Exercise mimetics are a proposed class of therapeutics that specifically mimic or enhance the therapeutic effects of exercise. Increased physical activity has demonstrated positive effects in ...preventing and ameliorating a wide range of diseases, including brain disorders such as Alzheimer disease and dementia, cancer, diabetes and cardiovascular disease. This article discusses the molecular mechanisms and signalling pathways associated with the beneficial effects of physical activity, focusing on effects on brain function and cognitive enhancement. Emerging therapeutic targets and strategies for the development of exercise mimetics, particularly in the field of central nervous system disorders, as well as the associated opportunities and challenges, are discussed.
The last decade has witnessed an exponentially growing interest in gut microbiota and the gut-brain axis in health and disease. Accumulating evidence from preclinical and clinical research indicate ...that gut microbiota, and their associated microbiomes, may influence pathogenic processes and thus the onset and progression of various diseases, including neurological and psychiatric disorders. In fact, gut dysbiosis (microbiota dysregulation) has been associated with a range of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and motor neuron disease, as well as multiple sclerosis. The gut microbiota constitutes a dynamic microbial system constantly challenged by many biological variables, including environmental factors. Since the gut microbiota constitute a changeable and experience-dependent ecosystem, they provide potential therapeutic targets that can be modulated as new interventions for dysbiosis-related disorders, including neurodegenerative diseases. This article reviews the evidence for environmental modulation of gut microbiota and its relevance to brain disorders, exploring in particular the implications for neurodegenerative diseases. We will focus on three major environmental factors that are known to influence the onset and progression of those diseases, namely exercise, diet and stress. Further exploration of environmental modulation, acting via both peripheral (e.g. gut microbiota and associated metabolic dysfunction or ‘metabolopathy’) and central (e.g. direct effects on CNS neurons and glia) mechanisms, may lead to the development of novel therapeutic approaches, such as enviromimetics, for a wide range of neurological and psychiatric disorders.
Huntington's disease (HD) is an extraordinary disorder that usually strikes when individuals are in the prime of their lives, as was the case for the influential 20th century musician Woody Guthrie. ...HD demonstrates the exceptionally fine line between life and death in such ‘genetic diseases’, as the only difference between those who suffer horribly and die slowly of this disease is often just a handful of extra tandem repeats (beyond the normal polymorphic range) in a genome that constitutes over 3 billion paired nucleotides of DNA. Furthermore, HD presents as a complex and heterogenous combination of psychiatric, cognitive and motor symptoms, so can appear as an unholy trinity of ‘three disorders in one’. The autosomal dominant nature of the disorder is also extremely challenging for affected families, as a ‘flip of a coin’ dictates which children inherit the mutation from their affected parent, and the gene-negative family members bear the burden of caring for the other half of the family that is affected. In this review, we will focus on one of the earliest, and most devastating, symptoms associated with HD, depression, which has been reported to affect approximately half of gene-positive HD family members. We will discuss the pathogenesis of HD, and depressive symptoms in particular, including molecular and cellular mechanisms, and potential genetic and environmental modifiers. This expanding understanding of HD pathogenesis may not only lead to novel therapeutic options for HD families, but may also provide insights into depression in the wider population, which has the greatest burden of disease of any disorder and an enormous unmet need for new therapies.
Here, we present a protocol that allows comparison of the effects of the standard home cage, environmentally enriched home cage with additional super-enrichment, and the exercise (running wheels ...only) home cage in laboratory mice. We first describe the steps to assemble these three types of cages, respectively. We then detail the assembly of super-enrichment arenas, which provide additional stimulation beyond that provided by home-cage enrichment. This protocol can help to improve reproducibility of results from studies involving environmental enrichment and exercise by offering consistent housing conditions between laboratories.
For complete details on the use and execution of this protocol, please refer to Gubert et al. (2021).
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•Protocol to modify levels of sensory, cognitive, and physical activity in laboratory mice•Steps to assemble standard cages, environmental enrichment cages, and exercise cages•Steps to assemble a super-enrichment arena•This protocol can be applied to other rodent models, including disease models
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Here, we present a protocol that allows comparison of the effects of the standard home cage, environmentally enriched home cage with additional super-enrichment, and the exercise (running wheels only) home cage in laboratory mice. We first describe the steps to assemble these three types of cages, respectively. We then detail the assembly of super-enrichment arenas, which provide additional stimulation beyond that provided by home-cage enrichment. This protocol can help to improve reproducibility of results from studies involving environmental enrichment and exercise by offering consistent housing conditions between laboratories.
The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of ...microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by
d
-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.
Gut dysbiosis in Huntington's disease (HD) has recently been reported using microbiome profiling in R6/1 HD mice and replicated in clinical HD. In HD mice, environmental enrichment (EE) and exercise ...(EX) were shown to have therapeutic impacts on the brain and associated symptoms. We hypothesize that these housing interventions modulate the gut microbiome, configuring one of the mechanisms that mediate their therapeutic effects observed in HD. We exposed R6/1 mice to a protocol of either EE or EX, relative to standard-housed control conditions, before the onset of gut dysbiosis and motor deficits. We characterized gut structure and function, as well as gut microbiome profiling using 16S rRNA sequencing. Multivariate analysis identified specific orders, namely Bacteroidales, Lachnospirales and Oscillospirales, as the main bacterial signatures that discriminate between housing conditions. Our findings suggest a promising role for the gut microbiome in mediating the effects of EE and EX exposures, and possibly other environmental interventions, in HD mice.
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•Gastrointestinal structure and motility are intact at an early stage in a HD mouse model•There is sexual dimorphism in the presentation of the HD gut dysbiosis phenotype•Bacteroidales, Lachnospirales and Oscillospirales bacteria are affected by experience•Environmental enrichment and exercise may modulate HD via the microbiota-gut-brain axis
Disease; Microbiology; Microbiome
Rationale
An important goal of addiction research is to discover neurobiological markers that could predict the severity of addiction and help to determine appropriate treatment. Brain-derived ...neurotrophic factor (BDNF) and thiobarbituric acid reactive substances (TBARS) are being related to cerebral plasticity and impairment caused by substance abuse.
Objectives
This study aims to evaluate alteration of TBARS and BDNF levels among crack cocaine users during early drug withdrawal and its relationship to severity of drug use.
Methods
Forty-nine adults crack cocaine users were recruited at a public psychiatric hospital with a specialized addiction treatment unit. Blood sample was collected at intake and discharge for the analysis of TBARS and BDNF measures. Information about drug use was assessed by the Addiction Severity Index 6th Version (ASI-6). Detailed information about crack cocaine use was obtained through the “Profile of the crack cocaine user.” Severity of crack use was estimated using information from age of first crack use, years of crack use, and crack rocks used in the previous 30 days.
Results
There is a positive correlation between TBARS levels and severity of crack cocaine use (
R
= 0.304,
p
= 0.04) and a negative correlation between BDNF and severity of crack cocaine use (
R
= −0.359,
p
= 0.01) at discharge. Also, we found an inverse correlation between TBARS and BDNF levels (
R
= −0.294,
p
= 0.004) at discharge.
Conclusions
Our findings suggest that BDNF and TBARS could be possible markers for the severity of drug use. Further studies may show how those markers could be related to staging, prognosis, and treatment in crack cocaine dependence.
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