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Optogenetics is among the most widely employed techniques to manipulate neuronal activity. However, a major drawback is the need for invasive implantation of optical fibers. To develop a minimally invasive optogenetic method that overcomes this challenge, we engineered a new step-function opsin with ultra-high light sensitivity (SOUL). We show that SOUL can activate neurons located in deep mouse brain regions via transcranial optical stimulation and elicit behavioral changes in SOUL knock-in mice. Moreover, SOUL can be used to modulate neuronal spiking and induce oscillations reversibly in macaque cortex via optical stimulation from outside the dura. By enabling external light delivery, our new opsin offers a minimally invasive tool for manipulating neuronal activity in rodent and primate models with fewer limitations on the depth and size of target brain regions and may further facilitate the development of minimally invasive optogenetic tools for the treatment of neurological disorders.

© 2020 Elsevier Inc. Optogenetics is among the most widely employed techniques to manipulate neuronal activity. However, a major drawback is the need for invasive implantation of optical fibers. To develop a minimally invasive optogenetic method that overcomes this challenge, we engineered a new step-function opsin with ultra-high light sensitivity (SOUL). We show that SOUL can activate neurons located in deep mouse brain regions via transcranial optical stimulation and elicit behavioral changes in SOUL knock-in mice. Moreover, SOUL can be used to modulate neuronal spiking and induce oscillations reversibly in macaque cortex via optical stimulation from outside the dura. By enabling external light delivery, our new opsin offers a minimally invasive tool for manipulating neuronal activity in rodent and primate models with fewer limitations on the depth and size of target brain regions and may further facilitate the development of minimally invasive optogenetic tools for the treatment of neurological disorders.

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition1–5. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders6–9. However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN–thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits., NIH/NIMH (Grants R01NS098505, R01NS113245), NIH (Grants R01NS098505, R01MH107680)

A neural prosthesis is designed to compensate for cognitive functional losses by modeling the information transmission among cortical areas. Existing methods generally build a generalized linear model to approximate the nonlinear transformation among two areas, and use the temporal information of the neural spike with low efficiency. It is essential to efficiently model the nonlinearity embedded in spike generation and transmission for the real-time. This paper proposes a nonlinear point-process model to describe spike-in and spike-out transformation using the theory of reproducing kernel Hilbert space (RKHS) and the binless kernel on spike trains. The binless kernel efficiently maps exact spike timing information to the RKHS to describe nonlinear transformations with global minimum regardless of the weight initialization. A streaming K-medoids algorithm is introduced to select typical and important features in this nonlinear binless kernel for further modeling. We test our model on the nonlinearly generated synthetic neural spike trains, and compare with the existing spike transformation methods, such as Volterra model and staged point-process model. The results show that our model has higher goodness-of-fit evaluated by Kolmogorov-Smirnov test and less variance on the prediction results, which indicates the potential better modeling approach for neural prosthesis application. © 2019 IEEE.

Neurons communicate nonlinearly through spike activities. Generalized linear models (GLMs) describe spike activities with a cascade of a linear combination across inputs, a static nonlinear function, and an inhomogeneous Bernoulli or Poisson process, or Cox process if a self-history term is considered. This structure considers the output nonlinearity in spike generation but excludes the nonlinear interaction among input neurons. Recent studies extend GLMs by modeling the interaction among input neurons with a quadratic function, which considers the interaction between every pair of input spikes. However, quadratic effects may not fully capture the nonlinear nature of input interaction. We therefore propose a staged point-process model to describe the nonlinear interaction among inputs using a few hidden units, which follows the idea of artificial neural networks. The output firing probability conditioned on inputs is formed as a cascade of two linear-nonlinear (a linear combination plus a static nonlinear function) stages and an inhomogeneous Bernoulli process. Parameters of this model are estimated by maximizing the log likelihood on output spike trains. Unlike the iterative reweighted least squares algorithm used in GLMs, where the performance is guaranteed by the concave condition, we propose a modified Levenberg-Marquardt (L-M) algorithm, which directly calculates the Hessian matrix of the log likelihood, for the nonlinear optimization in our model. The proposed model is tested on both synthetic data and real spike train data recorded from the dorsal premotor cortex and primary motor cortex of a monkey performing a center-out task. Performances are evaluated by discrete-time rescaled Kolmogorov-Smirnov tests, where our model statistically outperforms a GLM and its quadratic extension, with a higher goodness-of-fit in the prediction results. In addition, the staged point-process model describes nonlinear interaction among input neurons with fewer parameters than