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Role of the basal forebrain in sleep loss induced attention impairments

基底前脑在睡眠不足引起的注意力障碍中的作用

基本信息

批准号：
10620170
负责人：
ROBERT E STRECKER
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-10-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620170
关键词：
3-Dimensional Acceleration Accidents Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Arousal Association Learning Attention Attentional deficit Auditory Basic Science Behavior Behavioral Chronic Insomnia Cognition Cognitive Cues Data Dementia Discrimination Disease Drowsiness Electrophysiology (science)Excessive Daytime Sleepiness Fiber Frequencies Future Goals Grant Health Human Hunger Impaired cognition Impairment In Vitro Incidence Investigation Knowledge Lasers Lead Learning Light Literature Measures Mediating Mental Depression Methods Modeling Motivation Mus Neurons Parvalbumins Pathway interactions Pattern Performance Photometry Physiological Population Post-Traumatic Stress Disorders Productivity Proxy Reaction Time Regulation Reporting Rewards Rodent Role Schizophrenia Self Stimulation Sensory Signal Transduction Sleep Sleep Apnea Syndromes Sleep Deprivation Sleep Disorders Sleep disturbances Substance Use Disorder Symptoms Task Performances Testing Therapeutic Time Traumatic Brain Injury Veterans Visual Wakefulness Work Workplace alertness attentional control basal forebrain basal forebrain cholinergic neurons behavior measurement behavior test brain circuitry conditioned place preference experimental study habituation improved in vivo military veteran mouse model novel novel therapeutics optogenetics pharmacologic predictive modeling receptor response sensory cortex sensory stimulus side effect sustained attention therapy development vigilance

项目摘要

Sleep loss and sleep disorders (e.g., sleep apnea) lead to excessive daytime sleepiness and impaired attention & cognition. The symptoms of sleep disturbance are now recognized as major contributors to accident rates and decreased workplace productivity. Attention, concentration, and cognitive problems are also a major feature of other disorders that are prevalent in US veterans – e.g., TBI, PTSD, Alzheimer's disease, depression, substance use disorder, and schizophrenia. Understanding the brain circuitry controlling attention will guide the development of treatments to ameliorate the attention and cognitive impairments of these conditions. Abundant evidence indicates that the basal forebrain (BF) region contains cortically projecting & wakefulness promoting neurons that are important for cortical activation, behavioral arousal/alertness, and attention. Although previous work has focused on the role of BF cholinergic neurons in attention, advances in optogenetic methods allow the investigation of BF parvalbumin (PV) containing GABAergic neurons. Work on our current Merit grant indicates that selective excitation of BF PV neurons in mice produces cortical activation, wakefulness, and behavioral arousal. Our new preliminary data suggest that excitation of BF PV neurons can enhance attention, cognition, and rescue reaction time performance impairments produced by sleep loss. The findings described led us to two testable hypotheses: 1) BF PV neurons mediate rapid changes in alertness/attention by quickly activating the cortex in response to meaningful or surprising sensory stimuli. 2) Excitation of BF PV neurons does not alter motivation (e.g., hunger) and is not rewarding indicating these neurons can enhance attention and cognition with limited side effects and low addictive potential. Our model prediction: In response to meaningful or surprising sensory stimuli, BF PV neurons briefly activate the cortex, enhancing cortical processing and alertness which facilitates attention-dependent reaction time performance and associative learning. The work will address a gap in our knowledge by demonstrating that regulation of cortical activation by BF PV neurons is important for the control of attention. Methods used include fiber photometry to measure the activity of BF PV neurons and optogenetics to excite and inhibit these neurons in mice; both will be combined with behavioral tests and measures of cortical electrical activity. The 3 aims are: Aim 1 will demonstrate that increasing and decreasing the activity of BF PV neurons can modulate cortical responses to repetitive presentations of sensory stimuli. This finding will provide a plausible mechanism for how these neurons enhance the attention dependent behavioral performance studied in Aims 2 & 3. Aim 2 will demonstrate that BF PV excitation enhances sustained attention and performance in a mouse reaction time test like the test used in humans to detect sleepiness and sustained attention deficits. Experiments will demonstrate that sleep deprivation (SD) and BF PV inhibition slows reaction times, whereas BF PV excitation will quicken reaction times and will rescue deficits produced by SD. Aim 3. Attention is also important for learning and here BF PV manipulations are used to alter the attention needed for associative learning. Our predictions, supported by preliminary data, are that BF PV excitation enhances associative learning by broadcasting `surprise' signals to the cortex that are encoded in high frequency cortical gamma oscillations, and that BF PV excitation does not affect reward pathways. We also predict that BF PV inhibition and SD will impair attention-dependent associative learning. If successful, this project will show that the BF PV neuron excitation model enhances attention and cognition with limited side effects and low addictive potential. This model can be readily applied to mouse models of other conditions that are prevalent in the US Veteran population. Future work could also identify novel therapeutics to pharmacologically target receptors on BF PV neurons in order to activate them.

睡眠不足和睡眠障碍（如睡眠呼吸暂停）导致白天过度嗜睡和受损

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior.

DOI：
10.1007/s00429-021-02288-7
发表时间：
2021-07
期刊：
Brain structure & function
影响因子：
3.1
作者：
McKenna JT;Yang C;Bellio T;Anderson-Chernishof MB;Gamble MC;Hulverson A;McCoy JG;Winston S;Hodges E;Katsuki F;McNally JM;Basheer R;Brown RE
通讯作者：
Brown RE

Basal Forebrain Parvalbumin Neurons Mediate Arousals from Sleep Induced by Hypercarbia or Auditory Stimuli.

DOI：
10.1016/j.cub.2020.04.029
发表时间：
2020-06-22
期刊：
Current biology : CB
影响因子：
0
作者：
McKenna JT;Thankachan S;Uygun DS;Shukla C;McNally JM;Schiffino FL;Cordeira J;Katsuki F;Zant JC;Gamble MC;Deisseroth K;McCarley RW;Brown RE;Strecker RE;Basheer R
通讯作者：
Basheer R

Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia.

上行唤醒系统的光遗传学操纵可调节皮质宽带伽马功率，并揭示与精神分裂症相关的功能缺陷。

DOI：
10.1038/s41380-020-0840-3
发表时间：
2021-07
期刊：
Molecular psychiatry
影响因子：
11
作者：
McNally JM;Aguilar DD;Katsuki F;Radzik LK;Schiffino FL;Uygun DS;McKenna JT;Strecker RE;Deisseroth K;Spencer KM;Brown RE
通讯作者：
Brown RE

Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression.