Gerlinde A. Metz

Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore- and hindlimb stepping, placing, and co-ordination.

The ladder rung walking test is a new task to assess skilled walking and measure both forelimb and hindlimb placing, stepping, and inter-limb co-ordination. Rats spontaneously walk from a starting location to a goal along a horizontal ladder. The spacing between the rungs of the ladder is variable and can be changed to prevent the animal from learning either the absolute or relative location of the rungs. The testing procedure requires minimal training and allows detailed quantitative and qualitative analysis using video recording. The utility of the test is described with postoperative data obtained from animals with unilateral neocortical strokes produced by pial stripping over the motor cortex, neonatal and adult unilateral corticospinal tract lesions produced by tract section at the pyramids, and unilateral dopamine depletions produced by injection of 6-hydroxydopamine into the nigrostriatal bundle. In addition, a group of aged rats was examined. Deficits in limb placing, stepping and co-ordination displayed by the animals demonstrate that this test can discriminate between lesions of the motor system or age-associated impairments. The test is useful for assessing loss and recovery of function due to brain or spinal cord injury, the effectiveness of treatment therapies, as well as compensatory processes through which animals adapt to nervous system injury.

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.

Efficient testing of motor function in spinal cord injured rats.

In experimental spinal cord injury studies, animal models are widely used to examine anatomical and functional changes after different treatments and lesion types. A variety of behavioral paradigms exists in the literature, but definitions and criteria for motor performance vary considerably. In this study, we examined the outcome and relation of tests such as the BBB open field locomotion score, footprint analysis, kinematic analysis, placing response, grid walk and narrow beam crossing following two different lesion types. The information obtained was used to design an efficient and reliable testing strategy, which includes a broad spectrum of parameters to enhance sensitivity. This approach should help to standardize modular testing procedures across different laboratories working on spinal cord injury.

Enriched childhood experiences moderate age-related motor and cognitive decline

Aging is associated with deterioration of skilled manual movement. Specifically, aging corresponds with increased reaction time, greater movement duration, segmentation of movement, increased movement variability, and reduced ability to adapt to external forces and inhibit previously learned sequences. Moreover, it is thought that decreased lateralization of neural function in older adults may point to increased neural recruitment as a compensatory response to deterioration of key frontal and intra-hemispheric networks, particularly of callosal structures. However, factors that mediate age-related motor decline are not well understood. Here we show that music training in childhood is associated with reduced age-related decline of bimanual and unimanual motor skills in a MIDI keyboard motor learning task. Compared to older adults without music training, older adults with more than a year of music training demonstrated proficient bimanual and unimanual movement, evidenced by enhanced speed and decreased movement errors. Further, this group demonstrated significantly better implicit learning in the weather prediction task, a non-motor task. The performance of older adults with music training in those tasks was comparable to young adults. Older adults, however, displayed greater verbal ability compared to young adults irrespective of a past history of music training. Our results indicate that music training early in life may reduce age-associated decline of neural motor and cognitive networks.

Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health

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 models. We highlight the complex interplay between prenatal stress exposure, associated changes in miRNA expression and DNA methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety- or depression-related disorders later in life. Based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. The consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.

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 ladder rung walking task: a scoring system and its practical application.

Progress in the development of animal models for/stroke, spinal cord injury, and other neurodegenerative disease requires tests of high sensitivity to elaborate distinct aspects of motor function and to determine even subtle loss of movement capacity. To enhance efficacy and resolution of testing, tests should permit qualitative and quantitative measures of motor function and be sensitive to changes in performance during recovery periods. The present study describes a new task to assess skilled walking in the rat to measure both forelimb and hindlimb function at the same time. Animals are required to walk along a horizontal ladder on which the spacing of the rungs is variable and is periodically changed. Changes in rung spacing prevent animals from learning the absolute and relative location of the rungs and so minimize the ability of the animals to compensate for impairments through learning. In addition, changing the spacing between the rungs allows the test to be used repeatedly in long-term studies. Methods are described for both quantitative and qualitative description of both fore- and hindlimb performance, including limb placing, stepping, co-ordination. Furthermore, use of compensatory strategies is indicated by missteps or compensatory steps in response to another limb’s misplacement.

Impairment of pronation, supination, and body co-ordination in reach-to-grasp tasks in human Parkinson's disease (PD) reveals homology to deficits in animal models.

Animal (monkey, rat, mouse) models are widely used to investigate degenerative processes and potential therapeutic treatments for human Parkinsons disease (PD). One task that has proved useful in these investigations is a reach-to-grasp task (skilled reaching) in which an animal reaches for a piece of food that it then consumes. Rats with extensive unilateral Dopamine depletions are impaired in using the contralateral limb. The qualitative features of posture, lifting and advancing the limb, pronating the paw to grasp food, and in withdrawing and supinating the paw to place the food in the mouth are impaired, as is reaching success. Humans with PD are often described as having poor manual dexterity that worsens as the disease progresses. As there have been no detailed comparisons of reaching movements in the animal models and in PD subjects, the following descriptive analysis was performed. Ten subjects with PD, eight age matched controls and 14 young normal subjects were studied as they used a natural movement of reaching for a small piece of food that they then placed in the mouth to eat. The reaching movements were described using Eshkol-Wachman Movement Notation (EWMN), supplemented with kinematic analyses. From this description, a 21-point rating scale was devised to describe the component movements of the reach. Movements included: orienting the head and eyes to the target, adjusting posture, lifting the hand, shaping and aiming the digits to the target, pronating the hand to grasping the food with a pincer grip, lifting and supinating the hand to transporting the food to the mouth, and further supinating the hand and opening the digits to place food in the mouth, and finally returning the hand to the starting position. Analysis indicated that most aspects of the reaching movements of the PD subjects were significantly different relative to both young control subjects and old control subjects. As compared to the control groups, postural and reaching components of the movements were fragmented, movements were achieved using more proximal segments of the body, and rotatory movements of the hand were limited. The PD subjects did use a pincer grasp to obtain the food, but the grasp was less independent of other digit movements than was observed in the control subjects. These results are discussed in terms of a homology to impairments displayed animal models of PD.

Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring

The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.

Regeneration and sprouting of chronically injured corticospinal tract fibers in adult rats promoted by NT-3 and the mAb IN-1, which neutralizes myelin-associated neurite growth inhibitors.

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.