Moya Maria V, Cunningham William J, Vincent Jack P, Wang Tim, Economo Michael N
Department of Biomedical Engineering, Boston University, Boston, MA.
Center for Systems Neuroscience, Boston University, Boston, MA.
bioRxiv. 2025 Jun 25:2025.06.25.661552. doi: 10.1101/2025.06.25.661552.
Single-cell transcriptomics has uncovered the enormous heterogeneity of cell types that compose each region of the mammalian brain, but describing how such diverse types connect to form functional circuits has remained challenging. Current methods for measuring the probability and strength of cell-type specific connectivity motifs principally rely on low-throughput whole-cell recording approaches. The recent development of optical tools for perturbing and observing neural circuit activity, now notably including genetically encoded voltage indicators, presents an exciting opportunity to employ optical methods to greatly increase the throughput with which circuit connectivity can be mapped physiologically. At the same time, advances in spatial transcriptomics now enable the identification of cell types based on their unique gene expression signatures. Here, we demonstrate how long-range synaptic connectivity can be assayed optically with high sensitivity, high throughput, and cell-type specificity. We apply this approach in the motor cortex to examine cell-type-specific synaptic innervation patterns of long-range thalamic and contralateral input onto more than 1000 motor cortical neurons. We find that even cell types occupying the same cortical lamina receive vastly different levels of synaptic input, a finding which was previously not possible to uncover using lower-throughput approaches that can only describe the connectivity of broad cell types.
单细胞转录组学揭示了构成哺乳动物大脑每个区域的细胞类型的巨大异质性，但描述这些多样的细胞类型如何连接形成功能回路仍然具有挑战性。目前用于测量细胞类型特异性连接基序的概率和强度的方法主要依赖于低通量的全细胞记录方法。用于扰动和观察神经回路活动的光学工具最近得到了发展，目前特别包括基因编码电压指示器，这为采用光学方法极大地提高生理映射回路连接性的通量提供了一个令人兴奋的机会。与此同时，空间转录组学的进展现在能够根据细胞独特的基因表达特征来识别细胞类型。在这里，我们展示了如何以高灵敏度、高通量和细胞类型特异性光学检测长程突触连接性。我们将这种方法应用于运动皮层，以检查超过1000个运动皮层神经元上长程丘脑和对侧输入的细胞类型特异性突触支配模式。我们发现，即使占据相同皮质层的细胞类型也会接受截然不同水平的突触输入，这一发现使用只能描述宽泛细胞类型连接性的低通量方法以前是无法揭示的。
