Enhancing the function of hippocampal neurons after TBI

增强TBI后海马神经元的功能

• 批准号: 10211632
• 负责人: PRAMOD K DASH
• 金额: $ 54.51万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211632
• 关键词: Abbreviations; Acute; Animals; Area; Back; Brain Concussion; Brain Injuries; Brain region; Cell physiology; Cells; Cessation of life; Chemosensitization; Chronic; Cues; Cyclic AMP-Responsive DNA-Binding Protein; DUSP6 protein; Disinhibition; Electrodes; Electrophysiology (science); Environment; Event; Experimental Models; Failure; Frequencies; Gene Expression; Hippocampus (Brain); Human; Immunohistochemistry; Impaired cognition; Impairment; Injury; Interneurons; Lateral; Lead; Learning; Link; Medial; Medial Septal Nucleus; Memory; Memory impairment; Modality; Molecular; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Parvalbumins; Patients; Pattern; Periodicity; Persons; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Play; Property; Protein Biosynthesis; Protein Kinase; Public Health; Rattus; Role; Sensory; Somatostatin; Synaptic plasticity; Testing; Theta Rhythm; Time; Transcriptional Activation; Traumatic Brain Injury; base; disability; enhancing factor; experimental study; extracellular; fluid percussion injury; hippocampal pyramidal neuron; improved; improved functioning; improved outcome; in vivo; inhibitory neuron; long term memory; mild traumatic brain injury; neural circuit; neuromechanism; neuron loss; optogenetics; phosphodiesterase 4D; place fields; prevent; relating to nervous system; transcription factor

Abstract. The cognitive impairments that occur after a concussion (or mild TBI) can be long-lasting, and can interfere with every day activities. These deficits, especially memory dysfunction, are often due to perturbations of hippocampal function. In vivo recordings of neural activity in behaving animals have demonstrated that the firing of a subset of pyramidal neurons in the hippocampus increases when an animal moves through its environment. These cells, referred to as “place cells”, display localized firing patterns (i.e. place fields) that the animal uses to recognize an environment. Thus, a failure to form stable place fields has been linked to learning and memory dysfunction. Evidence has shown that theta oscillations (a rhythmic firing pattern seen in the hippocampus) play an important role in modulating place field stability, and in learning and memory. This rhythm is established by connections between inhibitory neurons present in the medial septum and the hippocampus. We present supportive results to indicate that the number of parvalbumin-expressing inhibitory neurons in the CA1 subfield of the hippocampus is decreased after a fluid percussion injury (FPI), an effect that occurs in the absence of overt loss of pyramidal neurons. Associated with this loss, electrophysiological recordings revealed a decrease in theta power and place cell instability that are evident for weeks after brain injury. The transcription factor cAMP response element binding protein (CREB) is phosphorylated and increases neuroplasticity-related gene expression following phosphorylation by specific protein kinases, and has been shown to be critical for place cell stability. Based on these results, we propose to test the hypothesis that stimulation of hippocampal CA1 pyramidal neurons at theta frequency or pharmacological potentiation of CREB will increase place cell function and improve memory formation in the chronic stage of FPI. The results from these proposed studies will reveal the neural basis for memory dysfunction and potential pharmacological strategy to restore neural function and improve learning and memory during subacute/chronic stage of traumatic brain injury.

抽象的。咨询（或轻度TBI）后发生的认知障碍可能是持久的，并且可以 干扰每天的活动。这些定义，尤其是内存功能障碍，通常是由于扰动引起的 海马功能。行为动物中神经活动的体内记录表明 当动物通过其移动时，海马中锥体神经元的一部分会增加 环境。这些单元格被称为“位置单元”，显示了局部的射击模式（即位置字段） 动物用来识别环境。那是一个未能形成稳定的地方领域与学习有关的 和内存功能障碍。有证据表明，theta振荡（在 海马）在调节场地稳定性以及学习和记忆中起重要作用。这个节奏 通过培养基隔膜中存在的抑制性神经元与海马抑制性神经元之间的连接建立。 我们提出了支持性结果，以表明表达白蛋白的抑制性神经元的数量 液体打击乐损伤（FPI）后，海马的CA1子场减少了，这种作用发生在 缺乏明显的锥体神经元丧失。与这种损失相关，电生理记录显示 theta功率和放置细胞不稳定性的降低是脑损伤后数周的证据。转录 因子cAMP反应元件结合蛋白（CREB）被磷酸化，并增加了与神经可塑性有关的 特异性蛋白激酶磷酸化后的基因表达，已被证明对 放置细胞稳定性。基于这些结果，我们建议测试海马刺激的假设 Ca1 theta频率下的锥体神经元或CREB的药物增强将增加一个细胞 在FPI的慢性阶段的功能并改善记忆形成。这些提出的研究的结果 将揭示记忆功能障碍和潜在的药物策略的神经元基础，以恢复神经元 在创伤性脑损伤的亚急性/慢性阶段的功能并改善学习和记忆。