Enhancing the function of hippocampal neurons after TBI

抽象的。脑震荡(或轻度脑外伤)后发生的认知障碍可能是长期的，也可能 干扰日常活动。这些缺陷，特别是记忆功能障碍，通常是由干扰引起的 海马区的功能。行为动物的神经活动的活体记录表明 当动物穿过海马区时，海马区锥体神经元的一个子集的放电增加 环境。这些单元被称为“位置单元”，它们显示局部的激发模式(即位置区域) 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，theta振荡(一种有节奏的激发模式，在 海马区)在调节位置场稳定性和学习记忆中起着重要作用。这种节奏 是由内侧隔区和海马区的抑制性神经元之间的连接建立的。 我们提出的支持性结果表明，小白蛋白表达抑制神经元的数量 液压冲击伤(FPI)后，海马区CA1亚区减少，这种影响发生在 没有明显的锥体神经元丢失。与这种丢失有关的是，电生理记录显示 脑损伤后数周内明显的theta功率下降和位置细胞不稳定。抄写 因子cAMP反应元件结合蛋白(CREB)被磷酸化并增加与神经可塑性相关的 在特定蛋白激酶磷酸化后的基因表达，已被证明是关键的 放置细胞稳定性。基于这些结果，我们建议检验刺激海马体的假设 位于theta频率的CA1锥体神经元或CREB的药物增强将增加位置细胞 改善FPI慢性期的功能和改善记忆形成。这些拟议研究的结果 将揭示记忆障碍的神经基础和潜在的恢复神经的药物策略 在创伤性脑损伤的亚急性期/慢性期改善学习和记忆能力。

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.