In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation.

One of the main hallmarks of Parkinson's disease (PD) is abnormal alpha-synuclein (α-syn) aggregation which forms the main component of intracellular Lewy body inclusions. This short report used preformed α-syn fibrils, as well as an A53T mutant α-syn adenovirus to mimic conditions of pathological protein aggregation in dopaminergic human derived SH-SY5Y neural cells. Since there is evidence that the mTOR pathway and glutamatergic signaling each influence protein aggregation, we also assessed the impact of the mTOR inhibitor, rapamycin and the mGluR5 allosteric modulator, CTEP.

Brain-derived neurotrophic factor (BDNF) has direct anti-inflammatory effects on microglia.

Microglia are the primary immunocompetent cells that protect the brain from environmental stressors, but can also be driven to release pro-inflammatory cytokines and induce a cytotoxic environment. Brain-derived neurotrophic factor (BDNF) is important for the regulation of plasticity, synapse formation, and general neuronal health. Yet, little is known about how BDNF impacts microglial activity.

Mood disturbances in Parkinson's disease: From prodromal origins to application of animal models.

Parkinson's disease (PD) is a complex illness with a constellation of environmental insults and genetic vulnerabilities being implicated. Strikingly, many studies only focus on the cardinal motor symptoms of the disease and fail to appreciate the major non-motor features which typically occur early in the disease process and are debilitating. Common comorbid psychiatric features, notably clinical depression, as well as anxiety and sleep disorders are thought to emerge before the onset of prominent motor deficits.

Neuroimmune multi-hit perspective of coronaviral infection.

It is well accepted that environmental stressors experienced over a one's life, from microbial infections to chemical toxicants to even psychological stressors, ultimately shape central nervous system (CNS) functioning but can also contribute to its eventual breakdown. The severity, timing and type of such environmental "hits", woven together with genetic factors, likely determine what CNS outcomes become apparent. This focused review assesses the current COVID-19 pandemic through the lens of a multi-hit framework and disuses how the SARS-COV-2 virus (causative agent) might impact the brain and potentially interact with other environmental insults.

LRRK2 and WAVE2 regulate microglial-transition through distinct morphological phenotypes to induce neurotoxicity in a novel two-hit in vitro model of neurodegeneration.

We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live-cell imaging was used to characterize transition through distinct morphological phenotypes, production of reactive oxygen species (ROS), formation of reactive microglial aggregates, and subsequent cytokine production. Transwell cultures were used to determine microglial migration (control and lipopolysaccharide (LPS) treated) to glutamate pre-stressed or healthy neurons.

Microglia and BDNF at the crossroads of stressor related disorders: Towards a unique trophic phenotype.

Stressors ranging from psychogenic/social to neurogenic/injury to systemic/microbial can impact microglial inflammatory processes, but less is known regarding their effects on trophic properties of microglia. Recent studies do suggest that microglia can modulate neuronal plasticity, possibly through brain derived neurotrophic factor (BDNF). This is particularly important given the link between BDNF and neuropsychiatric and neurodegenerative pathology.

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.

The impact of dextran sodium sulphate and probiotic pre-treatment in a murine model of Parkinson's disease.

Background: Recent work has established that Parkinson's disease (PD) patients have an altered gut microbiome, along with signs of intestinal inflammation. This could help explain the high degree of gastric disturbances in PD patients, as well as potentially be linked to the migration of peripheral inflammatory factors into the brain. To our knowledge, this is the first study to examine microbiome alteration prior to the induction of a PD murine model.

Depression, dementia and immune dysregulation.

Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer's disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia.

Erythropoietin modulates striatal antioxidant signalling to reduce neurodegeneration in a toxicant model of Parkinson's disease.

The current study sought to characterize the pro-survival effects of erythropoietin (EPO) in a toxicant model of Parkinson's disease (PD). EPO treatment induced time-dependent elevations of antioxidant glutathione peroxidase (GPx) and anti-apoptotic factors (pAkt and pBad/Bad) within the striatum and substantia nigra pars compacta (SNc). Intriguingly, our results indicated a region- and lesion size- dependence of pro-survival effects of EPO.

Early life stress facilitates synapse premature unsilencing to enhance AMPA receptor function in the developing hippocampus.

Chronic early life stress (ELS) increases vulnerability to psychopathologies and cognitive deficits in adulthood by disrupting the function of related neural circuits. However, whether this disruption emerges early in the developing brain remains largely unexplored. In the current study, using an established limited-bedding and nesting model of ELS in postnatal day (P)2-10 mice, we provide direct evidence that ELS caused early modification of hippocampal glutamatergic synapses in the developing brain.

Alleviating toxic α-Synuclein accumulation by membrane depolarization: evidence from an in vitro model of Parkinson's disease.

Parkinson's disease (PD) is characterized by the formation of toxic, fibrillar form alpha-synuclein (α-Syn) protein aggregates in dopaminergic neurons. Accumulating evidence has shown a multifactorial interplay between the intracellular calcium elevation and α-Syn dynamics. However, whether membrane depolarization regulates toxic α-Syn aggregates remains unclear.

Microglia depletion prior to lipopolysaccharide and paraquat treatment differentially modulates behavioral and neuronal outcomes in wild type and G2019S LRRK2 knock-in mice.

Background: Substantial data have implicated microglial-driven neuroinflammation in Parkinson's disease (PD) and environmental toxicants have been long expected as triggers of such inflammatory processes. Of course, these environmental insults act in the context of genetic vulnerability factors and in this regard, leucine rich repeat kinase 2 (LRRK2), may play a prominent role.

Methods: We used a double hit, lipopolysaccharide (LPS; endotoxin) followed by paraquat (pesticide toxicant) model of PD in mice with the most common LRRK2 mutation G2019S, knockin mice and wild type littermates.

Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration.

Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease and many inflammatory processes. Thus, we assessed the role of LRRK2 in the context of endotoxin (lipopolysaccharide, LPS)-induced inflammation of the substantia nigra together with the environmental toxicant, paraquat, that has been implicated in PD. Here we found that LRRK2 ablation prevented the loss of dopaminergic neurons and behavioral deficits (motor) induced by LPS priming followed by paraquat exposure.

Quantum dot conjugated saporin activates microglia and induces selective substantia nigra degeneration.

Parkinson's disease (PD) is characterized by profound microglial driven inflammatory processes and the loss of dopamine neurons of the substantia nigra (SNc). Both microglia and dopamine neurons that are affected in the SNc are particularly vulnerable to environmental toxicants and finding more selective ways of targeting these cell types is of importance. Quantum dots (QDs) might be a useful vehicle for selectively delivering toxicants to microglia and owing to their fluorescent capability, they can be microscopically tracked within the cell.

Early life selective knockdown of the TrkB receptor and maternal separation modulates adult stress phenotype.

Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been implicated in mood and anxiety disorders and is upregulated by antidepressants. It has marked effects on synaptic and extra-synaptic plasticity through tropomyosin receptor kinase B (TrkB). Importantly, early life stressors that affect BDNF production are known to predispose individuals towards the later development of depression or anxiety disorders.

alleles modulate inflammation during microbial infection of mice in a sex-dependent manner.

Variants in the leucine-rich repeat kinase-2 () gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested this hypothesis in two ways.

Chronic unpredictable stress influenced the behavioral but not the neurodegenerative impact of paraquat.

The impact of psychological stressors on the progression of motor and non-motor disturbances observed in Parkinson's disease (PD) has received little attention. Given that PD likely results from many different environmental "hits", we were interested in whether a chronic unpredictable stressor regimen would act additively or possibly even synergistically to augment the impact of the toxicant, paraquat, which has previously been linked to PD. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering glucocorticoid receptor (GR) expression in the hippocampus.

Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype.

Background: Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease (PD) and is also thought to be fundamentally involved in numerous immune functions. Thus, we assessed the role of LRRK2 in the context of the effects of the environmental toxicant, paraquat, that has been implicated in PD and is known to affect inflammatory processes.

Methods: Male LRRK2 knockout (KO) and transgenic mice bearing the G2019S LRRK2 mutation (aged 6-8 months) or their littermate controls were exposed to paraquat (two times per week for 3 weeks), and sickness measures, motivational scores, and total home-cage activity levels were assessed.

Paraquat Exposure Increases Oxidative Stress Within the Dorsal Striatum of Male Mice With a Genetic Deficiency in One-carbon Metabolism.

Paraquat is an herbicide that is commonly used worldwide. Exposure to paraquat results in Parkinson's disease (PD)-like symptoms including dopaminergic cell loss. Nutrition has also been linked in the pathogenesis of PD, such as reduced levels of folic acid, a B-vitamin, and component of one-carbon metabolism.

Perinatal antibiotic exposure alters composition of murine gut microbiota and may influence later responses to peanut antigen.

Background: Accumulating evidence suggests that the gut microbiota shapes developmental processes within the immune system. Early life antibiotic use is one factor which may contribute to immune dysfunction and the recent surge in allergies by virtue of its effects on gut microbiota.

Objective And Methods: As a first step towards determining whether a relationship exists between perinatal antibiotic induced changes in the gut microbiota and the later development of a peanut allergy, we exposed newborn mice to either the broad-spectrum antibiotic vancomycin or to a vehicle for 6 weeks and then used a novel murine model of peanut allergy.

Profiling changes in cortical astroglial cells following chronic stress.

Recent studies have suggested that cortical astroglia play an important role in depressive-like behaviors. Potential astroglial contributions have been proposed based on their known neuroplastic functions, such as glutamate recycling and synaptic plasticity. However, the specific mechanisms by which astroglial cells may contribute or protect against a depressive phenotype remain unknown.

Feeding-State-Dependent Modulation of Temperature Preference Requires Insulin Signaling in Drosophila Warm-Sensing Neurons.

Starvation is life-threatening and therefore strongly modulates many aspects of animal behavior and physiology [1]. In mammals, hunger causes a reduction in body temperature and metabolism [2], resulting in conservation of energy for survival. However, the molecular basis of the modulation of thermoregulation by starvation remains largely unclear.

The impact of murine LRRK2 G2019S transgene overexpression on acute responses to inflammatory challenge.

The most common Parkinson's disease (PD) mutation is the gain-of-function LRRK2 G2019S variant, which has also been linked to inflammatory disease states. Yet, little is known of the role of G2019S in PD related complex behavioral or immune/hormonal processes in response to inflammatory/toxicant challenges. Hence, we characterized the behavioral, neuroendocrine-immune and central monoaminergic responses in G2019S overexpressing mutants following systemic interferon-gamma (IFN-γ) or lipopolysaccharide (LPS) administration.