Coordinated head direction representations in mouse anterodorsal thalamic nucleus and retrosplenial cortex.

The sense of direction is critical for survival in changing environments and relies on flexibly integrating self-motion signals with external sensory cues. While the anatomical substrates involved in head direction (HD) coding are well known, the mechanisms by which visual information updates HD representations remain poorly understood. Retrosplenial cortex (RSC) plays a key role in forming coherent representations of space in mammals and it encodes a variety of navigational variables, including HD. Here, we use simultaneous two-area tetrode recording to show that RSC HD representation is nearly synchronous with that of the anterodorsal nucleus of thalamus (ADn), the obligatory thalamic relay of HD to cortex, during rotation of a prominent visual cue. Moreover, coordination of HD representations in the two regions is maintained during darkness. We further show that anatomical and functional connectivity are consistent with a strong feedforward drive of HD information from ADn to RSC, with anatomically restricted corticothalamic feedback. Together, our results indicate a concerted global HD reference update across cortex and thalamus.

A unified open-source platform for multimodal neural recording and perturbation during naturalistic behavior.

Behavioral neuroscience faces two conflicting demands: long-duration recordings from large neural populations and unimpeded animal behavior. To meet this challenge, we developed ONIX, an open-source data acquisition system with high data throughput (2GB/sec) and low closed-loop latencies (<1ms) that uses a novel 0.3 mm thin tether to minimize behavioral impact. Head position and rotation are tracked in 3D and used to drive active commutation without torque measurements. ONIX can acquire from combinations of passive electrodes, Neuropixels probes, head-mounted microscopes, cameras, 3D-trackers, and other data sources. We used ONIX to perform uninterrupted, long (~7 hours) neural recordings in mice as they traversed complex 3-dimensional terrain. ONIX allowed exploration with similar mobility as non-implanted animals, in contrast to conventional tethered systems which restricted movement. By combining long recordings with full mobility, our technology will enable new progress on questions that require high-quality neural recordings during ethologically grounded behaviors.

An easy-to-assemble, robust, and lightweight drive implant for chronic tetrode recordings in freely moving animals.

Tetrode arrays are a standard method for neuronal recordings in behaving animals, especially for chronic recordings of many neurons in freely-moving animals. OBJECTIVE: We sought to simplify tetrode drive designs with the aim of enabling building and implanting a 16-tetrode drive in a single day. APPROACH: Our design makes use of recently developed technologies to reduce the complexity of the drive while maintaining a low weight. MAIN RESULTS: The design presents an improvement over existing implants in terms of robustness, weight, and ease of use. We describe two variants: a 16 tetrode implant weighing ∼2 g for mice, bats, tree shrews and similar animals, and a 64 tetrode implant weighing ∼16 g for rats and similar animals. These designs were co-developed and optimized alongside a new class of drive-mounted feature-rich amplifier boards with ultra-thin radio-frequency tethers, as described in an upcoming paper (Newman, Zhang et al in prep). SIGNIFICANCE: This design significantly improves the data yield of chronic electrophysiology experiments.

Twister3: a simple and fast microwire twister.

OBJECTIVE: Twisted wire probes (TWPs, e.g. stereotrodes and tetrodes) provide a cheap and reliable method for obtaining high quality, multiple single-unit neural recordings in freely moving animals. Despite their ubiquity, TWPs are constructed using a tedious procedure consisting of manually folding, turning, and fusing microwire. This imposes a significant labor burden on research personnel who use TWPs in their experiments. APPROACH: To address this issue, we created Twister3, an open-source microwire twisting machine. This machine features a quick-draw wire feeder that eliminates manual wire folding, an auto-aligning motor attachment mechanism which results in consistently straight probes, and a high speed motor for rapid probe turning. MAIN RESULTS: Twister3 greatly increases the speed and repeatability of constructing twisted microwire probes compared to existing options. Users with less than one hour of experience using the device were able to make ~70 tetrodes per hour, on average. It is cheap, well documented, and all associated designs and source code are open-source. SIGNIFICANCE: Twister3 significantly reduces the labor burden of creating high-quality TWPs so electrophysiologists can spend more of their time performing recordings rather than making probes. Therefore, this device is of interest to any lab performing TWP neural recordings, for example, using microdrives.

A closed-loop, all-electronic pixel-wise adaptive imaging system for high dynamic range videography.

Digital cameras expose and readout all pixels in accordance with a global sample clock. This rigid global control of exposure and sampling is problematic for capturing scenes with large variance in brightness and motion, and may cause regions of motion blur, under- and overexposure. To address these issues, we developed a CMOS imaging system that automatically adjusts each pixel's exposure and sampling rate to fit local motion and brightness. This system consists of an image sensor with pixel-addressable exposure configurability in combination with a real-time, per-pixel exposure controller. It operates in a closed-loop to sample, detect and optimize each pixel's exposure and sampling rate for optimal acquisition. Per-pixel exposure control is implemented using all-integrated electronics without external optical modulation. This reduces system complexity and power consumption compared to existing solutions. Implemented using standard 130nm CMOS process, the chip has 256 × 256 pixels and consumes 7.31mW. To evaluate performance, we used this system to capture scenes with complex lighting and motion conditions that would lead to loss of information for globally-exposed cameras. These results demonstrate the advantage of pixel-wise adaptive imaging for a range of computer vision tasks such as segmentation, motion estimation and object recognition.

Optogenetic feedback control of neural activity.

Optogenetic techniques enable precise excitation and inhibition of firing in specified neuronal populations and artifact-free recording of firing activity. Several studies have suggested that optical stimulation provides the precision and dynamic range requisite for closed-loop neuronal control, but no approach yet permits feedback control of neuronal firing. Here we present the 'optoclamp', a feedback control technology that provides continuous, real-time adjustments of bidirectional optical stimulation in order to lock spiking activity at specified targets over timescales ranging from seconds to days. We demonstrate how this system can be used to decouple neuronal firing levels from ongoing changes in network excitability due to multi-hour periods of glutamatergic or GABAergic neurotransmission blockade in vitro as well as impinging vibrissal sensory drive in vivo. This technology enables continuous, precise optical control of firing in neuronal populations in order to disentangle causally related variables of circuit activation in a physiologically and ethologically relevant manner.

Upward synaptic scaling is dependent on neurotransmission rather than spiking.

Homeostatic plasticity encompasses a set of mechanisms that are thought to stabilize firing rates in neural circuits. The most widely studied form of homeostatic plasticity is upward synaptic scaling (upscaling), characterized by a multiplicative increase in the strength of excitatory synaptic inputs to a neuron as a compensatory response to chronic reductions in firing rate. While reduced spiking is thought to trigger upscaling, an alternative possibility is that reduced glutamatergic transmission generates this plasticity directly. However, spiking and neurotransmission are tightly coupled, so it has been difficult to determine their independent roles in the scaling process. Here we combined chronic multielectrode recording, closed-loop optogenetic stimulation, and pharmacology to show that reduced glutamatergic transmission directly triggers cell-wide synaptic upscaling. This work highlights the importance of synaptic activity in initiating signalling cascades that mediate upscaling. Moreover, our findings challenge the prevailing view that upscaling functions to homeostatically stabilize firing rates.

Neural ensemble communities: open-source approaches to hardware for large-scale electrophysiology.

One often-overlooked factor when selecting a platform for large-scale electrophysiology is whether or not a particular data acquisition system is 'open' or 'closed': that is, whether or not the system's schematics and source code are available to end users. Open systems have a reputation for being difficult to acquire, poorly documented, and hard to maintain. With the arrival of more powerful and compact integrated circuits, rapid prototyping services, and web-based tools for collaborative development, these stereotypes must be reconsidered. We discuss some of the reasons why multichannel extracellular electrophysiology could benefit from open-source approaches and describe examples of successful community-driven tool development within this field. In order to promote the adoption of open-source hardware and to reduce the need for redundant development efforts, we advocate a move toward standardized interfaces that connect each element of the data processing pipeline. This will give researchers the flexibility to modify their tools when necessary, while allowing them to continue to benefit from the high-quality products and expertise provided by commercial vendors.

Real-time in vivo optogenetic neuromodulation and multielectrode electrophysiologic recording with NeuroRighter.

Optogenetic channels have greatly expanded neuroscience's experimental capabilities, enabling precise genetic targeting and manipulation of neuron subpopulations in awake and behaving animals. However, many barriers to entry remain for this technology - including low-cost and effective hardware for combined optical stimulation and electrophysiologic recording. To address this, we adapted the open-source NeuroRighter multichannel electrophysiology platform for use in awake and behaving rodents in both open and closed-loop stimulation experiments. Here, we present these cost-effective adaptations, including commercially available LED light sources; custom-made optical ferrules; 3D printed ferrule hardware and software to calibrate and standardize output intensity; and modifications to commercially available electrode arrays enabling stimulation proximally and distally to the recording target. We then demonstrate the capabilities and versatility of these adaptations in several open and closed-loop experiments, demonstrate spectrographic methods of analyzing the results, as well as discuss artifacts of stimulation.

Delivery of continuously-varying stimuli using channelrhodopsin-2.

To study sensory processing, stimuli are delivered to the sensory organs of animals and evoked neural activity is recorded downstream. However, noise and uncontrolled modulatory input can interfere with repeatable delivery of sensory stimuli to higher brain regions. Here we show how channelrhodopsin-2 (ChR2) can be used to deliver continuous, subthreshold, time-varying currents to neurons at any point along the sensory-motor pathway. To do this, we first deduce the frequency response function of ChR2 using a Markov model of channel kinetics. We then confirm ChR2's frequency response characteristics using continuously-varying optical stimulation of neurons that express one of three ChR2 variants. We find that wild-type ChR2 and the E123T/H134R mutant ("CheTA") can pass continuously-varying subthreshold stimuli with frequencies up to ~70 Hz. Additionally, we find that wild-type ChR2 exhibits a strong resonance at ~6-10 Hz. Together, these results indicate that ChR2-derived optogenetic tools are useful for delivering highly repeatable artificial stimuli that mimic in vivo synaptic bombardment.

Stimulus-evoked high frequency oscillations are present in neuronal networks on microelectrode arrays.

Pathological high frequency oscillations (250-600 Hz) are present in the brains of epileptic animals and humans. The etiology of these oscillations and how they contribute to the diseased state remains unclear. This work identifies the presence of microstimulation-evoked high frequency oscillations (250-400 Hz) in dissociated neuronal networks cultured on microelectrode arrays (MEAs). Oscillations are more apparent with higher stimulus voltages. As with in vivo studies, activity is isolated to a single electrode, however, the MEA provides improved spatial resolution with no spread of the oscillation to adjacent electrodes 200 µm away. Oscillations develop across four weeks in vitro. Oscillations still occur in the presence of tetrodotoxin and synaptic blockers, and they cause no apparent disruption in the ability of oscillation-presenting electrodes to elicit directly evoked action potentials (dAPs) or promote the spread of synaptic activity throughout the culture. Chelating calcium with ethylene glycol tetraacetic acid (EGTA) causes a temporal prolongation of the oscillation. Finally, carbenoxolone significantly reduces or eliminates the high frequency oscillations. Gap junctions may play a significant role in maintaining the oscillation given the inhibitory effect of carbenoxolone, the propagating effect of reduced calcium conditions and the isolated nature of the activity as demonstrated in previous studies. This is the first demonstration of stimulus-evoked high frequency oscillations in dissociated cultures. Unlike current models that rely on complex in vivo recording conditions, this work presents a simple controllable model in neuronal cultures on MEAs to further investigate how the oscillations occur at the molecular level and how they may contribute to the pathophysiology of disease.

Closed-Loop, Multichannel Experimentation Using the Open-Source NeuroRighter Electrophysiology Platform.

Single neuron feedback control techniques, such as voltage clamp and dynamic clamp, have enabled numerous advances in our understanding of ion channels, electrochemical signaling, and neural dynamics. Although commercially available multichannel recording and stimulation systems are commonly used for studying neural processing at the network level, they provide little native support for real-time feedback. We developed the open-source NeuroRighter multichannel electrophysiology hardware and software platform for closed-loop multichannel control with a focus on accessibility and low cost. NeuroRighter allows 64 channels of stimulation and recording for around US $10,000, along with the ability to integrate with other software and hardware. Here, we present substantial enhancements to the NeuroRighter platform, including a redesigned desktop application, a new stimulation subsystem allowing arbitrary stimulation patterns, low-latency data servers for accessing data streams, and a new application programming interface (API) for creating closed-loop protocols that can be inserted into NeuroRighter as plugin programs. This greatly simplifies the design of sophisticated real-time experiments without sacrificing the power and speed of a compiled programming language. Here we present a detailed description of NeuroRighter as a stand-alone application, its plugin API, and an extensive set of case studies that highlight the system's abilities for conducting closed-loop, multichannel interfacing experiments.

Mechanism, dynamics, and biological existence of multistability in a large class of bursting neurons.

Multistability, the coexistence of multiple attractors in a dynamical system, is explored in bursting nerve cells. A modeling study is performed to show that a large class of bursting systems, as defined by a shared topology when represented as dynamical systems, is inherently suited to support multistability. We derive the bifurcation structure and parametric trends leading to multistability in these systems. Evidence for the existence of multirhythmic behavior in neurons of the aquatic mollusc Aplysia californica that is consistent with our proposed mechanism is presented. Although these experimental results are preliminary, they indicate that single neurons may be capable of dynamically storing information for longer time scales than typically attributed to nonsynaptic mechanisms.

Effect of sensory blind zones on milling behavior in a dynamic self-propelled particle model.

Emergent pattern formation in self-propelled particle (SPP) systems is extensively studied because it addresses a range of swarming phenomena that occur without leadership. Here we present a dynamic SPP model in which a sensory blind zone is introduced into each particle's zone of interaction. Using numerical simulations, we discovered that the degradation of milling patterns with increasing blind zone ranges undergoes two distinct transitions, including a spatially non-homogeneous transition that involves cessation of particles' motion caused by broken symmetries in the interaction fields. Our results also show the necessity of nearly complete panoramic sensory ability for milling behavior to emerge in dynamic SPP models, suggesting a possible relationship between collective behavior and the sensory systems of biological organisms.