Single-photon optogenetics enables precise, cell-type–specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bears promise for brain–machine interfaces for sensory and motor function restoration. However, achieving selective activation of functional cortical representations poses a challenge, as studies show that targeted optogenetic stimulation results in activity spread beyond one functional domain. While recurrent network mechanisms contribute to activity spread, here we demonstrate with detailed simulations of isolated pyramidal neurons from cats of unknown sex that already neuron morphology causes a complex spread of optogenetic activity at the scale of one cortical column. Since the shape of a neuron impacts its optogenetic response, we find that a single stimulator at the cortical surface recruits a complex spatial distribution of neurons that can be inhomogeneous and vary with stimulation intensity and neuronal morphology across layers. We explore strategies to enhance stimulation precision, finding that optimizing stimulator optics may offer more significant improvements than the preferentially somatic expression of the opsin through genetic targeting. Our results indicate that, with the right optical setup, single-photon optogenetics can precisely activate isolated neurons at the scale of functional cortical domains spanning several hundred micrometers.

单光子光遗传学能够对神经元回路进行精确的细胞类型特异性调节，使其成为神经科学中的重要工具。它以完全可植入的宽场刺激器阵列的形式小型化，能够对皮层回路进行长期询问，并有望用于恢复感觉和运动功能的脑机接口。然而，实现功能性皮层表征的选择性激活是一项挑战，因为研究表明，靶向光遗传学刺激会导致活动扩散到一个功能域之外。虽然循环网络机制有助于活动传播，但在这里我们通过对来自未知性别猫的分离锥体神经元的详细模拟来证明，神经元形态已经在一个皮质柱的尺度上导致光遗传学活动的复杂传播。由于神经元的形状会影响其光遗传学反应，我们发现皮质表面的单个刺激器募集了复杂的神经元空间分布，这些神经元可能是不均匀的，并且随着刺激强度和跨层神经元形态的变化而变化。我们探索了提高刺激精度的策略，发现优化刺激器光学可能比通过遗传靶向优先体细胞表达视蛋白提供更显着的改进。我们的结果表明，通过正确的光学设置，单光子光遗传学可以在跨越数百微米的功能皮层结构域的尺度上精确激活孤立的神经元。