Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in na & iuml;ve rats. Female Sprague-Dawley rats were imaged with [C-11]UCB-J (n = 11) or [F-18]fluorodeoxyglucose ([F-18]FDG) PET (n = 13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30 min). We calculated the regional volume of distribution (V-T) for [C-11]UCB-J and standard uptake values (SUV) for [F-18]FDG. We observed regional reductions of [C-11]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [F-18]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30 min can modulate in vivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

Parkinson's disease (PD) is a debilitating neurodegenerative multisystem disorder leading to motor and non-motor symptoms in millions of individuals. Despite intense research, there is still no cure, and early disease biomarkers are lacking. Animal models of PD have been inspired by basic elements of its pathogenesis, such as dopamine dysfunction, alpha-synuclein accumulation, neuroinflammation and disruption of protein degradation, and these have been crucial for a deeper understanding of the mechanisms of pathology, the identification of biomarkers, and evaluation of novel therapies. Imaging biomarkers are non-invasive tools to assess disease progression and response to therapies; their discovery and validation have been an active field of translational research. Here, we highlight different considerations of animal models of PD that can be applied to future research, in terms of their suitability to answer different research questions. We provide the reader with important considerations of the best choice of model to use based on the disease features of each model, including issues related to different species. In addition, positron emission tomography studies conducted in PD animal models in the last 5 years are presented. With a variety of different species, interventions and genetic information, the choice of the most appropriate model to answer research questions can be daunting, especially since no single model recapitulates all aspects of this complex disorder. Appropriate animal models in conjunction with in vivo molecular imaging tools, if selected properly, can be a powerful combination for the assessment of novel therapies and developing tools for early diagnosis.

Pain is a common non-motor symptom of Parkinson's disease (PD), which often occurs in the early disease stages. Despite the high prevalence, it remains inadequately treated. In a hemi-parkinsonian rat model, we aimed to investigate the neurochemical factors involved in orofacial pain development, with a specific focus on pain-related peptides and cannabinoid receptors. We also evaluated whether treadmill exercise could improve orofacial pain and modulate these mechanisms. Rats were unilaterally injected in the striatum with either 6-hydroxydopamine (6-OHDA) or saline. Fifteen days after stereotactic surgery, the animals were submitted to treadmill exercise (EX), or remained sedentary (SED). Pain assessment was performed before the surgical procedure and prior to each training session. Pain-related peptides, substance P (SP), calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid type 1 (TRPV1) activation and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated in the trigeminal nucleus. In order to confirm the possible involvement of cannabinoid receptors, we also injected antagonists of CB1 and CB2 receptors. We confirmed the presence of orofacial pain after unilateral 6-OHDA-injection, which improved after aerobic exercise training. We also observed increased pain-related expression of SP, CGRP and TRPV1 and decreased CB1 and CB2 in the trigeminal ganglion and caudal spinal trigeminal nucleus in animals with PD, which was reversed after aerobic exercise training. In addition, we confirm the involvement of cannabinoid receptors since both antagonists decreased the nociceptive threshold of PD animals. These data suggest that aerobic exercise effectively improved the orofacial pain associated with the PD model, and may be mediated by pain-related neuropeptides and cannabinoid receptors in the trigeminal system.

Physical exercise benefits Parkinson’s disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and animal models. We test the hypothesis that binding of the CB1R inverse agonist, [3H]SR141716A, is normalized by treadmill exercise in the toxin-induced 6-hydroxydopamine (6-OHDA) model of PD. Male rats had unilateral striatal injections of 6-OHDA or saline. After 15 days, half were submitted to treadmill exercise and half remained sedentary. [3H]SR141716A autoradiography was performed in postmortem tissue from striatum, substantia nigra (SN) and hippocampus. There was a 41% decrease of [3H]SR141716A specific binding in the ipsilateral SN of 6-OHDA-injected sedentary animals which was attenuated to 15% by exercise, when compared to saline-injected animals. No striatal differences were observed. A 30% bilateral hippocampal increase was observed in both healthy and 6-OHDA exercised groups. In addition, a positive correlation between nigral [3H]SR141716A binding and nociceptive threshold was observed in PD-exercised animals (p = 0.0008), suggesting a beneficial effect of exercise in the pain associated with the model. Chronic exercise can reduce the detrimental effects of PD on nigral [3H]SR141716A binding, similar to the reported reduction after dopamine replacement therapy, so should be considered as an adjunct therapy for PD.

Parkinson's disease (PD) has motor alterations as typical symptoms; however, there are also a high prevalence of nonmotor symptoms such as pain, balance, depression with high impact on patient quality life. Pain is present in around of 85% of PD patients and is associated with abnormal processing in central areas of pain pathway, and opioid and endocannabinoid system can be involved. Physical exercise has beneficial effects on PD, improving motor and nonmotor symptoms. This chapter aimed to highlight studies that report the effectiveness of the intervention through exercise on nonmotor symptoms of patients and animal models of PD, focusing on opioid and endocannabinoid system. In general, the exercise and physical activity can improve many PD symptoms; it helps maintain balance, mobility, and the ability to perform daily routines. That physical activity can play a preventive and maintenance role of physical fitness and mental health for patients with PD and consequently improve quality of life of PD patients.

Background: Vagus nerve stimulation (VNS) has been explored as an adjunct treatment for neurological disorders, such as epilepsy, chronic migraine, pain, and depression, as well as for its potential modulation of the immune response. A non-invasive form of VNS is transcutaneous auricular VNS (aVNS). The combination of animal models with non-invasive brain imaging may lead to a better understanding of its mechanisms. The aim of this study was to evaluate the acute effect of electrical stimulation of the left vagus nerve on brain glucose metabolism in naïve rat. Methods: Five female Sprague-Dawley rats were anesthetised with isoflurane and imaged with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) on two separate days, 1) at baseline, and 2) after a unilateral aVNS protocol initiated 10 minutes after 18F-FDG injection. The protocol consisted of 30 minutes of unilateral aVNS (left ear – 500-ms train of 15 biphasic pulses every 30s (0.8 mA, 30 Hz, 100 μs)). PET acquisition on both days was performed for 30 minutes at 45 minutes after 18F-FDG injection, and data were analyzed using PMODÔ. Standard uptake values (SUV) of the brain regions of interest were calculated. Baseline versus aVNS data were compared with paired t tests for each brain region, and significance was set at p < 0.05. Results: Significantly decreased 18F-FDG uptake was observed bilaterally in ventral tegmental area (13.5%), nucleus accumbens (11%), amygdala (14%), hypothalamus (13%) and hippocampus (10%) after aVNS. Conclusions: This proof-of-concept study shows decreased subcortical glucose metabolism in vivo in response to acute aVNS. The reduced uptake in limbic brain regions may, for example, shed light on the antidepressant potential of aVNS. We suggest that the use of disease models undergoing acute or chronic brain stimulation, and PET ligands of different targets, may be a powerful combination to assess the therapeutic potential of aVNS. Research Category and Technology and Methods Basic Research: 12. Vagus Nerve Stimulation (VNS) Keywords: auricular vagus nerve stimulation, glucose metabolism, brain metabolism, non-invasive therapy

•A pressure sensitive gait mat is a useful tool for quantitative motor assessment.•Pressure sensitive gait mats are simple alternatives to camera-sensor based systems.•The gait of minipigs displays symmetry and a slightly frontal center of gravity.•Subtle motor deterioration is detectable after lesions affecting the motor system.•Lesion-compensatory dynamics involve decreased velocity and increased stance time.

ABSTRACT. Clinical trials of the effects of physical activity have reported improvements in symptoms and quality of life in patients with Parkinson's disease (PD). Additionally, morphological brain changes after exercising were reported in PD animal models. However, these lifestyle-related changes were not evaluated in postmortem brain tissue. Objective: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules — MAP2) changes in postmortem brain samples of individuals with Lewy body pathology. Methods: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Aging Studies were classified into active (n=12) and non-active (n=12) groups, according to physical activity lifestyle, and paired by age, sex and Braak staging. Substantia nigra and basal ganglia were evaluated. Results: Groups were not different in terms of age or gender and had similar PD neuropathological burden (p=1.00). We observed higher TH expression in the active group in the substantia nigra and the basal ganglia (p=0.04). Astrocytes was greater in the non-active subjects in the midbrain (p=0.03) and basal ganglia (p=0.0004). MAP2 levels were higher for non-active participants in the basal ganglia (p=0.003) and similar between groups in the substantia nigra (p=0.46). Neurofilament levels for non-active participants were higher in the substantia nigra (p=0.006) but not in the basal ganglia (p=0.24). Conclusion: Active lifestyle seems to promote positive effects on brain by maintaining dopamine synthesis and structural protein expression in the nigrostriatal system and decrease astrogliosis in subjects with the same PD neuropathology burden.

Parkinson's disease (PD) is a progressive disabling brain disorder. Physical exercise has been shown to alleviate the symptoms of PD and, consequently, improve patient quality of life. Exercise mechanisms involved in beneficial effects on PD have been widely investigated. This study aims to systematically review the literature on the use of treadmill exercise in PD animal models. The study was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Searches were conducted in MEDLINE, EMBASE, and ISI databases. In total, 78 studies were included. The dopaminergic system, behavior, neuroplasticity, neuroinflammation, mitochondria, and musculoskeletal systems were some of the outcomes evaluated by the selected studies. Based on the systematic review center for laboratory animal experimentation (SYRCLE) RoB tool, the methodologies revealed a high risk of bias and lack of information about study design, which needs attention for data reproducibility. This review can guide future studies that aim to fill existing gaps regarding the effects of treadmill exercise in PD animal models.

The lifestyle choices of modern society, such as lack of physical activity, overeating, and poor sleep habits can lead to neuroinflammation which is detrimental to a number of processes in the brain and has been linked to accelerated brain aging, and psychiatric and neurological diseases. Exercise protocols have been described as potential non-pharmacological interventions to protect against, or reverse, the adverse effects of lifestyle habits on the brain. In this chapter, we focus on previous evidence of the beneficial effects of treadmill exercise on reducing neuroinflammation and its links with the aging process and neurodegenerative diseases.

Parkinson’s disease (PD) is typicaly caractherized by loss of dopaminergic neurons, as well as the presence of mitochondrial impairments. Although physical exercise is known to promote many beneficial effects in healthy subjects, such as enhancing mitocondrial biogenesis and function, it is not clear if these effects are evident after exercise in individuals with PD. The aim of this study was to investigate the effects of two different protocol durations on motor behavior (aphomorphine and gait tests), mitochondrial biogenesis signaling (PGC-1α, NRF-1 and TFAM), structure (oxidative phosphorylation system protein levels) and respiratory chain activity (complex I) in a unilateral PD rat model. For this, male Wistar rats were injected with 6-hydroxydopamine unilaterally into the striatum and submitted to an intermitent moderate treadmill exercise for one or four weeks. In the gait test, only stride width data revealed an improvement after one week of exercise. On the other hand, after 4 weeks of the exercise protocol all gait parameters analyzed and the aphomorphine test demonstrated a recovery. Analysis of protein revealed that one week of exercise was able to prevent PGC-1α and NRF-1 expression decrease in PD animals. In addition, after four weeks of physical exercise, besides PGC-1α and NRF-1, reduction in TFAM and complex I protein levels and increased complex I activity were also prevented in PD animals. Thus, our results suggest a neuroprotective and progressive effect of intermittent treadmill exercise, which could be related to its benefits on mitochondrial biogenesis signaling and respiratory chain modulation of the dopaminergic system in PD.