Laboratory of Neural Circuits and Behaviour (LNCB), Department of Biology, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra, 411008, India.
Mol Psychiatry. 2023 Nov;28(11):4693-4706. doi: 10.1038/s41380-023-02244-3. Epub 2023 Sep 19.
Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental approaches. As ELA can alter sensory perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesise the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The reduction in synaptic inhibition was nullified by the photo-activation of ChR2-expressing SOM-INs in ELS mice. The role of SOM-INs was revealed by learning-dependent refinement of Cadynamics quantified by GCaMP6f signals, which was absent in ELS mice. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic modulation during the odour discrimination learning. Photo-activating these neurons rescued the ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELA-dependent changes.
早期生活逆境 (ELA) 导致影响个体健康的神经回路异常运作。虽然 ELA 引起的感觉和认知障碍导致的行为障碍可以在临床上进行评估，但需要通过使用多方面的实验方法，在动物模型中探究神经机制。由于 ELA 可以改变感觉感知，我们研究了早期断奶对小鼠嗅觉的影响。通过实施 Go/No-Go 气味辨别范式，我们观察到早期生活应激 (ELS) 雄性小鼠的嗅觉学习和记忆障碍。由于嗅球 (OB) 回路在气味学习中起着关键作用，我们研究了 ELS 小鼠 OB 中可能发生的变化。ELS 小鼠外丛状层 c-Fos 活性降低和释放生长抑素的 GABA 能中间神经元 (SOM-INs) 的树突过程减少，使我们假设潜在的神经回路发生了变化。我们记录到来自 ELS 小鼠 OB 切片中的 M/T 细胞上抑制性突触反馈减少，解释了 OB 输出细化受损导致的学习缺陷。用光遗传学激活 ChR2 表达的 SOM-INs 可以消除 ELS 小鼠中抑制性突触减少的影响。通过 GCaMP6f 信号量化的 Cadynamics 的学习依赖性细化揭示了 SOM-INs 的作用，而 ELS 小鼠中则不存在这种细化。此外，通过在气味辨别学习期间进行光遗传调制，研究了 SOM-INs 涉及的回路的因果作用。光激活这些神经元可挽救 ELA 引起的学习缺陷。相反，光抑制在对照动物中引起学习缺陷，而在 ELS 小鼠中则完全消除了学习，证实了 SOM-INs 介导的不利影响。因此，我们的结果确立了特定抑制性回路在协调 ELA 依赖的变化中的前皮质感觉区中的作用。
