Brain Molecular Mechanisms Research Articles

Aquaporin-4 and Parkinson's Disease.

The water-selective channel aquaporin-4 (AQP4) is implicated in water homeostasis and the functioning of the glymphatic system, which eliminates various metabolites from the brain tissue, including amyloidogenic proteins. Misfolding of the α-synuclein protein and its post-translational modifications play a crucial role in the development of Parkinson's disease (PD) and other synucleopathies, leading to the formation of cytotoxic oligomers and aggregates that cause neurodegeneration. Human and animal studies have shown an interconnection between AQP4 dysfunction and α-synuclein accumulation; however, the specific role of AQP4 in these mechanisms remains unclear. This review summarizes the current knowledge on the role of AQP4 dysfunction in the progression of α-synuclein pathology, considering the possible effects of AQP4 dysregulation on brain molecular mechanisms that can impact α-synuclein modification, accumulation and aggregation. It also highlights future directions that can help study the role of AQP4 in the functioning of the protective mechanisms of the brain during the development of PD and other neurodegenerative diseases.

Metabolomic, proteomic, and transcriptomic changes in adults with epilepsy on modified Atkins diet.

High-fat and low-carbohydrate diets can reduce seizure frequency in some treatment-resistant epilepsy patients, including the more flexible modified Atkins diet (MAD), which is more palatable, mimicking fasting and inducing high ketone body levels. Low-carbohydrate diets may shift brain energy production, particularly impacting neuron- and astrocyte-linked metabolism. We evaluated the effect of short-term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to control participants consuming a nonmodified higher carbohydrate diet (n= 6 MAD, mean age=43.7 years, range=21-53, diet for average 10 days; n= 10 control, mean age=41.9 years, range=28-64). By metabolomics, there were 13 increased metabolites in plasma (n= 15 participants with available specimens), which included 4.10-fold increased ketone body 3-hydroxybutyric acid, decreased palmitic acid in cortex (n= 16), and 11 decreased metabolites in hippocampus (n= 6), which had top associations with mitochondrial functions. Cortex and plasma 3-hydroxybutyric acid levels had a positive correlation (p= .0088, R2 = .48). Brain proteomics and RNAseq identified few differences, including 2.75-fold increased hippocampal MT-ND3 and trends (p< .01, false discovery rate > 5%) in hippocampalnicotinamideadeninedinucleotide(NADH)-related signaling pathways (activated oxidative phosphorylation and inhibited sirtuin signaling). Short-term MAD was associated with metabolic differences in plasma and resected epilepsy brain tissue when compared to control participants, in combination with trending expression changes observed in hippocampal NADH-related signaling pathways. Future studies should evaluate how brain molecular mechanisms are altered with long-term MAD in a larger cohort of epilepsy patients, with correlations to seizure frequency, epilepsy syndrome, and other clinical variables. [Clinicaltrials.gov NCT02565966.].

Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure

Alcohol use disorder (AUD) is highly comorbid with depression. Withdrawal from chronic alcohol drinking results in depression and understanding brain molecular mechanisms that drive withdrawal-related depression is important for finding new drug targets to treat these comorbid conditions. Here, we performed RNA sequencing of the rat hippocampus during withdrawal from chronic alcohol drinking to discover key signaling pathways involved in alcohol withdrawal-related depressive-like behavior. Data were analyzed by weighted gene co-expression network analysis to identify several modules of co-expressed genes that could have a common underlying regulatory mechanism. One of the hub, or highly interconnected, genes in module 1 that increased during alcohol withdrawal was the transcription factor, signal transducer and activator of transcription 3 (Stat3), a known regulator of immune gene expression. Total and phosphorylated (p)STAT3 protein levels were also increased in the hippocampus during withdrawal after chronic alcohol exposure. Further, pSTAT3 binding was enriched at the module 1 genes Gfap, Tnfrsf1a, and Socs3 during alcohol withdrawal. Notably, pSTAT3 and its target genes were elevated in the postmortem hippocampus of human subjects with AUD when compared with control subjects. To determine the behavioral relevance of STAT3 activation during alcohol withdrawal, we treated rats with the STAT3 inhibitor stattic and tested for sucrose preference as a measure of anhedonia. STAT3 inhibition alleviated alcohol withdrawal-induced anhedonia. These results demonstrate activation of STAT3 signaling in the hippocampus during alcohol withdrawal in rats and in human AUD subjects, and suggest that STAT3 could be a therapeutic target for reducing comorbid AUD and depression.

Phenotyping in Mice Using Continuous Home Cage Monitoring and Ultrasonic Vocalization Recordings.

Over the last century, the study of mouse behavior has uncovered insights into brain molecular mechanisms while revealing potential causes of many neurological disorders. To this end, researchers have widely exploited the use of mutant strains, including those generated in mutagenesis screens and those produced using increasingly sophisticated genome engineering technologies. It is now relatively easy to access mouse models carrying alleles that faithfully recapitulate changes found in human patients or bearing variants of genes that provide data on those genes' functions. Concurrent with these developments has been an appreciation of the limitations of some current testing platforms, especially those monitoring complex behaviors. Out-of-cage observational testing is useful in describing overt persistent phenotypes but risks missing sporadic or intermittent events. Furthermore, measuring the progression of a phenotype, potentially over many months, can be difficult while relying on assays that may be susceptible to changes in the testing environment. In recent years, there has also been increasing awareness that measurement of behaviors in isolation can be limiting, given that mice attempt to hide behavioral cues of vulnerability. To overcome these limitations, laboratory animal science is capitalizing on progress in data capture and processing expertise. Moreover, as additional recording modes become commonplace, ultrasonic vocalization recording is an appealing focus, as mice use vocalizations in various social contexts. Using video and audio technologies, we record the voluntary, unprovoked behaviors and vocalizations of mice in social groups. Adoption of these approaches is undoubtedly set to increase, as they capture the round-the-clock behavior of mouse strains. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Continuous recording of home cage activity using the Home Cage Analyzer (HCA) system Support Protocol: Subcutaneous insertion of a radio frequency identification microchip in the inguinal area Basic Protocol 2: Continuous recording of mouse ultrasonic vocalizations in the home cage.

101. Brain molecular mechanisms of glucocorticoid resistance

101. Brain molecular mechanisms of glucocorticoid resistance