A neural circuit state change underlying skilled movements.

In motor neuroscience, state changes are hypothesized to time-lock neural assemblies coordinating complex movements, but evidence for this remains slender. We tested whether a discrete change from more autonomous to coherent spiking underlies skilled movement by imaging cerebellar Purkinje neuron complex spikes in mice making targeted forelimb-reaches. As mice learned the task, millimeter-scale spatiotemporally coherent spiking emerged ipsilateral to the reaching forelimb, and consistent neural synchronization became predictive of kinematic stereotypy. Before reach onset, spiking switched from more disordered to internally time-locked concerted spiking and silence. Optogenetic manipulations of cerebellar feedback to the inferior olive bi-directionally modulated neural synchronization and reaching direction. A simple model explained the reorganization of spiking during reaching as reflecting a discrete bifurcation in olivary network dynamics. These findings argue that to prepare learned movements, olivo-cerebellar circuits enter a self-regulated, synchronized state promoting motor coordination. State changes facilitating behavioral transitions may generalize across neural systems.

Fundamental bounds on the fidelity of sensory cortical coding.

How the brain processes information accurately despite stochastic neural activity is a longstanding question1. For instance, perception is fundamentally limited by the information that the brain can extract from the noisy dynamics of sensory neurons. Seminal experiments2,3 suggest that correlated noise in sensory cortical neural ensembles is what limits their coding accuracy4-6, although how correlated noise affects neural codes remains debated7-11. Recent theoretical work proposes that how a neural ensemble's sensory tuning properties relate statistically to its correlated noise patterns is a greater determinant of coding accuracy than is absolute noise strength12-14. However, without simultaneous recordings from thousands of cortical neurons with shared sensory inputs, it is unknown whether correlated noise limits coding fidelity. Here we present a 16-beam, two-photon microscope to monitor activity across the mouse primary visual cortex, along with analyses to quantify the information conveyed by large neural ensembles. We found that, in the visual cortex, correlated noise constrained signalling for ensembles with 800-1,300 neurons. Several noise components of the ensemble dynamics grew proportionally to the ensemble size and the encoded visual signals, revealing the predicted information-limiting correlations12-14. Notably, visual signals were perpendicular to the largest noise mode, which therefore did not limit coding fidelity. The information-limiting noise modes were approximately ten times smaller and concordant with mouse visual acuity15. Therefore, cortical design principles appear to enhance coding accuracy by restricting around 90% of noise fluctuations to modes that do not limit signalling fidelity, whereas much weaker correlated noise modes inherently bound sensory discrimination.

Skilled reaching tasks for head-fixed mice using a robotic manipulandum.

Skilled forelimb behaviors are among the most important for studying motor learning in multiple species including humans. This protocol describes learned forelimb tasks for mice using a two-axis robotic manipulandum. Our device provides a highly compact adaptation of actuated planar two-axis arms that is simple and inexpensive to construct. This paradigm has been dominant for decades in primate motor neuroscience. Our device can generate arbitrary virtual movement tracks, arbitrary time-varying forces or arbitrary position- or velocity-dependent force patterns. We describe several example tasks permitted by our device, including linear movements, movement sequences and aiming movements. We provide the mechanical drawings and source code needed to assemble and control the device, and detail the procedure to train mice to use the device. Our software can be simply extended to allow users to program various customized movement assays. The device can be assembled in a few days, and the time to train mice on the tasks that we describe ranges from a few days to several weeks. Furthermore, the device is compatible with various neurophysiological techniques that require head fixation.

Long-term optical brain imaging in live adult fruit flies.

Time-lapse in vivo microscopy studies of cellular morphology and physiology are crucial toward understanding brain function but have been infeasible in the fruit fly, a key model species. Here we use laser microsurgery to create a chronic fly preparation for repeated imaging of neural architecture and dynamics for up to 50 days. In fly mushroom body neurons, we track axonal boutons for 10 days and record odor-evoked calcium transients over 7 weeks. Further, by using voltage imaging to resolve individual action potentials, we monitor spiking plasticity in dopamine neurons of flies undergoing mechanical stress. After 24 h of stress, PPL1-α'3 but not PPL1-α'2α2 dopamine neurons have elevated spike rates. Overall, our chronic preparation is compatible with a broad range of optical techniques and enables longitudinal studies of many biological questions that could not be addressed before in live flies.

Cerebellar granule cells encode the expectation of reward.

The human brain contains approximately 60 billion cerebellar granule cells, which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes. Although evidence suggests a role for the cerebellum in cognition, granule cells are known to encode only sensory and motor context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.

Dexterous robotic manipulation of alert adult Drosophila for high-content experimentation.

We present a robot that enables high-content studies of alert adult Drosophila by combining operations including gentle picking; translations and rotations; characterizations of fly phenotypes and behaviors; microdissection; or release. To illustrate, we assessed fly morphology, tracked odor-evoked locomotion, sorted flies by sex, and dissected the cuticle to image neural activity. The robot's tireless capacity for precise manipulations enables a scalable platform for screening flies' complex attributes and behavioral patterns.

Visualizing mammalian brain area interactions by dual-axis two-photon calcium imaging.

Fluorescence Ca(2+) imaging enables large-scale recordings of neural activity, but collective dynamics across mammalian brain regions are generally inaccessible within single fields of view. Here we introduce a two-photon microscope possessing two articulated arms that can simultaneously image two brain areas (∼0.38 mm(2) each), either nearby or distal, using microendoscopes. Concurrent Ca(2+) imaging of ∼100-300 neurons in primary visual cortex (V1) and lateromedial (LM) visual area in behaving mice revealed that the variability in LM neurons' visual responses was strongly dependent on that in V1, suggesting that fluctuations in sensory responses propagate through extended cortical networks.

Investigation of rotational skin stretch for proprioceptive feedback with application to myoelectric systems.

We present a new wearable haptic device that provides a sense of position and motion by inducing rotational skin stretch on the user's skin. In the experiments described in this paper, the device was used to provide proprioceptive feedback from a virtual prosthetic arm controlled with myoelectric sensors on the bicep and tricep muscles in 15 able-bodied participants. Targeting errors in blind movements with the haptic device were compared to cases where no feedback and contralateral proprioception were provided. Average errors were lower with the device than with no feedback but larger than with contralateral proprioceptive feedback. Participants also had lower visual demand with the device than with no feedback while tracking a 30 ( degrees ) moving range. The results indicate that the rotational skin stretch may ultimately be effective for proprioceptive feedback in myoelectric prostheses, particularly when vision is otherwise occupied.

Real-Time Estimation of 3-D Needle Shape and Deflection for MRI-Guided Interventions.

We describe a MRI-compatible biopsy needle instrumented with optical fiber Bragg gratings for measuring bending deflections of the needle as it is inserted into tissues. During procedures, such as diagnostic biopsies and localized treatments, it is useful to track any tool deviation from the planned trajectory to minimize positioning errors and procedural complications. The goal is to display tool deflections in real time, with greater bandwidth and accuracy than when viewing the tool in MR images. A standard 18 ga × 15 cm inner needle is prepared using a fixture, and 350-µm-deep grooves are created along its length. Optical fibers are embedded in the grooves. Two sets of sensors, located at different points along the needle, provide an estimate of the bent profile, as well as temperature compensation. Tests of the needle in a water bath showed that it produced no adverse imaging artifacts when used with the MR scanner.

Atraumatic surgical approach to the cochlea with a micromanipulator.

CONCLUSIONS: Our design and preliminary results show that the the micromanipulator could be a great help to the surgeon in the atraumatic surgical approach to the lateral wall of the cochlea at the promontory. OBJECTIVES: Hearing preservation in cochlear implant opens new frontiers in the treatment of sensorineural hearing loss. To preserve the membranous labyrinth intact, new surgical tools are needed, either for cochlear implantation or for other applications. The objectives of this study were to design and test a micromanipulator coupled to a drilling tool for the atraumatic exposure of the spiral ligament. The micromanipulator is designed to increase precision when drilling the otic capsule bone. MATERIALS AND METHODS: A group from the University of Navarra worked on the device design -- based on a compliant mechanism -- and in vitro test. The components and functioning of the micromanipulator are described. It was tested in 10 formalinized temporal bones after a mastoidectomy, a posterior tympanotomy, and a transcanal tympanotomy were performed. The micromanipulator was placed over the cranial surface, and used to expose the endostium, anteriorly to the round window niche. RESULTS: A combined approach through the external auditory canal was feasible, together with a posterior tympanotomy to visually control the work and make complementary manoeuvres. Drilling was easy, and visual control through the posterior tympanotomy was excellent. A high degree of drilling precision was achieved. A little disruption of the membranous labyrinth was found only in the first bone of the series.

Micromanipulator for enhancing surgeon's dexterity in cochlear atraumatic surgery.

The hybrid stimulation in cochlear implants requires changes in the design of electrode arrays. A new generation of flat electrode arrays that does not damage the cochlea is being developed. For the insertion of these flat array electrodes a groove must be milled in the antero-inferior area of the round window niche. Even for the most experienced surgeon, it is very difficult to carry out this operation without damaging the cochlea. That is why external help is needed. For helping the surgeon to mill the groove, a compliant mechanism based micromanipulator has been designed, manufactured and tested. A surgical milling tool is attached to a specially designed compliant mechanism and positioned properly along the auditory canal. The compliant mechanism guides the motion of the surgical tool, keeping tactile feedback and enhancing the dexterity of the surgeon for an accurate milling of the groove.