Longitudinal assessment of skilled forelimb motor impairments in DJ-1 knockout rats.

BACKGROUND: DJ-1 knockout (DJ-1 KO) rats exhibit a moderate parkinsonian phenotype, with gross motor deficits and ca. 50% loss of midbrain dopaminergic neurons appearing around 6-8 months of age. Fine motor impairments are often observed in Parkinson's disease (PD), but skilled motor function in recently developed transgenic rat models of PD is not well characterized. OBJECTIVES: To assess the longitudinal performance of DJ-1 KO rats on a skilled forelimb reaching task. METHODS: DJ-1 KO and wild-type (WT) rats were trained from 2 to 10 months of age on an isometric pullbar task designed to test forelimb strength and coordination. After 36 consecutive weeks of training (ca. 10 months old), task difficulty was then increased to challenge the motor capabilities of the DJ-1 KO rats. Throughout the study, subjects also received weekly assessments of gross locomotor activity in an open field. RESULTS: Pull-task performance of the DJ-1 KO rats was impaired compared to WT, with deficits reaching significance around 7-9 months of age. When challenged, DJ-1 KO rats were able to exert increased force on the pullbar but continued to exhibit deficits compared to WT rats. Throughout the study, no differences in distance traveled or rearing frequency were observed in the open field, but DJ-1 KO rats were found to spend significantly more time in the center of the open field than WT rats. CONCLUSIONS: Using a sensitive, automated assay of forelimb strength and coordination, we find that skilled forelimb motor performance is impaired in DJ-1 KO rats.

Vagus Nerve Stimulation Induced Motor Map Plasticity Does Not Require Cortical Dopamine.

Background: Vagus nerve stimulation (VNS) paired with motor rehabilitation is an emerging therapeutic strategy to enhance functional recovery after neural injuries such as stroke. Training-paired VNS drives significant neuroplasticity within the motor cortex (M1), which is thought to underlie the therapeutic effects of VNS. Though the mechanisms are not fully understood, VNS-induced cortical plasticity is known to depend on intact signaling from multiple neuromodulatory nuclei that innervate M1. Cortical dopamine (DA) plays a key role in mediating M1 synaptic plasticity and is critical for motor skill acquisition, but whether cortical DA contributes to VNS efficacy has not been tested. Objective: To determine the impact of cortical DA depletion on VNS-induced cortical plasticity. Methods: Rats were trained on a skilled reaching lever press task prior to implantation of VNS electrodes and 6-hydroxydopamine (6-OHDA) mediated DA depletion in M1. Rats then underwent training-paired VNS treatment, followed by cortical motor mapping and lesion validation. Results: In both intact and DA-depleted rats, VNS significantly increased the motor map representation of task-relevant proximal forelimb musculature and reduced task-irrelevant distal forelimb representations. VNS also significantly increased tyrosine hydroxylase (TH+) fiber density in intact M1, but this effect was not observed in lesioned hemispheres. Conclusion: Our results reveal that though VNS likely upregulates catecholaminergic signaling in intact motor cortices, DA itself is not required for VNS-induced plasticity to occur. As DA is known to critically support M1 plasticity during skill acquisition, our findings suggest that VNS may engage a unique set of neuromodulatory signaling pathways to promote neocortical plasticity.

Preparation of Peripheral Nerve Stimulation Electrodes for Chronic Implantation in Rats.

Peripheral nerve cuff electrodes have long been used in the neurosciences and related fields for stimulation of, for example, vagus or sciatic nerves. Several recent studies have demonstrated the effectiveness of chronic VNS in enhancing central nervous system plasticity to improve motor rehabilitation, extinction learning, and sensory discrimination. Construction of chronically implantable devices for use in such studies is challenging due to rats' small size, and typical protocols require extensive training of personnel and time-consuming microfabrication methods. Alternatively, commercially available implantable cuff electrodes can be purchased at a significantly higher cost. In this protocol, we present a simple, low-cost method for construction of small, chronically implantable peripheral nerve cuff electrodes for use in rats. We validate the short and long-term reliability of our cuff electrodes by demonstrating that VNS in ketamine/xylazine anesthetized rats produces decreases in breathing rate consistent with activation of the Hering-Breuer reflex, both at the time of implantation and up to 10 weeks after device implantation. We further demonstrate the suitability of the cuff electrodes for use in chronic stimulation studies by pairing VNS with skilled lever press performance to induce motor cortical map plasticity.