Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell.
Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell.
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DOI：
10.1016/j.neuropharm.2017.01.020
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发表时间：
2017-05-01
影响因子：
4.7
通讯作者：
Green TA
中科院分区：
文献类型：
--
作者：
Crofton EJ;Nenov MN;Zhang Y;Scala F;Page SA;McCue DL;Li D;Hommel JD;Laezza F;Green TA
精神疾病，如焦虑，抑郁和成瘾，往往是共病的大脑病理认为共享共同的机械生物学。作为皮质-边缘回路的一部分，NAcSh在整合回路中的信息方面起着重要作用，因此NAcSh回路的调节改变了焦虑、抑郁和成瘾相关行为。NAcSh中的细胞内激酶级联已被证明是行为的重要介质。为了研究体内NAcSh中的糖原合成酶激酶3（GSK 3）β信号传导，我们用新型腺相关病毒载体（AAV 2）敲低GSK 3 β表达，并评估GSK 3 β敲低大鼠中焦虑和抑郁样行为和可卡因自我给药的变化。GSK 3 β敲低减少焦虑样行为，同时增加抑郁样行为和可卡因自我给药。使用急性脑切片中的相关电生理记录来评估AAV-shGSK 3 β对自发放电和紧张性活性中间神经元（TAN）的内在兴奋性的影响，所述紧张性活性中间神经元是NAcSh中输入和输出信号整合以及处理奖励相关行为所需的细胞。松散斑块记录显示，AAV-shGSK 3 β转导的TAN表现出强直性放电减少和峰电位半宽增加。当通过全细胞膜片钳记录评估时，这些变化反映为动作电位放电减少，并伴有超极化诱导的去极化凹陷电位降低，动作电位电流阈值增加和最大上升时间减少。这些结果表明，GSK 3 β在NAcSh沉默增加抑郁症和成瘾相关的行为，可能是通过降低内在的兴奋性的TAN。然而，这项研究并不排除其他神经元亚型的贡献。
Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types.