The Role Of Paraventricular Nucleus Of Thalamus In Time-Restricted Feeding Intervention In High-Fat Diet Induced Sleepiness

Overweight and obesity have become epidemic diseases in some countries and regions,and their complications have also become a serious health concern.Obesity is the result of the interaction of multiple factors,such as heredity and the environment,and diet is a major contributor to obesity.Among numerous obesity-related complications,excessive daytime sleepiness(EDS)seriously threatens the safety of life and work.Hence,it is urgent to determine the mechanism and treatment of EDS induced by an obesogenic diet.Time-restricted feeding(TRF)has been shown to alleviate weight gain and metabolic diseases induced by high-fat diet(HFD).Preliminary findings have suggested that TRF regulates the sleep/wake cycle,while the neural mechanisms are poorly understood.Paraventricular thalamus(PVT),which is located at the bottom of the third ventricle,is an important part of the cerebral limbic system.PVT is not only involved in regulating arousal,feeding,reward and various adaptive behaviors but also closely associated with food anticipatory activity.In conclusion,it is speculated that HFD may damage the function of the PVT and thus wakefulness maintenance in mice,while TRF could prevent and treat HFD-induced impaired PVT and fragmented wakefulness.In view of this,multiple techniques including polysomnography,slice patch clamp recordings,in vivo multi-channel recordings,electron microscopy and chemogenetics were used to explore the neural mechanism of HFD in wakefulness maintenance and TRF in wakefulness protection.The main research content of this thesis is summarized as follows:(1)This thesis found that the activity of PVT neurons was impaired by chronic HFD feeding: Ad libitum HFD decreased neuronal activity,reduced synaptic number,damaged synaptic transmission efficiency,and caused imbalance of the excitatory/inhibitory ratio of PVT neurons,which may affect their regulation of sleep-wake cycle.(2)The important role of HFD-induced PVT impairment in the fragmented wakefulness of obesity was clarified: EDS symptoms such as those of obese patients were observed in the HFD-induced obese mice,including decreased integrity of nocturnal(active phase of mice)wakefulness and sleepiness.Inactivation of PVT neurons in lean mice could mimick chronic HFD-induced fragmented wakefulness and sleepiness,whereas enhancing PVT neuronal activity could consolidate integrity of wakefulness of the active phase in obese mice.(3)It was verified that TRF could prevent and treat fragmented wakefulness induced by chronic HFD: 4～8 h TRF feeding patterns could effectively abrogate and reverse the damage of PVT synaptic transmission induced by chronic HFD.Correspondingly,TRF effectively prevented and treated the fragmented wakefulness and nocturnal sleepiness induced by HFD.(4)HFD-induced impairment in feeding-related brain regions was further explored:Chronic HFD also impaired synaptic transmission of some brain regions related to feeding and reward,which provided a basis for the study of the neural mechanism of obesity overeating.In conclusion,this research found that chronic HFD impaired function of the PVT and disrupted the integrity of active phase wakefulness in mice.TRF could effectively prevent and reverse HFD-induced PVT impairment and fragmented wakefulness.TRF could be a potential lifestyle-based intervention to resist EDS induced by an obesogenic diet and obesity.However,the neurological impairment of HFD goes beyond this.HFD remodeled the synaptic transmission of brain regions involved in feeding,which also revealed the neural mechanism of overeating in obese patients partly.