Abdominal Vagal Afferents Modulate the Brain Transcriptome and Behaviors Relevant to Schizophrenia. Brain Transcriptome and Behaviors Relevant to Schizophrenia

Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder’s pathophysiology as well. The present study explored this hypothesis using a rat model of subdiaphragmatic vagal deafferentation (SDA), which is the most complete and selective vagal deafferentation method existing to date. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which is manifest as increased sensitivity to acute amphetamine treatment and elevated levels of dopamine in the nucleus accumbens. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that various schizophrenia-related functions are subjected to visceral modulation through abdominal vagal afferents. Hence, afferent visceral signals may have a key role in shaping transcriptional, neurochemical and behavioral dysfunctions relevant to schizophrenia and related psychotic disorders.

迷走传出神经活动减弱长期以来被认为与精神分裂症相关，且被认为是导致患者副交感神经活动降低及相关外周症状的原因。与之相对，学界此前极少关注迷走传入信号受损同样可能与该疾病的病理生理学机制相关这一可能性。本研究借助膈下迷走传入切断术（subdiaphragmatic vagal deafferentation, SDA）的大鼠模型对该假说展开验证——该方法是目前已报道的最完整、选择性最优的迷走传入切断手段。通过下一代mRNA测序技术，我们证实SDA可引发大脑中与精神分裂症相关的功能网络出现转录组变化。我们进一步证实，SDA可诱导多巴胺能高活动状态，具体表现为对急性苯丙胺给药的敏感性升高，以及伏隔核内多巴胺水平上升。本研究同时发现，SDA会损伤感觉运动门控功能与联想学习的注意控制能力，这两项指标分别通过前脉冲抑制（prepulse inhibition, PPI）与潜伏抑制（latent inhibition）范式进行评估。上述数据提供了汇聚性证据，表明多种与精神分裂症相关的生理功能可通过腹部迷走传入神经接受内脏系统的调控。因此，内脏传入信号可能在塑造与精神分裂症及相关精神病性障碍相关的转录组、神经化学及行为功能异常过程中发挥关键作用。