Cohen Diversity Supplement

描述（由申请人提供）：创伤性脑损伤（TBI）是儿童和年轻人死亡和残疾的主要原因。TBI每21秒发生一次，在美国每年约有200万人受到影响。TBI是一种异质性损伤，其沉淀分子和生理级联反应，最终导致严重的长期神经病理学。海马和内侧前额叶皮质（mPFC），大脑结构的高级认知功能的关键，往往是在创伤性脑损伤。最佳的大脑功能需要这些大脑区域的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是必不可少的，而神经振荡是认知和执行功能的基础。 在TBI中，E/I平衡被破坏，恢复这种网络平衡对于恢复正常的认知功能至关重要。我们的初步数据表明，损伤诱导的CA 1区E/I失衡主要是由抑制性突触传递的改变介导的，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组分有助于TBI后的E/I失衡，并且也是E/I平衡的药理学重建的基础，其在脑损伤动物中带来全面的认知恢复。基于这些结果，我们假设，抑制电路的诱导和维持海马和皮质的θ和γ节律的关键选择性改变TBI，从而导致认知和工作记忆障碍。此外，支链氨基酸（BCAAs），在TBI后体内给药，通过恢复海马和皮质E/I平衡和正常振荡来挽救正常的认知功能。为了检验这一假设，在体内记录以及海马和皮质亚区的兴奋和抑制功能的测定将在系统的分子水平在一个完善的TBI小鼠模型进行了研究。网络兴奋性，作为E/I平衡的量度，将用场记录技术和电压敏感染料在细胞外记录。确定导致区域海马和皮层E/I失衡的特定抑制回路，并确定对BCAA干预反应的改变的抑制回路的独特元素，将能够开发有针对性的治疗干预措施，以减轻TBI引起的认知障碍。

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.