Activation of glucagon-like peptide-1 receptors and skilled reach foraging.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exendin-4 (Ex4), liraglutide and dulaglutide, regulate glucose homeostasis and are thus used to treat diabetes type II. GLP-1 also contributes towards a variety of additional physiological functions, including suppression of reward and improvement of learning. Acute activation of GLP-1R in the nucleus accumbens (NAc) shell, an area essential for motivation, reduces the motivation to consume sucrose or alcohol when assessed in a simple motor task. However, the effects of repeated administration of the different GLP-1R agonists on behaviours in a more complex motor task are unknown. The aim was therefore to investigate the effects of repeated Ex4, liraglutide or dulaglutide on the motivation and learning of a complex motor tasks such as skilled reach foraging in the Montoya staircase test. To explore the neurophysiological correlates of the different GLP-1R agonists on motivation, ex vivo electrophysiological recordings were conducted. In rats with an acquired skilled reach performance, Ex4 or liraglutide but not dulaglutide reduced the motivation of skilled reach foraging. In trained rats, Ex4 infusion into NAc shell decreased this motivated behaviour, and both Ex4 and liraglutide supressed the evoked field potentials in NAc shell. In rats without prior Montoya experience, dulaglutide but not Ex4 or liraglutide enhanced the learning of skilled reach foraging. Taken together, these findings indicate that the tested GLP-1R agonists have different behavioural outcomes depending on the context.

The topographic specificity of muscle reinnervation predicts function.

Functional testing has assumed a progressively dominant role in validating the success of experimental nerve repair. Results obtained in one model, however, cannot predict the results in others because they reflect the coordinated interaction of several muscles across multiple joints. As a result, many combinations of topographically correct and incorrect muscle reinnervation could produce the same result. We have developed a binary model in which elbow flexors and extensors are reinnervated, and elbow flexion and extension are the functions tested. The musculocutaneous and radial nerves of Lister-Hooded rats were subjected to axonotmetic injuries that produced increasing degrees of axonal misdirection at the site of injury ranging from simple crush to transection and rotational offset of proximal and distal stumps. Elbow function was tested with a device that requires coordinated elbow extension to reach sugar pellets and flexion to return them to the mouth. After 12 weeks of regeneration, motoneurons projecting to the distal musculocutaneous nerve were retrogradely labelled with WGA-Ruby and scored regarding their location within musculocutaneous or radial motoneuron pools. The severity of axonal misdirection resulting from the initial surgery was mirrored by progressive degrees of inappropriate reinnervation of the musculocutaneous nerve by radial nerve axons. The specificity of reinnervation predicted elbow function (r = 0.72), whereas the number of motoneurons regenerating did not. This model is thus well suited to study the interaction of regeneration specificity and function across a single joint, and to produce data that can be generalized more broadly than those obtained from more complex models.

Refining forelimb asymmetry analysis: Correlation with Montoya staircase contralateral function post-stroke.

BACKGROUND: Forelimb Asymmetry Test is a simple test of motor function, using exploration behavior of a rat in a novel environment and counting the number of times that a rat touches the wall with either forepaw. Our lab has noticed, however, that there appears to be an increased number of fingertip touches to the wall following a stroke in the impaired forelimb. NEW METHOD: We counted the number of times that the animal either laid its palm flat against the wall of the chamber or touched the wall with only its fingertips, for both the left and right forepaws. We also separated bouts of exploration, so we could clearly determine if fingertip touches normally were associated with a transition from resting state to exploration state. RESULTS AND COMPARISON WITH EXISTING METHODS: Fishers exact test indicated that there were significant differences in the way that the animals touched the wall pre-stroke compared to post-stroke, with more fingertip touches occurring post-stroke. Counting palm touches as normal and fingertip touches as abnormal increases the sensitivity of the Forelimb Asymmetry analysis and gives a good correlation with the contralateral functional deficits determined by Montoya Staircase post-stroke. If we counted every wall touch as normal (palm touches and fingertip touches), we see a loss of sensitivity and a poor correlation with contralateral function as determined by Montoya Staircase. CONCLUSIONS: This refinement of the Forelimb Asymmetry analysis improves correlation with Montoya Staircase contralateral function after stroke.

Oral methylphenidate alleviates the fine motor dysfunction caused by chronic postnatal manganese exposure in adult rats.

Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. Rats were orally exposed to 0 or 50 mg Mn/kg/day from postnatal day 1 until the end of the study (PND 145). The staircase test was used to assess skilled forelimb function. Oral MPH (2.5 mg/kg/day) was administered daily 1 h before staircase testing for 16 days. DA and NE levels were measured by dual probe microdialysis. Results show that Mn exposure impaired reaching and grasping skills and the evoked release of DA and NE in the PFC and striatum of adult rats. Importantly, oral MPH treatment fully alleviated the fine motor deficits in the Mn-exposed animals, but did not affect forelimb skills of control rats not exposed to Mn. These results suggest that catecholaminergic hypofunctioning in the PFC and striatum may underlie the Mn-induced fine motor dysfunction, and that oral MPH pharmacotherapy is an effective treatment approach for alleviating this dysfunction in adult animals. The therapeutic potential of MPH for the treatment of motor dysfunction in Mn-exposed children and adults appears promising pending further characterization of MPH efficacy in other functional areas (eg, attention) believed to be affected by developmental Mn exposure.