Heterogeneous side effects of cortical inactivation in behaving animals.
Heterogeneous side effects of cortical inactivation in behaving animals.
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DOI：
10.7554/elife.66400
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发表时间：
2021-09-10
期刊：
影响因子：
7.7
通讯作者：
Dragoi V
中科院分区：
文献类型：
--
作者：
Andrei AR;Debes S;Chelaru M;Liu X;Rodarte E;Spudich JL;Janz R;Dragoi V
皮质失活代表了一种关键的因果操作，可以研究皮质回路及其对行为的影响。失活研究的一个关键假设是目标区域的神经元变得沉默，而周围的皮质组织仅受到可忽略不计的影响。然而，单个神经元嵌入由兴奋性和抑制性细胞组成的复杂局部回路中，其连接延伸数百微米。这就提出了一种可能性，即沉默网络的一部分可能会导致目标失活区之外的神经元发生复杂的、不可预测的活动变化。这些脱靶副作用可能会使失活操作的解释复杂化，特别是当它们与行为变化相关时。在这里，我们证明猴子初级视觉皮层（V1）表层谷氨酸能神经元的光遗传学失活会在光靶向位点引起强烈抑制，但会破坏邻近非靶向网络中的刺激反应。我们确定了皮质柱内刺激诱发的神经元反应的四种类型，从完全抑制到促进，以及两者的混合。混合反应在中层和深层皮质层最为突出。这些结果表明，由横向网络连接驱动的响应调制在整个皮质柱中以不同方式实现。重要的是，只有当累积网络活动被均匀抑制时，光遗传学失活诱导的一致行为变化才能实现。因此，需要仔细考虑失活皮质区域之外的全方位网络变化，因为异质副作用可能会混淆失活实验的解释。
Cortical inactivation represents a key causal manipulation allowing the study of cortical circuits and their impact on behavior. A key assumption in inactivation studies is that the neurons in the target area become silent while the surrounding cortical tissue is only negligibly impacted. However, individual neurons are embedded in complex local circuits composed of excitatory and inhibitory cells with connections extending hundreds of microns. This raises the possibility that silencing one part of the network could induce complex, unpredictable activity changes in neurons outside the targeted inactivation zone. These off-target side effects can potentially complicate interpretations of inactivation manipulations, especially when they are related to changes in behavior. Here, we demonstrate that optogenetic inactivation of glutamatergic neurons in the superficial layers of monkey primary visual cortex (V1) induces robust suppression at the light-targeted site, but destabilizes stimulus responses in the neighboring, untargeted network. We identified four types of stimulus-evoked neuronal responses within a cortical column, ranging from full suppression to facilitation, and a mixture of both. Mixed responses were most prominent in middle and deep cortical layers. These results demonstrate that response modulation driven by lateral network connectivity is diversely implemented throughout a cortical column. Importantly, consistent behavioral changes induced by optogenetic inactivation were only achieved when cumulative network activity was homogeneously suppressed. Therefore, careful consideration of the full range of network changes outside the inactivated cortical region is required, as heterogeneous side effects can confound interpretation of inactivation experiments.