Chung Ain, Alipio Jason Bondoc, Ghosh Megha, Evans Liam, Miller Samara M, Goode Travis D, Mehta Iyanah, Ahmed Omar J, Sahay Amar
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.
Harvard Stem Cell Institute, Cambridge, MA.
Res Sq. 2025 Mar 21:rs.3.rs-6087158. doi: 10.21203/rs.3.rs-6087158/v1.
Adult-born dentate granule cells (abDGCs) contribute to hippocampal dentate gyrus (DG)-CA3/CA2 circuit functions in memory encoding, retrieval and consolidation. Heightened synaptic and structural plasticity of immature abDGCs is thought to govern their distinct contributions to circuit and network mechanisms of hippocampal-dependent memory operations. Protracted maturation or neoteny of abDGCs in higher mammals is hypothesized to offset decline in adult hippocampal neurogenesis by expanding the capacity for circuit and network plasticity underlying different memory operations. Here, we provide evidence for this hypothesis by genetically modelling the effective impact of neoteny of abDGCs on circuitry, network properties and social cognition in mice. We show that selective synchronous expansion of a single cohort of 4 weeks old immature, but not 8 weeks old mature abDGCs, increases functional recruitment of fast spiking parvalbumin expressing inhibitory interneurons (PV INs) in CA3/CA2, number of PV IN-CA3/CA2 synapses, and GABAergic inhibition of CA3/CA2. This transient increase in feed-forward inhibition in DG-CA2 decreased social memory interference and enhanced social memory consolidation. local field potential recordings revealed that the expansion of a single cohort of 4-week-old abDGCs increased baseline power, amplitude, and duration, as well as sensitivity to social investigation-dependent rate changes of sharp-wave ripples (SWRs) in CA1 and CA2, a neural substrate for memory consolidation. Inhibitory neuron-targeted chemogenetic manipulations implicate CA3/CA2 INs, including PV INs, as necessary and sufficient for social memory consolidation following neotenic expansion of the abDGC population and in wild-type mice, respectively. These studies suggest that neoteny of abDGCs may represent an evolutionary adaptation to support cognition by reconfiguring PV IN-CA3/CA2 circuitry and emergent network properties underlying memory consolidation.
成年新生齿状颗粒细胞（abDGCs）在记忆编码、检索和巩固过程中对海马齿状回（DG）-CA3/CA2回路功能有贡献。未成熟abDGCs增强的突触和结构可塑性被认为决定了它们对海马依赖性记忆操作的回路和网络机制的独特贡献。据推测，高等哺乳动物中abDGCs的长期成熟或幼态持续通过扩大不同记忆操作背后的回路和网络可塑性能力来抵消成年海马神经发生的下降。在这里，我们通过对abDGCs幼态持续对小鼠回路、网络特性和社会认知的有效影响进行基因建模，为这一假设提供了证据。我们表明，选择性同步扩大一组4周龄未成熟而非8周龄成熟的abDGCs，会增加CA3/CA2中表达快速放电小白蛋白的抑制性中间神经元（PV INs）的功能募集、PV IN-CA3/CA2突触的数量以及CA3/CA2的GABA能抑制。DG-CA2中前馈抑制的这种短暂增加减少了社会记忆干扰并增强了社会记忆巩固。局部场电位记录显示，一组4周龄abDGCs的扩大增加了CA1和CA2中基线功率、振幅和持续时间，以及对与社会调查相关的尖波涟漪（SWRs）速率变化的敏感性，而尖波涟漪是记忆巩固的神经基础。针对抑制性神经元的化学遗传学操作表明，CA3/CA2中间神经元，包括PV INs，分别对于abDGC群体幼态持续扩大后和野生型小鼠中的社会记忆巩固是必要且充分的。这些研究表明，abDGCs的幼态持续可能代表了一种进化适应，通过重新配置PV IN-CA3/CA2回路和记忆巩固背后的新兴网络特性来支持认知。
