Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; BROAD Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell Rep. 2020 Feb 18;30(7):2360-2373.e5. doi: 10.1016/j.celrep.2020.01.055.
Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However, the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual fear discrimination learning paradigm, we identify opposing roles for dorsal CA3-CA1 (dCA3-dCA1) projections and dorsal CA3-dorsolateral septum (dCA3-DLS) projections in calibrating fear responses to certain and ambiguous contextual threats, respectively. Ventral CA3-DLS (vCA3-DLS) projections suppress fear responses in both certain and ambiguous contexts, whereas ventral CA3-CA1 (vCA3-vCA1) projections promote fear responses in both these contexts. Lastly, using retrograde monosynaptic tracing, ex vivo electrophysiological recordings, and optogenetics, we identify a sparse population of DLS parvalbumin (PV) neurons as putative relays of dCA3-DLS projections to diverse subcortical circuits. Taken together, these studies illuminate how distinct dCA3 and vCA3 outputs calibrate contextual fear discrimination.
大量研究强调了海马回路在调节情境恐惧辨别中的作用。然而，将情境信息路由到皮质和皮质下回路以指导适应性行为反应的海马内和海马外途径仍知之甚少。我们在情境恐惧辨别学习范式中使用特定末端的光遗传学沉默技术，确定了背侧 CA3-CA1（dCA3-dCA1）投射和背侧 CA3-外侧隔核（dCA3-DLS）投射在分别校准对确定和模糊情境威胁的恐惧反应中的相反作用。腹侧 CA3-DLS（vCA3-DLS）投射在确定和模糊的情境中均抑制恐惧反应，而腹侧 CA3-CA1（vCA3-vCA1）投射则在这两种情境中促进恐惧反应。最后，通过逆行单突触追踪、离体电生理记录和光遗传学，我们确定了一小部分外侧隔核的 parvalbumin（PV）神经元作为 dCA3-DLS 投射到不同皮质下回路的假定中继。总之，这些研究阐明了不同的 dCA3 和 vCA3 输出如何校准情境恐惧辨别。
