{"doi":"10.1002/ctm2.900","title":"The brake matters: Hyperexcitable arousal circuits in sleep fragmentation with age","abstract":"High-quality sleep is essential for maintaining our physical and mental health. However, sleep quality declines with age. Aging not only brings daytime sleepiness, difficulty falling asleep and early awakenings, it also introduces conspicuous sleep fragmentation, which is the most common reason preventing the elderly from getting a restorative sleep.1 Despite the broad awareness of its high prevalence and detrimental effect on the body, the mechanistic underpinnings of sleep instability have been underexplored. Recently, we have studied why the brain loses its control of consolidated sleep during aging with a focus on investigation of arousal-promoting neural circuits.2 We first hypothesized that the decline of sleep quality with age could be due to dysfunctional brain arousal circuits. Among these circuits, neurons producing the neuropeptide hypocretin3 (Hcrt, also known as orexin4) were very strong candidates with an established role in initiating and maintaining proper wakefulness.5-8 Using laboratory mice, we found a significant loss of Hcrt neurons in the aged group, which exhibited a more fragmented sleep pattern. By recording calcium signals using fibre photometry, we found that aged Hcrt neurons displayed a higher frequency of Hcrt neuronal GCaMP6f activity driving more frequent wake bouts. The increase in Hcrt activity amplitude necessary to generate a successful sleep-to-wake transition was smaller in old mice compared to the young group, demonstrating a lower threshold for Hcrt-induced awakenings in older mice (Figure 1A). Even though the aged group harboured fewer Hcrt neurons, optogenetic stimulation of these neurons elicited longer wake bouts compared with the young group using the same stimulation paradigm. Our in vivo optogenetic data indicated that the threshold of Hcrt neuronal activity defining sleep-to-wake transition is lower in aged mice, consistent with our calcium recording of spontaneous Hcrt activity. These data, accumulated with top-down and bottom-up strategies collectively support the hypothesis that emerging hyperexcitability of Hcrt neurons drives sleep fragmentation arising with age. To unveil the cause of increased spontaneous Hcrt neuronal activity and a higher efficiency of Hcrt neuron activation in driving wakefulness in aged mice, patch-clamp experiments were performed to determine the difference in electrophysiological properties between young and aged Hcrt neurons. The resting membrane potential (RMP) of aged Hcrt neurons was found to be depolarized, priming them to fire action potentials easier with smaller excitatory inputs. Light train optogenetic stimulation or current injection in aged Hcrt neurons expressing light-sensitive ChR2 showed more spikelet activities, further validating our hypothesis. A successful action potential is initiated with a depolarization sufficiently propelling the membrane potential to reach the firing threshold, then repolarization follows its peak appearance, and eventually the membrane potential reaches the resting state again.9 Considering the re-polarization process functions as a “brake” system of a neuron's activity, we hypothesized that potassium (K+) re-polarization currents are impaired with age. Voltage-gated potassium channels (KCNQs) allow K+ to efflux from the intracellular to extracellular space, playing a critical role in the repolarizing phase of an action potential and maintaining the RMP.10 Recording of the M-current, mediated by KCNQ2/3 channels, revealed a smaller M-current amplitude in aged Hcrt neurons confirming a potential impairment of re-polarizing ion channels in aged Hcrt neurons. Array tomography at ultra-resolution demonstrated that the expression density of KCNQ2 was lower in aged Hcrt neurons, therefore, further corroborating the impaired M-current from an anatomical perspective (Figure 1B and C). Single-nucleus RNA sequencing revealed a lower fraction of Hcrt nuclei actively expressing the dominant sub-types Kcnq1/2/3/5 mRNAs,","journal":"Clinical and Translational Medicine","year":2022,"id":299287,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":264713,"name":"Luı́s de Lecea","orcid":"0000-0002-8921-5942","position":1,"is_corresponding":false},{"id":264712,"name":"Shi‐Bin Li","orcid":"0000-0002-5699-3035","position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":null,"created_at":"2026-07-19T00:31:44.904250Z","pmid":"35696605","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}