Design and Fabrication of Ultralight Weight, Adjustable Multi-electrode Probes for Electrophysiological Recordings in Mice

The number of physiological investigations in the mouse, mus musculus, has experienced a recent surge, paralleling the growth in methods of genetic ...

Massachusetts Institute of Technology

In order to optimally characterize full-body self-motion perception during passive translations, changes in perceived location, velocity, and acceleration must be quantified in real time and with high spatial resolution. Past methods have failed to effectively measure these critical variables. Here, we introduce continuous pointing as a novel method with several advantages over previous methods. Participants point continuously to the mentally updated location of a previously viewed target during passive, full-body movement. High-precision motion-capture data of arm angle provide a measure of a participant's perceived location and, in turn, perceived velocity at every moment during a motion trajectory. In two experiments, linear movements were presented in the absence of vision by passively translating participants with a robotic wheelchair or an anthropomorphic robotic arm (MPI Motion Simulator). The movement profiles included constant-velocity trajectories, two successive movement intervals separated by a brief pause, and reversed-motion trajectories. Results indicate a steady decay in perceived velocity during constant-velocity travel and an attenuated response to mid-trial accelerations.

Measurement of instantaneous perceived self-motion using continuous pointing.

The extent to which actual movements and imagined movements maintain a shared internal representation has been a matter of much scientific debate. Of the studies examining such questions, few have directly compared actual full-body movements to imagined movements through space. Here we used a novel continuous pointing method to a) provide a more detailed characterization of self-motion perception during actual walking and b) compare the pattern of responding during actual walking to that which occurs during imagined walking.

Imagined self-motion differs from perceived self-motion: evidence from a novel continuous pointing method.

In sensory substitution, the user may be directly aware of distal objects, as in everyday perception, or make explicit cognitive inferences based on an awareness of the proximal stimulation. Anecdotal evidence supports the experience of distal attribution, but so far there have been few rigorous experimental tests of the claim. In this study, blindfolded participants observed a target light using a device consisting of a finger-mounted photodiode that drives tactile vibra-tion on the back. With the blindfold off and the target removed, participants moved a reference object to match the perceived egocentric distance of the target. Participants who were instructed to attend to the distal target improved significantly during 2 h of practice, whereas those instructed to attend to proximal variables showed no improvement. Unsigned error increased with ratings of proximal attention, but decreased with ratings of target object solidity, consistent with distal attribution. Performance transferred to the non-dominant arm and to a rotated body orientation, demonstrating that learning did not depend on a joint-specific sensorimotor relationship between target distance and arm configuration. The results experimentally confirm that distal attribution can occur in sensory substitution, based on a perceptual strategy rather than an explicit cognitive strategy. Moreover, they suggest that the informational basis for distal attribution is not a joint-specific sensorimotor relation, but a more abstract spatial invariant.

Distal attribution and distance perception in sensory substitution.

Gamma oscillations in neocortex are hypothesized to improve information transmission between groups of neurons. We recently showed that optogenetic drive of fast-spiking interneurons (FS) at 40 Hz in mouse neocortex in vivo modulates the spike count and precision of sensory evoked responses. At specific phases of alignment between stimuli and FS activation, total evoked spike count was unchanged compared to baseline, but precision was increased. In the present study, we used computational modeling to investigate the origin of these local transformations, and to make predictions about their impact on downstream signal transmission. We replicated the prior experimental findings, and found that the local gain observed can be explained by mutual inhibition of fast-spiking interneurons, leading to more robust sensory-driven spiking in a brief temporal window post-stimulus, increasing local synchrony. Enhanced spiking in a second neocortical area, without a net increase in overall driven spikes in the first area, resulted from faster depolarization of target neurons due to increased pre-synaptic synchrony. In addition, we found that the precise temporal structure of spiking in the first area impacted the gain between cortical areas. The optimal spike distribution matched the "window of opportunity" defined by the timing of inhibition in the target area: spiking beyond this window did not contribute to downstream spike generation, leading to decreased overall gain. This result predicts that efficient transmission between neocortical areas requires a mechanism to dynamically match the temporal structure of the output of one area to the timing of inhibition in the recipient zone.

What do we gain from gamma? Local dynamic gain modulation drives enhanced efficacy and efficiency of signal transmission.

The thalamic reticular nucleus (TRN) is hypothesized to regulate neocortical rhythms and behavioral states. Using optogenetics and multi-electrode recording in behaving mice, we found that brief selective drive of TRN switched the thalamocortical firing mode from tonic to bursting and generated state-dependent neocortical spindles. These findings provide causal support for the involvement of the TRN in state regulation in vivo and introduce a new model for addressing the role of this structure in behavior.

Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles.

Maintaining the right balance between excitation and inhibition is crucial to healthy brain function. A recent study has used optogenetics to show how quickly and effectively inhibition clamps down a novel burst of excitation in the neocortex.

Cortical circuits: finding balance in the brain.

Neural stimulation technology has undergone a revolutionary advance with the introduction of light sensitive ion channels and pumps into genetically identified subsets of cells. To exploit this technology, it is necessary to incorporate optical elements into traditional electrophysiology devices. Here we describe the design, construction and use of a "hyperdrive" capable of simultaneous electrical recordings and optical stimulation. The device consists of multiple microdrives for moving electrodes independently and a stationary fiber for delivering light to the tissue surrounding the electrodes. We present data demonstrating the effectiveness of inhibitory recruitment via optical stimulation and its interaction with physiological and behavioral states, determined by electrophysiological recording and videographic monitoring.

Chronically implanted hyperdrive for cortical recording and optogenetic control in behaving mice.

Electrophysiological recordings from ensembles of neurons in behaving mice are a central tool in the study of neural circuits. Despite the widespread use of chronic electrophysiology, the precise positioning of recording electrodes required for high-quality recordings remains a challenge, especially in behaving mice. The complexity of available drive mechanisms, combined with restrictions on implant weight tolerated by mice, limits current methods to recordings from no more than 4-8 electrodes in a single target area. We developed a highly miniaturized yet simple drive design that can be used to independently position 16 electrodes with up to 64 channels in a package that weighs ~2 g. This advance over current designs is achieved by a novel spring-based drive mechanism that reduces implant weight and complexity. The device is easy to build and accommodates arbitrary spatial arrangements of electrodes. Multiple optical fibers can be integrated into the recording array and independently manipulated in depth. Thus, our novel design enables precise optogenetic control and highly parallel chronic recordings of identified single neurons throughout neural circuits in mice.

The flexDrive: an ultra-light implant for optical control and highly parallel chronic recording of neuronal ensembles in freely moving mice.

Assessing the behavioral relevance of the hippocampal theta rhythm has proven difficult, due to a shortage of experiments that selectively manipulate phase-specific information processing. Using closed-loop stimulation, we triggered inhibition of dorsal CA1 at specific phases of the endogenous theta rhythm in freely behaving mice. This intervention enhanced performance on a spatial navigation task that requires the encoding and retrieval of information related to reward location on every trial. In agreement with prior models of hippocampal function, the behavioral effects depended on both the phase of theta and the task segment at which we stimulated. Stimulation in the encoding segment enhanced performance when inhibition was triggered by the peak of theta. Conversely, stimulation in the retrieval segment enhanced performance when inhibition was triggered by the trough of theta. These results suggest that processes related to the encoding and retrieval of task-relevant information are preferentially active at distinct phases of theta.DOI: http://dx.doi.org/10.7554/eLife.03061.001.

Enhancement of encoding and retrieval functions through theta phase-specific manipulation of hippocampus.

We tested the sensory impact of repeated synchronization of fast-spiking interneurons (FS), an activity pattern thought to underlie neocortical gamma oscillations. We optogenetically drove 'FS-gamma' while mice detected naturalistic vibrissal stimuli and found enhanced detection of less salient stimuli and impaired detection of more salient ones. Prior studies have predicted that the benefit of FS-gamma is generated when sensory neocortical excitation arrives in a specific temporal window 20-25 ms after FS synchronization. To systematically test this prediction, we aligned periodic tactile and optogenetic stimulation. We found that the detection of less salient stimuli was improved only when peripheral drive led to the arrival of excitation 20-25 ms after synchronization and that other temporal alignments either had no effects or impaired detection. These results provide causal evidence that FS-gamma can enhance processing of less salient stimuli, those that benefit from the allocation of attention.

Joshua H. Siegle

Department of Brain and Cognitive Science

Massachusetts Institute of Technology

Design and Fabrication of Ultralight Weight, Adjustable Multi-electrode Probes for Electrophysiological Recordings in Mice

Joshua H. Siegle

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Massachusetts Institute of Technology

Design and Fabrication of Ultralight Weight, Adjustable Multi-electrode Probes for Electrophysiological Recordings in Mice

Department of Brain and Cognitive Science