in animals and electrophysiological studies, which shed light on the nature of the disorder, are briefly considered. Neglect is behaviorally defined as a deficit in processing or responding to sensory stimuli in the contralateral hemispace, a part of the own body, the part of an imagined scene, or may include the failure to act with the contralesional limbs despite intact motor functions. Neglect in humans is frequently encountered after right parieto-temporal lesions and leads to a multicomponent syndrome of sensory, motor and representational deficits. Relevant findings relating to neglect, extinction and unawareness are reviewed and include the following topics: etiological and anatomical basis, recovery; allocentric, egocentric, object-centered and representational neglect; motor neglect and directional hypokinesia; elementary sensorimotor and associated disorders; subdivisions of space and frames of reference; extinction versus neglect; covert processing of information; unawareness of deficits; human and animal models; effects of sensory stimulation and rehabilitation techniques.     

Marked differences in neurochemistry and aggregates despite similar behavioural and neuropathological features of Huntington disease in the full-length BACHD and YAC128 mice

The development of animal models of Huntington disease (HD) has enabled studies that help define the molecular aberrations underlying the disease. The BACHD and YAC128 transgenic mouse models of HD harbor a full-length mutant huntingtin (mHTT) and recapitulate many of the behavioural and neuropathological features of the human condition. Here, we demonstrate that while BACHD and YAC128 animals exhibit similar deficits in motor learning and coordination, depressive-like symptoms, striatal volume loss and forebrain weight loss, they show obvious differences in key features characteristic of HD. While YAC128 mice exhibit significant and widespread accumulation of mHTT striatal aggregates, these mHTT aggregates are absent in BACHD mice. Furthermore, the levels of several striatally enriched mRNA for genes, such as DARPP-32, enkephalin, dopamine receptors D1 and D2 and cannabinoid receptor 1, are significantly decreased in YAC128 but not BACHD mice. These findings may reflect sequence differences in the human mHTT transgenes harboured by the BACHD and YAC128 mice, including both single nucleotide polymorphisms as well as differences in the nature of CAA interruptions of the CAG tract. Our findings highlight a similar profile of HD-like behavioural and neuropathological deficits and illuminate differences that inform the use of distinct endpoints in trials of therapeutic agents in the YAC128 and BACHD mice.     

Fetal tissue transplants in animal models of Huntington's disease: the effects on damaged neuronal circuitry and behavioral deficits

Accumulating evidence indicates that grafts of embryonic neurons achieve the anatomical and functional reconstruction of damaged neuronal circuitry. The restorative capacity of grafted embryonic neural tissue is most illustrated by studies with striatal tissue transplantation in animals with striatal lesions. Striatal neurons implanted into the lesioned striatum receive some of the major striatal afferents such as the nigrostriatal dopaminergic inputs and the gluatmatergic afferents from the neocortex and thalamus. The grafted neurons also send efferents to the primary striatal targets, including the globus pallidus (GP, the rodent homologue of the external segment of the globus pallidus) and the entopeduncular nucleus (EP, the rodent homologue of the internal segment of the globus pallidus). These anatomical connections provide the reversal of the lesion-induced alterations in neuronal activities of primary and secondary striatal targets. Furthermore, intrastriatal striatal grafts improve motor and cognitive deficits seen in animals with striatal lesions. Since the grafts affect motor and cognitive behaviors that are critically dependent on the integrity of neuronal circuits of the basal ganglia, the graft-mediated recovery in these behavioral deficits is most likely attributable to the functional reconstruction of the damaged neuronal circuits. The fact that the extent of the behavioral recovery is positively correlated to the amount of grafted neurons surviving in the striatum encourages this view. Based on the animal studies, embryonic striatal tissue grafting could be a viable strategy to alleviate motor and cognitive disorders seen in patients with Huntington's disease where massive degeneration of striatal neurons occurs.     

Morphofunctional characteristics of skeletal muscle in rats with cerebral palsy

Knowledge of skeletal muscle adaptations is important to understand the functional deficits in cerebral palsy (CP). This study aimed to investigate the morphofunctional characteristics of skeletal muscle in a CP animal model. Initially, pregnant Wistar rats were injected intraperitoneally with saline or lipopolysaccharide over the last five days of pregnancy. The control group (n = 8) consisted of male pups born to females injected with saline. The CP group (n = 8) consisted of male pups born to females injected with lipopolysaccharide, which were submitted to perinatal anoxia [day of birth, postnatal day 0 (P0)] and sensorimotor restriction (P1‐P30). The open‐field test was undertaken on P29 and P45. On P48, the animals were weighed, and the plantaris muscle was collected and its weight and length were measured. Transverse sections were stained with haematoxylin‐eosin, NADH‐TR, Masson's trichrome and non‐specific esterase reaction for analysis. and transmission electron microscopy was performed. In the CP group, reductions were observed in mobility time, number of crossings and rearing frequency, body weight, muscle weight and length, and nucleus‐to‐fibre and capillary‐to‐fibre ratios. There was a statistically significant increase in the percentage area of the muscle section occupied by collagen; reduction in the area and increase in the number of type I muscle fibres; increase in myofibrillar disorganization and Z‐line disorganization and dissolution; and reduction in the area and largest and smallest diameters of neuromuscular junctions. Thus this animal model of CP produced morphofunctional alterations in skeletal muscle, that were associated with evidence of motor deficits as demonstrated by the open‐field test.     

Seizures are associated with brain injury severity in a neonatal model of hypoxia–ischemia

Hypoxia–ischemia is a significant cause of brain damage in the human newborn and can result in long-term neurodevelopmental disability. The loss of oxygen and glucose supply to the developing brain leads to excitotoxic neuronal cell damage and death; such over-excitation of nerve cells can also manifest as seizures. The newborn brain is highly susceptible to seizures although it is unclear what role they have in hypoxic-ischemic (H/I) injury. The aim of this study was to determine an association between seizures and severity of brain injury in a piglet model of perinatal H/I and, whether injury severity was related to type of seizure, i.e. sub-clinical (electrographic seizures only) or clinical (electrographic seizures+physical signs). Hypoxia (4% O₂) was induced in anaesthetised newborn piglets for 30 min with a final 10 min period of hypotension; animals were recovered and survived to 72 h. Animals were monitored daily for seizures both visually and with electroencephalogram (EEG) recordings. Brain injury was assessed with magnetic resonance imaging (MRI), ¹H-MR spectroscopy (¹H-MRS), EEG and by histology (haematoxylin and eosin). EEG seizures were observed in 75% of all H/I animals, 46% displayed clinical seizures and 29% sub-clinical seizures. Seizure animals showed significantly lower background amplitude EEG across all post-insult days. Presence of seizures was associated with lower cortical apparent diffusion coefficient (ADC) scores and changes in ¹H-MRS metabolite ratios at both 24 and 72 h post-insult. On post-mortem examination animals with seizures showed the greatest degree of neuropathological injury compared to animals without seizures. Furthermore, clinical seizure animals had significantly greater histological injury compared with sub-clinical seizure animals; this difference was not apparent on MRI or ¹H-MRS measures. In conclusion we report that both sub-clinical and clinical seizures are associated with increased severity of H/I injury in a term model of neonatal H/I.     

Motor cortex injury has different behavioral and anatomical effects in early and late adolescence

Although there are many studies investigating the effects of early cortical injury on brain and behavioral development in laboratory animals, there are virtually no studies examining the effects of cortical injury in adolescence. The purpose of present study was to investigate the effects of unilateral motor cortex lesion received in early and late adolescence periods (Postnatal days 35 and 55 [P35, P55]) on spontaneous neural reorganization and behavioral recovery in adulthood. Rats were given unilateral motor cortex lesions at P35 or P55 and their motor behaviors were compared to sham controls in adulthood. The results of behavioral tests (skilled reaching, postural asymmetry, sunflower seed manipulation, forepaw inhibition in swimming) revealed that rats with P35 lesions had significant functional deficits whereas the rats with P55 lesions showed nearly complete recovery. Golgi-Cox analysis of pyramidal neurons showed bilateral hypertrophy of dendritic fields in the remaining sensorimotor cortex in P55 but not P35 rat brains. Thus, there appears to be an age-related pattern of morphological and behavioral changes in response to cortical injury in the early and late adolescent periods leading to better functional recovery from later injuries, much as is seen in human children.     

Acute but not chronic differences in skilled reaching for food following motor cortex devascularization vs. photothrombotic stroke in the rat

The variability in the behavioral outcome of human and nonhuman animals after stroke raises the question whether the way that a stroke occurs is a contributing factor. Photothrombotic stroke in rats has been reported to produce especially variable results, with some animals showing either slight to no impairment to other animals displaying severe impairments. The present study investigated this variability. Rats received three different-sized photothrombotic treatments and were contrasted to rats receiving a "standard" motor cortex stroke produced by pial stripping. Rats were assessed acutely and chronically on a skilled reaching for food task using end-point measures and movement assessment in a constraint-induced rehabilitation paradigm. The results indicated that as the size of the photothrombotic infarct approached the size of the pial strip infarct so did chronic behavioral deficits. Nevertheless there were differences in the time course of recovery. Rats with photothrombotic lesions of all sizes were less impaired in the acute period of recovery both on measures of learned nonuse and constrained-induced recovery. The findings are discussed in relation to the idea that whereas the course of recovery might be altered as a function of the type of stroke, chronic deficits are more closely related to the ensuing damage.     

Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease

An expanded CAG repeat is the underlying genetic defect in Huntington disease, a disorder characterized by motor, psychiatric and cognitive deficits and striatal atrophy associated with neuronal loss. An accurate animal model of this disease is crucial for elucidation of the underlying natural history of the illness and also for testing experimental therapeutics. We established a new yeast artificial chromosome (YAC) mouse model of HD with the entire human HD gene containing 128 CAG repeats (YAC128) which develops motor abnormalities and age-dependent brain atrophy including cortical and striatal atrophy associated with striatal neuronal loss. YAC128 mice exhibit initial hyperactivity, followed by the onset of a motor deficit and finally hypokinesis. The motor deficit in the YAC128 mice is highly correlated with striatal neuronal loss, providing a structural correlate for the behavioral changes. The natural history of HD-related changes in the YAC128 mice has been defined, demonstrating the presence of huntingtin inclusions after the onset of behavior and neuropathological changes. The HD-related phenotypes of the YAC128 mice show phenotypic uniformity with low inter-animal variability present, which together with the age-dependent striatal neurodegeneration make it an ideal mouse model for the assessment of neuroprotective and other therapeutic interventions.     

Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions

Anatomical plasticity and functional recovery after lesions of the rodent corticospinal tract (CST) decrease postnatally in parallel with myelin formation. Myelin-associated neurite growth inhibitory proteins prevent regenerative fiber growth, but whether they also prevent reactive sprouting of unlesioned fibers is less clear. Here we show that after unilateral CST lesion in the adult rat brainstem, both intact and lesioned tracts show topographically appropriate sprouting after treatment with a monoclonal antibody that neutralizes these inhibitory proteins. Antibody-treated animals showed full recovery in motor and sensory tests, whereas untreated lesioned rats exhibited persistent severe deficits. Neutralization of myelin-associated neurite growth inhibitors thus restores in adults the structural plasticity and functional recovery normally found only at perinatal ages.     

Motor dysfunction in a mouse model for Down syndrome

Motor deficits are among the most frequently occurring features of Down syndrome (DS). Individuals with DS exhibit disturbances in the dynamics of movement production and postural control that are thought to have a significant impact in delaying their acquisition of motor skills. The origin of these deficits has been hypothesized to be cerebellar. The Ts65Dn mouse is the most robust and genetically sound animal model for DS currently available. Ts65Dn mice show many DS-like features, including significant learning deficits in different behavioral tasks and neurodegeneration of cholinergic neurons. In the present study, we investigate the motor function of these animals. We have analyzed hind paw print patterns during walking, running speeds, rotarod performance, grip force production, swim paths, and swimming speeds. Our results indicate that Ts65Dn mice present mild to severe dysfunction according to all of the above assessments. The most evident impairments presented by these mice were related to equilibrium and motor coordination, which agrees with reported clinical observations made on individuals with DS. Because none of these findings were readily apparent by simple inspection of these animals, these findings reiterate the need for a careful evaluation of any mutant mouse strain for which there is reason to suspect motor deficits. The identification of motor dysfunction in Ts65Dn mice may have important consequences for the interpretation of some previous assessments of learning and memory of these animals that assumed intact motor function, and further strengthens the use of this aneuploid mouse strain as a model for DS.     

Perinatal methylmercury intoxication: Behavioral effects in rats

Sprague-Dawley rats were subjected to perinatal (4th gestational day until Postnatal Day 21) methylmercury intoxication to determine the long-term behavioral effect of the mercury poisoning. Experimental and control animals were evaluated at 110–140 days of age. Compared to controls, the methylmercury animals demonstrated significant behavioral deficits characterized by hypoactivity and by reduced appetitive, escape, and avoidance learning.     

Social neuroscience,empathy, brain integration,and neurodevelopmental disorders

Paul MacLean has investigated integrated brain functioning through selected brain lesions in animals that disturb circuits necessary for complex behaviors, such as social displays. MacLean is unique in his comparative neurobehavioral approach that emphasizes the evolutionary origins of parenting and social behaviors and the implications of brain changes in the evolution from reptiles (social displays) to mammals (nursing, audiovocal communication, play) to man (self-awareness, intentionality, social context) that link affect and cognition. Subjectively, how "looking with feeling toward others," the basic element in empathy, evolved has been a central concern of his. Neuroimaging studies of social cognition, mother-infant communication, moral behavior, forgiveness, and trust are consistent with particular brain systems being activated in cooperative social behaviors. The identification of mirror neurons is pertinent to MacLean's model of isopraxis and studies of thalamocortical resonances may be pertinent to his neurobehavioral models. Studies of behavioral phenotypes in human neurodevelopmental disorders are consistent with MacLean's model of brain circuits being linked to complex behaviors during development. In autistic disorder, the behavioral phenotype involves disrupted social communication, deviant imaginative play, and motor stereotypies. In Lesch-Nyhan syndrome (LNS), self-injury occurs in individuals with normal sensory systems intact who require and request physical restraint to prevent self-injury; they ask for assistance from others to prevent them from harming themselves. Autism involves the lack of subjective awareness of others intentions and LNS involves a failure in self-regulation and self-control of self-injurious behavior. MacLean's models laid the groundwork for studies focused on understanding brain functioning in these conditions.     

Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia

Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.     

Neuropeptides in the developing human hippocampus under hypoxic–ischemic conditions

The perinatal period, sensitive for newborn survival, is also one of the most critical moments in human brain development. Perinatal hypoxia due to reduced blood supply to the brain (ischemia) is one of the main causes of neonatal mortality. Brain damage caused by perinatal hypoxia–ischemia (HI) can lead to neuro‐ and psychological disorders. However, its impact seems to be region‐dependent, with the hippocampus being one of the most affected areas. Among the neuronal populations of the hippocampus, some interneuron groups – such as somatostatin‐ or neuropeptide Y‐expressing neurons – seem to be particularly vulnerable. The limited information available about the effects of HI in the hippocampus comes mainly from animal models and adult human studies. This article presents an immunohistochemical analysis of somatostatin (SOM) and neuropeptide Y (NPY) expression in the developing human hippocampus after perinatal HI. Two rostrocaudal sections of the body of the hippocampus were analysed, and the number of immunostained cells in the polymorphic layer of the dentate gyrus (DG) and the pyramidal cell layer and stratum oriens of the CA3, CA2 and CA1 fields of the hippocampus proper were quantified. The results showed a lower density of both neuropeptides in hypoxic compared to control cases. In the HI group, the number of SOM‐immunoreactive cell bodies was statistically significantly lower in the pyramidal cell layer and stratum oriens of CA1, while the number of NPY‐expressing neurons was statistically lower in the pyramidal cell layer of CA2. Besides, the number of SOM‐expressing neurons was significantly higher in the stratum oriens of CA1 compared to that in CA2. In sum, we observed a different vulnerability of SOM‐ and NPY‐containing neurons in the developing human hippocampus following perinatal HI damage. Our results could contribute to a better understanding of the behaviour of these neuronal populations under stressful conditions during the perinatal period.     

Brain tissue transplantation in neonatal rats prevents a lesion-induced syndrome of adipsia,aphagia and akinesia

Summary Previous experiments have proven brain tissue transplantation effective in reversing lesioninduced behavioral deficits in mature rats. This study reversed the usual experimental paradigm, so that fetal substantia nigra was transplanted into intact neonatal rats and allowed to mature in the host brain. Upon maturation substantia nigra lesions were made bilaterally to reveal the functional contribution of the transplanted tissue. In control animals these lesions depleted striatal dopamine, producing rigidity, poverty of movement and abnormal posture comparable to Parkinson's disease in the human; cessation of feeding and drinking led to progressive weight loss and death. In contrast, fetal substantia nigra transplanted into the neonatal rat became well-integrated in the host brain and was shown to protect the animal from this syndrome produced by subsequent substantia nigra lesions. We suggest that transplantation in these neonatal rats was performed during a crucial period of synaptogenesis, an environment particularly favorable to host-transplant interaction.     

Midline and lateral field sound localization in the ferret (Mustela putorius): contribution of the superior olivary complex.

1. The ability of ferrets to localize sound in space was determined before and after unilateral or bilateral lesions of the superior olivary complex (SOC). Lesions were made by pressure injection of kainic acid into the SOC through a stereotaxically positioned glass micropipette. The lesions destroyed the cell bodies in the superior olive without disrupting fibers of passage in the trapezoid body or other pathways in the auditory brain stem. The integrity of fibers was demonstrated by protargol staining of axonal processes and by the retrograde transport of horseradish peroxidase (HRP) from the inferior colliculus to other auditory brain stem nuclei. Behavioral tests were carried out separately for sound localization at midline and lateral field positions. Minimum audible angles were determined for single 45-ms noise bursts presented through paired loudspeakers positioned symmetrically around 0, -60, and +60 degrees azimuth. 2. Four ferrets received complete lesions of the left SOC, and two received complete lesions of the right SOC. In general, unilateral destruction of the superior olive resulted in impairments in sound localization in both left and right lateral fields. In some cases, deficits were also apparent on midline. Four additional animals received unilateral lesions that spared cells within the SOC. In most cases, deficits were apparent despite incomplete lesions of the SOC. The pattern of deficits was generally consistent with that found in animals with complete lesions. Most animals had difficulty localizing sounds in the lateral fields. 3. Four animals received bilateral lesions of the SOC. Three had complete or near-complete destruction of the superior olive on one side of the brain with relatively minor damage on the other side. Each of these animals exhibited behavioral deficits that were particularly severe ipsilateral to the more extensively damaged superior olive. One animal with complete bilateral destruction of the SOC was incapable of sound localization, even with 2-s noise bursts. This animal, however, suffered severe motor impairments after surgery that might have contributed to the apparent inability to localize sound. 4. Two animals with kainic acid lesions that caused little or no damage to the SOC were still capable of high levels of performance in tests of sound localization and had no elevation in minimum audible angles. These cases served as controls for the possible effects of nonspecific brain damage and demonstrated that kainic acid injections per se resulted in no obvious deficits in our test situation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acute perinatal asphyxia impairs non-spatial memory and alters motor coordination in adult male rats

A large body of clinical evidence suggests a possible association between perinatal asphyxia and the onset of early, as well as long-term, neurological and psychiatric disorders including cognitive deficits. The present study investigated cognitive and motor function modifications in a well characterized and clinically relevant experimental rat model of human perinatal asphyxia. The results reported here show that adult rats exposed to a single (20 min) asphyctic episode at delivery displayed: (a) a deficit in non-spatial memory, assessed in a novel object recognition task; (b) an impaired motor coordination, measured by the rotarod test. On the other hand, gross motor activity and spatial memory, evaluated in both the Y maze and the Barnes maze, were not affected by perinatal asphyxia. The results of this study provide further insights into the long-term effects of perinatal asphyxia on neurobehavioural functions.     

L-DOPA reverses motor deficits associated with normal aging in mice

We wished to determine whether L-DOPA, a common treatment for the motor deficits in Parkinson's disease, could also reverse the motor deficits that occur during aging. We assessed motor performance in young (2–3 months) and old (20–21 months) male C57BL/6 mice using the challenge beam and cylinder tests. Prior to testing, mice were treated with L-DOPA or vehicle. Following testing, striatal tissue was analyzed for phenotypic markers of dopamine neurons: dopamine, dopamine transporter, and tyrosine hydroxylase. Although the dopaminergic markers were unchanged with age or L-DOPA treatment, L-DOPA reversed the motor deficits in the old animals such that their motor coordination was that of a young mice. These findings suggest that some of the locomotor deficits that accompany normal aging are responsive to L-DOPA treatment and may be due to subtle alterations in dopaminergic signaling.