STEER: 3D Printed Guide for Nerve Regrowth Control and Neural Interface in Non-Human Primate Model.

OBJECTIVE: Peripheral neural interface (PNI) with a stable integration of synthetic elements with neural tissue is key for successfulneuro-prosthetic applications. An inevitable phenomenon of reactive fibrosis is a primary hurdle for long term functionality of PNIs. This proof-of-concept study aimed to fabricate and test a novel, stable PNI that harnesses fibro-axonal outgrowth at the nerve end and includes fibrosis in the design. METHODS: Two non-human primates were implanted with Substrate-guided, Tissue-Electrode Encapsulation and Integration (STEER) PNIs. The implant included a 3D printed guide that strove to steer the regrowing nerve towards encapsulation of the electrodes into a fibro-axonal tissue. After four months from implantation, we performed electrophysiological measurements to test STEER's functionality and examined the macro and micro- morphology of the outgrowth tissue. RESULTS: We observed a highly structured fibro-axonal composite within the STEER PNI. A conduction of intracranially generated action potentials was successfully recorded across the neural interface. Immunohistology demonstrated uniquely configured laminae of myelinated axons encasing the implant. CONCLUSION: STEER PNI reconfigured the structure of the fibro-axonal tissue and facilitated long-term functionality and stability of the neural interface. SIGNIFICANCE: The results point to the feasibility of our concept for creating a stable PNI with long-term electrophysiologic functionality by using simple design and materials.

Probing Photoinduced Two-Body Loss of Ultracold Nonreactive Bosonic

We probe photoinduced loss for chemically stable bosonic ^{23}Na^{87}Rb and ^{23}Na^{39}K molecules in chopped optical dipole traps, where the molecules spend a significant time in the dark. We expect the effective two-body decay to be significantly suppressed due to the small expected complex lifetimes of about 13 and 6 µs for ^{23}Na^{87}Rb and ^{23}Na^{39}K, respectively. However, instead we do not observe any suppression of the two-body loss in parameter ranges where large loss suppressions are expected. We believe these unexpected results are most probably due to drastic underestimation of the complex lifetime by at least 1-2 orders of magnitude.

Ultracold Gas of Bosonic

We report the creation of ultracold bosonic dipolar ^{23}Na^{39}K molecules in their absolute rovibrational ground state. Starting from weakly bound molecules immersed in an ultracold atomic mixture, we coherently transfer the dimers to the rovibrational ground state using an adiabatic Raman passage. We analyze the two-body decay in a pure molecular sample and in molecule-atom mixtures and find an unexpectedly low two-body decay coefficient for collisions between molecules and ^{39}K atoms in a selected hyperfine state. The preparation of bosonic ^{23}Na^{39}K molecules opens the way for future comparisons between fermionic and bosonic ultracold ground-state molecules of the same chemical species.

A Highly Selective 3D Spiked Ultraflexible Neural (SUN) Interface for Decoding Peripheral Nerve Sensory Information.

Artificial sensors on the skin are proposed as a way to capture information that can be used in intracortical microstimulation or peripheral intraneural stimulation to restore sensory feedback to persons with tetraplegia. However, the ability of these artificial sensors to replicate the density and complexity of the natural mechanoreceptors is limited. One relatively unexplored approach is to make use of the signals from surviving tactile and proprioceptive receptors in existing limbs by recording from their transmitting axons within the primary sensory nerves. Here, a novel spiked ultraflexible neural (SUN) interface that is implanted into the peripheral nervous system to capture sensory information from these mechanoreceptors in acute rat experiments is described. The novel 3D design, which integrates spiked structures for intrafascicular nerve recording with an ultraflexible substrate, enables a unique conformal interface to the target nerve. With the high-quality recording (average signal-to-noise-ratio of 1.4) provided by the electrode, tactile from proprioceptive stimuli can be differentiated in terms of the firing rate. In toe pinching experiments, high spatial resolution classification can be achieved with support vector machine classifier. Further work remains to be done to assess the chronic recording capability of the SUN interface.

Mechanisms underlying vestibulo-cerebellar motor learning in mice depend on movement direction.

KEY POINTS: Directionality, inherent to movements, has behavioural and neuronal correlates. Direction of vestibular stimulation determines motor learning efficiency. Vestibulo-ocular reflex gain-increase correlates with Purkinje cell simple spike potentiation. The locus of neural correlates for vestibulo-ocular reflex adaptation is paradigm specific. ABSTRACT: Compensatory eye movements elicited by head rotation, also known as vestibulo-ocular reflex (VOR), can be adapted with the use of visual feedback. The cerebellum is essential for this type of movement adaptation, although its neuronal correlates remain to be clarified. In the present study, we show that the direction of vestibular input determines the magnitude of eye movement adaptation induced by mismatched visual input in mice, with larger changes during contraversive head rotation. Moreover, the location of the neural correlate of this changed behaviour depends on the type of paradigm. Gain-increase paradigms induce increased simple spike (SS) activity in ipsilateral cerebellar Purkinje cells (PC), which is in line with eye movements triggered by optogenetic PC activation. By contrast, gain-decrease paradigms do not induce changes in SS activity, indicating that the murine vestibulo-cerebellar cortical circuitry is optimally designed to enhance ipsiversive eye movements.

Tactile Stimulation Evokes Long-Lasting Potentiation of Purkinje Cell Discharge In Vivo.

In the cerebellar network, a precise relationship between plasticity and neuronal discharge has been predicted. However, the potential generation of persistent changes in Purkinje cell (PC) spike discharge as a consequence of plasticity following natural stimulation patterns has not been clearly determined. Here, we show that facial tactile stimuli organized in theta-patterns can induce stereotyped N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA-A) receptor-dependent changes in PCs and molecular layer interneurons (MLIs) firing: invariably, all PCs showed a long-lasting increase (Spike-Related Potentiation or SR-P) and MLIs a long-lasting decrease (Spike-Related Suppression or SR-S) in baseline activity and spike response probability. These observations suggests that tactile sensory stimulation engages multiple long-term plastic changes that are distributed along the mossy fiber-parallel fiber (MF-PF) pathway and operate synergistically to potentiate spike generation in PCs. In contrast, theta-pattern electrical stimulation (ES) of PFs indistinctly induced SR-P and SR-S both in PCs and MLIs, suggesting that tactile sensory stimulation preordinates plasticity upstream of the PF-PC synapse. All these effects occurred in the absence of complex spike changes, supporting the theoretical prediction that PC activity is potentiated when the MF-PF system is activated in the absence of conjunctive climbing fiber (CF) activity.

Differential Purkinje cell simple spike activity and pausing behavior related to cerebellar modules.

The massive computational capacity of the cerebellar cortex is conveyed by Purkinje cells onto cerebellar and vestibular nuclei neurons through their GABAergic, inhibitory output. This implies that pauses in Purkinje cell simple spike activity are potentially instrumental in cerebellar information processing, but their occurrence and extent are still heavily debated. The cerebellar cortex, although often treated as such, is not homogeneous. Cerebellar modules with distinct anatomical connectivity and gene expression have been described, and Purkinje cells in these modules also differ in firing rate of simple and complex spikes. In this study we systematically correlate, in awake mice, the pausing in simple spike activity of Purkinje cells recorded throughout the entire cerebellum, with their location in terms of lobule, transverse zone, and zebrin-identified cerebellar module. A subset of Purkinje cells displayed long (>500-ms) pauses, but we found that their occurrence correlated with tissue damage and lower temperature. In contrast to long pauses, short pauses (<500 ms) and the shape of the interspike interval (ISI) distributions can differ between Purkinje cells of different lobules and cerebellar modules. In fact, the ISI distributions can differ both between and within populations of Purkinje cells with the same zebrin identity, and these differences are at least in part caused by differential synaptic inputs. Our results suggest that long pauses are rare but that there are differences related to shorter intersimple spike intervals between and within specific subsets of Purkinje cells, indicating a potential further segregation in the activity of cerebellar Purkinje cells.

Cerebellar modules operate at different frequencies.

Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions.DOI: http://dx.doi.org/10.7554/eLife.02536.001.

Cerebellar potentiation and learning a whisker-based object localization task with a time response window.

Whisker-based object localization requires activation and plasticity of somatosensory and motor cortex. These parts of the cerebral cortex receive strong projections from the cerebellum via the thalamus, but it is unclear whether and to what extent cerebellar processing may contribute to such a sensorimotor task. Here, we subjected knock-out mice, which suffer from impaired intrinsic plasticity in their Purkinje cells and long-term potentiation at their parallel fiber-to-Purkinje cell synapses (L7-PP2B), to an object localization task with a time response window (RW). Water-deprived animals had to learn to localize an object with their whiskers, and based upon this location they were trained to lick within a particular period ("go" trial) or refrain from licking ("no-go" trial). L7-PP2B mice were not ataxic and showed proper basic motor performance during whisking and licking, but were severely impaired in learning this task compared with wild-type littermates. Significantly fewer L7-PP2B mice were able to learn the task at long RWs. Those L7-PP2B mice that eventually learned the task made unstable progress, were significantly slower in learning, and showed deficiencies in temporal tuning. These differences became greater as the RW became narrower. Trained wild-type mice, but not L7-PP2B mice, showed a net increase in simple spikes and complex spikes of their Purkinje cells during the task. We conclude that cerebellar processing, and potentiation in particular, can contribute to learning a whisker-based object localization task when timing is relevant. This study points toward a relevant role of cerebellum-cerebrum interaction in a sophisticated cognitive task requiring strict temporal processing.

Climbing fiber input shapes reciprocity of Purkinje cell firing.

The cerebellum fine-tunes motor activity via its Purkinje cell output. Purkinje cells produce two different types of spikes, complex spikes and simple spikes, which often show reciprocal activity: a periodical increase in complex spikes is associated with a decrease in simple spikes, and vice versa. This reciprocal firing is thought to be essential for coordinated motor behavior, yet how it is accomplished is debated. Here, we show in Ptf1a::cre;Robo3(lox/lox) mice that selectively rerouting the climbing fibers from a contralateral to an ipsilateral projection reversed the complex-spike modulation during sensory stimulation. Strikingly, modulation of simple spikes, which is supposed to be controlled by mossy fibers, reversed as well. Climbing fibers enforce this reciprocity in part by influencing activity of inhibitory interneurons, because the phase of their activity was also converted. Ptf1a::cre;Robo3(lox/lox) mice showed severe ataxia highlighting that climbing fiber input and its impact on reciprocity of Purkinje cell firing play an important role in motor coordination.

Two-dimensional receptive fields of midbrain lateral line units in the goldfish, Carassius auratus.

We determined the receptive fields of midbrain lateral line units in goldfish, Carassius auratus, with a 50 Hz vibrating sphere placed at various azimuths and elevations alongside the fish and studied how responses were affected by different directions of sphere vibration. The receptive fields of toral lateral line units, in contrast to those of primary afferent nerve fibers, did not represent the pressure gradient pattern generated by a vibrating sphere. Thus, unlike primary afferents, single toral lateral line units did not code for source location in their spatial discharge patterns. The two-dimensional receptive fields were round, horizontally or vertically stretched, or complex. While some toral lateral line units were sensitive to the direction of sphere vibration others were not.