Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
Harvard Stem Cell Institute, Cambridge, MA, USA.
Nat Neurosci. 2019 Mar;22(3):436-446. doi: 10.1038/s41593-018-0330-y. Epub 2019 Feb 4.
Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.
对外部威胁的适应性恐惧反应依赖于将上下文编码的计算有效地传递到皮质下回路。对上下文恐惧辨别后高度共激活集合的全脑分析确定了外侧隔核（DLS）作为齿状回-CA3 回路的中继。逆行单突触追踪和电生理全细胞记录表明，DLS 生长抑素表达中间神经元（SST-IN）接收直接的 CA3 输入。在清醒、行为小鼠的 DLS SST-IN 进行纵向活体钙成像，在上下文条件下识别出稳定的足部电击反应 SST-IN 群体，其活性在随后的回忆中跟踪并预测了训练环境中的非冻结期，但在类似的中性环境或开阔场中则没有。DLS SST-IN 的光遗传衰减或刺激可双向调节条件性恐惧反应，并招募近端和远端皮质下靶标。总之，这些观察结果表明，一个潜在的硬连线 DLS SST-IN 亚群作为可移动性的仲裁者，可校准适当的行为恐惧反应。
