Wick Zoé Christenson, Philipsberg Paul A, Lamsifer Sophia I, Kohler Cassidy, Katanov Elizabeth, Feng Yu, Humphrey Corin, Shuman Tristan
Icahn School of Medicine at Mount Sinai, New York NY.
New York University, New York NY.
bioRxiv. 2023 Feb 22:2023.02.21.529420. doi: 10.1101/2023.02.21.529420.
The precise timing of neuronal spiking relative to the brain's endogenous oscillations (i.e., phase-locking or spike-phase coupling) has long been hypothesized to coordinate cognitive processes and maintain excitatory-inhibitory homeostasis. Indeed, disruptions in theta phase-locking have been described in models of neurological diseases with associated cognitive deficits and seizures, such as Alzheimer's disease, temporal lobe epilepsy, and autism spectrum disorders. However, due to technical limitations, determining if phase-locking causally contributes to these disease phenotypes has not been possible until recently. To fill this gap and allow for the flexible manipulation of single-unit phase-locking to on-going endogenous oscillations, we developed PhaSER, an open-source tool that allows for phase-specific manipulations. PhaSER can deliver optogenetic stimulation at defined phases of theta in order to shift the preferred firing phase of neurons relative to theta in real-time. Here, we describe and validate this tool in a subpopulation of inhibitory neurons that express somatostatin (SOM) in the CA1 and dentate gyrus (DG) regions of the dorsal hippocampus. We show that PhaSER is able to accurately deliver a photo-manipulation that activates opsin+ SOM neurons at specified phases of theta in real-time in awake, behaving mice. Further, we show that this manipulation is sufficient to alter the preferred firing phase of opsin+ SOM neurons without altering the referenced theta power or phase. All software and hardware requirements to implement real-time phase manipulations during behavior are available online (https://github.com/ShumanLab/PhaSER).
长期以来，人们一直假设神经元放电相对于大脑内源性振荡的精确时间（即锁相或放电相位耦合）能够协调认知过程并维持兴奋性-抑制性稳态。事实上，在伴有认知缺陷和癫痫发作的神经疾病模型中，如阿尔茨海默病、颞叶癫痫和自闭症谱系障碍，已发现θ波锁相存在破坏情况。然而，由于技术限制，直到最近才有可能确定锁相是否因果性地导致了这些疾病表型。为了填补这一空白并实现对单个神经元与持续内源性振荡的锁相进行灵活操控，我们开发了PhaSER，这是一种允许进行相位特异性操控的开源工具。PhaSER能够在θ波的特定相位进行光遗传学刺激，以便实时改变神经元相对于θ波的偏好放电相位。在此，我们在背侧海马体CA1和齿状回（DG）区域中表达生长抑素（SOM）的抑制性神经元亚群中描述并验证了该工具。我们表明，PhaSER能够在清醒、行为活动的小鼠中，在θ波的特定相位准确地进行光操控，实时激活视蛋白+SOM神经元。此外，我们表明这种操控足以改变视蛋白+SOM神经元的偏好放电相位，而不改变参考θ波功率或相位。在行为过程中实施实时相位操控所需的所有软件和硬件要求均可在线获取（https://github.com/ShumanLab/PhaSER）。
