Exploring the Connection Between the Gut Microbiome and Parkinson's Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options.

The contribution of the microbiota to induce gastrointestinal inflammation is hypothesized to be a key component of alpha-synuclein (aSyn) aggregation within the gastrointestinal (GI) tract in the pathological progression of Parkinson's disease (PD). The function of the GI tract is governed by a system of neurons that form part of the enteric nervous system (ENS). The ENS hosts  100-500 million nerve cells within two thin layers lining the GI tract. The gut-brain axis (GBA) is the major communication pathway between the ENS and the central nervous system. It has become increasingly clear that the microbiota in the gut are key regulators of GBA function and help to maintain homeostasis in the immune and endocrine systems. The GBA may act as a possible etiological launching pad for the pathogenesis of age-related neurodegenerative diseases, such as PD, because of an imbalance in the gut microbiota. PD is a multi-faceted illness with multiple biological, immunological, and environmental factors contributing to its pathological progression. Interestingly, individuals with PD have an altered gut microbiota compared to healthy individuals. However, there is a lack of literature describing the relationship between microbiota composition in the gut and symptom progression in PD patients. This review article examines how the pathology and symptomology of PD may originate from dysregulated signaling in the ENS. We then discuss by targeting the imbalance within the gut microbiota such as prebiotics and probiotics, some of the prodromal symptoms might be alleviated, possibly curtailing the pathological spread of aSyn and ensuing debilitating motor symptoms.

Canada's Colonial Genocide of Indigenous Peoples: A Review of the Psychosocial and Neurobiological Processes Linking Trauma and Intergenerational Outcomes.

The policies and actions that were enacted to colonize Indigenous Peoples in Canada have been described as constituting cultural genocide. When one considers the long-term consequences from the perspective of the social and environmental determinants of health framework, the impacts of such policies on the physical and mental health of Indigenous Peoples go well beyond cultural loss. This paper addresses the impacts of key historical and current Canadian federal policies in relation to the health and well-being of Indigenous Peoples. Far from constituting a mere lesson in history, the connections between colonialist policies and actions on present-day outcomes are evaluated in terms of transgenerational and intergenerational transmission processes, including psychosocial, developmental, environmental, and neurobiological mechanisms and trauma responses. In addition, while colonialist policies have created adverse living conditions for Indigenous Peoples, resilience and the perseverance of many aspects of culture may be maintained through intergenerational processes.

Characterizing the protracted neurobiological and neuroanatomical effects of paraquat in a murine model of Parkinson's disease.

The primary motor symptoms of Parkinson's disease (PD) result from the degeneration of dopamine-producing neurons of the substantia nigra pars compacta (SNc), and often, the loss is asymmetrical, resulting in unilateral tremor presentation. Notably, age is the primary risk factor for PD, and it is likely that the disease ultimately stems from the impact of environmental factors, which interact with the aging process. Recent research has focused on the role of microglia and pro-oxidative responses in dopaminergic neuronal death. In this study, we sought to examine the neurodegenerative, inflammatory, and stress effects of exposure to the etiologically relevant pesticide, paraquat, over time (up to 6 months after injections). We also were interested in whether a high-resolution, 7-Tesla animal magnetic resonance imaging would be sensitive enough to detect the degenerative impact of paraquat. We found that paraquat induced a loss of dopaminergic SNc neurons and activation of microglia that surprisingly did not change over 6 months after the last injection. A long-lasting reduction was evident for body weight, and alterations in organ (lung and heart) weight were evident, which reflect the peripheral impact of the toxicant. The microglial proinflammatory actin-remodeling factor, WAVE2, along with the inflammatory transcription factor, nuclear factor kappa B were also elevated within the brain. Remarkably, the stress hormone, corticosterone, was still significantly elevated 1 month after paraquat, whereas the inflammasome factor, caspase-1, and antigen presentation factor, MFG-E8, both displayed delayed rises after the 6-month time. Using high-resolution magnetic resonance imaging, we detected no striatal changes but modest hemispheric differences in the SNc and time-dependent volumetric enlargement of the ventricles in paraquat-treated mice. These data suggest that paraquat induces long-term nigrostriatal pathology (possibly asymmetric) and inflammatory changes and stress and trophic/apoptotic effects that appear to either increase with the passage of time or are evident for at least 1 month. In brief, paraquat may be a useful nonspecific means to model widespread stress and inflammatory changes related to PD or age-related disease in general, but not the progressive nature of such diseases.

In Vivo Use of a Multi-DNA Aptamer-Based Payload/Targeting System To Study Dopamine Dysregulation in the Central Nervous System.

The delivery of therapeutics across the blood-brain barrier remains a considerable challenge in investigating central nervous system related processes. In this work, a liposome vehicle was surface-modified with an aptamer that binds to the transferrin receptor and was loaded with two different dopamine-binding aptamer payloads. This system was effectively used to promote the delivery of the aptamer cargo from the peripheral injection site into the brain. The effect of these delivered aptamers on behavior was investigated in vivo in a locomotor task. The first dopamine binding aptamer assessed was a DNA aptamer, the binding of which had been previously validated through the aptamer-based biosensor development reported by several independent research groups. The second aptamer investigated was the result of a novel in vitro selection experiment described herein. Our data suggest that systemic administration of the modified liposomes led to delivery of the dopamine aptamers into the brain. Fluorescence microscopy revealed differential distribution of fluorescence based on the presence or absence of the transferrin receptor aptamer on the surface of fluorescently modified liposomes. In a behavioral experiment using cocaine administration to induce elevated concentrations of neural dopamine, systemic pretreatment with the dopamine aptamer-loaded liposomes reduced cocaine-induced hyperlocomotion. Multiple controls including a transferrin-negative liposome control and transferrin-positive liposomes loaded with either a nonbinding, base-substituted dopamine aptamer or a random oligonucleotide were investigated. None of these controls altered cocaine-induced hyperlocomotion. Chronic systemic administration of the modified liposomes produced no deleterious neurobehavioral or neural degenerative effects. Importantly, this work is one example of an application for this versatile multiaptamer payload/targeting system. Its general application is limited only by the availability of aptamers for specific neural targets.