Williams Brandon, Srinivas Ananth Vedururu, Baravalle Roman, Fernandez Fernando R, Canavier Carmen C, White John A
Department of Biomedical Engineering, Center for Systems Neuroscience, Neurophotonics Center, Boston University, Boston, MA, 02215, USA.
Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
bioRxiv. 2025 Sep 5:2025.09.05.674527. doi: 10.1101/2025.09.05.674527.
Gamma oscillations (40-140 Hz) play a fundamental role in neural coordination, facilitating communication and cognitive functions in the medial entorhinal cortex (mEC). While previous studies suggest that pyramidal-interneuron network gamma (PING) and interneuron network gamma (ING) mechanisms contribute to these oscillations, the precise role of inhibitory circuits remains unclear. Using optogenetic stimulation and whole-cell electrophysiology in acute mouse brain slices, we examined synaptic input and spike timing in neurons across layer II/III mEC. We found that fast-spiking interneurons exhibited robust gamma-frequency firing, while excitatory neurons engaged in gamma cycle skipping. Stellate and pyramidal cells received minimal recurrent excitation, whereas fast-spiking interneurons received strong excitatory input. Both excitatory neurons and fast-spiking interneurons received gamma frequency inhibition, emphasizing the role of recurrent inhibition in gamma rhythm generation. Notably, gamma activity persisted after AMPA/kainate receptor blockade, indicating that interneurons can sustain gamma oscillations independently through an ING mechanism. Selective activation of PV+ interneurons confirmed their ability to sustain fast gamma inhibition autonomously. To further assess the interplay of excitation and inhibition, we developed computational network models constrained by our experimental data. Simulations revealed that weak excitatory input to interneurons supports fast ING-dominated rhythms (~100-140 Hz), while strengthening excitatory drive induces a transition to slower PING-dominated oscillations (60-80 Hz). These findings highlight the dominant role of inhibitory circuits in sustaining gamma rhythms, demonstrate how excitation strength tunes the oscillatory regime, and refine models of entorhinal gamma oscillations critical for spatial memory processing.
伽马振荡（40 - 140赫兹）在神经协调中起着基础性作用，促进内嗅皮质（mEC）的信息交流和认知功能。虽然先前的研究表明锥体细胞-中间神经元网络伽马（PING）和中间神经元网络伽马（ING）机制促成了这些振荡，但抑制性回路的确切作用仍不清楚。我们利用急性小鼠脑片的光遗传学刺激和全细胞膜片钳电生理学技术，研究了mEC第II/III层神经元的突触输入和放电时间。我们发现，快速放电中间神经元表现出强烈的伽马频率放电，而兴奋性神经元则出现伽马周期跳跃。星状细胞和锥体细胞接受的反馈性兴奋极少，而快速放电中间神经元则接受强烈的兴奋性输入。兴奋性神经元和快速放电中间神经元均接受伽马频率抑制，这突出了反馈性抑制在伽马节律产生中的作用。值得注意的是，在AMPA/海人藻酸受体阻断后，伽马活动仍然持续，这表明中间神经元可以通过ING机制独立维持伽马振荡。对PV + 中间神经元的选择性激活证实了它们自主维持快速伽马抑制的能力。为了进一步评估兴奋与抑制之间的相互作用，我们根据实验数据开发了计算网络模型。模拟结果显示，对中间神经元的弱兴奋性输入支持以快速ING为主导的节律（~100 - 140赫兹），而增强兴奋性驱动则会导致向以较慢PING为主导的振荡（60 - 80赫兹）转变。这些发现突出了抑制性回路在维持伽马节律中的主导作用，展示了兴奋强度如何调节振荡状态，并完善了对空间记忆处理至关重要的内嗅伽马振荡模型。
