Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science, and Odontostomatology, University of Naples Federico II, 80131, Napoli, Italy.
Medical Statistics Unit, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.
Behav Brain Res. 2021 Apr 23;404:113160. doi: 10.1016/j.bbr.2021.113160. Epub 2021 Feb 9.
Although extensively studied, the effect of antipsychotics is not completely understood at a network level. We tested the hypothesis that acute administration of haloperidol would modulate functional connectivity of brain regions relevant to schizophrenia pathophysiology. To assess putative changes in brain network properties and regional interactivity, we studied the expression of Homer1a, an Immediate Early Gene (IEG) demonstrated to be induced by antipsychotic administration and coding for a protein involved in glutamatergic synapses remodeling.
Sprague-Dawley rats (n = 26) assigned to vehicle (VEH; NaCl 0.9%) or haloperidol (HAL; 0.8 mg/kg) were included in the network analysis. Homer1a mRNA induction was evaluated by in situ hybridization. Signal intensity analysis was performed in 33 Regions of Interest (ROIs) in the cortex, the caudate putamen, and the nucleus accumbens. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs in the two groups. Two networks were generated for HAL and VEH groups, and their properties and topography were explored.
VEH and HAL networks showed qualitative differences in global efficiency and clustering coefficient. The HAL network showed enhanced interactivity between cortical and striatal regions, and within caudate putamen subdivisions. On the other hand, it exhibited reduced inter-correlations between cingulate cortex and anterior insula and caudate putamen and nucleus accumbens. Moreover, haloperidol was able to modulate centrality of crucial functional hubs. These preclinical results corroborate and expand the clinical evidence that antipsychotics may modulate specific brain network properties and disease-related circuits' interactivity.
尽管抗精神病药物已经被广泛研究，但它们在网络层面的作用仍不完全清楚。我们检验了这样一个假设，即氯丙嗪的急性给药会调节与精神分裂症病理生理学相关的脑区的功能连通性。为了评估大脑网络属性和区域相互作用的潜在变化，我们研究了 Homer1a 的表达，这是一种已被证明可被抗精神病药物诱导的即时早期基因（IEG），编码一种参与谷氨酸能突触重塑的蛋白质。
将 26 只 Sprague-Dawley 大鼠分为对照组（VEH；NaCl 0.9%）或氯丙嗪组（HAL；0.8mg/kg），并纳入网络分析。通过原位杂交评估 Homer1a mRNA 的诱导。对皮质、尾状核和伏隔核中的 33 个感兴趣区（ROI）进行信号强度分析。在两组中进行了信号相关分析，计算了 ROI 之间所有可能的成对 Pearson 相关性。为 HAL 和 VEH 组生成了两个网络，并探索了它们的属性和拓扑结构。
VEH 和 HAL 网络在全局效率和聚类系数方面表现出定性差异。HAL 网络显示皮质和纹状体区域之间的相互作用增强，尾状核内部分区之间的相互作用增强。另一方面，它显示出扣带回皮质和前岛叶与尾状核和伏隔核之间的相互关联减少。此外，氯丙嗪能够调节关键功能枢纽的中心度。这些临床前结果证实并扩展了临床证据，表明抗精神病药物可能调节特定的大脑网络属性和与疾病相关的回路的相互作用。
