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Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience


Intracellular Ca(2+) signals control the development and regeneration of spinal axons downstream of chemical guidance cues, but little is known about the roles of mechanical cues in axon guidance. Here we show that transient receptor potential canonical 1 (TRPC1) subunits assemble mechanosensitive (MS) channels on Xenopus neuronal growth cones that regulate the extension and direction of axon outgrowth on rigid, but not compliant, substrata. Reducing expression of TRPC1 by antisense morpholinos inhibits the effects of MS channel blockers on axon outgrowth and local Ca(2+) transients. Ca(2+) influx through MS TRPC1 activates the protease calpain, which cleaves the integrin adaptor protein talin to reduce Src-dependent axon outgrowth, likely through altered adhesion turnover. We found that talin accumulates at the tips of dynamic filopodia, which is lost upon cleavage of talin by active calpain. This pathway may also be important in axon guidance decisions since asymmetric inhibition of MS TRPC1 is sufficient to induce growth cone turning. Together our results suggest that Ca(2+) influx through MS TRPC1 on filopodia activates calpain to control growth cone turning during development.

Concepts: Nervous system, Neuron, Developmental biology, Action potential, Axon, Axon guidance, Growth cone, Filopodia


Myelination and voltage-gated ion channel clustering at the nodes of Ranvier are essential for the rapid saltatory conduction of action potentials. Whether myelination influences the structural organization of the axon initial segment (AIS) and action potential initiation is poorly understood. Using the cuprizone mouse model, we combined electrophysiological recordings with immunofluorescence of the voltage-gated Nav1.6 and Kv7.3 subunits and anchoring proteins to analyze the functional and structural properties of single demyelinated neocortical L5 axons. Whole-cell recordings demonstrated that neurons with demyelinated axons were intrinsically more excitable, characterized by increased spontaneous suprathreshold depolarizations as well as antidromically propagating action potentials ectopically generated in distal parts of the axon. Immunofluorescence examination of demyelinated axons showed that βIV-spectrin, Nav1.6, and the Kv7.3 channels in nodes of Ranvier either dissolved or extended into the paranodal domains. In contrast, while the AIS in demyelinated axons started more closely to the soma, ankyrin G, βIV-spectrin, and the ion channel expression were maintained. Structure-function analysis and computational modeling, constrained by the AIS location and realistic dendritic and axonal morphologies, confirmed that a more proximal onset of the AIS slightly reduced the efficacy of action potential generation, suggesting a compensatory role. These results suggest that oligodendroglial myelination is not only important for maximizing conduction velocity, but also for limiting hyperexcitability of pyramidal neurons.

Concepts: Nervous system, Neuron, Action potential, Axon, Myelin, Oligodendrocyte, Saltatory conduction, Nodes of Ranvier


Due to capacity limits on perception, conditions of high perceptual load lead to reduced processing of unattended stimuli (Lavie et al., 2014). Accumulating work demonstrates the effects of visual perceptual load on visual cortex responses, but the effects on auditory processing remain poorly understood. Here we establish the neural mechanisms underlying “inattentional deafness”-the failure to perceive auditory stimuli under high visual perceptual load. Participants performed a visual search task of low (target dissimilar to nontarget items) or high (target similar to nontarget items) load. On a random subset (50%) of trials, irrelevant tones were presented concurrently with the visual stimuli. Brain activity was recorded with magnetoencephalography, and time-locked responses to the visual search array and to the incidental presence of unattended tones were assessed. High, compared to low, perceptual load led to increased early visual evoked responses (within 100 ms from onset). This was accompanied by reduced early (∼100 ms from tone onset) auditory evoked activity in superior temporal sulcus and posterior middle temporal gyrus. A later suppression of the P3 “awareness” response to the tones was also observed under high load. A behavioral experiment revealed reduced tone detection sensitivity under high visual load, indicating that the reduction in neural responses was indeed associated with reduced awareness of the sounds. These findings support a neural account of shared audiovisual resources, which, when depleted under load, leads to failures of sensory perception and awareness.

Concepts: Psychology, Brain, Understanding, Cognition, Perception, Sense, Mind, Evoked potential


In the past, we showed that large electrolytic lesions of the dorsomedial hypothalamus (DMH) promoted hypothermia in cold-exposed restrained rats, but attenuated hypothermia in rats challenged with a high dose of bacterial lipopolysaccharide (LPS) in a thermogradient apparatus. The goal of this study was to identify the thermoeffector mechanisms and DMH representation of the two phenomena and, hence, understand how the same lesion could produce two opposite effects on body temperature. We found that the permissive effect of large electrolytic DMH lesions on cold-induced hypothermia was due to suppressed thermogenesis. DMH-lesioned rats also could not develop fever autonomically: they did not increase thermogenesis in response to a low, pyrogenic dose of LPS (10 μg/kg, i.v.). In contrast, changes in thermogenesis were uninvolved in the attenuation of the hypothermic response to a high, shock-inducing dose of LPS (5,000 μg/kg, i.v.); this attenuation was due to a blockade of cold-seeking behavior. To compile DMH maps for the autonomic cold defense and for the cold-seeking response to LPS, we studied rats with small thermal lesions in different parts of the DMH. Cold thermogenesis had the highest representation in the dorsal hypothalamic area. Cold seeking was represented by a site at the ventral border of the dorsomedial nucleus. Because LPS causes both fever and hypothermia, we originally thought that the DMH contained a single thermoregulatory site that worked as a fever-hypothermia switch. Instead, we have found two separate sites: one that drives thermogenesis, and the other, previously unknown, that drives inflammation-associated cold seeking.SIGNIFICANCE STATEMENTCold-seeking behavior is a life-saving response that occurs in severe systemic inflammation. We studied this behavior in rats with lesions in the dorsomedial hypothalamus (DMH) challenged with a shock-inducing dose of bacterial endotoxin. We built functional maps of the DMH and found the strongest representation of cold-seeking behavior at the ventral border of the dorsomedial nucleus. We also built maps for cold-induced thermogenesis in unanesthetized rats and found the dorsal hypothalamic area to be its main representation site. Our work identifies the neural substrate of cold-seeking behavior in systemic inflammation and expands the functional topography of the DMH – a structure that modulates autonomic, endocrine, and behavioral responses and is a potential therapeutic target in anxiety and panic disorders.

Concepts: Inflammation, Hypothalamus, Lipopolysaccharide, Thermoregulation, Hyperthermia, Fever, Endotoxin, Shivering


The perception of duration in the subsecond range has been hypothesized to be mediated by the population response of duration-sensitive units, each tuned to a preferred duration. One line of support for this hypothesis comes from neuroimaging studies showing that cortical regions, such as in parietal cortex exhibit duration tuning. It remains unclear if this representation is based on the physical duration of the sensory input or the subjective duration, a question that is important given that our perception of the passage of time is often not veridical, but rather, biased by various contextual factors. Here we used fMRI to examine the neural correlates of subjective time perception in human participants. To manipulate perceived duration while holding physical duration constant, we employed an adaptation method, in which, prior to judging the duration of a test stimulus, the participants were exposed to a train of adapting stimuli of a fixed duration. Behaviorally, this procedure produced a pronounced negative aftereffect: A short adaptor biased participants to judge stimuli as longer and a long adaptor biased participants to judge stimuli as shorter. Duration tuning modulation, manifest as an attenuated BOLD response to stimuli similar in duration to the adaptor, was only observed in the right supramarginal gyrus (SMG) of the parietal lobe and middle occipital gyrus, bilaterally. Across individuals, the magnitude of the behavioral aftereffect was positively correlated with the magnitude of duration tuning modulation in SMG. These results indicate that duration-tuned neural populations in right SMG reflect the subjective experience of time.SIGNIFICANCE STATEMENTThe subjective sense of time is a fundamental dimension of sensory experience. To investigate the neural basis of subjective time, we conducted an fMRI study, using an adaptation procedure that allowed us to manipulate perceived duration while holding physical duration constant. Regions within the occipital cortex and right parietal lobe showed duration tuning that was modulated when the test stimuli were similar in duration to the adaptor. Moreover, the magnitude of the distortion in perceived duration was correlated with the degree of duration tuning modulation in the parietal region. These results provide strong physiological evidence that the population coding of time in the right parietal cortex reflects our subjective experience of time.


Humans are better at integrating desirable information into their beliefs than undesirable. This asymmetry poses an evolutionary puzzle, as it can lead to an underestimation of risk and thus failure to take precautionary action. Here, we suggest a mechanism that can speak to this conundrum. In particular, we show that the bias vanishes in response to perceived threat in the environment. We report that an improvement in participants' tendency to incorporate bad news into their beliefs is associated with physiological arousal in response to threat indexed by galvanic skin response and self-reported anxiety. This pattern of results was observed in a controlled laboratory setting (Experiment I), where perceived threat was manipulated, and in firefighters on duty (Experiment II), where it naturally varied. Such flexibility in how individuals integrate information may enhance the likelihood of responding to warnings with caution in environments rife with threat, while maintaining a positivity bias otherwise, a strategy that can increase well-being.SIGNIFICANCE STATEMENTThe human tendency to be overly optimistic has mystified scholars and lay people for decades: how could biased beliefs have been selected for over unbiased beliefs? Scholars have suggested that while the optimism bias can lead to negative outcomes, including financial collapse and war, it can also facilitate health and productivity. Here, we demonstrate that a mechanism generating the optimism bias, namely asymmetric information integration, evaporates under threat. Such flexibility could result in enhanced caution in dangerous environments while supporting an optimism bias otherwise, potentially increasing well-being.


It is well-established that active rehearsal increases the efficacy of memory consolidation. It is also known that complex events are interpreted with reference to prior knowledge. However, comparatively little attention has been given to the neural underpinnings of these effects. In healthy adults humans, we investigated the impact of effortful, active rehearsal on memory for events by showing people several short video clips and then asking them to recall these clips, either aloud (Experiment 1) or silently while in an MRI scanner (Experiment 2). In both experiments, actively rehearsed clips were remembered in far greater detail than unrehearsed clips when tested a week later. In Experiment 1, highly similar descriptions of events were produced across retrieval trials, suggesting a degree of semanticization of the memories had taken place. In Experiment 2, spatial patterns of BOLD signal in medial temporal and posterior midline regions were correlated when encoding and rehearsing the same video. Moreover, the strength of this correlation in the posterior cingulate predicted the amount of information subsequently recalled. This is likely to reflect a strengthening of the representation of the video’s content. We argue that these representations combine both new episodic information and stored semantic knowledge (or “schemas”). We therefore suggest that posterior midline structures aid consolidation by reinstating and strengthening the associations between episodic details and more generic schematic information. This leads to the creation of coherent memory representations of lifelike, complex events that are resistant to forgetting, but somewhat inflexible and semantic-like in nature.

Concepts: Memory, Cerebrum, Hippocampus, Episodic memory, Semantic memory, Cingulate cortex, Memory consolidation, Video clip


Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in two female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST) and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6kg, close to the animal’s body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a two-week washout period without weights. After a further three months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared to the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST.Significance StatementWe provide the first report of a strength training intervention in non-human primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whilst corticospinal and motoneuronal adaptations are not dominant factors.


Humans have bred different lineages of domestic dogs for different tasks, like hunting, herding, guarding, or companionship. These behavioral differences must be the result of underlying neural differences, but surprisingly, this topic has gone largely unexplored. The current study examined whether and how selective breeding by humans has altered the gross organization of the brain in dogs. We assessed regional volumetric variation in MRI studies of 62 male and female dogs of 33 breeds. Notably, neuroanatomical variation is plainly visible across breeds. This variation is distributed non-randomly across the brain. A whole-brain, data-driven independent components analysis established that specific regional sub-networks covary significantly with each other. Variation in these networks is not simply the result of variation in total brain size, total body size, or skull shape. Furthermore, the anatomy of these networks correlates significantly with different behavioral specialization(s) such as sight hunting, scent hunting, guarding, and companionship. Importantly, a phylogenetic analysis revealed that most change has occurred in the terminal branches of the dog phylogenetic tree, indicating strong, recent selection in individual breeds. Together, these results establish that brain anatomy varies significantly in dogs, likely due to human-applied selection for behavior.Significance statement:Dog breeds are known to vary in cognition, temperament, and behavior, but the neural origins of this variation are unknown. In an MRI-based analysis, we found that brain anatomy covaries significantly with behavioral specializations like sight hunting, scent hunting, guarding, and companionship. Neuroanatomical variation is not simply driven by brain size, body size, or skull shape, and is focused in specific networks of regions. Nearly all of the identified variation occurs in the terminal branches of the dog phylogenetic tree, indicating strong, recent selection in individual breeds. These results indicate that through selective breeding, humans have significantly altered the brains of different lineages of domestic dogs in different ways.


Artificial agents are becoming prevalent across human life domains. However, the neural mechanisms underlying human responses to these new, artificial social partners remain unclear. The Uncanny-Valley (UV) hypothesis predicts that humans prefer anthropomorphic agents but reject them if they become too human-like-the so-called UV reaction. Using functional MRI, we investigated neural activity when subjects evaluated artificial agents and made decisions about them. Across two experimental tasks, the ventromedial prefrontal cortex (VMPFC) encoded an explicit representation of subjects' UV reactions. Specifically, VMPFC signaled the subjective likability of artificial agents as a nonlinear function of human-likeness, with selective low likability for highly humanlike agents. In exploratory across-subject analyses, these effects explained individual differences in psychophysical evaluations and preference choices. Functionally connected areas encoded critical inputs for these signals: the temporo-parietal junction encoded a linear human-likeness continuum, whereas nonlinear representations of human-likeness in dorsomedial prefrontal cortex (DMPFC) and fusiform gyrus emphasized a human-nonhuman distinction. Following principles of multisensory integration, multiplicative combination of these signals reconstructed VMPFC’s valuation function. During decision-making, separate signals in VMPFC and DMPFC encoded subjects' decision variable for choices involving humans or artificial agents, respectively. A distinct amygdala signal predicted rejection of artificial agents. Our data suggest that human reactions toward artificial agents are governed by a neural mechanism that generates a selective, nonlinear valuation in response to a specific feature combination (human-likeness in nonhuman agents). Thus, a basic principle known from sensory coding-neural feature selectivity from linear-nonlinear transformation-may also underlie human responses to artificial social partners.SIGNIFICANCE STATEMENTWould you trust a robot to make decisions for you? Autonomous artificial agents are increasingly entering our lives but how the human brain responds to these new, artificial social partners remains unclear. The Uncanny Valley hypothesis-an influential psychological framework-captures the observation that human responses to artificial agents are nonlinear: we like increasingly anthropomorphic artificial agents, but feel uncomfortable if they become too human-like. Here we investigated neural activity when humans evaluated artificial agents and made personal decisions about them. Our findings suggest a novel neurobiological conceptualization of human responses toward artificial agents: The Uncanny Valley reaction-a selective dislike of highly human-like agents-is based on nonlinear value-coding in VMPFC, a key component of the brain’s reward system.