ABSTRACT
Study Objectives: Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related illnesses. Family studies indicate that chronotype is a heritable trait, thus directing attention toward its genetic basis. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWAS), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. This review discusses the findings of these landmark GWASs in the context of prior research. Methods: We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype. Results: A good deal of consistency was observed across studies with 9 genes identified in 2 of the 3 GWASs. Several genes previously unknown to influence chronotype were identified. Conclusions: GWAS is an important tool in identifying common variants associated with the complex chronotype phenotype, the findings of which can supplement and guide molecular science. Future directions in model systems and discovery of rare variants are discussed.
Subject(s)
Circadian Rhythm/genetics , Genome-Wide Association Study/methods , Sleep/genetics , Animals , Humans , Phenotype , White People/geneticsABSTRACT
Diabetes and Alzheimer's disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator-activating receptor gamma (PPARγ), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer's disease. However, direct molecular signaling targets that improve memory by PPARγ in the hippocampus have not been investigated. We compared outcomes from oral versus intracerebroventricular (ICV) administration of rosi on memory and changes in synaptic plasticity in type 2 diabetic (db/db) mice. Db/db mice treated with rosi (ICV) showed significant improvement in memory, long-term potentiation, and post-tetanic potentiation but did not improve peripheral insulin sensitivity. Gene and protein analysis revealed increased brain-derived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPARγ regulation of BDNF promoter activity. Transient transfection of constitutively active PPARγ plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPARγ-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cognition Disorders/etiology , Cognition Disorders/therapy , Diabetes Mellitus, Type 2/complications , Gene Expression/drug effects , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacology , Neuronal Plasticity/drug effects , Neuronal Plasticity/genetics , PPAR gamma/agonists , PPAR gamma/physiology , Thiazolidinediones/administration & dosage , Thiazolidinediones/pharmacology , Administration, Oral , Animals , Cognition Disorders/genetics , Cognition Disorders/psychology , Disease Models, Animal , Hippocampus/metabolism , Injections, Intraventricular , Insulin Resistance , Male , Memory/drug effects , Mice, Inbred C57BL , Molecular Targeted Therapy , PPAR gamma/metabolism , RosiglitazoneABSTRACT
Smoking during pregnancy is associated with long lasting, hippocampus dependent, cognitive deficits in children. The current study was performed to investigate the effect of prenatal nicotine exposure on excitatory synaptic physiology and cellular signaling in the hippocampus using a rodent model. Excitatory synaptic physiology was analyzed using electrophysiological methods to detect changes in synaptic plasticity, excitatory synaptic transmission and synaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the hippocampus. Additionally, western blot experiments were performed to quantify alterations in protein expression levels in the hippocampus. Prenatal nicotine exposure resulted in a decrease in long term potentiation (LTP) and an increase in long term depression (LTD). Basal synaptic transmission was also reduced with a concomitant decline in AMPAR mediated synaptic currents at the cellular and single channel levels. Presynaptic pool of vesicles docked close to release sites were also diminished in nicotine exposed rats. Moreover, reduced levels of ß2 subunit containing nicotinic receptors and extracellular signal regulated kinase1/2 (ERK1/2) were observed in nicotine exposed rats. These results suggest that long lasting alterations in excitatory synaptic physiology, AMPAR synaptic currents and ERK1/2 signaling may serve as the molecular mechanisms for cognitive deficits associated with prenatal nicotine exposure.
