Systemic application of therapeutics to the CNS tissue often results in subtherapeutic drug levels, because of restricted and selective penetration through the blood-brain barrier (BBB). Here, we give a detailed description of a standardized technique for intrathecal drug delivery in rodents, analogous to the technique used in humans. The intrathecal drug delivery method bypasses the BBB and thereby offers key advantages over oral or intravenous administration, such as maximized local drug doses with minimal systemic side effects. We describe how to deliver antibodies or drugs over several days or weeks from a s.c. minipump and a fine catheter inserted into the subdural space over the spinal cord (20 min operative time) or into the cisterna magna (10 min operative time). Drug levels can be sampled by quick and minimally invasive cerebrospinal fluid (CSF) collection from the cisterna magna (5 min procedure time). These techniques enable targeted application of any compound to the CNS for therapeutic studies in a wide range of CNS disease rodent models. Basic surgery skills are helpful for carrying out the procedures described in this protocol.
Motor skills represent high-precision movements performed at optimal speed and accuracy. Such motor skills are learned with practice over time. Besides practice, effects of motivation have also been shown to influence speed and accuracy of movements, suggesting that fast movements are performed to maximize gained reward over time as noted in previous studies. In rodents, skilled motor performance has been successfully modeled with the skilled grasping task, in which animals use their forepaw to grasp for sugar pellet rewards through a narrow window. Using sugar pellets, the skilled grasping task is inherently tied to motivation processes. In the present study, we performed three experiments modulating animals' motivation during skilled grasping by changing the motivational state, presenting different reward value ratios, and displaying Pavlovian stimuli. We found in all three studies that motivation affected the speed of skilled grasping movements, with the strongest effects seen due to motivational state and reward value. Furthermore, accuracy of the movement, measured in success rate, showed a strong dependence on motivational state as well. Pavlovian cues had only minor effects on skilled grasping, but results indicate an inverse Pavlovian-instrumental transfer effect on movement speed. These findings have broad implications considering the increasing use of skilled grasping in studies of motor system structure, function, and recovery after injuries.
Skilled upper limb function heavily depends on the corticospinal tract. After bilateral lesions to this tract, motor control is disrupted but can be partially substituted by other motor systems to allow functional recovery. However, the remaining roles of motor cortex and especially of axotomized corticospinal neurons (CSNs) are not well understood. Using the single pellet retrieval task in adult rats, we induced significant recovery of skilled reaching after bilateral pyramidotomy by rehabilitative reaching training, and show that reach-related motor cortex activity, recorded in layer V, topographically reappeared shortly after axotomy. Using a chemogenetic neuronal silencing technique, we found that axotomized CSNs retained a crucial role for the recovered pellet retrieval success. The axotomized CSNs sprouted extensively in the red nucleus supplying new innervation to its magnocellular and parvocellular parts. Specific silencing of the rubrospinal tract (RST) also strongly abolished the recovered pellet retrieval success, suggesting a role of this cervically projecting nucleus in relaying cortical motor control. In summary, our results show that after bilateral corticospinal axotomy, motor cortex still actively engages in forelimb motor control and axotomized CSNs are crucially involved in the recovered reaching movement, potentially by relaying motor control via the RST.
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