Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98104
Departments of Pathology.
J Neurosci. 2022 Jul 6;42(27):5361-5372. doi: 10.1523/JNEUROSCI.0097-22.2022. Epub 2022 May 24.
Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated whether alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion in both male and female mice that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch-clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast-spiking and somatostatin-expressing (SOM+) subtypes of inhibitory neurons in layer V of the orbitofrontal cortex 2 months after injury. These subtypes exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons, respectively. By contrast, the fast-spiking and parvalbumin-expressing interneurons did not show changes in intrinsic excitability or synaptic output, respectively. Impairments in non-fast-spiking/SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI. TBI frequently leads to chronic deficits in cognitive and behavioral functions that involve the prefrontal cortex, yet the maladaptive changes that occur in these cortical microcircuits are unknown. Our data indicate that alterations in subtype-specific inhibitory circuits, specifically vulnerability in the non-fast-spiking/somatostatin-expressing interneurons, occurs in the orbitofrontal cortex in the context of chronic deficits in reversal learning. These neurons exhibit reduced excitability and synaptic output, whereas the other prominent inhibitory population in layer V, the fast-spiking/parvalbumin-expressing interneurons as well as pyramidal neurons are not affected. Our work offers mechanistic insight into the subtype-specific function of neurons that may contribute to mental inflexibility after TBI.
创伤性脑损伤 (TBI) 是导致神经功能障碍的主要原因；最常见的缺陷影响前额叶皮层依赖的功能，如注意力、工作记忆、社会行为和心理灵活性。尽管这种情况很普遍，但对于 TBI 后前额皮质微电路中发展的病理生理学知之甚少。我们研究了在雄性和雌性小鼠的额叶挫裂伤模型中，特定抑制性回路的改变是否与认知灵活性障碍有关，该模型通过规则反转学习缺陷来衡量异常的心理灵活性。使用膜片钳记录和光遗传学刺激，我们在损伤后 2 个月时发现眶额皮层第 V 层的非快速放电和生长抑素表达 (SOM+) 抑制性神经元的亚型存在选择性易损性。这些亚型分别表现出内在兴奋性降低和对锥体神经元突触输出减少。相比之下，快速放电和钙调蛋白结合蛋白表达的中间神经元分别在内在兴奋性或突触输出方面没有变化。非快速放电/SOM+抑制性回路功能的损伤也与网络过度兴奋有关。这些发现为特定抑制性微回路中存在选择性破坏提供了证据，这可能为 TBI 的新型治疗方法提供指导。TBI 经常导致涉及前额叶皮质的认知和行为功能的慢性缺陷，但这些皮质微电路中发生的适应性变化尚不清楚。我们的数据表明，在慢性反转学习缺陷的情况下，特定抑制性回路的亚型改变，特别是非快速放电/生长抑素表达中间神经元的易损性，发生在眶额皮层中。这些神经元表现出兴奋性和突触输出降低，而 V 层中的另一个主要抑制性群体，即快速放电/钙调蛋白结合蛋白表达中间神经元以及锥体神经元不受影响。我们的工作为神经元的亚型特异性功能提供了机制上的见解，这可能有助于 TBI 后的心理灵活性。
