Gerlinde Metz - Academia.edu (original) (raw)
Papers by Gerlinde Metz
Behavioural brain …, 2009
Previous studies have associated stress with poor outcome in individuals affected by stroke. It w... more Previous studies have associated stress with poor outcome in individuals affected by stroke. It was suggested that the effects of stress depend on the stressor's type and strength. Here we compare the effects of chronic predictable restraint stress and chronic unpredictable variable stress on motor recovery after focal lesion in the rat motor cortex. Adult male rats were pre-trained and tested in skilled reaching and skilled walking tasks. Animals were assigned to daily treatments of either restraint stress or variable stress starting 1 week prior to lesion up to 2 weeks post-lesion. One group served as lesion only control. The results revealed a distinct pattern of recovery and compensation of skilled movement. Animals exposed to predictable restraint stress had significantly lower reaching success at both pre-and post-lesion time points, and higher error rates in skilled walking when compared to lesion controls. Overall, restraint stress induced more pronounced motor impairments prior to and after injury than variable stress. Variable stress increased the number of attempts required to grasp food pellets and changed movement pattern performance. By contrast, variable stress improved limb placement accuracy when compared to lesion controls. The behavioural changes were not accompanied by differences in infarct size. These findings are in agreement with other studies reporting that both chronic predicable restraint stress and unpredictable variable stress influence the course of recovery following stroke, however, restraint stress might affect stroke recovery through a different route than variable stress.
In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate... more In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.
Any behavioral testing induces stress to some degree. A meaningful interpretation of behavioral r... more Any behavioral testing induces stress to some degree. A meaningful interpretation of behavioral results can be difficult if stress, caused by handling or the testing situation, modifies the experimental outcome. Especially for neurological animal models, it is important to know how stress affects motor and sensory performance. Therefore, we investigated the effects of varying degrees of stress on several motor and sensory tasks that are frequently used to assess functional recovery after lesion-induced impairments in adult rats. Acute, subchronic, and chronic stress impaired ladder walking and prolonged the duration of grasping a bar. Stress also altered walking patterns by increasing the base of support and foot rotation and reducing stride length. Furthermore, chronic stress induced hypersensitivity to painful stimuli, but did not significantly influence the latency to remove sticky papers from the hindpaws (sticky paper test). In the light ± dark (L/D) test, stress reduced the latency to enter the dark compartment and enhanced the number of transitions supporting that cold swim stress modifies the animal's level of anxiety. These data point towards a critical influence of acute or chronic stress on motor control and sensory performance of rats, suggesting that stress might be a critical intervening variable of the outcome of behavioral tests. D
Stress as a Modulator of Motor System Function and Pathology
Reviews in the Neurosciences, 2000
Stress is one of the most significant influences on behaviour and performance. The classical acco... more Stress is one of the most significant influences on behaviour and performance. The classical account is that stress mainly affects functions of the limbic system, such as learning, memory and emotion. Recent evidence, however, suggests that stress also modulates motor system function and influences the pathology of movement disorders. Most parts of the motor system show the presence of glucocorticoid receptors that render their circuits susceptible to the influence of stress hormones. Stress and glucocorticoids have been shown to modulate temporal and spatial aspects of motor performance. Skilled movements seem to be most prone to stress-induced disturbances, but locomotion and posture can also be affected. Stress can modulate movement through activation of the hypothalamic-pituitary-adrenal axis and via stress-associated emotional changes. The dopaminergic system seems to play a central role in mediating the effects of stress on motor function. This route might also account for the finding that stress influences the pathology of dopamine-related diseases of the motor system, such as Parkinson's disease. Clinical observations have indicated that stress might lead to the onset of Parkinsonian symptoms or accelerate their progression. Glucocorticoids are modulators of neuronal plasticity, thus determining the degree of structural and functional compensation of the damaged motor system. This may particularly affect slowly progressive neurodegenerative diseases, such as Parkinson's disease. That stress represents a significant modulator of motor system function in both the healthy and the damaged brain should be recognized when developing future therapies for neurodegenerative diseases.
Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice
Neuroscience, 2004
The growth-associated protein (GAP)-43 is a major neuronal protein associated with axonal growth,... more The growth-associated protein (GAP)-43 is a major neuronal protein associated with axonal growth, neuronal plasticity and learning. The observation that only 5-10% of mice with a full GAP-43 gene deletion survive weaning suggests that basic neural functions are disturbed. Here we used a comprehensive test battery to characterise and quantify the motor and sensory function of surviving adult homozygous GAP-43 (-/-) mice as compared with GAP-43 (+/-) and wild-type animals. The test battery was comprised of motor, sensory, and reflex tests producing 25 measures of locomotion, as well as epicritic, auditory, olfactory and visual function. The analysis revealed significant impairments in muscle strength, limb coordination and balance in GAP-43 (-/-) mice. Furthermore, GAP-43 (-/-) animals were hyperactive and showed reduced anxiety as measured by open field and light dark tests. In sensory tests, GAP-43 (-/-) mice were tested for impaired tactile and labyrinthine function. Abnormal reflexes were found in the contact and vibrissa placing responses, and in the crossed extensor reflex. GAP-43 (+/-) animals showed only moderate abnormalities as compared with wild-type animals. We conclude that GAP-43 is necessary for the development and function of a variety of neuronal systems. The results also show that the comprehensive test battery used in the present study represents a sensitive approach to assess the functional integrity of ascending and descending pathways in genetically manipulated mice.
Neuroscience, 2009
Experiential therapies, such as enriched environment (EE), have been shown to influence the neuro... more Experiential therapies, such as enriched environment (EE), have been shown to influence the neurodegenerative processes that underlie Parkinson's disease. We have previously demonstrated that EE promotes functional improvement in dopamine-depleted rats. Here we compare the influence of exposure to EE prior to versus after dopamine depletion in the 6-hydroxydopamine rat model of Parkinson's disease. Two groups of female rats were placed in an EE while two groups were housed in a standard environment (SE) for 6 weeks prior to receiving a unilateral nigrostriatal bundle infusion of the neurotoxin 6-hydroxydopamine. After the lesion, one group remained in EE, while the second EE group (Pre-Lesion EE) was moved into SE conditions. In addition, a third group of rats was now moved into EE (Postlesion EE). A fourth group remained in SE throughout the experimental period. Rats were tested in skilled reaching and skilled walking tasks and in non-skilled motor function up to 4 weeks after lesion. The observations demonstrated beneficial effects of both pre-and post-lesion exposure to EE on skilled movement performance by promoting compensatory limb use and partial protection or restoration of skilled movement. Exposure to pre-lesion EE in particular promoted structural plasticity as indicated by increased expression of the main cytoskeletal component microtubule associated protein-2 in the lesion dorsal striatum. Continuous EE showed absence of rotational bias suggesting attenuated dopamine loss. These data indicate that enriched lifestyle before the onset of motor symptoms and rehabilitation programs after diagnosis might be beneficial in patients with Parkinson's disease.
Enriched environment promotes efficiency of compensatory movements after cerebral ischemia in rats
Neuroscience, 2009
Rehabilitation therapy is known to drive motor improvement in stroke patients. However, the inter... more Rehabilitation therapy is known to drive motor improvement in stroke patients. However, the interplay of functional recovery and compensation in postischemic motor behavior is poorly understood. This study focused on the time course of functional recovery versus motor compensation in skilled forelimb movements after cerebral ischemia in rats. Young adult male rats underwent a focal cerebral ischemia by unilateral photothrombotic lesion of the motor cortex related to the preferred forelimb. In a first set of experiments animals were exposed to small cortical lesions comprising the forelimb motor cortex (n=8) or to larger lesions additionally extending into the hind limb motor area (n=8). In a second set of experiments animals with large lesion were either housed in standard (n=10) or enriched environment (n=14). Skilled reaching was assessed for 25 to 28 days postischemia. This task allows the distinction between recovery and compensation by parallel quantitative (reaching success) and qualitative (movement pattern) analysis. The results reveal that lesion size determines the initial magnitude of motor deficits, but not the degree of chronic impairments in movement pattern in all experimental groups. Compensatory movements represent the major mechanism of functional improvement and were accompanied by a partial functional restitution. Enriched environment facilitates effective compensation in skilled reaching, while it does not promote restitution of function. In particular, rotating movements of the forelimb during reaching were permanently impaired and required functional compensation through intensified use of the upper body. We conclude an activity dependent postischemic restoration of movement success. Enriched environment provides benefit by increased motor activity mainly due to compensation. Furthermore, these findings emphasize the power of comprehensive movement analysis to gain insight into recovery processes after stroke.
Validation of the Weight-Drop Contusion Model in Rats: A Comparative Study of Human Spinal Cord Injury
Journal of Neurotrauma, 2000
Animal models are widely used for studying the pathophysiology as well as treatment strategies fo... more Animal models are widely used for studying the pathophysiology as well as treatment strategies for injuries of the central nervous system. However, it is still unclear in how far the rat model of spinal cord injury (SCI) is valid for human SCI. Therefore, comparisons were made among functional, electrophysiological, and morphological outcome parameters following SCI in rats and humans. Contusion of the mid-thoracic spinal cord in 27 adult rats was induced by a weight-drop, leading to severe deficits in open field locomotion at a chronic stage. The data of 85 human patients with chronic SCI were collected and compared with the rat data. In electrophysiological recordings, prolonged latencies and reduced amplitudes in both motor evoked potentials (MEP) and somatosensory evoked potentials (SSEP) were closely correlated to the impairment of locomotor capacity of lower limbs in rats and humans. The morphological parameters assessed by high-resolution magnetic resonance imaging (MRI) in both species indicated that the lesion length and spinal cord atrophy were significantly related to the electrophysiological and functional outcome parameters. In rats, histological analysis was performed and showed, in addition to the MRI, a close relationship between spared white matter and locomotor capacity. Our results suggest an analogous relationship in rats and humans with respect to functional, electrophysiological, and morphological outcomes. Thus, the techniques for evaluating the extent and severity of SCI in humans and rats are of comparable value. This indicates that the rat can serve as an adequate animal model for research on functional and morphological changes after SCI and the effects of new treatment strategies.
Experimental Neurology, 1998
Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure... more Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5-6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2-11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery. 1998 Academic Press
The development of skilled walking in the rat
Behavioural Brain Research, 2009
The rat is an altricial species and consequently undergoes considerable postnatal development. Ca... more The rat is an altricial species and consequently undergoes considerable postnatal development. Careful analysis of the emergence and disappearance of motor behaviours is essential to gain insight into the temporal pattern of maturation of motor system structures. This study presents a qualitative analysis of the developmental progression of skilled movement in the rat by using a skilled walking task. A new rung bridge task was used to expose rat pups to a novel environment in order to reveal their potential capabilities. Ten rat pups were filmed daily from postnatal day 7 through postnatal day 30 as they explored the rung bridge task. Discrete changes in skilled and non-skilled walking in fore- and hind-limbs were evaluated by scoring seven categories and 24 subcategories of motor behaviour, including limb flexion and extension, coordination, posture, sensorimotor responses, distal control, and tail use in rat pups. Frame-by-frame analysis of ambulatory movement revealed six distinct stages of locomotor development. The most significant transformation to mature gait patterns was found between postnatal days 15 and 19, and maturation of all motor behaviour was completed by postnatal day 27. The findings are discussed in relation to the maturation of underlying structures and their relevance to studies of brain damage.
Behavioural Brain Research, 2005
Initial functional impairments after cerebral ischemia often improve considerably during the earl... more Initial functional impairments after cerebral ischemia often improve considerably during the early period after the insult. Although pathological changes associated with post-lesion improvements have been widely investigated, it has not been resolved whether behavioral improvement represents true restoration of function (recovery) or development of new strategies (compensation). This study investigated whether early motor improvements after focal cerebral ischemia reflect recovery or compensation. Adult female Wistar rats were trained to retrieve food pellets in a skilled reaching task prior to receiving a unilateral cortical infarction induced by photothrombosis in forelimb motor cortex. Animals were continuously tested in the reaching task up to 3 weeks after lesion. The end point measures revealed that reaching success rates remained at pre-lesion levels, however, qualitative analysis of reaching movements indicated permanent changes in forelimb movement patterns. Similar observations were made in a skilled walking task and a test for forelimb asymmetry. These data indicate that lesion animals adopted alternative movement strategies in order to successfully perform the tasks. The changes in postoperative performance were compared to anatomical data in individual animals. The finding that reaching success was not related to lesion size supports the idea that the degree of adaptive behavior after cortical ischemia depends on plastic properties of the remaining intact tissue.
Behavioural Brain Research, 2010
Ageing and stress represent critical influences on stroke risk and outcome. These variables are i... more Ageing and stress represent critical influences on stroke risk and outcome. These variables are intricately linked, as ageing is frequently associated with gradual dysregulation of the hypothalamic-pituitary-adrenal axis. This study determined the effects of stress on motor function in aged rats, and explored possible interactions of age and stress on motor recovery following stroke in a rat model. Young adult (4 months) and aged (18 months) male Wistar rats were tested in skilled and non-skilled movement before and after focal ischemia in motor cortex. One group of each age received restraint stress starting seven days pre-lesion until three weeks post-lesion. Aged rats were less mobile and stress further diminished their overall exploratory activity. Aged rats were also less proficient in motor skill acquisition and slower to improve after lesion. Stress diminished post-lesion improvement and prevented recovery of endpoint measures. The larger functional loss in aged rats vs. young rats was accompanied by greater damage of cortical tissue and persistent elevations in corticosterone levels. The behavioural and physiological measures suggest limited ability of aged animals to adapt to chronic stress. These findings show that age or stress alone can modulate motor performance but may have greater influence by synergistically affecting stroke recovery.
Behavioural Brain Research, 2008
Sex differences exist in skilled movement, and skilled motor performance is also influenced by st... more Sex differences exist in skilled movement, and skilled motor performance is also influenced by stress. As shown for cognitive function, the effects of stress are usually characterized by considerable sexual dimorphism. The purpose of this study was to investigate sex differences in skilled motor function in response to stress. Male and female Long-Evans rats were trained and tested in skilled reaching and skilled walking tasks. Both groups of animals were then exposed to daily restraint stress for 15 days. Recovery from daily stress was assessed by comparing reaching performance at 10 min versus 60 min after restraint stress, and recovery from chronic stress was tested for 21 days after cessation of stress. Animals were tested daily in skilled reaching for the entire period. Observations showed that females performed significantly better than males during the stress period in terms of reaching success and number of attempts needed to grasp a food pellet. No difference between testing at 10 or 60 min after daily stress was found. Analysis of movement patterns and recovery from stress indicated that males and females use different strategies to overcome stress-induced motor disturbance. While male rats preferred to use original movement patterns, females tended to modify these patterns in order to increase reaching success. Modification of movement patterns in female rats was accompanied by a faster recovery in success rate after the cessation of stress. These results indicate sex differences in skilled reaching in response to stress, and in the recovery period after stress.
Translating knowledge to practice: An occupational therapy perspective
Australian Occupational Therapy Journal, 2010
Translating knowledge to practice, also called 'knowledge translation&... more Translating knowledge to practice, also called 'knowledge translation', is increasingly recognised as a driving force to strengthen and improve the healthcare system. How knowledge translation fits with occupational therapy practice deserves examination. This paper will explore how an action process model, the Knowledge-To-Action Process, may advance knowledge translation in occupational therapy. Occupational therapists typically view knowledge in a broad sense, encompassing research, tacit knowledge, expert opinion and client evidence. The Knowledge-To-Action Process facilitates application of client, therapist and research knowledge to occupational therapy practice. Examination of knowledge translation through the lens of the Knowledge-To-Action Process creates awareness of the value of client, therapist and research knowledge. It also highlights opportunities as practitioners to implement knowledge translation. Models able to flexibly reflect an occupational therapy perspective of knowledge have a potentially vital role in successful knowledge translation. Furthermore, these models allow therapists and other stakeholders to analyse complex situations and identify targeted knowledge translation strategies.
Analyzing the barriers and supports of knowledge translation using the PEO model
Knowledge translation is a current and growing force in Canada's health c... more Knowledge translation is a current and growing force in Canada's health care environment. The intent of this paper is to examine current research related to barriers and facilitators of knowledge translation relevant to occupational therapy from the perspective of the person-environment-occupation (PEO) model. Minimum competency and best practice are established drivers of research use in occupational therapy. Knowledge translation is not only complementary to these established drivers but offers a valuable contribution to the profession. Current research offers insight into the facilitators and obstacles of knowledge translation in occupational therapy, and the PEO model provides a framework for this analysis. Several influences across different levels of the practice system may facilitate or hinder knowledge translation. Awareness of the current research related to these influences, in concert with an awareness of individual circumstances, is an essential precursor to developing more effective knowledge translation strategies.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2001
The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enha... more The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
After lesions of the developing mammalian CNS, structural plasticity and functional recovery are ... more After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible ...
Neuroscience and biobehavioral reviews, 2015
Research efforts during the past decades have provided intriguing evidence suggesting that stress... more Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal ...
Ancestral experience as a game changer in stress vulnerability and disease outcomes
BioEssays : news and reviews in molecular, cellular and developmental biology, Jan 11, 2015
Stress is one of the most powerful experiences to influence health and disease. Through epigeneti... more Stress is one of the most powerful experiences to influence health and disease. Through epigenetic mechanisms, stress may generate a footprint that propagates to subsequent generations. Programming by prenatal stress or adverse experience in parents, grandparents, or earlier generations may thus be a critical determinant of lifetime health trajectories. Changes in regulation of microRNAs (miRNAs) by stress may enhance the vulnerability to certain pathogenic factors. This review explores the hypothesis that miRNAs represent stress-responsive elements in epigenetic regulation that are potentially heritable. Recent findings suggest that miRNAs are key players linking adverse early environments or ancestral stress with disease risk, thus they represent useful predictive disease biomarkers. Since miRNA signatures of disease are potentially heritable, big data management platforms will be vital to harness multi-generational information and capture succinct yet potent biomarkers capable of...
Behavioural brain research, Jan 15, 2014
Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-te... more Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-term motor and cognitive impairments with limited therapeutic possibilities. Treatment options have proven efficient in preclinical models of cerebral ischemia but have failed in the clinical setting. This limited translation may be due to the suitability of models used and outcomes measured as most studies have focused on the early period after injury with gross motor scales, which have limited correlation to the clinical situation. The aim of this study was to determine long-term functional outcomes after cerebral ischemia in rats, focusing on fine motor function, social and depressive behavior as clinically relevant measures. A secondary objective was to evaluate the effects of an anti-inflammatory treatment (interleukin-1 receptor antagonist (IL-1Ra)) on functional recovery and compensation. Infarct volume was correlated with long-term (25 days) impairments in fine motor skills, but no...
Behavioural brain …, 2009
Previous studies have associated stress with poor outcome in individuals affected by stroke. It w... more Previous studies have associated stress with poor outcome in individuals affected by stroke. It was suggested that the effects of stress depend on the stressor's type and strength. Here we compare the effects of chronic predictable restraint stress and chronic unpredictable variable stress on motor recovery after focal lesion in the rat motor cortex. Adult male rats were pre-trained and tested in skilled reaching and skilled walking tasks. Animals were assigned to daily treatments of either restraint stress or variable stress starting 1 week prior to lesion up to 2 weeks post-lesion. One group served as lesion only control. The results revealed a distinct pattern of recovery and compensation of skilled movement. Animals exposed to predictable restraint stress had significantly lower reaching success at both pre-and post-lesion time points, and higher error rates in skilled walking when compared to lesion controls. Overall, restraint stress induced more pronounced motor impairments prior to and after injury than variable stress. Variable stress increased the number of attempts required to grasp food pellets and changed movement pattern performance. By contrast, variable stress improved limb placement accuracy when compared to lesion controls. The behavioural changes were not accompanied by differences in infarct size. These findings are in agreement with other studies reporting that both chronic predicable restraint stress and unpredictable variable stress influence the course of recovery following stroke, however, restraint stress might affect stroke recovery through a different route than variable stress.
In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate... more In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.
Any behavioral testing induces stress to some degree. A meaningful interpretation of behavioral r... more Any behavioral testing induces stress to some degree. A meaningful interpretation of behavioral results can be difficult if stress, caused by handling or the testing situation, modifies the experimental outcome. Especially for neurological animal models, it is important to know how stress affects motor and sensory performance. Therefore, we investigated the effects of varying degrees of stress on several motor and sensory tasks that are frequently used to assess functional recovery after lesion-induced impairments in adult rats. Acute, subchronic, and chronic stress impaired ladder walking and prolonged the duration of grasping a bar. Stress also altered walking patterns by increasing the base of support and foot rotation and reducing stride length. Furthermore, chronic stress induced hypersensitivity to painful stimuli, but did not significantly influence the latency to remove sticky papers from the hindpaws (sticky paper test). In the light ± dark (L/D) test, stress reduced the latency to enter the dark compartment and enhanced the number of transitions supporting that cold swim stress modifies the animal's level of anxiety. These data point towards a critical influence of acute or chronic stress on motor control and sensory performance of rats, suggesting that stress might be a critical intervening variable of the outcome of behavioral tests. D
Stress as a Modulator of Motor System Function and Pathology
Reviews in the Neurosciences, 2000
Stress is one of the most significant influences on behaviour and performance. The classical acco... more Stress is one of the most significant influences on behaviour and performance. The classical account is that stress mainly affects functions of the limbic system, such as learning, memory and emotion. Recent evidence, however, suggests that stress also modulates motor system function and influences the pathology of movement disorders. Most parts of the motor system show the presence of glucocorticoid receptors that render their circuits susceptible to the influence of stress hormones. Stress and glucocorticoids have been shown to modulate temporal and spatial aspects of motor performance. Skilled movements seem to be most prone to stress-induced disturbances, but locomotion and posture can also be affected. Stress can modulate movement through activation of the hypothalamic-pituitary-adrenal axis and via stress-associated emotional changes. The dopaminergic system seems to play a central role in mediating the effects of stress on motor function. This route might also account for the finding that stress influences the pathology of dopamine-related diseases of the motor system, such as Parkinson's disease. Clinical observations have indicated that stress might lead to the onset of Parkinsonian symptoms or accelerate their progression. Glucocorticoids are modulators of neuronal plasticity, thus determining the degree of structural and functional compensation of the damaged motor system. This may particularly affect slowly progressive neurodegenerative diseases, such as Parkinson's disease. That stress represents a significant modulator of motor system function in both the healthy and the damaged brain should be recognized when developing future therapies for neurodegenerative diseases.
Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice
Neuroscience, 2004
The growth-associated protein (GAP)-43 is a major neuronal protein associated with axonal growth,... more The growth-associated protein (GAP)-43 is a major neuronal protein associated with axonal growth, neuronal plasticity and learning. The observation that only 5-10% of mice with a full GAP-43 gene deletion survive weaning suggests that basic neural functions are disturbed. Here we used a comprehensive test battery to characterise and quantify the motor and sensory function of surviving adult homozygous GAP-43 (-/-) mice as compared with GAP-43 (+/-) and wild-type animals. The test battery was comprised of motor, sensory, and reflex tests producing 25 measures of locomotion, as well as epicritic, auditory, olfactory and visual function. The analysis revealed significant impairments in muscle strength, limb coordination and balance in GAP-43 (-/-) mice. Furthermore, GAP-43 (-/-) animals were hyperactive and showed reduced anxiety as measured by open field and light dark tests. In sensory tests, GAP-43 (-/-) mice were tested for impaired tactile and labyrinthine function. Abnormal reflexes were found in the contact and vibrissa placing responses, and in the crossed extensor reflex. GAP-43 (+/-) animals showed only moderate abnormalities as compared with wild-type animals. We conclude that GAP-43 is necessary for the development and function of a variety of neuronal systems. The results also show that the comprehensive test battery used in the present study represents a sensitive approach to assess the functional integrity of ascending and descending pathways in genetically manipulated mice.
Neuroscience, 2009
Experiential therapies, such as enriched environment (EE), have been shown to influence the neuro... more Experiential therapies, such as enriched environment (EE), have been shown to influence the neurodegenerative processes that underlie Parkinson's disease. We have previously demonstrated that EE promotes functional improvement in dopamine-depleted rats. Here we compare the influence of exposure to EE prior to versus after dopamine depletion in the 6-hydroxydopamine rat model of Parkinson's disease. Two groups of female rats were placed in an EE while two groups were housed in a standard environment (SE) for 6 weeks prior to receiving a unilateral nigrostriatal bundle infusion of the neurotoxin 6-hydroxydopamine. After the lesion, one group remained in EE, while the second EE group (Pre-Lesion EE) was moved into SE conditions. In addition, a third group of rats was now moved into EE (Postlesion EE). A fourth group remained in SE throughout the experimental period. Rats were tested in skilled reaching and skilled walking tasks and in non-skilled motor function up to 4 weeks after lesion. The observations demonstrated beneficial effects of both pre-and post-lesion exposure to EE on skilled movement performance by promoting compensatory limb use and partial protection or restoration of skilled movement. Exposure to pre-lesion EE in particular promoted structural plasticity as indicated by increased expression of the main cytoskeletal component microtubule associated protein-2 in the lesion dorsal striatum. Continuous EE showed absence of rotational bias suggesting attenuated dopamine loss. These data indicate that enriched lifestyle before the onset of motor symptoms and rehabilitation programs after diagnosis might be beneficial in patients with Parkinson's disease.
Enriched environment promotes efficiency of compensatory movements after cerebral ischemia in rats
Neuroscience, 2009
Rehabilitation therapy is known to drive motor improvement in stroke patients. However, the inter... more Rehabilitation therapy is known to drive motor improvement in stroke patients. However, the interplay of functional recovery and compensation in postischemic motor behavior is poorly understood. This study focused on the time course of functional recovery versus motor compensation in skilled forelimb movements after cerebral ischemia in rats. Young adult male rats underwent a focal cerebral ischemia by unilateral photothrombotic lesion of the motor cortex related to the preferred forelimb. In a first set of experiments animals were exposed to small cortical lesions comprising the forelimb motor cortex (n=8) or to larger lesions additionally extending into the hind limb motor area (n=8). In a second set of experiments animals with large lesion were either housed in standard (n=10) or enriched environment (n=14). Skilled reaching was assessed for 25 to 28 days postischemia. This task allows the distinction between recovery and compensation by parallel quantitative (reaching success) and qualitative (movement pattern) analysis. The results reveal that lesion size determines the initial magnitude of motor deficits, but not the degree of chronic impairments in movement pattern in all experimental groups. Compensatory movements represent the major mechanism of functional improvement and were accompanied by a partial functional restitution. Enriched environment facilitates effective compensation in skilled reaching, while it does not promote restitution of function. In particular, rotating movements of the forelimb during reaching were permanently impaired and required functional compensation through intensified use of the upper body. We conclude an activity dependent postischemic restoration of movement success. Enriched environment provides benefit by increased motor activity mainly due to compensation. Furthermore, these findings emphasize the power of comprehensive movement analysis to gain insight into recovery processes after stroke.
Validation of the Weight-Drop Contusion Model in Rats: A Comparative Study of Human Spinal Cord Injury
Journal of Neurotrauma, 2000
Animal models are widely used for studying the pathophysiology as well as treatment strategies fo... more Animal models are widely used for studying the pathophysiology as well as treatment strategies for injuries of the central nervous system. However, it is still unclear in how far the rat model of spinal cord injury (SCI) is valid for human SCI. Therefore, comparisons were made among functional, electrophysiological, and morphological outcome parameters following SCI in rats and humans. Contusion of the mid-thoracic spinal cord in 27 adult rats was induced by a weight-drop, leading to severe deficits in open field locomotion at a chronic stage. The data of 85 human patients with chronic SCI were collected and compared with the rat data. In electrophysiological recordings, prolonged latencies and reduced amplitudes in both motor evoked potentials (MEP) and somatosensory evoked potentials (SSEP) were closely correlated to the impairment of locomotor capacity of lower limbs in rats and humans. The morphological parameters assessed by high-resolution magnetic resonance imaging (MRI) in both species indicated that the lesion length and spinal cord atrophy were significantly related to the electrophysiological and functional outcome parameters. In rats, histological analysis was performed and showed, in addition to the MRI, a close relationship between spared white matter and locomotor capacity. Our results suggest an analogous relationship in rats and humans with respect to functional, electrophysiological, and morphological outcomes. Thus, the techniques for evaluating the extent and severity of SCI in humans and rats are of comparable value. This indicates that the rat can serve as an adequate animal model for research on functional and morphological changes after SCI and the effects of new treatment strategies.
Experimental Neurology, 1998
Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure... more Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5-6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2-11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery. 1998 Academic Press
The development of skilled walking in the rat
Behavioural Brain Research, 2009
The rat is an altricial species and consequently undergoes considerable postnatal development. Ca... more The rat is an altricial species and consequently undergoes considerable postnatal development. Careful analysis of the emergence and disappearance of motor behaviours is essential to gain insight into the temporal pattern of maturation of motor system structures. This study presents a qualitative analysis of the developmental progression of skilled movement in the rat by using a skilled walking task. A new rung bridge task was used to expose rat pups to a novel environment in order to reveal their potential capabilities. Ten rat pups were filmed daily from postnatal day 7 through postnatal day 30 as they explored the rung bridge task. Discrete changes in skilled and non-skilled walking in fore- and hind-limbs were evaluated by scoring seven categories and 24 subcategories of motor behaviour, including limb flexion and extension, coordination, posture, sensorimotor responses, distal control, and tail use in rat pups. Frame-by-frame analysis of ambulatory movement revealed six distinct stages of locomotor development. The most significant transformation to mature gait patterns was found between postnatal days 15 and 19, and maturation of all motor behaviour was completed by postnatal day 27. The findings are discussed in relation to the maturation of underlying structures and their relevance to studies of brain damage.
Behavioural Brain Research, 2005
Initial functional impairments after cerebral ischemia often improve considerably during the earl... more Initial functional impairments after cerebral ischemia often improve considerably during the early period after the insult. Although pathological changes associated with post-lesion improvements have been widely investigated, it has not been resolved whether behavioral improvement represents true restoration of function (recovery) or development of new strategies (compensation). This study investigated whether early motor improvements after focal cerebral ischemia reflect recovery or compensation. Adult female Wistar rats were trained to retrieve food pellets in a skilled reaching task prior to receiving a unilateral cortical infarction induced by photothrombosis in forelimb motor cortex. Animals were continuously tested in the reaching task up to 3 weeks after lesion. The end point measures revealed that reaching success rates remained at pre-lesion levels, however, qualitative analysis of reaching movements indicated permanent changes in forelimb movement patterns. Similar observations were made in a skilled walking task and a test for forelimb asymmetry. These data indicate that lesion animals adopted alternative movement strategies in order to successfully perform the tasks. The changes in postoperative performance were compared to anatomical data in individual animals. The finding that reaching success was not related to lesion size supports the idea that the degree of adaptive behavior after cortical ischemia depends on plastic properties of the remaining intact tissue.
Behavioural Brain Research, 2010
Ageing and stress represent critical influences on stroke risk and outcome. These variables are i... more Ageing and stress represent critical influences on stroke risk and outcome. These variables are intricately linked, as ageing is frequently associated with gradual dysregulation of the hypothalamic-pituitary-adrenal axis. This study determined the effects of stress on motor function in aged rats, and explored possible interactions of age and stress on motor recovery following stroke in a rat model. Young adult (4 months) and aged (18 months) male Wistar rats were tested in skilled and non-skilled movement before and after focal ischemia in motor cortex. One group of each age received restraint stress starting seven days pre-lesion until three weeks post-lesion. Aged rats were less mobile and stress further diminished their overall exploratory activity. Aged rats were also less proficient in motor skill acquisition and slower to improve after lesion. Stress diminished post-lesion improvement and prevented recovery of endpoint measures. The larger functional loss in aged rats vs. young rats was accompanied by greater damage of cortical tissue and persistent elevations in corticosterone levels. The behavioural and physiological measures suggest limited ability of aged animals to adapt to chronic stress. These findings show that age or stress alone can modulate motor performance but may have greater influence by synergistically affecting stroke recovery.
Behavioural Brain Research, 2008
Sex differences exist in skilled movement, and skilled motor performance is also influenced by st... more Sex differences exist in skilled movement, and skilled motor performance is also influenced by stress. As shown for cognitive function, the effects of stress are usually characterized by considerable sexual dimorphism. The purpose of this study was to investigate sex differences in skilled motor function in response to stress. Male and female Long-Evans rats were trained and tested in skilled reaching and skilled walking tasks. Both groups of animals were then exposed to daily restraint stress for 15 days. Recovery from daily stress was assessed by comparing reaching performance at 10 min versus 60 min after restraint stress, and recovery from chronic stress was tested for 21 days after cessation of stress. Animals were tested daily in skilled reaching for the entire period. Observations showed that females performed significantly better than males during the stress period in terms of reaching success and number of attempts needed to grasp a food pellet. No difference between testing at 10 or 60 min after daily stress was found. Analysis of movement patterns and recovery from stress indicated that males and females use different strategies to overcome stress-induced motor disturbance. While male rats preferred to use original movement patterns, females tended to modify these patterns in order to increase reaching success. Modification of movement patterns in female rats was accompanied by a faster recovery in success rate after the cessation of stress. These results indicate sex differences in skilled reaching in response to stress, and in the recovery period after stress.
Translating knowledge to practice: An occupational therapy perspective
Australian Occupational Therapy Journal, 2010
Translating knowledge to practice, also called 'knowledge translation&... more Translating knowledge to practice, also called 'knowledge translation', is increasingly recognised as a driving force to strengthen and improve the healthcare system. How knowledge translation fits with occupational therapy practice deserves examination. This paper will explore how an action process model, the Knowledge-To-Action Process, may advance knowledge translation in occupational therapy. Occupational therapists typically view knowledge in a broad sense, encompassing research, tacit knowledge, expert opinion and client evidence. The Knowledge-To-Action Process facilitates application of client, therapist and research knowledge to occupational therapy practice. Examination of knowledge translation through the lens of the Knowledge-To-Action Process creates awareness of the value of client, therapist and research knowledge. It also highlights opportunities as practitioners to implement knowledge translation. Models able to flexibly reflect an occupational therapy perspective of knowledge have a potentially vital role in successful knowledge translation. Furthermore, these models allow therapists and other stakeholders to analyse complex situations and identify targeted knowledge translation strategies.
Analyzing the barriers and supports of knowledge translation using the PEO model
Knowledge translation is a current and growing force in Canada's health c... more Knowledge translation is a current and growing force in Canada's health care environment. The intent of this paper is to examine current research related to barriers and facilitators of knowledge translation relevant to occupational therapy from the perspective of the person-environment-occupation (PEO) model. Minimum competency and best practice are established drivers of research use in occupational therapy. Knowledge translation is not only complementary to these established drivers but offers a valuable contribution to the profession. Current research offers insight into the facilitators and obstacles of knowledge translation in occupational therapy, and the PEO model provides a framework for this analysis. Several influences across different levels of the practice system may facilitate or hinder knowledge translation. Awareness of the current research related to these influences, in concert with an awareness of individual circumstances, is an essential precursor to developing more effective knowledge translation strategies.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2001
The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enha... more The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
After lesions of the developing mammalian CNS, structural plasticity and functional recovery are ... more After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible ...
Neuroscience and biobehavioral reviews, 2015
Research efforts during the past decades have provided intriguing evidence suggesting that stress... more Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal ...
Ancestral experience as a game changer in stress vulnerability and disease outcomes
BioEssays : news and reviews in molecular, cellular and developmental biology, Jan 11, 2015
Stress is one of the most powerful experiences to influence health and disease. Through epigeneti... more Stress is one of the most powerful experiences to influence health and disease. Through epigenetic mechanisms, stress may generate a footprint that propagates to subsequent generations. Programming by prenatal stress or adverse experience in parents, grandparents, or earlier generations may thus be a critical determinant of lifetime health trajectories. Changes in regulation of microRNAs (miRNAs) by stress may enhance the vulnerability to certain pathogenic factors. This review explores the hypothesis that miRNAs represent stress-responsive elements in epigenetic regulation that are potentially heritable. Recent findings suggest that miRNAs are key players linking adverse early environments or ancestral stress with disease risk, thus they represent useful predictive disease biomarkers. Since miRNA signatures of disease are potentially heritable, big data management platforms will be vital to harness multi-generational information and capture succinct yet potent biomarkers capable of...
Behavioural brain research, Jan 15, 2014
Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-te... more Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-term motor and cognitive impairments with limited therapeutic possibilities. Treatment options have proven efficient in preclinical models of cerebral ischemia but have failed in the clinical setting. This limited translation may be due to the suitability of models used and outcomes measured as most studies have focused on the early period after injury with gross motor scales, which have limited correlation to the clinical situation. The aim of this study was to determine long-term functional outcomes after cerebral ischemia in rats, focusing on fine motor function, social and depressive behavior as clinically relevant measures. A secondary objective was to evaluate the effects of an anti-inflammatory treatment (interleukin-1 receptor antagonist (IL-1Ra)) on functional recovery and compensation. Infarct volume was correlated with long-term (25 days) impairments in fine motor skills, but no...
Introduction: Preterm birth (PTB) is the world's leading cause of perinatal morbidity and mortali... more Introduction: Preterm birth (PTB) is the world's leading cause of perinatal morbidity and mortality. It has been suggested that perinatal programming by stress may increase PTB risk. We have shown that ancestral stress augments PTB risk and is linked with changes in the miR-200 family and targets (Stat5b, Zeb1 and 2) in rat uterus. We propose a two-hit hypothesis in which prenatal stressors affect the expression of genes involved in IL-1 signaling, the stress response or identified as miR200 family targets differently when combined than either hit alone.