Spontaneous activity competes with externally evoked responses in sensory cortex.

The interaction between spontaneous and externally evoked neuronal activity is fundamental for a functional brain. Increasing evidence suggests that bursts of high-power oscillations in the 15- to 30-Hz beta-band represent activation of internally generated events and mask perception of external cues. Yet demonstration of the effect of beta-power modulation on perception in real time is missing, and little is known about the underlying mechanism. Here, we used a closed-loop stimulus-intensity adjustment system based on online burst-occupancy analyses in rats involved in a forepaw vibrotactile detection task. We found that the masking influence of burst occupancy on perception can be counterbalanced in real time by adjusting the vibration amplitude. Offline analysis of firing rates (FRs) and local field potentials across cortical layers and frequency bands confirmed that beta-power in the somatosensory cortex anticorrelated with sensory evoked responses. Mechanistically, bursts in all bands were accompanied by transient synchronization of cell assemblies, but only beta-bursts were followed by a reduction of FR. Our closed loop approach reveals that spontaneous beta-bursts reflect a dynamic state that competes with external stimuli.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

3D pose estimation enables virtual head fixation in freely moving rats.

The impact of spontaneous movements on neuronal activity has created the need to quantify behavior. We present a versatile framework to directly capture the 3D motion of freely definable body points in a marker-free manner with high precision and reliability. Combining the tracking with neural recordings revealed multiplexing of information in the motor cortex neurons of freely moving rats. By integrating multiple behavioral variables into a model of the neural response, we derived a virtual head fixation for which the influence of specific body movements was removed. This strategy enabled us to analyze the behavior of interest (e.g., front paw movements). Thus, we unveiled an unexpectedly large fraction of neurons in the motor cortex with tuning to the paw movements, which was previously masked by body posture tuning. Once established, our framework can be efficiently applied to large datasets while minimizing the experimental workload caused by animal training and manual labeling.

Multichannel optogenetics combined with laminar recordings for ultra-controlled neuronal interrogation.

Simultaneous large-scale recordings and optogenetic interventions may hold the key to deciphering the fast-paced and multifaceted dialogue between neurons that sustains brain function. Here we have taken advantage of thin, cell-sized, optical fibers for minimally invasive optogenetics and flexible implantations. We describe a simple procedure for making those fibers side-emitting with a Lambertian emission distribution. Here we combined those fibers with silicon probes to achieve high-quality recordings and ultrafast multichannel optogenetic inhibition. Furthermore, we developed a multi-channel optical commutator and general-purpose patch-cord for flexible experiments. We demonstrate that our framework allows to conduct simultaneous laminar recordings and multifiber stimulations, 3D optogenetic stimulation, connectivity inference, and behavioral quantification in freely moving animals. Our framework paves the way for large-scale photo tagging and controlled interrogation of rapid neuronal communication in any combination of brain areas.

Effects of Optogenetic Stimulation of Primary Somatosensory Cortex and Its Projections to Striatum on Vibrotactile Perception in Freely Moving Rats.

Tactile sensation is one of our primary means to collect information about the nearby environment and thus crucial for daily activities and survival. Therefore, it is of high importance to restore sensory feedback after sensory loss. Optogenetic manipulation allows local or pathway-specific write-in of information. However, it remains elusive whether optogenetic stimulation can be interpreted as tactile sensation to guide operant behavior and how it is integrated with tactile stimuli. To address these questions, we employed a vibrotactile detection task combined with optogenetic neuromodulation in freely moving rats. By bidirectionally manipulating the activity of neurons in primary somatosensory cortex (S1), we demonstrated that optical activation as well as inhibition of S1 reduced the detection rate for vibrotactile stimuli. Interestingly, activation of corticostriatal terminals improved the detection of tactile stimuli, while inhibition of corticostriatal terminals did not affect the performance. To manipulate the corticostriatal pathway more specifically, we employed a dual viral system. Activation of corticostriatal cell bodies disturbed the tactile perception while activation of corticostriatal terminals slightly facilitated the detection of vibrotactile stimuli. In the absence of tactile stimuli, both corticostriatal cell bodies as well as terminals caused a reaction. Taken together, our data confirmed the possibility to restore sensation using optogenetics and demonstrated that S1 and its descending projections to striatum play differential roles in the neural processing underlying vibrotactile detection.

Real-time detection of neural oscillation bursts allows behaviourally relevant neurofeedback.

Neural oscillations as important information carrier in the brain, are increasingly interpreted as transient bursts rather than as sustained oscillations. Short (<150 ms) bursts of beta-waves (15-30 Hz) have been documented in humans, monkeys and mice. These events were correlated with memory, movement and perception, and were even suggested as the primary ingredient of all beta-band activity. However, a method to measure these short-lived events in real-time and to investigate their impact on behaviour is missing. Here we present a real-time data analysis system, capable to detect short narrowband bursts, and demonstrate its usefulness to increase the beta-band burst-rate in rats. This neurofeedback training induced changes in overall oscillatory power, and bursts could be decoded from the movement of the rats, thus enabling future investigation of the role of oscillatory bursts.

A Toolbox for Optophysiological Experiments in Freely Moving Rats.

Simultaneous recordings and manipulations of neural circuits that control the behavior of animals is one of the key techniques in modern neuroscience. Rapid advances in optogenetics have led to a variety of probes combining multichannel readout and optogenetic write in. Given the complexity of the brain, it comes as no surprise that the choice of the device is constrained by several factors such as the animal model, the structure and location of the brain area of interest, as well as the behavioral read out. Here we provide an overview of available devices for chronic simultaneous neural recordings and optogenetic manipulation in awake behaving rats. We focus on two fixed arrays and two moveable drives. For both options, we present data from one custom-made (in house) and one commercially available device. Here we provide evidence that simultaneous neural recordings and optogenetic manipulations are feasible with all four tested devices. Further we give detailed information about the recording quality, and also contrast the different features of the probes. As we provide detailed information about equipment and building procedures for combined chronic multichannel readout and optogenetic control with maximum performance at minimized costs, this overview might help especially researchers who want to enter the field of in vivo optophysiology.