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As the evidence of predictive processes playing a role in a wide variety of cognitive domains increases, the brain as a predictive machine becomes a central idea in neuroscience. In auditory processing, a considerable amount of progress has been made using variations of the Oddball design, but most of the existing work seems restricted to predictions based on physical features or conditional rules linking successive stimuli. To characterize the predictive capacity of the brain to abstract rules, we present here two experiments that use speech-like stimuli to overcome limitations and avoid common confounds. Pseudowords were presented in isolation, intermixed with infrequent deviants that contained unexpected phoneme sequences. As hypothesized, the occurrence of unexpected sequences of phonemes reliably elicited an early prediction error signal. These prediction error signals do not seemed to be modulated by attentional manipulations due to different task instructions, suggesting that the predictions are deployed even when the task at hand does not volitionally involve error detection. In contrast, the amount of syllables congruent with a standard pseudoword presented before the point of deviance exerted a strong modulation. Prediction error’s amplitude doubled when two congruent syllables were presented instead of one, despite keeping local transitional probabilities constant. This suggests that auditory predictions can be built integrating information beyond the immediate past. In sum, the results presented here further contribute to the understanding of the predictive capabilities of the human auditory system when facing complex stimuli and abstract rules.

Localization of odors is essential to animal survival, and thus animals are adept at odor navigation. In natural conditions animals encounter odor sources in which odor is carried by air flow varying in complexity. We sought to identify potential minimalist strategies that can effectively be used for odor-based navigation and asses their performance in an increasingly chaotic environment., Localization of odors is essential to animal survival, and thus animals are adept at odor navigation. In natural conditions animals encounter odor sources in which odor is carried by air flow varying in complexity. We sought to identify potential minimalist strategies that can effectively be used for odor-based navigation and asses their performance in an increasingly chaotic environment. To do so, we compared mouse, in silico model, and Arduino-based robot odor-localization behavior in a standardized odor landscape. Mouse performance remains robust in the presence of increased complexity, showing a shift in strategy towards faster movement with increased environmental complexity. Implementing simple binaral and temporal models of tropotaxis and klinotaxis, an in silico model and Arduino robot, in the same environment as the mice, are equally successful in locating the odor source within a plume of low complexity. However, performance of these algorithms significantly drops when the chaotic nature of the plume is increased. Additionally, both algorithm-driven systems show more successful performance when using a strictly binaral model at a larger sensor separation distance and more successful performance when using a temporal and binaral model when using a smaller sensor separation distance. This suggests that with an increasingly chaotic odor environment, mice rely on complex strategies that allow for robust odor localization that cannot be resolved by minimal algorithms that display robust performance at low levels of complexity. Thus, highlighting that an animal’s ability to modulate behavior with environmental complexity is beneficial for odor localization.

Inherited retinal degenerations originate from mutations in >300 genes, many of which cause the production of misfolded mutant photoreceptor proteins that are ultimately degraded by the ubiquitin-proteasome system (UPS). It was previously shown that rod photoreceptors in multiple mouse models of retinal degeneration suffer from proteostatic stress consisting of an insufficient cellular capacity for degrading UPS substrates. In this study, we focused on a specific UPS component required for the degradation of a subset of proteasome targets: the substrate-processing complex formed by the AAA+ ATPase P97/VCP and associated cofactors. To assess whether P97 capacity may be insufficient in degenerating rods, we employed two complementaryin vivoproteasomal activity reporters whose degradation is either P97-dependent or P97-independent. Retinal accumulation of each reporter was measured in two models of retinal degeneration: the transducinγ-subunit knock-out (Gγ1-/-) and P23H rhodopsin knock-in (P23H) mice. Strikingly, the patterns of reporter accumulation differed between these models, indicating that the proteostatic stress observed inGγ1-/-and P23H rods likely originates from different pathobiological mechanisms, in which UPS substrate degradation may or may not be limited by P97-dependent substrate processing. Further, we assessed whether P97 overexpression could ameliorate pathology inGγ1-/-mice, in which proteostatic stress appears to result from P97 insufficiency. However, despite P97 overexpression being aphenotypic in other tissues, the ∼2.4-fold increase in retinal P97 content was toxic to rods, which complicated the interpretation of the observed phenotype. Our results highlight the complexity of pathophysiological mechanisms related to degrading misfolded proteins in mutant photoreceptors.

Although within-modality sensory plasticity is limited to early developmental periods, cross-modal plasticity can occur even in adults. In vivo electrophysiological studies have shown that transient visual deprivation (dark exposure, DE) in adult mice improves the frequency selectivity and discrimination of neurons in thalamorecipient layer 4 (L4) of primary auditory cortex (A1)., Although within-modality sensory plasticity is limited to early developmental periods, cross-modal plasticity can occur even in adults. In vivo electrophysiological studies have shown that transient visual deprivation (dark exposure, DE) in adult mice improves the frequency selectivity and discrimination of neurons in thalamorecipient layer 4 (L4) of primary auditory cortex (A1). Since sound information is processed hierarchically in A1 by populations of neurons, we investigated whether DE alters network activity in A1 L4 and layer 2/3 (L2/3). We examined neuronal populations in both L4 and L2/3 using in vivo two-photon calcium (Ca2+) imaging of transgenic mice expressing GCaMP6s. We find that one week of DE in adult mice increased the sound evoked responses and frequency selectivity of both L4 and L2/3 neurons. Moreover, after DE the frequency representation changed with L4 and L2/3 showing a reduced representation of cells with best frequencies (BFs) between 8 and 16 kHz and an increased representation of cells with BFs above 32 kHz. Cells in L4 and L2/3 showed decreased pairwise signal correlations (SCs) consistent with sharper tuning curves. The decreases in SCs were larger in L4 than in L2/3. The decreased pairwise correlations indicate a sparsification of A1 responses to tonal stimuli. Thus, cross-modal experience in adults can both alter the sound-evoked responses of A1 neurons and change activity correlations within A1 potentially enhancing the encoding of auditory stimuli.

The ability to selectively attend to speech in the presence of other competing talkers is critical for everyday communication; yet the neural mechanisms facilitating this process are poorly understood. Here, we use electroencephalography (EEG) to study how a mixture of two speech streams is represented in the brain as subjects attend to one stream or the other. To characterize the speech-EEG relationships and how they are modulated by attention, we estimate the statistical association between each canonical EEG frequency band (delta, theta, alpha, beta, low-gamma, and high-gamma) and the envelope of each of ten different frequency bands in the input speech. Consistent with previous literature, we find that low-frequency (delta and theta) bands show greater speech-EEG coherence when the speech stream is attended compared to when it is ignored. We also find that the envelope of the low-gamma band shows a similar attention effect, a result not previously reported with EEG. This is consistent with the prevailing theory that neural dynamics in the gamma range are important for attention-dependent routing of information in cortical circuits. In addition, we also find that the greatest attention-dependent increases in speech-EEG coherence are seen in the mid-frequency acoustic bands (0.5–3 kHz) of input speech and the temporal-parietal EEG sensors. Finally, we find individual differences in the following: (1) the specific set of speech-EEG associations that are the strongest, (2) the EEG and speech features that are the most informative about attentional focus, and (3) the overall magnitude of attentional enhancement of speech-EEG coherence.

The potassium-chloride cotransporter (KCC2) maintains the low intracellular chloride found in mature central neurons and controls the strength and direction of GABA/glycine synapses. We found that following axotomy as a consequence of peripheral nerve injuries (PNIs), KCC2 protein is lost throughout the somatodendritic membrane of axotomized spinal cord motoneurons after downregulation ofkcc2mRNA expression. This large loss likely depolarizes the reversal potential of GABA/glycine synapses, resulting in GABAergic-driven spontaneous activity in spinal motoneurons similar to previous reports in brainstem motoneurons. We hypothesized that the mechanism inducing KCC2 downregulation in spinal motoneurons following peripheral axotomy might be mediated by microglia or motoneuron release of BDNF and TrkB activation as has been reported on spinal cord dorsal horn neurons after nerve injury, motoneurons after spinal cord injury (SCI), and in many other central neurons throughout development or a variety of pathologies. To test this hypothesis, we used genetic approaches to interfere with microglia activation or deletebdnffrom specifically microglia or motoneurons, as well as pharmacology (ANA-12) and pharmacogenetics (F616A mice) to block TrkB activation. We show that KCC2 dysregulation in axotomized motoneurons is independent of microglia, BDNF, and TrkB. KCC2 is instead dependent on neuromuscular innervation; KCC2 levels are restored only when motoneurons reinnervate muscle. Thus, downregulation of KCC2 occurs specifically while injured motoneurons are regenerating and might be controlled by target-derived signals. GABAergic and glycinergic synapses might therefore depolarize motoneurons disconnected from their targets and contribute to augment motoneuron activity known to promote motor axon regeneration.

It is currently unclear whether mice use their ultrasonic vocalizations (USVs) for communication purposes. It is also unknown whether mice require previous experience with USVs to understand conspecifics. There is some evidence that experience changes the perception of juvenile USVs; however, it is unclear whether similar plasticity also occurs for adult USVs. To examine whether social exposure or deprivation throughout development leads to changes in USV perception, eleven female CBA/CaJ mice were trained to discriminate between 18 USVs of three different categories using operant conditioning procedures. Mice were group housed with four females or housed individually from weaning for the duration of the experiment. Socially housed and isolated mice differed in initial training times on pure tones, suggesting isolated mice had a more difficult time learning the task. Both groups completed USV discrimination conditions quicker at the end of the testing phases relative to the beginning. The overall discrimination of USVs did not differ between the two housing conditions, but a multidimensional scaling analysis revealed that socially experienced and isolated mice perceive some USVs differently, illustrated by differences in locations of USVs on the scaling maps from the two groups. Finally, a negative correlation was found between spectrotemporal similarity and percent discrimination, and analyses support the idea that mice may show categorical perception of at least two of the three USV categories. Thus, experience with USVs changes USV perception.

Visual Abstract, The flavoring agent menthol elicits complex orosensory and behavioral effects including perceived cooling at low concentrations and irritation and ingestive avoidance at higher intensities. Oral menthol engages the cold-activated transient receptor potential (TRP) ion channel TRP melastatin 8 (TRPM8) on trigeminal fibers, although its aversive feature was discussed to involve activation of TRP ankyrin 1 (TRPA1) associated with nociceptive processing. Here, we studied the roles of TRPM8 and TRPA1 in orosensory responding to menthol by subjecting mice gene deficient for either channel to brief-access exposure tests, which measure immediate licking responses to fluid stimuli to capture sensory/tongue control of behavior. Stimuli included aqueous concentration series of (−)-menthol [0 (water), 0.3, 0.5, 0.7, 1.0, 1.5, and 2.3 mM] and the aversive bitter taste stimulus quinine-HCl (0, 0.01, 0.03, 0.1, 0.3, 1, and 3 mM). Concentration-response data were generated from daily brief-access tests conducted in lickometers, which recorded the number of licks water-restricted mice emitted to a randomly selected stimulus concentration over a block of several 10-s stimulus presentations. Wild-type mice showed aversive orosensory responses to menthol above 0.7 mM. Oral aversion to menthol was reduced in mice deficient for TRPA1 but not TRPM8. Oral aversion to quinine was similar between TRPA1 mutant and control mice but stronger than avoidance of menthol. This implied menthol avoidance under the present conditions represented a moderate form of oral aversion. These data reveal TRPA1 contributes to the oral sensory valence of menthol and have implications for how input from TRPA1 and TRPM8 shapes somatosensory-guided behaviors.

The ability to understand speech relies on accurate auditory processing of complex sounds. Individuals with Parkinson’s disease suffer from speech perception deficits, suggesting that dopamine is involved in the encoding of complex sounds. Recent studies have demonstrated that dopamine has heterogeneous effects on the responses of many neurons in the inferior colliculus (IC) of mice, although the strongest effect is to suppress neural activity. However, it was previously unknown which dopamine receptors are involved in modulating neuronal responses, and whether the observed preponderance of depressive effects reflects the endogenous dopamine system in the IC. In this study, we tested whether dopamine acts via D1- and/or D2-like receptors to alter responses of IC neurons in female and male mice. We also tested the effect of optogenetically induced dopamine release on auditory responses in the IC. We found that the effects of dopamine in the IC occur via D2-like receptors. In iontophoretic and freely behaving experiments, the single-unit and multi-unit effects of dopamine and a D2-like agonist were heterogeneous as both either increased or decreased responses of IC neurons to tones, while a D2-like antagonist had opposite effects. We also found that optogenetic activation of the endogenous dopamine system in the IC alters responses of auditory neurons. Similar to the effects of exogenous dopamine application, optogenetic induction of endogenous dopamine release heterogeneously altered auditory responses in the majority of cells in mice expressing channelrhodopsin-2 (ChR2). Understanding how dopamine modulates auditory processing will ultimately inform therapies targeting mechanisms underlying auditory-related communication disorders.

The auditory cortex is topographically organized for sound frequency and contains highly selective frequency-tuned neurons, yet the role of auditory cortex in the perception of sound frequency remains unclear. Lesion studies have shown that auditory cortex is not essential for frequency discrimination of pure tones. However, transient pharmacological inactivation has been reported to impair frequency discrimination. This suggests the possibility that successful tone discrimination after recovery from lesion surgery could arise from long-term reorganization or plasticity of compensatory pathways. Here, we compared the effects of lesions and optogenetic suppression of auditory cortex on frequency discrimination in mice. We found that transient bilateral optogenetic suppression partially but significantly impaired discrimination performance. In contrast, bilateral electrolytic lesions of auditory cortex had no effect on performance of the identical task, even when tested only 4 h after lesion. This suggests that when auditory cortex is destroyed, an alternative pathway is almost immediately adequate for mediating frequency discrimination. Yet this alternative pathway is insufficient for task performance when auditory cortex is intact but has its activity suppressed. These results indicate a fundamental difference between the effects of brain lesions and optogenetic suppression, and suggest the existence of a rapid compensatory process possibly induced by injury.

We investigated the calcium dynamics of dorsal root ganglion (DRG) neurons using transgenic mice to target expression of the genetically encoded calcium indicator (GECI), GCaMP6s, to a subset of neurons containing parvalbumin (PV), a calcium-binding protein present in proprioceptors and low-threshold mechanoreceptors. This study provides the first analysis of GECI calcium transient parameters from large-diameter DRG neurons. Our approach generated calcium transients of consistent shape and time-course, with quantifiable characteristics. Four parameters of calcium transients were determined to vary independently from each other and thus are likely influenced by different calcium-regulating mechanisms: peak amplitude, rise time (RT), decay time, and recovery time. Pooled analysis of 188 neurons demonstrated unimodal distributions, providing evidence that PV+ DRG neurons regulate calcium similarly as a population despite their differences in size, electrical properties, and functional sensitivities. Calcium transients increased in size with elevated extracellular calcium, longer trains of action potentials, and higher stimulation frequencies. RT and decay time increased with the addition of the selective sarco/endoplasmic reticulum calcium ATPases (SERCA) blocker, thapsigargin (TG), while peak amplitude and recovery time remained the same. When elevating bath pH to 8.8 to block plasma-membrane calcium ATPases (PMCA), all measured parameters significantly increased. These results illustrate that GECI calcium transients provide sufficient resolution to detect changes in electrical activity and intracellular calcium concentration, as well as discern information about the activity of specific subclasses of calcium regulatory mechanisms.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are rare mammalian photoreceptors essential for non-image-forming vision functions, such as circadian photoentrainment and the pupillary light reflex. They comprise multiple subtypes distinguishable by morphology, physiology, projections, and levels of expression of melanopsin (Opn4), their photopigment. The molecular programs that distinguish ipRGCs from other ganglion cells and ipRGC subtypes from one another remain elusive. Here, we present comprehensive gene expression profiles of early postnatal and adult mouse ipRGCs purified from two lines of reporter mice that mark different sets of ipRGC subtypes. We find dozens of novel genes highly enriched in ipRGCs. We reveal thatRasgrp1andTbx20are selectively expressed in subsets of ipRGCs, though these molecularly defined groups imperfectly match established ipRGC subtypes. We demonstrate that the ipRGCs regulating circadian photoentrainment are diverse at the molecular level. Our findings reveal unexpected complexity in gene expression patterns across mammalian ipRGC subtypes.

Once thought to simply reflect passive cortical idling, recent studies have demonstrated that α oscillations play a causal role in cognition and perception. However, whether and how cognitive or sensory processes modulate various components of the α rhythm is poorly understood. Sensory input and resting states were manipulated in human subjects while electroencephalography (EEG) activity was recorded in three conditions: eyes-open fixating on a visual stimulus, eyes-open without visual input (darkness), and eyes-closed without visual input (darkness). We show that α power and peak frequency increase when visual input is reduced compared to the eyes open, fixating condition. These results suggest that increases in α power reflect a shift from an exteroceptive to interoceptive state and that increases in peak frequency following restricted visual input (darkness) may reflect increased sampling of the external environment in order to detect stimuli. They further demonstrate how sensory information modulates α and the importance of selecting an appropriate resting condition in studies of α.

In situations requiring immediate action, humans can generate visually-guided responses at remarkably short latencies. Here, to better understand the visual attributes that best evoke such rapid responses, we recorded upper limb muscle activity while participants performed visually-guided reaches towards Gabor patches composed of differing spatial frequencies. We studied reaches initiated from a stable posture (experiment 1, a static condition), or during on-line reach corrections to an abruptly displaced target (experiment 2, a dynamic condition). In both experiments, we detail the latency and prevalence of stimulus-locked responses (SLRs), which are brief bursts of EMG activity that are time-locked to target presentation rather than movement onset. SLRs represent the first wave of EMG recruitment influenced by target presentation, and enable quantification of rapid visuomotor transformations. In both experiments, reach targets composed of low spatial frequencies elicited the shortest latency and most prevalent SLRs, with SLR latency increasing and SLR prevalence decreasing for reach targets composed of progressively higher spatial frequencies. SLRs could be evoked in either the static or dynamic condition, and when present in experiment 2, were associated with shorter latency and larger magnitude corrections. Furthermore, SLRs evolved at shorter latencies (~20 ms) when the arm was already in motion. These results demonstrate that stimuli composed of low spatial frequencies preferentially evoke the most rapid visuomotor responses which, in the context of rapidly correcting an on-going reaching movement, are associated with earlier and larger on-line reach corrections.Significance StatementHumans have a remarkable capacity to respond quickly to changes in our visual environment. Although our visual world is composed of a range of spatial frequencies, surprisingly little is known about which frequencies preferentially evoke rapid reaching responses. Here, we systematically varied the spatial frequency of peripheral reach targets while measuring EMG activity on an upper limb muscle. We found that visual stimuli composed of low-spatial frequencies elicit the most rapid and robust EMG responses and corrective reaches. Thus, when time is of the essence, low spatial frequencies preferentially drive fast visuomotor responses.

Visual Abstract, External thermosensation is crucial to regulate animal behavior and homeostasis, but the development of the mammalian thermosensory system is not well known. We investigated whether temperature could play a role in the control of movements in a mammalian model born very immature, the opossum (Monodelphis domestica). Like other marsupials, at birth the opossum performs alternate and rhythmic movements with its forelimbs (FLs) to reach a teat where it attaches in order to continue its development. It was shown that FL movements can be induced by mechanical stimulation of the snout in in vitro preparations of newborns consisting of the neuraxis with skin and FLs intact. In the present study, we used puff ejections of cold, neutral (bath temperature) and hot liquid directed toward the snout to induce FL responses in such preparations. Either the responses were visually observed under a microscope or triceps muscle activity was recorded. Cold liquid systematically induced FL movements and triceps contractions, but neutral and hot temperatures were less potent to do so. Sections of the trigeminal nerves and removal of the facial skin diminished responses to cold and nearly abolished those to hot and neutral stimulations. Transient receptor potential melastatin 8 (TRPM8) being the major cold receptor cation channel in adult mammals, we employed immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to test for its expression, but found that it is not expressed before 13 postnatal days. Overall our results indicate that cold thermosensation exerts a strong influence on motor behaviors in newborn opossums.

Reward modulation (M1) could be exploited in developing an autonomously updating brain-computer interface (BCI) based on a reinforcement learning (RL) architecture. For an autonomously updating RL-based BCI system, we would need a reward prediction error, or a state-value representation from the user’s neural activity, which the RL-BCI agent could use to update its BCI decoder. In order to understand the multifaceted effects of reward on M1 activity, we investigated how neural spiking, oscillatory activities and their functional interactions are modulated by conditioned stimuli related reward expectation. To do so, local field potentials (LFPs) and single/multi-unit activities were recorded simultaneously and bilaterally from M1 cortices while four non-human primates (NHPs) performed cued center-out reaching or grip force tasks either manually using their right arm/hand or observed passively. We found that reward expectation influenced the strength of α (8–14 Hz) power, α-γ comodulation, α spike-field coherence (SFC), and firing rates (FRs) in general in M1. Furthermore, we found that an increase in α-band power was correlated with a decrease in neural spiking activity, that FRs were highest at the trough of the α-band cycle and lowest at the peak of its cycle. These findings imply that α oscillations modulated by reward expectation have an influence on spike FR and spike timing during both reaching and grasping tasks in M1. These LFP, spike, and spike-field interactions could be used to follow the M1 neural state in order to enhance BCI decoding (An et al., 2018; Zhao et al., 2018).

Visual Abstract, Information processing in sensory cortex is highly sensitive to nonsensory variables such as anesthetic state, arousal, and task engagement. Recent work in mouse visual cortex suggests that evoked firing rates, stimulus–response mutual information, and encoding efficiency increase when animals are engaged in movement. A disinhibitory circuit appears central to this change: inhibitory neurons expressing vasoactive intestinal peptide (VIP) are activated during movement and disinhibit pyramidal cells by suppressing other inhibitory interneurons. Paradoxically, although movement activates a similar disinhibitory circuit in auditory cortex (ACtx), most ACtx studies report reduced spiking during movement. It is unclear whether the resulting changes in spike rates result in corresponding changes in stimulus–response mutual information. We examined ACtx responses evoked by tone cloud stimuli, in awake mice of both sexes, during spontaneous movement and still conditions. VIP+ cells were optogenetically activated on half of trials, permitting independent analysis of the consequences of movement and VIP activation, as well as their intersection. Movement decreased stimulus-related spike rates as well as mutual information and encoding efficiency. VIP interneuron activation tended to increase stimulus-evoked spike rates but not stimulus–response mutual information, thus reducing encoding efficiency. The intersection of movement and VIP activation was largely consistent with a linear combination of these main effects: VIP activation recovered movement-induced reduction in spike rates, but not information transfer.

Type III taste cells in mammalian taste buds are implicated in the detection and communication of sour and some salty stimuli, as well as carbonation and water. With this variety of proposed roles, it is unclear what information activated type III cells are communicating to the CNS. To better elucidate the role of type III cells in the taste bud, we use a type III cell-specific protein (polycystic kidney disease 2-like 1) to drive Cre-dependent expression of light-sensitive channelrhodopsin (Ai32) in mouse type III taste cells. Activation of these cells with light produces a taste nerve response in both the chorda tympani and glossopharyngeal nerves, and elicits a slight but significant aversion in two-bottle preference tests in both male and female mice. Unlike previous reports (Zocchi et al., 2017), our mice did not react to blue light stimulation with sustained drinking responses. These data suggest that type III cells are capable of communicating the presence of aversive stimuli in the oral cavity, which is in line with their responsiveness to sour and high concentrations of salt stimuli.

Reconstructing three-dimensional (3D) scenes from two-dimensional (2D) retinal images is an ill-posed problem. Despite this, 3D perception of the world based on 2D retinal images is seemingly accurate and precise. The integration of distinct visual cues is essential for robust 3D perception in humans, but it is unclear whether this is true for non-human primates (NHPs). Here, we assessed 3D perception in macaque monkeys using a planar surface orientation discrimination task., Reconstructing three-dimensional (3D) scenes from two-dimensional (2D) retinal images is an ill-posed problem. Despite this, 3D perception of the world based on 2D retinal images is seemingly accurate and precise. The integration of distinct visual cues is essential for robust 3D perception in humans, but it is unclear whether this is true for non-human primates (NHPs). Here, we assessed 3D perception in macaque monkeys using a planar surface orientation discrimination task. Perception was accurate across a wide range of spatial poses (orientations and distances), but precision was highly dependent on the plane’s pose. The monkeys achieved robust 3D perception by dynamically reweighting the integration of stereoscopic and perspective cues according to their pose-dependent reliabilities. Errors in performance could be explained by a prior resembling the 3D orientation statistics of natural scenes. We used neural network simulations based on 3D orientation-selective neurons recorded from the same monkeys to assess how neural computation might constrain perception. The perceptual data were consistent with a model in which the responses of two independent neuronal populations representing stereoscopic cues and perspective cues (with perspective signals from the two eyes combined using nonlinear canonical computations) were optimally integrated through linear summation. Perception of combined-cue stimuli was optimal given this architecture. However, an alternative architecture in which stereoscopic cues, left eye perspective cues, and right eye perspective cues were represented by three independent populations yielded two times greater precision than the monkeys. This result suggests that, due to canonical computations, cue integration for 3D perception is optimized but not maximized.

The photoreceptor cyclic nucleotide-gated (CNG) channel plays a pivotal role in phototransduction and cellular calcium homeostasis. Mutations in the cone photoreceptor CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. CNG channel deficiency leads to endoplasmic reticulum (ER) stress-associated cone apoptosis, protein mislocalization, and ER calcium dysregulation. This work investigated the potential mechanisms of protein mislocalization associated with ER calcium dysregulation usingCnga3-/-mice lacking ER Ca2+channel ryanodine receptor 2 (RyR2) specifically in cones. Deletion ofRyr2improved outer segment (OS) localization of the cone proteins M-opsin, S-opsin, and cone phosphodiesterase subunit α′ (PDE6C) and decreased inner segment localization. One-month-oldCnga3-/-mice showed ∼30% of M-opsin, 55% of S-opsin, and 50% of PDE6C localized to the OS.Cnga3-/-mice withRyr2deletion at the same age showed almost 60% of M-opsin, 70% of S-opsin, and 70% of PDE6C localized to the OS. Deletion ofRyr2nearly completely reversed elevations of the ER stress markers phospho-IRE1α and phospho-eIF2α and suppressed cone apoptosis. Consistent with the improved cone protein localization and reduced ER stress/cone apoptosis, cone survival was improved by deletion ofRyr2. The number of cones was increased by ∼28% in 2- to 4-month-oldCnga3-/-mice withRyr2deletion compared with age-matchedCnga3-/-mice. This work demonstrates a role of RyR2/ER calcium dysregulation in protein mislocalization, ER stress, and cone death. The findings provide novel insights into the mechanisms of photoreceptor degeneration and support strategies targeting ER calcium regulation to manage retinal degeneration.

Multisensory effects are found when the input from single senses combines, and this has been well researched in the brain. Presently, we examined in humans the potential impact of visuo-proprioceptive interactions at the peripheral level, using microneurography, and compared it with a similar behavioral task. We used a paradigm where participants had either proprioceptive information only (no vision) or combined visual and proprioceptive signals (vision). We moved the foot to measure changes in the sensitivity of single muscle afferents, which can be altered by the descending fusimotor drive. Visual information interacted with proprioceptive information, where we found that for the same passive movement, the response of muscle afferents increased when the proprioceptive channel was the only source of information, as compared with when visual cues were added, regardless of the attentional level. Behaviorally, when participants looked at their foot moving, they more accurately judged differences between movement amplitudes, than in the absence of visual cues. These results impact our understanding of multisensory interactions throughout the nervous system, where the information from different senses can modify the sensitivity of peripheral receptors. This has clinical implications, where future strategies may modulate such visual signals during sensorimotor rehabilitation.

In mammalian olfaction, inhalation drives the temporal patterning of neural activity that underlies early olfactory processing. However, it remains poorly understood how the neural circuits that process incoming olfactory information are engaged in the context of inhalation-linked dynamics. Here, we used artificial inhalation and two-photon calcium imaging to compare the dynamics of activity evoked by odorant inhalation across major cell types of the mouse olfactory bulb (OB). We expressed GCaMP6f or jRGECO1a in mitral and tufted cell subpopulations, olfactory sensory neurons and two major juxtaglomerular interneuron classes, and imaged responses to a single inhalation of odorant. Activity in all cell types was strongly linked to inhalation, and all cell types showed some variance in the latency, rise-times and durations of their inhalation-linked response. Juxtaglomerular interneuron dynamics closely matched that of sensory inputs, while mitral and tufted cells showed the highest diversity in responses, with a range of latencies and durations that could not be accounted for by heterogeneity in sensory input dynamics. Diversity was apparent even among ‘sister’ tufted cells innervating the same glomerulus. Surprisingly, inhalation-linked responses of mitral and tufted cells were highly overlapping and could not be distinguished on the basis of their inhalation-linked dynamics, with the exception of a subpopulation of superficial tufted cells expressing cholecystokinin. Overall, our results support a model in which diversity in inhalation-linked patterning of OB output arises first at the level of sensory input and is enhanced by feedforward inhibition from juxtaglomerular interneurons which differentially impact different subpopulations of OB output neurons. SIGNIFICANCE STATEMENT Inhalation drives the temporal patterning of neural activity that underlies olfactory processing and rapid odor perception, yet the dynamics of the neural circuit elements mediating this processing are poorly understood. By comparing inhalation-linked dynamics of major olfactory bulb subpopulations, we find that diversity in the timing of neural activation arises at the level of sensory input, which is then mirrored by inhibitory interneurons in the glomerular layer. Temporal diversity is higher among olfactory bulb output neurons, with different subpopulations showing distinct but nonetheless highly overlapping ranges of inhalation-linked dynamics. These results implicate feedforward inhibition by glomerular-layer interneurons in diversifying temporal responses among output neurons, which may be important for generating and shaping timing-based odor representations during natural odor sampling.

Mutations in theKCNV2gene, which encodes the voltage-gated K+channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by theKCNB1gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K+channels in the generation of the a-, b-, and c-wave components of the ERG.

Visual Abstract, Current theories suggest that the ability to control the body and to predict its associated sensory consequences is key for skilled motor behavior. It is also suggested that these abilities need to be updated when the mapping between motor commands and sensory consequences is altered. Here we challenge this view by investigating the transfer of adaptation to rotated visual feedback between one task in which human participants had to control a cursor with their hand in order to track a moving target, and another in which they had to predict with their eyes the visual consequences of their hand movement on the cursor. Hand and eye tracking performances were evaluated respectively through cursor–target and eye–cursor distance. Results reveal a striking dissociation: although prior adaptation of hand tracking greatly facilitates eye tracking, the adaptation of eye tracking does not transfer to hand tracking. We conclude that although the update of control is associated with the update of prediction, prediction can be updated independently of control. To account for this pattern of results, we propose that task demands mediate the update of prediction and control. Although a joint update of prediction and control seemed mandatory for success in our hand tracking task, the update of control was only facultative for success in our eye tracking task. More generally, those results promote the view that prediction and control are mediated by separate neural processes and suggest that people can learn to predict movement consequences without necessarily promoting their ability to control these movements.

The auditory system relies on binaural differences and spectral pinna cues to localize sounds in azimuth and elevation. However, the acoustic input can be unreliable, due to uncertainty about the environment, and neural noise. A possible strategy to reduce sound-location uncertainty is to integrate the sensory observations with sensorimotor information from previous experience, to infer where sounds are more likely to occur. We investigated whether and how human sound localization performance is affected by the spatial distribution of target sounds, and changes thereof. We tested three different open-loop paradigms, in which we varied the spatial range of sounds in different ways. For the narrowest ranges, target-response gains were highly idiosyncratic and deviated from an optimal gain predicted by error-minimization; in the horizontal plane the deviation typically consisted of a response overshoot. Moreover, participants adjusted their behavior by rapidly adapting their gain to the target range, both in elevation and in azimuth, yielding behavior closer to optimal for larger target ranges. Notably, gain changes occurred without any exogenous feedback about performance. We discuss how the findings can be explained by a sub-optimal model in which the motor-control system reduces its response error across trials to within an acceptable range, rather than strictly minimizing the error.

Visual Abstract, Skilled motor behavior relies on the ability to control the body and to predict the sensory consequences of this control. Although there is ample evidence that manual dexterity depends on handedness, it remains unclear whether control and prediction are similarly impacted. To address this issue, right-handed human participants performed two tasks with either the right or the left hand. In the first task, participants had to move a cursor with their hand so as to track a target that followed a quasi-random trajectory. This hand-tracking task allowed testing the ability to control the hand along an imposed trajectory. In the second task, participants had to track with their eyes a target that was self-moved through voluntary hand motion. This eye-tracking task allowed testing the ability to predict the visual consequences of hand movements. As expected, results showed that hand tracking was more accurate with the right hand than with the left hand. In contrast, eye tracking was similar in terms of spatial and temporal gaze attributes whether the target was moved by the right or the left hand. Although these results extend previous evidence for different levels of control by the two hands, they show that the ability to predict the visual consequences of self-generated actions does not depend on handedness. We propose that the greater dexterity exhibited by the dominant hand in many motor tasks stems from advantages in control, not in prediction. Finally, these findings support the notion that prediction and control are distinct processes.

Spontaneous otoacoustic emissions (SOAEs) recorded from the ear canal in the absence of sound reflect cochlear amplification, an outer hair cell (OHC) process required for the extraordinary sensitivity and frequency selectivity of mammalian hearing. Although wild-type mice rarely emit, those with mutations that influence the tectorial membrane (TM) show an incidence of SOAEs similar to that in humans. In this report, we characterized mice with a missense mutation inTecta,a gene required for the formation of the striated-sheet matrix within the core of the TM. Mice heterozygous for the Y1870C mutation (TectaY1870C/+) are prolific emitters, despite a moderate hearing loss. Additionally, Kimura’s membrane, into which the OHC stereocilia insert, separates from the main body of the TM, except at apical cochlear locations. Multimodal SOAEs are also observed inTectaY1870C/+mice where energy is present at frequencies that are integer multiples of a lower-frequency SOAE (the primary). Second-harmonic SOAEs, at twice the frequency of a lower-frequency primary, are the most frequently observed. These secondary SOAEs are found in spatial regions where stimulus-evoked OAEs are small or in the noise floor. Introduction of high-level suppressors just above the primary SOAE frequency reduce or eliminate both primary and second-harmonic SOAEs. In contrast, second-harmonic SOAEs are not affected by suppressors, either above or below the second-harmonic SOAE frequency, even when they are much larger in amplitude. Hence, second-harmonic SOAEs do not appear to be spatially separated from their primaries, a finding that has implications for cochlear mechanics and the consequences of changes to TM structure.

In awake mice, sniffing behavior is subject to complex contextual modulation. It has been hypothesized that variance in inhalation dynamics alters odor concentration profiles in the naris despite a constant environmental concentration. Using whole-cell recordings in the olfactory bulb of awake mice, we directly demonstrate that rapid sniffing mimics the effect of odor concentration increase at the level of both mitral and tufted cell (MTC) firing rate responses and temporal responses. Paradoxically, we find that mice are capable of discriminating fine concentration differences within short timescales despite highly variable sniffing behavior. One way that the olfactory system could differentiate between a change in sniffing and a change in concentration would be to receive information about the inhalation parameters in parallel with information about the odor. We find that the sniff-driven activity of MTCs without odor input is informative of the kind of inhalation that just occurred, allowing rapid detection of a change in inhalation. Thus, a possible reason for sniff modulation of the early olfactory system may be to directly inform downstream centers of nasal flow dynamics, so that an inference can be made about environmental concentration independent of sniff variance.

The nervous system seamlessly integrates perception and action. This ability is essential for stable representation of and appropriate responses to the external environment. How the sensorimotor integration underlying this ability occurs at the level of individual neurons is of keen interest. InCaenorhabditis elegans, RIA interneurons receive input from sensory pathways and have reciprocal connections with head motor neurons. RIA simultaneously encodes both head orientation and sensory stimuli, which may allow it to integrate these two signals to detect the spatial distribution of stimuli across head sweeps and generate directional head responses. Here, we show that blocking synaptic release from RIA disrupts head orientation behaviors in response to unilaterally presented stimuli. We found that sensory encoding in RIA is gated according to head orientation. This dependence on head orientation is independent of motor encoding in RIA, suggesting a second, posture-dependent pathway upstream of RIA. This gating mechanism may allow RIA to selectively attend to stimuli that are asymmetric across head sweeps. Attractive odor removal during head bends triggers rapid head withdrawal in the opposite direction. Unlike sensory encoding, this directional response is dependent on motor inputs to and synaptic output from RIA. Together, these results suggest that RIA is part of a sensorimotor pathway that is dynamically regulated according to head orientation at two levels: the first is a gate that filters sensory representations in RIA, and the second is a switch that routes RIA synaptic output to dorsal or ventral head motor neurons.

GABAergic cells constitute 20–40% of the cells that project from the inferior colliculus [(IC) a midbrain auditory hub] to the medial geniculate body [(MG) the main auditory nucleus of the thalamus]. Four subtypes of GABAergic IC cells have been identified based on their association with perineuronal nets (PNs) and dense rings of axosomatic terminals expressing vesicular glutamate transporter 2 (VGLUT2 rings). These subtypes differ in their soma size and distribution within the IC. Based on previous work emphasizing large GABAergic cells as the origin of GABAergic IC–MG projections, we hypothesized that GABAergic IC cells surrounded by PNs and VGLUT2 rings, which tend to have larger somas, were more likely to project to the MG than smaller cells lacking these extracellular markers. Here, we injected retrograde tract tracers into the MG of guinea pigs of either sex and analyzed retrogradely labeled GABAergic cells in the ipsilateral IC for soma size and association with PNs and/or VGLUT2 rings. We found a range of GABAergic soma sizes present within the IC–MG pathway, which were reflective of the full range of GABAergic soma sizes present within the IC. Further, we found that all four subtypes of GABAergic IC cells participate in the IC–MG pathway, and that GABAergic cells lacking PNs and VGLUT2 rings were more prevalent within the pathway than would be expected based on their overall prevalence in the IC. These results may provide an anatomical substrate for the multiple roles of inhibition in the IC–MG pathway, which have emerged in electrophysiological studies.

Visual Abstract, Striatal dopamine (DA) is a major player in action selection and reinforcement. DA release is under strong local control by striatal ACh acting at axonal nicotinic ACh receptors (nAChRs) on DA axons. Striatal nAChRs have been shown to control how DA is released in response to ascending activity from DA neurons, and they also directly drive DA release following synchronized activity in a small local cholinergic network. The source of striatal ACh has been thought to arise solely from intrinsic cholinergic interneurons (ChIs), but recent findings have identified a source of cholinergic inputs to striatum from brainstem nuclei, the pedunculopontine nucleus (PPN) and laterodorsal tegmentum (LDT). Here, we used targeted optogenetic activation alongside DA detection with fast-scan cyclic voltammetry to test whether ChIs alone and/or brainstem afferents to the striatum can account for how ACh drives and modulates DA release in rat striatum. We demonstrate that targeted transient light activation of rat striatal ChIs drives striatal DA release, corroborating and extending previous observations in mouse to rat. However, the same light stimulation targeted to cholinergic brainstem afferents did not drive DA release, and nor did it modulate DA release activated subsequently by electrical stimulation, whereas targeted activation of ChIs did so. We were unable to obtain any evidence for DA modulation by PPN/LDT stimulation. By contrast, we could readily identify that striatal ChIs alone are sufficient to provide a source of ACh that powerfully regulates DA via nAChRs.

The membrane guanylate cyclase, ROS-GC, that synthesizes cyclic GMP for use as a second messenger for visual transduction in retinal rods and cones, is stimulated by bicarbonate. Bicarbonate acts directly on ROS-GC1, because it enhanced the enzymatic activity of a purified, recombinant fragment of bovine ROS-GC1 consisting solely of the core catalytic domain. Moreover, recombinant ROS-GC1 proved to be a true sensor of bicarbonate, rather than a sensor for CO2. Access to bicarbonate differed in rods and cones of larval salamander,Ambystoma tigrinum, of unknown sex. In rods, bicarbonate entered at the synapse and diffused to the outer segment, where it was removed by Cl--dependent exchange. In contrast, cones generated bicarbonate internally from endogenous CO2or from exogenous CO2that was present in extracellular solutions of bicarbonate. Bicarbonate production from both sources of CO2was blocked by the carbonic anhydrase inhibitor, acetazolamide. Carbonic anhydrase II expression was verified immunohistochemically in cones but not in rods. In addition, cones acquired bicarbonate at their outer segments as well as at their inner segments. The multiple pathways for access in cones may support greater uptake of bicarbonate than in rods and buffer changes in its intracellular concentration.

The Giant Fiber System (GFS) is a multi-component neuronal pathway mediating rapid escape response in the adult fruit-flyDrosophila melanogaster, usually in the face of a threatening visual stimulus. Two branches of the circuit promote the response by stimulating an escape jump followed by flight initiation. Our recent work demonstrated an age-associated decline in the speed of signal propagation through the circuit, measured as the stimulus-to-muscle depolarization response latency. The decline is likely due to the diminishing number of interneuronal gap junctions in the GFS of ageing flies. In this work, we presented a realistic conductance-based, computational model of the GFS that recapitulates our experimental results and identifies some of the critical anatomical and physiological components governing the circuit’s response latency. According to our model, anatomical properties of the GFS neurons have a stronger impact on the transmission than neuronal membrane conductance densities. The model provides testable predictions for the effect of experimental interventions on the circuit’s performance in young and ageing flies.

Odor information is transmitted from olfactory sensory neurons to principal neurons at the glomeruli of the olfactory bulb. The intraglomerular neuronal circuit also includes hundreds of interneurons referred to as juxtaglomerular (JG) cells. Stimulus selectivity is well correlated among many JG cells that are associated with the same glomerulus, consistent with their highly homogeneous sensory inputs. However, much less is known about the temporal aspects of their activity, including the temporal coordination of their odor-evoked responses. As many JG cells within a glomerular module respond to the same stimulus, the extent to which their activity is temporally aligned will affect the temporal profile of their population inhibitory inputs. Using random-access high-speed two-photon microscopy, we recorded the odor-evoked calcium transients of mouse JG cells and compared the onset latency and rise time among neurons putatively associated with the same and different glomeruli. Whereas the overall onset latencies of odor-evoked transients were distributed across a ∼150 ms time window, those from cells putatively associated with the same glomerulus were confined to a much narrower window of several tens of milliseconds. This result suggests that onset latency primarily depends on the associated glomerulus. We also observed glomerular specificity in the rise time. The glomerulus-specific temporal pattern of odor-evoked activity implies that the temporal patterns of inputs from the intraglomerular circuit are unique to individual glomerulus–odor pairs, which may contribute to efficient shaping of the temporal pattern of activity in the principal neurons.

Broad neuronal classes are surprisingly heterogeneous across many parameters, and subclasses often exhibit partially overlapping traits including transmitter coexpression. However, the extent to which transmitter coexpression occurs in predictable, consistent patterns is unknown. Here, we demonstrate that pairwise coexpression of GABA and multiple neuropeptide families by olfactory local interneurons (LNs) of the moth Manduca sexta is highly heterogeneous, with a single LN capable of expressing neuropeptides from at least four peptide families and few instances in which neuropeptides are consistently coexpressed. Using computational modeling, we demonstrate that observed coexpression patterns cannot be explained by independent probabilities of expression of each neuropeptide. Our analyses point to three organizing principles that, once taken into consideration, allow replication of overall coexpression structure: (1) peptidergic neurons are highly likely to coexpress GABA; (2) expression probability of allatotropin depends on myoinhibitory peptide expression; and (3) the all-or-none coexpression patterns of tachykinin neurons with several other neuropeptides. For other peptide pairs, the presence of one peptide was not predictive of the presence of the other, and coexpression probability could be replicated by independent probabilities. The stochastic nature of these coexpression patterns highlights the heterogeneity of transmitter content among LNs and argues against clear-cut definition of subpopulation types based on the presence of single neuropeptides. Furthermore, the receptors for all neuropeptides and GABA were expressed within each population of principal neuron type in the antennal lobe (AL). Thus, activation of any given LN results in a dynamic cocktail of modulators that have the potential to influence every level of olfactory processing within the AL.

Sensory prostheses can restore aspects of natural sensation by delivering electrical current directly into sensory circuits. An effective sensory prosthetic should be capable of generating reliable real-time perceptual signals for hours each day over many years. However, we still know little regarding the stability of percepts produced by electrical microstimulation of cerebral sensory cortex when stimulation is delivered repeatedly over long periods. Developing methods that yield highly sensitive and reliable assessments of a subject’s sensitivity to stimulation is important for developing prosthetic devices that can mimic the constant stream of information inherent in daily experience. Here, we trained rhesus monkeys to report electrical microstimulation of their primary visual cortex (V1) and measured how repeated stimulation affected the minimal electrical current needed to generate a percept (behavioral detection threshold). Using adaptive staircase procedures with a two-alternative forced-choice (2AFC) detection task, we obtained highly reliable detection threshold measures with as few as 100 trials. Using either chronically implanted or acutely inserted microelectrodes, we found that repeated electrical microstimulation elevated detection thresholds, with effects persisting between daily testing sessions. Our results demonstrate task designs that can support rapid and reliable measurements of detection thresholds, and point to the need for validation that detection thresholds in targeted structures will be sufficiently stable in the face of the amount of chronic stimulation that will be required for effective sensory prosthetics.

The study of neuronal responses to random-dot motion patterns has provided some of the most valuable insights into how the activity of neurons is related to perception. In the opposite directions of motion paradigm, the motion signal strength is decreased by manipulating the coherence of random dot patterns to examine how well the activity of single neurons represents the direction of motion. To extend this paradigm to populations of neurons, studies have used modelling based on data from pairs of neurons, but several important questions require further investigation with larger neuronal datasets. We recorded neuronal populations in the middle temporal (MT) and medial superior temporal (MST) areas of anaesthetized marmosets with electrode arrays, while varying the coherence of random dot patterns in two opposite directions of motion (left and right). Using the spike rates of simultaneously recorded neurons, we decoded the direction of motion at each level of coherence with linear classifiers. We found that the presence of correlations had a detrimental effect to decoding performance, but that learning the correlation structure produced better decoding performance compared to decoders that ignored the correlation structure. We also found that reducing motion coherence increased neuronal correlations, but decoders did not need to be optimized for each coherence level. Finally, we showed that decoder weights depend of left-right selectivity at 100% coherence, rather than the preferred direction. These results have implications for understanding how the information encoded by populations of neurons is affected by correlations in spiking activity.

Alterations in fractional anisotropy (FA) have been considered to reflect microstructural white matter (WM) changes in disease conditions; however, no study to date has examined WM changes using diffusion tensor imaging (DTI) in adolescents with irritable bowel syndrome (IBS). The objective of the present study was two-fold: (1) to determine whether differences in FA, and other non-FA metrics, were present in adolescents with IBS compared to healthy controls using whole-brain, region of interest (ROI)-restricted tract-based spatial statistics (TBSS) and canonical ROI DTI analyses for the cingulum bundle, and (2) to determine whether these metrics were related to clinical measures of disease duration and pain intensity in the IBS group. A total of 16 adolescents with a Rome III diagnosis of IBS (females = 12; mean age = 16.29, age range: 11.96–18.5 years) and 16 age- and gender-matched healthy controls (females = 12; mean age = 16.24; age range: 11.71–20.32 years) participated in this study. Diffusion-weighted images were acquired using a Siemens 3-T Trio Tim Syngo MRI scanner with a 32-channel head coil. The ROI-restricted TBSS and canonical ROI-based DTI analyses revealed that adolescents with IBS showed decreased FA in the right dorsal cingulum bundle compared to controls. No relationship between FA and disease severity measures was found. Microstructural WM alterations in the right dorsal cingulum bundle in adolescents with IBS may reflect a premorbid brain state or the emergence of a disease-driven process that results from complex changes in pain- and affect-related processing via spinothalamic and corticolimbic pathways.

Visual Abstract, Human balance is a complex process in healthy adults, requiring precisely timed coordination among sensory information, cognitive processing, and motor control. It has been difficult to quantify brain dynamics during human balance control due to limitations in brain-imaging modalities. The goal of this study was to determine whether by using high-density electroencephalography (EEG) and independent component analysis, we can identify common cortical responses to visual and physical balance perturbations during walking and standing. We studied the responses of 30 healthy young adults to sensorimotor perturbations that challenged their balance. Subjects performed four 10 min trials of beam walking and tandem stance while either being mediolaterally pulled at the waist or viewing brief 20° field-of-view rotations in virtual reality. We recorded high-density EEG, motion capture, lower leg electromyography (EMG), and neck EMG. We hypothesized that both physical pull and visual rotation perturbations would elicit time–frequency fluctuations in theta (4–8 Hz) and beta (13–30 Hz) bands, with increased occipito-parietal activity during visual rotations compared with pull perturbations. Our results confirmed this hypothesis. For both perturbations, we found early theta synchronization and late alpha–beta (8–30 Hz) desynchronization following perturbation onset. This pattern was strongest in occipito-parietal areas during visual perturbations and strongest in sensorimotor areas during pull perturbations. These results suggest a similar time–frequency electrocortical pattern when humans respond to sensorimotor conflict, but with substantive differences in the brain areas involved for visual versus physical perturbations. Our findings may have important implications for assessing and training balance in individuals with and without motor disabilities.

Many animals depend on descending information from the brain for the initiation and proper execution of locomotion. Interestingly, after injury and the loss of such inputs, locomotor function can sometimes be regained without the regrowth of central connections. In the medicinal leech,Hirudo verbana, we have shown that crawling reemerges after removal of descending inputs. Here, we studied the mechanisms underlying this return of locomotion by asking if central pattern generators (CPGs) in crawl-recovered leeches are sufficient to produce crawl-specific intersegmental coordination. From recovered animals, we treated isolated chains of ganglia with dopamine to activate the crawl CPGs (one crawl CPG per ganglion) and observed fictive crawl-like bursting in the dorsal-longitudinal-excitor motoneuron (DE-3), an established crawl-monitor neuron. However, these preparations did not exhibit crawl-specific coordination across the CPGs. Although the crawl CPGs always generated bidirectional activation of adjacent CPGs, we never observed crawl-appropriate intersegmental phase delays. Because central circuits alone were unable to organize crawl-specific coordination, we tested the coordinating role of the peripheral nervous system. In transected leeches normally destined for recovery, we removed afferent information to the anterior-most (lead) ganglion located below the nerve-cord transection site. In these dually treated animals, overt crawling was greatly delayed or prevented. After filling the peripheral nerves with Neurobiotin tracer distal to the nerve-root lesion, we found a perfect correlation between regrowth of peripheral neuronal fibers and crawl recovery. Our study establishes that during recovery after injury, crawl-specific intersegmental coordination switches to a new dependence on afferent information.

Creating three-dimensional (3D) representations of the world from two-dimensional retinal images is fundamental to many visual guided behaviors including reaching and grasping. A critical component of this process is determining the 3D orientation of objects. Previous studies have shown that neurons in the caudal intraparietal area (CIP) of the macaque monkey represent 3D planar surface orientation (i.e., slant and tilt). Here we compare the responses of neurons in areas V3A (which is implicated in 3D visual processing and which precedes CIP in the visual hierarchy) and CIP to 3D oriented planar surfaces. We then examine whether activity in these areas correlates with perception during a fine slant discrimination task in which monkeys report if the top of a surface is slanted towards or away from them. Although we find that V3A and CIP neurons show similar sensitivity to planar surface orientation, significant choice-related activity during the slant discrimination task is rare in V3A but prominent in CIP. These results implicate both V3A and CIP in the representation of 3D surface orientation, and suggest a functional dissociation between the areas based on slant-related decision signals.Significance StatementSurface orientation perception is fundamental to visually guided behaviors such as reaching, grasping, and navigation. Previous studies implicate the caudal intraparietal area (CIP) in the representation of 3D surface orientation. Here we show that responses to 3D oriented planar surfaces are similar in CIP and V3A, which precedes CIP in the cortical hierarchy. However, we also find a qualitative distinction between the two areas: only CIP neurons show robust choice-related activity during a fine visual orientation discrimination task.

The role of orexin during development, and especially in terms of spinal cord function, is not well understood. It is for this reason that we focused on the network actions of orexin during the first week of development. We found that orexinergic fibers were present in the lumbar spinal cord of postnatal day 0 (P0) to P3 mice. The fibers were expressed mainly in the dorsal horn, but occasional fibers were observed in the ventral horn. Both orexin (OX) A and OXB increased the motoneurons (MNs) tonic neurogram discharge. However, only OXA was found to significantly increase spontaneous bursting activity and the frequency of fictive locomotor bursts. We show that OXA is able to act directly on MNs. To test the contribution of the recurrent MN collaterals, we blocked the nicotinic cholinergic drive and observed that OXA retained its ability to increase fictive locomotor activity. Additionally, we recorded neurograms from ventral lateral funiculi, where OXA had no effect on population discharge. These effects were also confirmed by recording from descending commissural interneurons via patch recordings. The loci of the effects of OXA were further investigated in a dorsal horn-removed preparation where OXA also shows an increase in the discharge from ventral root neurograms but no increase in the frequency of spontaneous or fictive locomotion burst activity. In summary, multiple lines of evidence from our work demonstrate the robust effects of orexins on spinal cord networks and MNs at the time of birth.

Several recently developed Channelrhodopsin (ChR) variants are characterized by rapid kinetics and reduced desensitization in comparison to the widely used ChR2. However, little is known about how varying opsin properties may regulate their interaction with local network dynamics. We compared evoked cortical activity in mice expressing three ChR variants with distinct temporal profiles under the CamKII promoter: Chronos, Chrimson, and ChR2. We assessed overall neural activation by measuring the amplitude and temporal progression of evoked spiking. Using γ-range (30–80 Hz) local field potential (LFP) power as an assay for local network engagement, we examined the recruitment of cortical network activity by each tool. All variants caused light-evoked increases in firingin vivo, but each demonstrated different temporal patterning of evoked activity. In addition, the three ChRs had distinct effects on cortical γ-band activity. Our findings suggest the properties of optogenetic tools can substantially affect their efficacyin vivo, as well their engagement of circuit resonance.

The mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors in Tsc2-deleted mice. In addition to these changes in innervation and gene expression, Tsc2-deleted mice exhibited reduced noxious heat sensitivity and decreased injury-induced cold hypersensitivity, but normal baseline sensitivity to cold and mechanical stimuli. Together, these data show that excess mTORC1 activity in sensory neurons produces changes in gene expression, neuron morphology and sensory behavior.

A neural correlate for saccadic reaction times (SRTs) in the gap saccade task is the level of low-frequency activity in the intermediate layers of the superior colliculus (iSC) just before visual target onset: greater levels of suchpreparatoryiSC low-frequency activity precede shorter SRTs. The frontal eye fields (FEFs) are one likely source of iSC preparatory activity, since FEF preparatory activity is also inversely related to SRT. To better understand the FEF’s role in saccade preparation, and the way in which such preparation relates to SRT, in two male rhesus monkeys, we compared iSC preparatory activity across unilateral reversible cryogenic inactivation of the FEF. FEF inactivation increased contralesional SRTs, and lowered ipsilesional iSC preparatory activity. FEF inactivation also reduced rostral iSC activity during the gap period. Importantly, the distributions of SRTs generated with or without FEF inactivation overlapped, enabling us to conduct a novel population-level analyses examining iSC preparatory activity just before generation of SRT-matched saccades. When matched for SRTs, we observed no change during FEF inactivation in the relationship between iSC preparatory activity and SRT-matched saccades across a range of SRTs, even for the occasional express saccade. Thus, while our results emphasize that the FEF has an overall excitatory influence on preparatory activity in the iSC, the communication between the iSC and downstream oculomotor brainstem is unaltered for SRT-matched saccades.

Promoter-based genetic recombination (via, e.g., Cre-lox) is most useful when all cells of interest express a particular gene. The discovery that the actin-binding protein advillin is expressed in all somatic sensory neurons has been exploited repeatedly to drive DNA recombination therein, yet specificity of expression has not been well demonstrated. Here, we characterize advillin expression amongst sensory neurons and in several other neural and non-neural tissues. We first validate an advillin antibody against advillin knock-out tissue, advillin promoter-driven EGFP, and advillin mRNA expression. In the dorsal root ganglion (DRG), advillin is enriched in non-peptidergic nociceptors. We also show that advillin expression, and advillin promotor-driven EGFP and Cre-recombinase expression, occurs in multiple tissues including the dorsal habenula of the epithalamus, endocrine cells of the gut, Merkel cells in the skin, and most strikingly, throughout the autonomic nervous system (sympathetic, parasympathetic, and enteric neurons) in mice, rats, and non-human primates. In the mouse pelvic ganglion, advillin immunoreactivity is most intense in pairs of small neurons, and concentrated in spine-like structures on the axon initial segment contacted by sympathetic preganglionic axons. In autonomic targets (iris and blood vessels), advillin is distributed along cholinergic parasympathetic axons and in sympathetic varicosities. Developmentally, advillin expression is absent from sympathetics at postnatal day 4 but begins to emerge by day 7, accounting for previous reports (based on embryonic expression) of advillin’s specificity to sensory neurons. These results indicate that caution is warranted in interpreting previous studies in which advillin-driven genomic editing is either constitutive or performed after postnatal day 4.

Uncovering the neural dynamics of facial identity processing along with its representational basis outlines a major endeavor in the study of visual processing. To this end, here, we record human electroencephalography (EEG) data associated with viewing face stimuli; then, we exploit spatiotemporal EEG information to determine the neural correlates of facial identity representations and to reconstruct the appearance of the corresponding stimuli. Our findings indicate that multiple temporal intervals support: facial identity classification, face space estimation, visual feature extraction and image reconstruction. In particular, we note that both classification and reconstruction accuracy peak in the proximity of the N170 component. Further, aggregate data from a larger interval (50–650 ms after stimulus onset) support robust reconstruction results, consistent with the availability of distinct visual information over time. Thus, theoretically, our findings shed light on the time course of face processing while, methodologically, they demonstrate the feasibility of EEG-based image reconstruction.

Visual perception includes ventral and dorsal stream processes. However, it is still unclear whether the former is predominantly related to conscious and the latter to nonconscious visual perception as argued in the literature. In this study upright and inverted body postures were rendered either visible or invisible under continuous flash suppression (CFS), while brain activity of human participants was measured with functional MRI (fMRI). Activity in the ventral body-sensitive areas was higher during visible conditions. In comparison, activity in the posterior part of the bilateral intraparietal sulcus (IPS) showed a significant interaction of stimulus orientation and visibility. Our results provide evidence that dorsal stream areas are less associated with visual awareness.

In many brain regions involved in learning NMDA receptors (NMDARs) act as coincidence detectors of pre- and postsynaptic activity, mediating Hebbian plasticity. Intriguingly, the parallel fiber (PF) to Purkinje cell (PC) input in the cerebellar cortex, which is critical for procedural learning, shows virtually no postsynaptic NMDARs. Why is this? Here, we address this question by generating and testing independent transgenic lines that overexpress NMDAR containing the type 2B subunit (NR2B) specifically in PCs. PCs of the mice that show larger NMDA-mediated currents than controls at their PF input suffer from a blockage of long-term potentiation (LTP) at their PF-PC synapses, while long-term depression (LTD) and baseline transmission are unaffected. Moreover, introducing NMDA-mediated currents affects cerebellar learning in that phase-reversal of the vestibulo-ocular reflex (VOR) is impaired. Our results suggest that under physiological circumstances PC spines lack NMDARs postsynaptically at their PF input so as to allow LTP to contribute to motor learning.

Action and perception are tightly coupled systems requiring coordination and synchronization over time. How the brain achieves synchronization is still a matter of debate, but recent experiments suggest that brain oscillations may play an important role in this process. Brain oscillations have been also proposed to be fundamental in determining time perception. Here, we had subjects perform an audiovisual temporal order judgment task to investigate the fine dynamics of temporal bias and sensitivity before and after the execution of voluntary hand movement (button-press). The reported order of the audiovisual sequence was rhythmically biased as a function of delay from hand action execution. Importantly, we found that it oscillated at a theta range frequency, starting ∼500 ms before and persisting ∼250 ms after the button-press, with consistent phase-locking across participants. Our results show that the perception of cross-sensory simultaneity oscillates rhythmically in synchrony with the programming phase of a voluntary action, demonstrating a link between action preparation and bias in temporal perceptual judgments.