Task-specific compensation and recovery following focal motor cortex lesion in stressed rats.

One reason for the difficulty to develop effective therapies for stroke is that intrinsic factors, such as stress, may critically influence pathological mechanisms and recovery. In cognitive tasks, stress can both exaggerate and alleviate functional loss after focal ischemia in rodents. Using a comprehensive motor assessment in rats, this study examined if chronic stress and corticosterone treatment affect skill recovery and compensation in a task-specific manner. Groups of rats received daily restraint stress or oral corticosterone supplementation for two weeks prior to a focal motor cortex lesion. After lesion, stress and corticosterone treatments continued for three weeks. Motor performance was assessed in two skilled reaching tasks, skilled walking, forelimb inhibition, forelimb asymmetry and open field behavior. The results revealed that persistent stress and elevated corticosterone levels mainly limit motor recovery. Treated animals dropped larger amounts of food in successful reaches and showed exaggerated loss of forelimb inhibition early after lesion. Stress also caused a moderate, but non-significant increase in infarct size. By contrast, stress and corticosterone treatments promoted reaching success and other quantitative measures in the tray reaching task. Comparative analysis revealed that improvements are due to task-specific development of compensatory strategies. These findings suggest that stress and stress hormones may partially facilitate task-specific and adaptive compensatory movement strategies. The observations support the notion that hypothalamic-pituitary-adrenal axis activation may be a key determinant of recovery and motor system plasticity after ischemic stroke.

Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model of Parkinson's disease.

The causes of most cases of Parkinson's disease (PD) are still poorly understood. Here we show that chronic stress and elevated corticosterone levels exaggerate motor deficits and neurodegenerative events in a Parkinson's disease rat model. Animals were tested in skilled and non-skilled movement while being exposed to daily restraint stress or oral corticosterone treatment. Stress and corticosterone compromised normal motor function and exaggerated motor deficits caused by unilateral 6-hydroxydopamine lesion of the nigrostriatal bundle. Moreover, stress and corticosterone treatments diminished the ability to acquire compensatory strategies in limb use during skilled reaching and skilled walking. In contrast, lesion control animals were able to significantly improve in the ability of skilled limb use during the repeated test sessions. The exaggerated motor impairments in stress-treated animals were related to accelerated loss of midbrain dopamine-producing neurons during the first week postlesion. Correlation analysis revealed a significant connection between loss of tyrosine hydroxylase-positive cells and increase in Fluoro-Jade-positive cells only in stress- and corticosterone-treated animals. Furthermore, stress and elevated corticosterone levels caused greater permanent loss of midbrain neurons than found in non-treated lesion animals. These findings demonstrate that stress and elevated corticosterone levels can exaggerate nigral neuronal loss and motor symptoms in a rat analogue of PD. It is therefore possible that stress represents a key factor in the pathogenesis of human PD by impeding functional and structural compensation and exaggerating neurodegenerative processes.

The effects of environmental exposure to DDT on the brain of a songbird: changes in structures associated with mating and song.

Dichlorodiphenyltrichloroethane (DDT) is a persistent organochlorine compound found worldwide that causes significant anatomical, physiological and behavioural abnormalities in humans and wildlife. However, little is known about whether environmental exposure to DDT affects the brain. Here, we show that environmental exposure to DDT alters the brains of American Robins (Turdus migratorius) in several ways. Increasing levels of DDT resulted in: (i) smaller brain and relative forebrain volumes; (ii) a reduction in the size of two song nuclei, nucleus robustus arcopallialis (RA) and HVC; and (iii) a drastic reduction in neuronal size and overall volume of nucleus intercollicularis (ICo), a structure that is critical for normal sexual behaviour. These changes likely result from stress, direct neurotoxicity and androgen receptor antagonism by the primary metabolite of DDT, p,p'-DDE and this is corroborated by analyses of brain region volumes and p,p'-DDE levels. Our results therefore demonstrate that environmental exposure to DDT is correlated with significant changes in the brain and specifically those structures related to mating and song. Given the magnitude of these changes in the brain and the fact that environmental DDT exposure was restricted to early development, we conclude that both humans and wildlife that live in DDT contaminated environments may be at risk of neurological damage.

Modulation of motor function by stress: a novel concept of the effects of stress and corticosterone on behavior.

Stress and stress hormones affect a variety of behaviors and cognitive abilities. The influences of stress and glucocorticoids on motor function, however, have not been characterized although the presence of glucocorticoid receptors in the motor system has been documented. Here we demonstrate that stress and the stress hormone corticosterone influence motor system function in rats. Groups of adult female Long-Evans rats underwent either a daily stress-inducing procedure (immobilization or swimming in cold water) or oral corticosterone treatment. While these treatments continued, animals were tested in skilled reaching and skilled walking tasks for a period of 2 weeks. Both acute (day 1) and chronic (day 14) stress and corticosterone treatment reduced skilled movement accuracy in reaching and walking and increased performance speed. Furthermore, both chronic stress and chronic corticosterone treatment altered skilled movement patterns in the reaching task. These findings indicate that stress modulates motor system function and that these effects are partially mediated by glucocorticoids. To examine whether stress-induced changes might also derive from enhanced emotionality, rats were treated with the benzodiazepine diazepam. Based on an inverted U-shaped dose-response relationship, a moderate dose of diazepam significantly improved reaching success while at the same time reducing corticosterone levels. Thus, stress-associated emotional responses such as anxiety might account for diminished movement accuracy. These results suggest that stress affects the motor system both directly via hormonal changes and indirectly via changes in emotionality. These findings are discussed with respect to the role of stress in motor system function and movement disorders.

The unilateral 6-OHDA rat model of Parkinson's disease revisited: an electromyographic and behavioural analysis.

The characteristic locomotor disturbances of Parkinson's disease (PD) include shuffling gait, short steps and low walking velocity. In this study we investigated features of walking and turning in a rat model of PD caused by unilateral infusion of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed gait and electromyographic (EMG) patterns of the ankle flexor tibialis anterior and the knee extensor vastus lateralis of the hindlimb, and triceps brachii of the forelimb, during overground locomotion, spontaneous rotation (turning) and apomorphine-induced rotation. When compared with control rats, rats with unilateral dopamine depletion displayed a shuffling gait and short stride lengths. This locomotor pattern was accompanied by prolonged ankle flexor activity on the ipsilateral side, and prolonged activity of knee extensors on the contralateral side. The dopamine depletion also led to enhanced contraversive rotations after an apomorphine challenge. The EMG recordings during drug-induced rotation suggested that hindlimb stepping was a reflective response to an active drive produced by forelimbs. The EMG recordings of the contralateral side during rotation were marked by reduced ankle flexor activity and increased knee extensor activity. Furthermore, EMG recordings indicated that dopamine-agonists induce rotational bias by altering the coupling between ipsi- and contralateral hindlimbs, and between forelimbs. In straight walking, however, the gait of 6-OHDA lesion animals reflected normal, coupled hindlimb stepping as controlled by spinal pattern generators. The data suggest that the unilateral rat model of PD resembles key features of human parkinsonian gait, and that asymmetric descending input may underlie the observed changes in gait patterns.

Dietary restriction alters fine motor function in rats.

A number of standard behavioral tasks in animal research utilize food rewards for positive reinforcement. In order to enhance the motivation to participate in these tasks, animals are usually placed on a restricted diet. While dietary restriction (DR) has been shown to have beneficial effects on recovery after brain injury, life span and aging processes, it might also represent a stressor. Since stress can influence a broad range of behaviors, the purpose of this study was to assess whether DR may have similar effects on skilled movement. Adult male Long-Evans rats were trained and tested in a skilled reaching task both prior to and during a mild food restriction regimen that maintained their body weights at 90-95% of baseline weight for eight days. The observations revealed that DR decreased reaching success and increased the number of attempts to grasp a single food pellet. The animals appeared to be more frantic when attempting to reach for food pellets, and the time taken to reach for 20 pellets decreased following the onset of DR. A second experiment investigating behaviors that do not require food rewards, including a ladder rung walking task and an open field test, confirmed that rats on DR display deficits in skilled movements and are hyperactive. These findings suggest that results obtained in motor tasks using food rewards need to be interpreted with caution. The findings are discussed with respect to stress associated with DR.