Neuroscience Institute, New York University, New York, NY 10016, USA.
Neuroscience Institute, New York University, New York, NY 10016, USA.
Curr Biol. 2023 Aug 21;33(16):3465-3477.e5. doi: 10.1016/j.cub.2023.07.021. Epub 2023 Aug 4.
Regional brain activity often decreases from baseline levels in response to external events, but how neurons develop such negative responses is unclear. To study this, we leveraged the negative response that develops in the primary motor cortex (M1) after classical fear learning. We trained mice with a fear conditioning paradigm while imaging their brains with standard two-photon microscopy. This enabled monitoring changes in neuronal responses to the tone with synaptic resolution through learning. We found that M1 layer 5 pyramidal neurons (L5 PNs) developed negative tone responses within an hour after conditioning, which depended on the weakening of their dendritic spines that were active during training. Blocking this form of anti-Hebbian plasticity using an optogenetic manipulation of CaMKII activity disrupted negative tone responses and freezing. Therefore, reducing the strength of spines active at the time of memory encoding leads to negative responses of L5 PNs. In turn, these negative responses curb M1's capacity for promoting movement, thereby aiding freezing. Collectively, this work provides a mechanistic understanding of how area-specific negative responses to behaviorally relevant cues can be achieved.
区域脑活动通常会因外部事件而从基线水平下降，但神经元如何产生这种负响应尚不清楚。为了研究这一点，我们利用经典恐惧学习后在初级运动皮层（M1）中产生的负响应。我们在对老鼠进行恐惧条件反射训练的同时，用标准双光子显微镜对其大脑进行成像。这使得我们能够通过学习以突触分辨率监测神经元对音调反应的变化。我们发现，M1 层 5 锥体神经元（L5 PNs）在条件反射后一个小时内就产生了负音响应，这取决于在训练过程中活跃的树突棘的减弱。使用 CaMKII 活性的光遗传学操作来阻断这种形式的反海伯可塑性会破坏负音响应和冻结。因此，降低记忆编码时活跃的棘突的强度会导致 L5 PNs 的负响应。反过来，这些负响应会抑制 M1 促进运动的能力，从而有助于冻结。总的来说，这项工作提供了对与行为相关的线索产生特定区域负响应的机制的理解。
