Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto/SP, 14049-900, Brazil.
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA, 15260, USA.
Neuropsychopharmacology. 2018 Nov;43(12):2459-2467. doi: 10.1038/s41386-018-0128-3. Epub 2018 Jun 23.
Schizophrenia patients typically exhibit prominent negative symptoms associated with deficits in extinction recall and decreased ventromedial prefrontal cortex activity (vmPFC, analogous to medial PFC infralimbic segment in rodents). mPFC activity modulates the activity of basolateral amygdala (BLA) and this connectivity is related to extinction. mPFC and BLA activity has been shown to be altered in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. However, it is unknown if there are alterations in extinction processes in this model. Therefore, we investigated extinction and the role of mPFC-BLA balance in MAM rats. Male offspring of pregnant rats treated with Saline or MAM (20 mg/kg; i.p.) on gestational day 17 were used in fear conditioning (contextual/tone) and electrophysiological experiments (mPFC-BLA plasticity). No difference was observed in conditioning, extinction, and test sessions in contextual fear conditioning. However, MAM-treated rats demonstrated impairment in extinction learning and recall in tone fear conditioning. Furthermore, high frequency stimulation (HFS) of the BLA decreased spike probability in the mPFC of saline-treated rats but not in MAM rats. NMDA antagonist microinjected into the BLA disrupted extinction learning and recall in control rats, resulting in a similar deficit as that observed in MAM-treated rats. These data demonstrate extinction impairment in the MAM model that is analogous to that observed in schizophrenia patients, that was probably due to disruption in the regulation of mPFC activity by glutamatergic neurotransmission in the BLA.
精神分裂症患者通常表现出明显的阴性症状，这些症状与消退回忆缺陷和腹内侧前额叶皮层（vmPFC，类似于啮齿动物的内侧前额叶 infralimbic 段）活性降低有关。mPFC 活动调节外侧杏仁核（BLA）的活动，这种连接与消退有关。已经表明，在精神分裂症的甲基乙氧甲酰胺乙酸盐（MAM）发育破坏模型中，mPFC 和 BLA 的活动发生了改变。然而，尚不清楚在该模型中是否存在消退过程的改变。因此，我们研究了 MAM 大鼠中的消退过程和 mPFC-BLA 平衡的作用。用生理盐水或 MAM（20mg/kg；ip）处理妊娠第 17 天的孕鼠的雄性后代用于恐惧条件反射（上下文/音调）和电生理实验（mPFC-BLA 可塑性）。在上下文恐惧条件反射中，没有观察到条件反射、消退和测试阶段的差异。然而，MAM 处理的大鼠在音调恐惧条件反射中表现出消退学习和回忆受损。此外，高频刺激（HFS）BLA 降低了生理盐水处理大鼠的 mPFC 中的尖峰概率，但不能降低 MAM 大鼠的 mPFC 中的尖峰概率。NMDA 拮抗剂微注射到 BLA 中破坏了对照大鼠的消退学习和回忆，导致与 MAM 处理大鼠观察到的相似缺陷。这些数据表明，MAM 模型中的消退受损类似于精神分裂症患者观察到的消退受损，这可能是由于 BLA 中的谷氨酸能神经传递对 mPFC 活动的调节中断所致。
