Traumatic brain injury and aging: targeting the cholinergic system for deficits in sustained attention and executive function

创伤性脑损伤和衰老：针对胆碱能系统的持续注意力和执行功能缺陷

• 批准号: 10847725
• 负责人: Corina Oana Bondi
• 金额: $ 3.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10847725
• 关键词: Abbreviations; Acetylcholine; Acetylcholinesterase; Address; Affect; Age Years; Aging; Agonist; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Anti-Inflammatory Agents; Anxiety; Attention; Behavior; Behavioral; Biological Markers; Brain; Brain region; Choline O-Acetyltransferase; Chronic; Clinic; Cognition; Cognitive; Combined Modality Therapy; Complex; Corpus striatum structure; Cytoskeleton; Dimensions; Dorsal; Elderly; Exhibits; Exposure to; Female; Functional disorder; Glial Fibrillary Acidic Protein; Goals; Growth; Hippocampus; Housing; Impaired cognition; Impairment; Impulsivity; Individual; Injury; Ipsilateral; Laboratories; Learning; Mass Spectrum Analysis; Measures; Mediating; Memory; Menstrual cycle; Mental Depression; Modeling; Motivation; Motor; Neurobiology; Neuron-Specific Enolase; Neurons; Neurotransmitters; Nicotinic Receptors; Parietal; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacotherapy; Play; Pre-Clinical Model; Predisposition; Process; Proteins; Proteomics; Psychopathology; Rattus; Reaction Time; Regulation; Rehabilitation therapy; Reporting; Research Personnel; Rewards; Risk; Role; Serum; Short-Term Memory; Signal Transduction; Survivors; Synaptic plasticity; System; Testing; Therapeutic; Tissues; Translating; Traumatic Brain Injury; United States; Western Blotting; Woman; affective disturbance; age related; aged; arm; behavior test; behavioral impairment; behavioral outcome; bench-to-bedside translation; cholinergic; clinically relevant; cognitive process; controlled cortical impact; desensitization; design; environmental enrichment for laboratory animals; executive function; falls; flexibility; frontotemporal degeneration; male; methyllycaconitine; neurobehavior; neurobehavioral; neurogenesis; neurological rehabilitation; neuroprotection; neurotransmission; novel; positive allosteric modulator; pre-clinical; predictive marker; premature; receptor; rehabilitation research; response; self-reported anxiety; sustained attention; therapeutic target; tool; transmission process; young adult

Traumatic brain injury (TBI) impacts 2.8 million individuals in the US each year, with older adults over 65 years being at greater risk. Survivors exhibit long-lasting cognitive impairments and psychopathologies, such as anxiety, and are more susceptible for Alzheimer's disease and related dementias, such as frontotemporal degeneration. TBI models have typically not focused on complex attentional impairments, which are common in most TBIs, such as deficits of sustained attention, goal-directed behavior, and cognitive flexibility. The cholinergic system is an important modulator of cognition, with nicotinic receptors (nACHRs) found throughout the brain. The α7 receptors play important roles in attention, working memory, reward, as well as in neuroprotective and anti-inflammatory pathways. Positive allosteric modulators (PAMs) of α7 nAChRs are novel and promising therapeutic tools that can potentiate α7 currents in the presence of endogenous acetylcholine, display high receptor selectivity, and may provide neuroprotective effects. Type I PAMs enhance agonist-evoked peak currents without delaying desensitization and do not reactivate desensitized receptors. Therefore, this New/Early Stage Investigator R01 application aims to a) assess cognitive-behavioral and anxiety-like dimensions sensitive to both TBI and aging, b-c) evaluate potential benefits of subacute (7 days) and chronic (4 weeks) administration of NS 1738, a Type I PAM, alone or in combination with abbreviated environmental enrichment (EE), a preclinical rehabilitation model, on attentional dysfunction after TBI in young adult and aged rats, as well as d) address mechanistic questions regarding altered cholinergic neurotransmission responsible for such behavioral deficits by investigating proteomic and neurotransmitter regulation markers in relevant brain regions. Specifically, the aims are designed to 1) evaluate interactions of moderate parietal TBI and aging on sustained attention (3- choice serial reaction time task), cognitive flexibility (attentional set-shifting test), and anxiety-like responses (elevated plus-maze test), 2) assess age-dependent effects of the combined approach of NS 1738 treatment and abbreviated EE (4hrs daily) to restore neurobehavioral function, as well as test receptor selectivity by blocking α7 nAChRs with methyllycaconitine, 3) quantitate proteomic profiling using mass spectrometry to identify key biomarkers (tissue and serum) correlating with neurobiological responses to aging, brain trauma, and treatment paradigms, and 4) measure brain markers of cholinergic transmission (e.g., choline acetyltransferase, acetylcholinesterase, vesicular cholinergic transporter, α7 nAChRs), as they correlate with neurobehavior. Studies will employ both male and normal cycling female rats, as women represent up to 45% of TBIs, with injuries occurring independent of menstrual cycles. Integrating animal models of higher-order attention after TBI, as well as assessing pharmacotherapy- and rehabilitation-related cholinergic and proteomic regulation in relevant cortical regions is pivotal to developing treatment approaches relevant to the clinic.

脑外伤（TBI）每年影响美国280万人，老年人超过65岁 面临更大的风险。幸存者暴露了长期持久的认知障碍和心理病理学，例如 焦虑，并且更容易患阿尔茨海默氏病和相关痴呆症，例如额颞 退化。 TBI模型通常不关注复杂的注意力障碍，这是 在大多数TBI中常见，例如持续关注，目标指导行为和认知灵活性的定义。 胆碱能系统是认知的重要调节剂，发现烟碱受体（NACHR） 整个大脑。 α7受体在注意力，工作记忆，奖励以及在 神经保护和抗炎途径。 α7NACHR的阳性变构调节剂（PAM）为 新颖的和承诺的治疗工具，可以在内源性的情况下进行潜在α7电流 乙酰胆碱，表现出高受体选择性，并可能提供神经保护作用。类型I PAMS增强 激动剂引起的峰值电流而不会延迟脱敏，也不会重新激活脱敏受体。 因此，这个新的/早期调查员R01应用旨在a）评估认知行为 对TBI和衰老敏感的动画状尺寸，B-C）评估潜在的好处 亚急性（7天）和NS 1738的慢性（4周），单独或单独或IN 与缩写环境富集（EE）（一种临床前康复模型）的结合， 年轻大鼠和年龄大鼠TBI后的注意力障碍以及d）地址机械 有关改变胆碱能神经传递的问题，负责这种行为的定义 研究相关大脑区域中的蛋白质组学和神经递质调节标记。具体来说， 目的旨在1）评估现代顶壁TBI的相互作用和持续关注的衰老（3-- 选择序列反应时间任务），认知灵活性（注意设置转移测试）和类似焦虑的反应 （升高的迷宫测试），2）评估NS 1738治疗联合方法的年龄依赖性效应 和缩写的EE（每天4小时）以恢复神经行为功能，以及测试接收器的选择性 用甲基环甲酸甲酯阻止α7NACHR，3）使用质谱量化蛋白质组学分析 识别与对衰老的神经生物学反应相关的关键生物标志物（组织和血清），脑创伤， 和治疗范例，以及4）测量胆碱能传播的脑标志物（例如胆碱 乙酰转移酶，乙酰胆碱酯酶，囊泡胆碱能转运蛋白，α7NACHRS），因为它们与 神经行为。研究将采用男性和正常骑自行车的雌性大鼠，因为女性代表高达45％ tbis，损伤发生独立于月经周期。整合高阶动物模型 TBI之后的注意以及评估药物治疗和康复相关的胆碱能和蛋白质组学 相关皮质区域的调节对于开发与诊所相关的治疗方法至关重要。

项目成果

Enriching adult male rats prior to traumatic brain injury does not attenuate neurobehavioral or histological deficits.

在创伤性脑损伤之前丰富成年雄性大鼠并不能减轻神经行为或组织学缺陷。

• DOI: 10.1016/j.brainres.2023.148314
• 发表时间: 2023
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Moschonas,EleniH;Niesman,PeterJ;Vozzella,VincentJ;Bittner,RachelA;Brennan,ConnorJ;Cheng,JeffreyP;Bondi,CorinaO;Kline,AnthonyE
• 通讯作者: Kline,AnthonyE

A combined therapeutic regimen of citalopram and environmental enrichment ameliorates attentional set-shifting performance after brain trauma.

• DOI: 10.1016/j.ejphar.2021.174174
• 发表时间: 2021-08-05
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: Minchew HM;Radabaugh HL;LaPorte ML;Free KE;Cheng JP;Bondi CO
• 通讯作者: Bondi CO

Antipsychotic Drugs: The Antithesis to Neurorehabilitation in Models of Pre-Clinical Traumatic Brain Injury.

• DOI: 10.1089/neur.2023.0082
• 发表时间: 2023
• 期刊: NEUROTRAUMA REPORTS
• 影响因子: 2.4
• 作者: Race, Nicholas S.;Moschonas, Eleni H.;Cheng, Jeffrey P.;Bondi, Corina O.;Kline, Anthony E.
• 通讯作者: Kline, Anthony E.

Disruption of basal forebrain cholinergic neurons after traumatic brain injury does not compromise environmental enrichment-mediated cognitive benefits.

• DOI: 10.1016/j.brainres.2020.147175
• 发表时间: 2021-01-15
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Moschonas EH;Leary JB;Memarzadeh K;Bou-Abboud CE;Folweiler KA;Monaco CM;Cheng JP;Kline AE;Bondi CO
• 通讯作者: Bondi CO

Preclinical neurorehabilitation with environmental enrichment confers cognitive and histological benefits in a model of pediatric asphyxial cardiac arrest.

• DOI: 10.1016/j.expneurol.2020.113522
• 发表时间: 2021-01
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Manole MD;Hook MJA;Nicholas MA;Nelson BP;Liu AC;Stezoski QC;Rowley AP;Cheng JP;Alexander H;Moschonas EH;Bondi CO;Kline AE
• 通讯作者: Kline AE