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.

摘要。脑震荡（或轻度脑外伤）后发生的认知障碍可能是持久的，并且可能