Significance: When we are awake, purposeful thinking and behavior require the synchronization of brain cells involved in different aspects of the same task. Cerebral cortex electrical oscillations in the gamma (30–80 Hz) range are particularly important in such synchronization. In this report we identify a particular subcortical cell type which has increased activity during waking and is involved in activating the cerebral cortex and generating gamma oscillations, enabling active cortical processing. Abnormalities of the brain mechanisms controlling gamma oscillations are involved in the disordered thinking typical of neuropsychiatric disorders such as schizophrenia. Thus, these findings may pave the way for targeted therapies to treat schizophrenia and other disorders involving abnormal cortical gamma oscillations.

Sleep is one of the most pervasive biological phenomena, but one whose function remains elusive. Although many theories of function, indirect evidence, and even common sense suggest sleep is needed for an increase in brain energy, brain energy levels have not been directly measured with modern technology. We here report that ATP levels, the energy currency of brain cells, show a surge in the initial hours of spontaneous sleep in wake-active but not in sleep-active brain regions of rat. The surge is dependent on sleep but not time of day, since preventing sleep by gentle handling of rats for 3 or 6 h also prevents the surge in ATP. A significant positive correlation was observed between the surge in ATP and EEG non-rapid eye movement delta activity (0.5–4.5 Hz) during spontaneous sleep. Inducing sleep and delta activity by adenosine infusion into basal forebrain during the normally active dark period also increases ATP. Together, these observations suggest that the surge in ATP occurs when the neuronal activity is reduced, as occurs during sleep. The levels of phosphorylated AMP-activated protein kinase (P-AMPK), well known for its role in cellular energy sensing and regulation, and ATP show reciprocal changes. P-AMPK levels are lower during the sleep-induced ATP surge than during wake or sleep deprivation. Together, these results suggest that sleep-induced surge in ATP and the decrease in P-AMPK levels set the stage for increased anabolic processes during sleep and provide insight into the molecular events leading to the restorative biosynthetic processes occurring during sleep.

Various behavioral and physiological pathways follow a pre-determined, 24 hour cycle known as the circadian rhythm. Metabolic homeostasis is regulated by the circadian rhythm. Time-restricted eating (TRE) is a type of intermittent fasting based on the circadian rhythm. In this study, we aim to analyze systemically the effects of TRE on body weight, body composition, and other metabolic parameters. We reviewed articles from PubMed, EMBASE, and the Cochrane Library to identify clinical trials that compared TRE to a regular diet. We included 19 studies for meta-analysis. Participants following TRE showed significantly reduced body weight (mean difference (MD), −0.90; 95% confidence interval (CI): −1.71 to −0.10) and fat mass (MD: −1.58, 95% CI: −2.64 to −0.51), while preserving fat-free mass (MD, −0.24; 95% CI: −1.15 to 0.67). TRE also showed beneficial effects on cardiometabolic parameters such as blood pressure (systolic BP, MD, −3.07; 95% CI: −5.76 to −0.37), fasting glucose concentration (MD, −2.96; 95% CI, −5.60 to −0.33), and cholesterol profiles (triglycerides, MD: −11.60, 95% CI: −23.30 to −0.27). In conclusion, TRE is a promising therapeutic strategy for controlling weight and improving metabolic dysfunctions in those who are overweight or obese. Further large-scale clinical trials are needed to confirm these findings and the usefulness of TRE.

Understanding the control of sleep–wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep–wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that “selective” stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recentin vitrostudy from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of “selective” optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneousin vivomicrodialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons.SIGNIFICANCE STATEMENTOptogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel “opto-dialysis” probe to couple optogenetics andin vivomicrodialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of “opto-dialysis” for dissecting the complex brain circuitry underlying behavior.

This study investigates the brain functional connectivity in the rest and sleep states. We collected EEG, EOG, and fNIRS signals simultaneously during rest and sleep phases. The rest phase was defined as a quiet wake-eyes open (w_o) state, while the sleep phase was separated into three states; quiet wake-eyes closed (w_c), non-rapid eye movement sleep stage 1 (N1), and non-rapid eye movement sleep stage 2 (N2) using the EEG and EOG signals. The fNIRS signals were used to calculate the cerebral hemodynamic responses (oxy-, deoxy-, and total hemoglobin). We grouped 133 fNIRS channels into five brain regions (frontal, motor, temporal, somatosensory, and visual areas). These five regions were then used to form fifteen brain networks. A network connectivity was computed by calculating the Pearson correlation coefficients of the hemodynamic responses between fNIRS channels belonging to the network. The fifteen networks were compared across the states using the connection ratio and connection strength calculated from the normalized correlation coefficients. Across all fifteen networks and three hemoglobin types, the connection ratio was high in the w_c and N1 states and low in the w_o and N2 states. In addition, the connection strength was similar between the w_c and N1 states and lower in the w_o and N2 states. Based on our experimental results, we believe that fNIRS has a high potential to be a main tool to study the brain connectivity in the rest and sleep states.