Injury-Induced Alterations in Limbic Functional Circuity

描述(申请人提供)：创伤性脑损伤(TBI)是导致儿童和年轻人死亡和残疾的主要原因。创伤性脑损伤每21秒发生一次，每年在美国约有200万人受到影响。脑外伤是一种异质性的侮辱，它会导致分子和生理上的级联反应，最终导致严重的、持久的神经病理。海马体和内侧前额叶皮质(MPFC)是脑内对高级认知功能至关重要的结构，在颅脑损伤中常受到损害。最佳的大脑功能需要这些脑区兴奋性和抑制性神经传递(E/I平衡)之间的微妙平衡。此外，E/I平衡对于神经振荡的诱导和维持至关重要，而神经振荡是认知和执行功能的基础。在脑损伤中，E/I平衡被破坏，恢复这种网络平衡是恢复正常认知功能的关键。我们的初步数据表明，损伤引起的CA1区E/I失衡主要是由抑制性突触传递的改变所介导的，脑损伤降低了mPFC网络的兴奋性。此外，抑制性神经元回路的不同成分导致了脑损伤后E/I失衡，也是药物重建E/I平衡的基础，从而导致脑损伤动物认知的全面恢复。基于这些结果，我们假设抑制电路--对诱导和维持海马区和皮质区的theta和Gamma节律至关重要--被脑损伤选择性地改变，从而导致认知和工作记忆损伤。此外，颅脑损伤后体内应用支链氨基酸(BCAA)，通过恢复海马区和大脑皮层E/I平衡和正常振荡，挽救正常的认知功能。为了验证这一假设，将从系统到分子水平对脑外伤小鼠模型进行体内记录以及对海马区和大脑皮层亚区兴奋和抑制功能的分析。网络兴奋性作为E/I平衡的一种度量，将使用场记录技术和电压敏感染料进行细胞外记录。确定导致局部海马区和皮质E/I失衡的特定抑制电路，并确定响应支链氨基酸干预的改变抑制电路的独特元素，将有助于开发有针对性的治疗干预措施，以减轻脑外伤造成的认知损害。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults. TBI occurs every 21 sec and afflicts approximately two million people annually in the United States. TBI is a heterogeneous insult that precipitates molecular and physiological cascades that culminate in severe long-lasting neuropathologies. The hippocampus and the medial prefrontal cortex (mPFC), brain structures crucial for higher cognitive function, are often damaged in TBI. Optimal brain function requires the delicate balance between excitatory and inhibitory neurotransmission (E/I balance) in these brain regions. Furthermore, E/I balance is essential for the induction and maintenance of neural oscillations, which underlie cognitive and executive function. In TBI, E/I balance is disrupted and restoring this network balance is critical to recovering normal cognitive function. Our preliminary data demonstrate that injury- induced E/I imbalance in area CA1 is predominately mediated by alterations in inhibitory synaptic transmission and that brain injury diminishes mPFC network excitability. Furthermore, distinct components of inhibitory neuronal circuitry contribute to E/I imbalances following TBI and also underlie the pharmacologic re-establishment of E/I balance which brings about comprehensive cognitive restoration in brain injured animals. Based on these results, we hypothesize that inhibitory circuits-crucial for the induction and maintenance of hippocampal and cortical theta and gamma rhythms-are selectively altered by TBI, thus causing cognitive and working memory impairments. Moreover, branched chain amino acids (BCAAs), administered in vivo following TBI, rescue normal cognitive functions by restoring hippocampal and cortical E/I balance and normal oscillations. To test this hypothesis, in vivo recordings as well as assays of excitatory and inhibitory function in hippocampal and cortical subregions will be studied at the systemic to molecular level in a well-established mouse model of TBI. Network excitability, as a measure of E/I balance, will be recorded extracellularly with field recording techniques and voltage sensitive dyes. Determining the specific inhibitory circuitry that causes regional hippocampal and cortical E/I imbalances and identifying the distinctive elements of altered inhibitory circuitry responsive to BCAA intervention will enable development of targeted therapeutic interventions to alleviate cognitive impairments caused by TBI.