Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury
Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury
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DOI：
10.1089/neu.2015.4190
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发表时间：
2016-09-01
影响因子：
4.2
通讯作者：
Conti, Alana C.
中科院分区：
文献类型：
--
作者：
Schneider, Brandy L.;Ghoddoussi, Farhad;Conti, Alana C.
轻度创伤性脑损伤（mTBI）有助于情感障碍的发展，包括创伤后应激障碍（PTSD）。精神症状通常在创伤性脑损伤后以迟发的方式出现，对康复有负面影响。创伤后应激障碍患者以及创伤后应激障碍啮齿动物模型显示，介导恐惧学习的大脑区域发生了结构和功能变化，包括前额叶皮质（PFC）、杏仁核（AMYG）和海马体（HC）。这些变化可能反映了自上而下控制的丧失，PFC通常通过这种控制对AMYG对恐惧刺激的反应表现出抑制作用，HC起作用。考虑到这些区域对损伤的易感性，我们使用小鼠mTBI模型检测了延迟损伤后时期的恐惧条件反射（FC）。mTBI小鼠表现出增强的FC获取和延迟的FC消失。利用质子磁共振波谱法，我们分别检测了γ -氨基丁酸（GABA）和谷氨酸的PFC、AMYG和HC水平，作为抑制性和兴奋性神经传递的替代指标。损伤后8天，PFC中GABA升高，AMYG无明显变化。在接受FC和mTBI的动物中，损伤后25天，腹部HC中谷氨酸有增加的趋势，GABA/谷氨酸比值下降，而背部HC中GABA减少，GABA/谷氨酸比值下降。这些神经化学变化与早期tbi诱导的PFC失活一致，促进了恐惧学习回路并加剧了行为恐惧反应。尽管HC背侧和腹侧脑区具有明显的可塑性，但HC中兴奋性张力整体增强的潜在出现可能与记忆功能紊乱有关，表现为不完全消退和FC回忆增强。
Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall.