A cortico-collicular circuit for orienting to shelter during escape.

When faced with predatory threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. Animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions1,2. Although previous work has identified neural mechanisms of escape initiation3,4, it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that the mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes the shelter-direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP-SC pathway disrupts the orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network because of higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter-direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically constrained spiking network model in which RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP-SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible.

Correction: A system for tracking whisker kinematics and whisker shape in three dimensions.

[This corrects the article DOI: 10.1371/journal.pcbi.1007402.].

A system for tracking whisker kinematics and whisker shape in three dimensions.

Quantification of behaviour is essential for biology. Since the whisker system is a popular model, it is important to have methods for measuring whisker movements from behaving animals. Here, we developed a high-speed imaging system that measures whisker movements simultaneously from two vantage points. We developed a whisker tracker algorithm that automatically reconstructs 3D whisker information directly from the 'stereo' video data. The tracker is controlled via a Graphical User Interface that also allows user-friendly curation. The algorithm tracks whiskers, by fitting a 3D Bezier curve to the basal section of each target whisker. By using prior knowledge of natural whisker motion and natural whisker shape to constrain the fits and by minimising the number of fitted parameters, the algorithm is able to track multiple whiskers in parallel with low error rate. We used the output of the tracker to produce a 3D description of each tracked whisker, including its 3D orientation and 3D shape, as well as bending-related mechanical force. In conclusion, we present a non-invasive, automatic system to track whiskers in 3D from high-speed video, creating the opportunity for comprehensive 3D analysis of sensorimotor behaviour and its neural basis.

Photoreceptive retinal ganglion cells control the information rate of the optic nerve.

Information transfer in the brain relies upon energetically expensive spiking activity of neurons. Rates of information flow should therefore be carefully optimized, but mechanisms to control this parameter are poorly understood. We address this deficit in the visual system, where ambient light (irradiance) is predictive of the amount of information reaching the eye and ask whether a neural measure of irradiance can therefore be used to proactively control information flow along the optic nerve. We first show that firing rates for the retina's output neurons [retinal ganglion cells (RGCs)] scale with irradiance and are positively correlated with rates of information and the gain of visual responses. Irradiance modulates firing in the absence of any other visual signal confirming that this is a genuine response to changing ambient light. Irradiance-driven changes in firing are observed across the population of RGCs (including in both ON and OFF units) but are disrupted in mice lacking melanopsin [the photopigment of irradiance-coding intrinsically photosensitive RGCs (ipRGCs)] and can be induced under steady light exposure by chemogenetic activation of ipRGCs. Artificially elevating firing by chemogenetic excitation of ipRGCs is sufficient to increase information flow by increasing the gain of visual responses, indicating that enhanced firing is a cause of increased information transfer at higher irradiance. Our results establish a retinal circuitry driving changes in RGC firing as an active response to alterations in ambient light to adjust the amount of visual information transmitted to the brain.

Prediction of Choice from Competing Mechanosensory and Choice-Memory Cues during Active Tactile Decision Making.

Perceptual decision making is an active process where animals move their sense organs to extract task-relevant information. To investigate how the brain translates sensory input into decisions during active sensation, we developed a mouse active touch task where the mechanosensory input can be precisely measured and that challenges animals to use multiple mechanosensory cues. Male mice were trained to localize a pole using a single whisker and to report their decision by selecting one of three choices. Using high-speed imaging and machine vision, we estimated whisker-object mechanical forces at millisecond resolution. Mice solved the task by a sensory-motor strategy where both the strength and direction of whisker bending were informative cues to pole location. We found competing influences of immediate sensory input and choice memory on mouse choice. On correct trials, choice could be predicted from the direction and strength of whisker bending, but not from previous choice. In contrast, on error trials, choice could be predicted from previous choice but not from whisker bending. This study shows that animal choices during active tactile decision making can be predicted from mechanosensory and choice-memory signals, and provides a new task well suited for the future study of the neural basis of active perceptual decisions.SIGNIFICANCE STATEMENT Due to the difficulty of measuring the sensory input to moving sense organs, active perceptual decision making remains poorly understood. The whisker system provides a way forward since it is now possible to measure the mechanical forces due to whisker-object contact during behavior. Here we train mice in a novel behavioral task that challenges them to use rich mechanosensory cues but can be performed using one whisker and enables task-relevant mechanical forces to be precisely estimated. This approach enables rigorous study of how sensory cues translate into action during active, perceptual decision making. Our findings provide new insight into active touch and how sensory/internal signals interact to determine behavioral choices.

Melanopsin-driven increases in maintained activity enhance thalamic visual response reliability across a simulated dawn.

Twice a day, at dawn and dusk, we experience gradual but very high amplitude changes in background light intensity (irradiance). Although we perceive the associated change in environmental brightness, the representation of such very slow alterations in irradiance by the early visual system has been little studied. Here, we addressed this deficit by recording electrophysiological activity in the mouse dorsal lateral geniculate nucleus under exposure to a simulated dawn. As irradiance increased we found a widespread enhancement in baseline firing that extended to units with ON as well as OFF responses to fast luminance increments. This change in baseline firing was equally apparent when the slow irradiance ramp appeared alone or when a variety of higher-frequency artificial or natural visual stimuli were superimposed upon it. Using a combination of conventional knockout, chemogenetic, and receptor-silent substitution manipulations, we continued to show that, over higher irradiances, this increase in firing originates with inner-retinal melanopsin photoreception. At the single-unit level, irradiance-dependent increases in baseline firing were strongly correlated with improvements in the amplitude of responses to higher-frequency visual stimuli. This in turn results in an up to threefold increase in single-trial reliability of fast visual responses. In this way, our data indicate that melanopsin drives a generalized increase in dorsal lateral geniculate nucleus excitability as dawn progresses that both conveys information about changing background light intensity and increases the signal:noise for fast visual responses.

Microsecond-scale timing precision in rodent trigeminal primary afferents.

Communication in the nervous system occurs by spikes: the timing precision with which spikes are fired is a fundamental limit on neural information processing. In sensory systems, spike-timing precision is constrained by first-order neurons. We found that spike-timing precision of trigeminal primary afferents in rats and mice is limited both by stimulus speed and by electrophysiological sampling rate. High-speed video of behaving mice revealed whisker velocities of at least 17,000°/s, so we delivered an ultrafast "ping" (>50,000°/s) to single whiskers and sampled primary afferent activity at 500 kHz. Median spike jitter was 17.4 µs; 29% of neurons had spike jitter < 10 µs. These results indicate that the input stage of the trigeminal pathway has extraordinary spike-timing precision and very high potential information capacity. This timing precision ranks among the highest in biology.

Thalamic amplification of sensory input in experimental diabetes.

Diabetic neuropathy is a common, and often debilitating, secondary complication of diabetes mellitus. As pain, hypersensitivity and paraesthesias present in a distal-proximal distribution, symptoms are generally believed to originate from damaged afferents within the peripheral nervous system. Increasing evidence suggests altered processing within the central nervous system in diabetic neuropathy contributes towards somatosensory dysfunction, but whether the accurate coding and relay of peripherally encoded information through the central nervous system is altered in diabetes is not understood. Here, we applied the strengths of the rodent whisker-barrel system to study primary afferent-thalamic processing in diabetic neuropathy. We found that neurons in the thalamic ventral posteromedial nucleus from rats with experimental diabetic neuropathy showed increased firing to precisely graded, multidirectional whisker deflection compared to non-diabetic rats. This thalamic hyperactivity occurred without any overt primary afferent dysfunction, as recordings from the trigeminal ganglion showed these primary afferents to be unaffected by diabetes. These findings suggest that central amplification can substantially transform ascending sensory input in diabetes, even in the absence of a barrage of ectopic primary afferent activity.

Low-dimensional sensory feature representation by trigeminal primary afferents.

In any sensory system, the primary afferents constitute the first level of sensory representation and fundamentally constrain all subsequent information processing. Here, we show that the spike timing, reliability, and stimulus selectivity of primary afferents in the whisker system can be accurately described by a simple model consisting of linear stimulus filtering combined with spike feedback. We fitted the parameters of the model by recording the responses of primary afferents to filtered, white noise whisker motion in anesthetized rats. The model accurately predicted not only the response of primary afferents to white noise whisker motion (median correlation coefficient 0.92) but also to naturalistic, texture-induced whisker motion. The model accounted both for submillisecond spike-timing precision and for non-Poisson spike train structure. We found substantial diversity in the responses of the afferent population, but this diversity was accurately captured by the model: a 2D filter subspace, corresponding to different mixtures of position and velocity sensitivity, captured 94% of the variance in the stimulus selectivity. Our results suggest that the first stage of the whisker system can be well approximated as a bank of linear filters, forming an overcomplete representation of a low-dimensional feature space.

Three-dimensional unsupervised probabilistic pose reconstruction (3D-UPPER) for freely moving animals.

A key step in understanding animal behaviour relies in the ability to quantify poses and movements. Methods to track body landmarks in 2D have made great progress over the last few years but accurate 3D reconstruction of freely moving animals still represents a challenge. To address this challenge here we develop the 3D-UPPER algorithm, which is fully automated, requires no a priori knowledge of the properties of the body and can also be applied to 2D data. We find that 3D-UPPER reduces by [Formula: see text] fold the error in 3D reconstruction of mouse body during freely moving behaviour compared with the traditional triangulation of 2D data. To achieve that, 3D-UPPER performs an unsupervised estimation of a Statistical Shape Model (SSM) and uses this model to constrain the viable 3D coordinates. We show, by using simulated data, that our SSM estimator is robust even in datasets containing up to 50% of poses with outliers and/or missing data. In simulated and real data SSM estimation converges rapidly, capturing behaviourally relevant changes in body shape associated with exploratory behaviours (e.g. with rearing and changes in body orientation). Altogether 3D-UPPER represents a simple tool to minimise errors in 3D reconstruction while capturing meaningful behavioural parameters.

Comparison of latency and rate coding for the direction of whisker deflection in the subcortical somatosensory pathway.

The response of many neurons in the whisker somatosensory system depends on the direction in which a whisker is deflected. Although it is known that the spike count conveys information about this parameter, it is not known how important spike timing might be. The aim of this study was to compare neural codes based on spike count and first-spike latency, respectively. We extracellularly recorded single units from either the rat trigeminal ganglion (primary sensory afferents) or ventroposteromedial (VPM) thalamic nucleus in response to deflection in different directions and quantified alternative neural codes using mutual information. We found that neurons were diverse: some (58% in ganglion, 32% in VPM) conveyed information only by spike count; others conveyed additional information by latency. An issue with latency coding is that latency is measured with respect to the time of stimulus onset, a quantity known to the experimenter but not directly to the subject's brain. We found a potential solution using the integrated population activity as an internal timing signal: in this way, 91% of the first-spike latency information could be recovered. Finally, we asked how well direction could be decoded. For large populations, spike count and latency codes performed similarly; for small ones, decoding was more accurate using the latency code. Our findings indicate that whisker deflection direction is more efficiently encoded by spike timing than by spike count. Spike timing decreases the population size necessary for reliable information transmission and may thereby bring significant advantages in both wiring and metabolic efficiency.

Look-up and look-down neurons in the mouse visual thalamus during freely moving exploration.

Visual information reaches cortex via the thalamic dorsal lateral geniculate nucleus (dLGN). dLGN activity is modulated by global sleep/wake states and arousal, indicating that it is not simply a passive relay station. However, its potential for more specific visuomotor integration is largely unexplored. We addressed this question by developing robust 3D video reconstruction of mouse head and body during spontaneous exploration paired with simultaneous neuronal recordings from dLGN. Unbiased evaluation of a wide range of postures and movements revealed a widespread coupling between neuronal activity and few behavioral parameters. In particular, postures associated with the animal looking up/down correlated with activity in >50% neurons, and the extent of this effect was comparable with that induced by full-body movements (typically locomotion). By contrast, thalamic activity was minimally correlated with other postures or movements (e.g., left/right head and body torsions). Importantly, up/down postures and full-body movements were largely independent and jointly coupled to neuronal activity. Thus, although most units were excited during full-body movements, some expressed highest firing when the animal was looking up ("look-up" neurons), whereas others expressed highest firing when the animal was looking down ("look-down" neurons). These results were observed in the dark, thus representing a genuine behavioral modulation, and were amplified in a lit arena. Our results demonstrate that the primary visual thalamus, beyond global modulations by sleep/awake states, is potentially involved in specific visuomotor integration and reveal two distinct couplings between up/down postures and neuronal activity.

Shifts in coding properties and maintenance of information transmission during adaptation in barrel cortex.

Neuronal responses to ongoing stimulation in many systems change over time, or "adapt." Despite the ubiquity of adaptation, its effects on the stimulus information carried by neurons are often unknown. Here we examine how adaptation affects sensory coding in barrel cortex. We used spike-triggered covariance analysis of single-neuron responses to continuous, rapidly varying vibrissa motion stimuli, recorded in anesthetized rats. Changes in stimulus statistics induced spike rate adaptation over hundreds of milliseconds. Vibrissa motion encoding changed with adaptation as follows. In every neuron that showed rate adaptation, the input-output tuning function scaled with the changes in stimulus distribution, allowing the neurons to maintain the quantity of information conveyed about stimulus features. A single neuron that did not show rate adaptation also lacked input-output rescaling and did not maintain information across changes in stimulus statistics. Therefore, in barrel cortex, rate adaptation occurs on a slow timescale relative to the features driving spikes and is associated with gain rescaling matched to the stimulus distribution. Our results suggest that adaptation enhances tactile representations in primary somatosensory cortex, where they could directly influence perceptual decisions.

Somatosensation: The Cellular and Physical Basis of Tactile Experience.

A fundamental question in sensory neuroscience is how perceptual experience arises from the cellular properties of sensory neurons. A new, tour de force study has dissected out the functional properties of identified mechanosensory nerve endings that innervate whisker follicles.

Transformation in the neural code for whisker deflection direction along the lemniscal pathway.

A prominent characteristic of neurons in the whisker system is their selectivity to the direction in which a whisker is deflected. The aim of this study was to determine how information about whisker direction is encoded at successive levels of the lemniscal pathway. We made extracellular recordings under identical conditions from the trigeminal ganglion, ventro-posterior medial thalamus (VPM), and barrel cortex while varying the direction of whisker deflection. We found a marked increase in the variability of single unit responses along the pathway. To study the consequences of this for information processing, we quantified the responses using mutual information. VPM units conveyed 48% of the mutual information conveyed by ganglion units, and cortical units conveyed 12%. The fraction of neuronal bandwidth used for transmitting direction information decreased from 40% in the ganglion to 24% in VPM and 5% in barrel cortex. To test whether, in cortex, population coding might compensate for this information loss, we made simultaneous recordings. We found that cortical neuron pairs conveyed 2.1 times the mutual information conveyed by single neurons. Overall, these findings indicate a marked transformation from a subcortical neural code based on small numbers of reliable neurons to a cortical code based on populations of unreliable neurons. However, the basic form of the neural code in ganglion, thalamus, and cortex was similar-at each stage, the first poststimulus spike carried the majority of the information.

Neural coding and contextual influences in the whisker system.

A fundamental problem in neuroscience, to which Prof. Segundo has made seminal contributions, is to understand how action potentials represent events in the external world. The aim of this paper is to review the issue of neural coding in the context of the rodent whiskers, an increasingly popular model system. Key issues we consider are: the role of spike timing; mechanisms of spike timing; decoding and context-dependence. Significant insight has come from the development of rigorous, information theoretic frameworks for tackling these questions, in conjunction with suitably designed experiments. We review both the theory and experimental studies. In contrast to the classical view that neurons are noisy and unreliable, it is becoming clear that many neurons in the subcortical whisker pathway are remarkably reliable and, by virtue of spike timing with millisecond-precision, have high bandwidth for conveying sensory information. In this way, even small (approximately 200 neuron) subcortical modules are able to support the sensory processing underlying sophisticated whisker-dependent behaviours. Future work on neural coding in cortex will need to consider new findings that responses are highly dependent on context, including behavioural and internal states.

What the whiskers tell the brain.

A fundamental question in the investigation of any sensory system is what physical signals drive its sensory neurons during natural behavior. Surprisingly, in the whisker system, it is only recently that answers to this question have emerged. Here, we review the key developments, focussing mainly on the first stage of the ascending pathway - the primary whisker afferents (PWAs). We first consider a biomechanical framework, which describes the fundamental mechanical forces acting on the whiskers during active sensation. We then discuss technical progress that has allowed such mechanical variables to be estimated in awake, behaving animals. We discuss past electrophysiological evidence concerning how PWAs function and reinterpret it within the biomechanical framework. Finally, we consider recent studies of PWAs in awake, behaving animals and compare the results to related studies of the cortex. We argue that understanding 'what the whiskers tell the brain' sheds valuable light on the computational functions of downstream neural circuits, in particular, the barrel cortex.

Modulation of Fast Narrowband Oscillations in the Mouse Retina and dLGN According to Background Light Intensity.

Background light intensity (irradiance) substantially impacts the visual code in the early visual system at synaptic and single-neuron levels, but its influence on population activity is largely unexplored. We show that fast narrowband oscillations, an important feature of population activity, systematically increase in amplitude as a function of irradiance in both anesthetized and awake, freely moving mice and at the level of the retina and dorsal lateral geniculate nucleus (dLGN). Narrowband coherence increases with irradiance across large areas of the dLGN, but especially for neighboring units. The spectral sensitivity of these effects and their substantial reduction in melanopsin knockout animals indicate a contribution from inner retinal photoreceptors. At bright backgrounds, narrowband coherence allows pooling of single-unit responses to become a viable strategy for enhancing visual signals within its frequency range.

Population coding in somatosensory cortex.

Computational analyses have begun to elucidate which components of somatosensory cortical population activity may encode basic stimulus features. Recent results from rat barrel cortex suggest that the essence of this code is not synergistic spike patterns, but rather the precise timing of single neuron's first post-stimulus spikes. This may form the basis for a fast, robust population code.

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy.

High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. We integrated proteomics and metabolomics from the sciatic nerve (SN), the lumbar 4/5 dorsal root ganglia (DRG), and the trigeminal ganglia (TG) of streptozotocin-diabetic and healthy control rats. Even though all tissues showed a dramatic increase in glucose and polyol pathway intermediates in diabetes, a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism was found in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This finding suggests that the most severe molecular consequences of diabetes in the nervous system present in the SN, the region most affected by neuropathy. Such spatial metabolic dysfunction suggests a failure of energy homeostasis and/or oxidative stress, specifically in the distal axon/Schwann cell-rich SN. These data provide a detailed molecular description of the distinct compartmental effects of diabetes on the PNS that could underlie the distal-proximal distribution of pathology.