Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.
Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.
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DOI：
10.1038/s41380-021-01389-3
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发表时间：
2022-03
影响因子：
11
通讯作者：
Tomoda, Toshifumi
中科院分区：
文献类型：
--
作者：
Jaaro-Peled, Hanna;Kumar, Sunil;Hughes, Dalton;Sumitomo, Akiko;Kim, Sun-Hong;Zoubovsky, Sandra;Hirota-Tsuyada, Yuki;Zala, Diana;Bruyere, Julie;Katz, Brittany M.;Huang, Beverly;Flores, Rafael;Narayan, Soumya;Hou, Zhipeng;Economides, Aris N.;Hikida, Takatoshi;Wetsel, William C.;Deisseroth, Karl;Mori, Susumu;Brandon, Nicholas J.;Tanaka, Motomasa;Ishizuka, Koko;Houslay, Miles D.;Saudou, Frederic;Dzirasa, Kafui;Sawa, Akira;Tomoda, Toshifumi
感觉运动信息加工是正常认知和行为特征的基础，通常通过惊吓反射的脉冲前抑制（PPI）来评估。PPI在一些神经和精神疾病中是一种不受控制的行为维度，然而这些疾病中PPI缺陷的交叉诊断性质的机制仍有待了解。为了确定PPI的电路机制，我们使用野生型（WT）小鼠与Disc1-locus-impairment （LI）小鼠（一种代表神经精神疾病的模型）比较，在前额叶皮层和纹状体这两个先前与PPI有关的大脑区域进行了电路记录。我们证明了皮质纹状体投射在WT的PPI测试中调节神经生理反应，而这些电路反应在Disc1-LI小鼠中被破坏。由于我们的生化分析显示，在Disc1-LI小鼠中，脑源性神经营养因子（Bdnf）沿皮质纹状体回路的运输减弱，因此我们研究了Bdnf在该回路中调节PPI的潜在作用。病毒介导的Bdnf进入纹状体可挽救Disc1-LI小鼠的PPI缺陷。慢性锂给药在药理学上增加Bdnf转运，部分通过磷酸化亨廷顿蛋白（Htt）丝氨酸-421及其整合到运动机械中，恢复纹状体Bdnf水平，并恢复Disc1-LI小鼠的PPI缺陷。此外，皮质Bdnf表达的降低否定了锂的这种挽救作用，证实了Bdnf在锂介导的PPI挽救中的关键作用。总的来说，这些数据表明纹状体Bdnf的供应，由Htt和Disc1沿皮质纹状体回路协同调节，参与感觉运动门控，突出了维度方法在研究神经精神疾病病理生理机制中的效用。
Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.
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影响因子：
3.5
作者：
Balu, Darrick T.;Carlson, Gregory C.;Talbot, Konrad;Kazi, Hala;Hill-Smith, Tiffany E.;Easton, Rachel M.;Birnbaum, Morris J.;Lucki, Irwin
通讯作者：
Lucki, Irwin
DOI：
10.1073/pnas.1004744108
发表时间：
2011-01-25
影响因子：
11.1
作者：
Baydyuk, Maryna;Russell, Theron;Xu, Baoji
通讯作者：
Xu, Baoji
DOI：
10.1073/pnas.1432927100
发表时间：
2003-07-22
影响因子：
11.1
作者：
Gerber, DJ;Hall, D;Tonegawa, S
通讯作者：
Tonegawa, S
影响因子：
3.8
作者：
Amann, Laura C.;Gandal, Michael J.;Siegel, Steven J.
通讯作者：
Siegel, Steven J.
影响因子：
16.2
作者：
Bae, BI;Xu, H;Sawa, A
通讯作者：
Sawa, A