Enhancing the function of hippocampal neurons after TBI

增强TBI后海马神经元的功能

• 批准号: 10406341
• 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/10406341
• 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。脑震荡（或轻度TBI）后发生的认知障碍可能是持久的， 干扰日常活动。这些缺陷，特别是记忆功能障碍，往往是由于干扰 海马体功能。在有行为的动物中的神经活动的体内记录已经证明， 当动物穿过其海马体时，海马体中锥体神经元的子集的放电增加。 环境这些细胞，被称为“位置细胞”，显示局部放电模式（即位置场）， 动物用来识别环境。因此，未能形成稳定的位置场与学习有关 和记忆障碍有证据表明，θ振荡（在大脑中看到的有节奏的放电模式） 海马）在调节位置场稳定性以及在学习和记忆中起重要作用。这个节奏 是通过存在于内侧隔和海马中的抑制性神经元之间的连接建立的。 我们目前的支持性结果表明，表达小清蛋白的抑制性神经元的数量在脑内的分布不均匀。 海马CA 1亚区在液压冲击损伤（FPI）后减少，这是一种发生在海马CA 1亚区的效应。 没有锥体神经元的明显损失。与这种损失相关的电生理记录显示， 脑损伤后数周内θ功率和位置细胞不稳定性明显下降。转录 因子cAMP反应元件结合蛋白（CREB）被磷酸化，并增加神经可塑性相关 在特定蛋白激酶磷酸化后的基因表达，并且已被证明对于 放置细胞稳定性。基于这些结果，我们提出了一个假设，即刺激海马 CA 1锥体神经元在θ频率或CREB的药理学增强将增加位置细胞 功能和改善记忆形成的慢性阶段的FPI。这些拟议研究的结果 将揭示记忆功能障碍的神经基础和恢复神经功能的潜在药理学策略。 功能和改善亚急性/慢性期脑外伤的学习记忆。