Aging is associated with a modality-specific decline in taste.

Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders, including Alzheimer's disease (AD). The fruit fly, Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging and neurodegeneration on taste function remain largely unexplored. Aging impaired response to sugars, but not medium-chain fatty acids that are sensed by a shared population of neurons. Selective expression of the human amyloid beta (Aß) peptide phenocopied the effects of aging. Functional imaging of gustatory axon terminals revealed reduced response to sugar, but not fatty acids. Axonal innervation of the fly taste center was largely intact in aged flies; however, axonal innervation was reduced upon expression of Aß. A comparison of transcript expression within the sugar-sensing taste neurons revealed age-related changes in 66 genes. Together, these findings suggest that different mechanisms underly taste deficits in aged and AD model flies.

Reduction of cognitive fatigue and improved performance at a VR-based driving simulator using tRNS.

Cognitive fatigue (CF) increases accident risk reducing performance, especially during complex tasks such as driving. We evaluated whether transcranial random noise stimulation (tRNS) could mitigate CF and improve driving performance. In a double-blind study, thirty participants performed a virtual reality truck driving task during real (n = 15) or sham (n = 15) tRNS applied bilaterally on the "anti-fatigue network". They completed two 30-min driving sessions while their driving performances were constantly monitored; heart rate was also monitored to evaluate arousal (Root-Mean-Square of successive R-R difference). tRNS was applied only during the first driving session to evaluate both online and offline stimulation effects. The primary outcome was CF reduction and performance improvement in the second (non-stimulated) driving session. Real tRNS significantly improved driving performances in the second driving session and reduced perceived CF. These results might also lead to the use of tRNS in those neurological disorders characterized by fatigue.

Divergent input patterns to the central lateral amygdala play a duet in fear memory formation.

Somatostatin (SOM)-expressing neurons in the central lateral amygdala (CeL) are responsible for fear memory learning, but the circuit and molecular mechanisms underlying this biology remain elusive. Here, we found that glutamatergic neurons in the lateral parabrachial nucleus (LPB) directly dominated the activity of CeLSOM neurons, and that selectively inhibiting the LPBGlu→CeLSOM pathway suppressed fear memory acquisition. By contrast, inhibiting CeL-projecting glutamatergic neurons in the paraventricular thalamic nucleus (PVT) interfered with consolidation-related processes. Notably, CeLSOM-innervating neurons in the LPB were modulated by presynaptic cannabinoid receptor 1 (CB1R), and knock down of CB1Rs in LPB glutamatergic neurons enhanced excitatory transmission to the CeL and partially rescued the impairment in fear memory induced by CB1R activation in the CeL. Overall, our study reveals the mechanisms by which CeLSOM neurons mediate the formation of fear memories during fear conditioning in mice, which may provide a new direction for the clinical research of fear-related disorders.

Spike transmission failures in axons from cortical neurons in vivo.

The propagation of action potentials along axons is traditionally considered reliable due to the high safety factor for axonal spike transmission. However, numerical simulations suggest that high-frequency spikes could fail to invade distal axonal branches. To explore this experimentally in vivo, we used an axonal-targeted calcium indicator to image action potentials at axonal terminal branches in the superficial layers of mouse somatosensory cortical neurons. We activated axons with an extracellular electrode, varying stimulation frequencies, and analyzed the images to computationally extract axonal morphologies and associated calcium responses. We found that axonal boutons have higher calcium accumulations than their axonal shafts, as was reported in vitro. However, contrary to previous in vitro results, our data reveal spike failures at high spike frequencies in a significant subset of branches as a function of branching geometry. These findings suggest that axonal morphologies could contribute to signal processing in the cortex.

Noradrenaline modulates sensory information in mouse vomeronasal sensory neurons.

During the induction of the body's alert state, the sympathetic system modulates sensory modalities and fine-tunes peripheral organs for improved stimulus detection. We explored noradrenaline (NA)'s role in modulating signaling in vomeronasal sensory neurons (VSNs), responsible for detecting pheromones and other semiochemicals. In current-clamp recordings, NA increased the firing frequency in response to natural stimuli of responsive VSNs and induced spiking activity in previously unresponsive neurons. Current injections into VSNs showed an increase in firing frequency during NA application. Combining transcriptomic analysis, electrophysiology, Ca2+ imaging, and a pharmacological approach, we identified alpha 1 adrenergic receptors as crucial for NA-induced firing frequency increases in VSNs. Immunohistochemistry revealed catecholaminergic fibers in the vomeronasal sensory epithelium, suggesting localized NA release near VSNs. This study unveils NA as a key regulator of VSN signaling, shedding light on the intricate interplay between the sympathetic nervous system and chemosensory processing, advancing our understanding of sensory modulation.

Sensorimotor variability distinguishes early features of cognition in toddlers with autism.

The potential role of early sensorimotor features to atypical human cognition in autistic children has received surprisingly little attention given that appropriate movements are a crucial element that connects us to other people. We examined quantitative and observation-based movements in over 1,000 toddlers diagnosed with autism spectrum disorder (ASD) with different levels of cognitive abilities (intelligence quotient, IQ). Relative to higher-IQ ASD toddlers, those with lower-IQ had significantly altered sensorimotor features. Remarkably, we found that higher IQ in autistic toddlers confers resilience to atypical movement, as sensorimotor features in higher-IQ ASD children were indistinguishable from those of typically developing healthy control toddlers. We suggest that the altered movement patterns may affect key autistic behaviors in those with lower intelligence by affecting sensorimotor learning mechanisms. Atypical sensorimotor functioning is a key feature in lower-IQ early childhood autism. These findings have implications for the development of individualized interventions for subtypes of autism.

Illumination by short-wavelength light inside the blind spot decreases light detectability.

Although the optic disk corresponding to the blind spot contains no classical photoreceptors, it contains photopigment melanopsin. To clarify whether melanopsin is involved in light detection, we conducted detection tasks for light stimuli presented in the normal visual field, with and without another illumination inside the blind spot. We found that a blue blind-spot illumination decreased the light detectability on a dark background. This effect was replicable when it was determined immediately after the blind-spot illumination was turned off, suggesting the contribution of a sluggish system rather than scattering. Moreover, the aforementioned effect was not observed when the blind-spot illumination was in red, indicating wavelength specificity in favor of melanopsin's sensitivity profile. These findings suggest that melanopsin is activated by the blind-spot illumination and thereby interferes with light detection near the absolute threshold. Light detection originating from conventional photoreceptors is modulated by melanopsin-based computation presumably estimating a baseline noise level.

Specified functions of the first two fixations in face recognition: Sampling the general-to-specific facial information.

Visual perception is enacted and constrained by the constantly moving eyes. Although it is well known that the first two fixations are crucial for face recognition, the function of each fixation remains unspecified. Here we demonstrate a central-to-divergent pattern of the two fixations and specify their functions: Fix I clustered along the nose bridge to cover the broad facial information; Fix II diverged to eyes, nostrils, and lips to get the local information. Fix II correlated more than Fix I with the differentiating information between faces and contributed more to recognition responses. While face categories can be significantly discriminated by Fix II's but not Fix I's patterns alone, the combined patterns of the two yield better discrimination. Our results suggest a functional division and collaboration of the two fixations in sampling the general-to-specific facial information and add to understanding visual perception as an active process undertaken by structural motor programs.

High-dimensional encoding of movement by single neurons in basal ganglia output.

The substantia nigra pars reticulata (SNpr), an output structure of the basal ganglia, is hypothesized to gate movement execution. Previous studies in the eye movement system focusing mostly on saccades have reported that SNpr neurons are tonically active and either pause or increase their firing during movements, consistent with the gating role. We recorded activity in the SNpr of two monkeys during smooth pursuit and saccadic eye movements. SNpr neurons exhibited highly diverse reaction patterns during pursuit, including frequent increases and decreases in firing rate, uncorrelated responses in different movement directions and in reward conditions that resulted in the high dimensional activity of single neurons. These diverse temporal patterns surpassed those in other oculomotor areas in the medial-temporal cortex, frontal cortex, basal ganglia, and cerebellum. These findings suggest that temporal properties of the responses enrich the coding capacity of the basal ganglia output beyond gating or permitting movement.

Beyond the face: An interdisciplinary evaluation of satisfaction with appearance in young people with orofacial clefts.

Orofacial clefts are the most common congenital anomaly of the face, and they significantly affect appearance. The combined effects of demographics, psychology, neurophysiology, and cleft characteristics to explain satisfaction with appearance in young people with a cleft have not yet been comprehensively studied in an interdisciplinary manner. We found that interpersonal difficulties, age, and conscientiousness were significant explanatory factors for satisfaction with appearance (tinterpersonal difficulties = -3.022, p = 0.006; tage = -3.563, p = 0.016; tconscientiousness = 4.161, p = 0.003); the model explained 50% of variance in satisfaction with appearance (R2 Adjusted = 0.504, Fvs. constant = 4.05, p = 0.00117). Furthermore, frontal alpha asymmetry was complexly intertwined with other variables, affecting the overall accuracy of the model, but explaining only 10.5% of variance in satisfaction with appearance when used as a factor alone. The results show that an interdisciplinary approach can substantially expand our understanding of the factors influencing self-perception in young people with orofacial clefts.

Highly compromised auditory spatial perception in aided congenitally hearing-impaired and rapid improvement with tactile technology.

Spatial understanding is a multisensory construct while hearing is the only natural sense enabling the simultaneous perception of the entire 3D space. To test whether such spatial understanding is dependent on auditory experience, we study congenitally hearing-impaired users of assistive devices. We apply an in-house technology, which, inspired by the auditory system, performs intensity-weighting to represent external spatial positions and motion on the fingertips. We see highly impaired auditory spatial capabilities for tracking moving sources, which based on the "critical periods" theory emphasizes the role of nature in sensory development. Meanwhile, for tactile and audio-tactile spatial motion perception, the hearing-impaired show performance similar to typically hearing individuals. The immediate availability of 360° external space representation through touch, despite the lack of such experience during the lifetime, points to the significant role of nurture in spatial perception development, and to its amodal character. The findings show promise toward advancing multisensory solutions for rehabilitation.

Working memory expedites the processing of visual signals within the extrastriate cortex.

Working memory is the ability to maintain information in the absence of sensory input. In this study, we investigated how working memory benefits processing in visual areas. Using a measure of phase consistency to detect the arrival time of visual signals to the middle temporal (MT) area, we assessed the impact of working memory on the speed of sensory processing. We recorded from MT neurons in two monkeys during a spatial working memory task with visual probes. When the memorized location closely matches the receptive field center of the recording site, visual input arrives sooner, but if the memorized location does not match the receptive field center then the arrival of visual information is delayed. Thus, working memory expedites the arrival of visual input in MT. These results reveal that even in the absence of firing rate changes, working memory can still benefit the processing of information within sensory areas.

Coding of self and environment by Pacinian neurons in freely moving animals.

Pacinian corpuscle neurons are specialized low-threshold mechanoreceptors (LTMRs) that are tuned to detect high-frequency vibration (∼50-2,000 Hz); however, it is unclear how Pacinians and other LTMRs encode mechanical forces encountered during naturalistic behavior. Here, we developed methods to record LTMRs in awake, freely moving mice. We find that Pacinians, but not other LTMRs, encode subtle vibrations of surfaces encountered by the animal, including low-amplitude vibrations initiated over 2 m away. Strikingly, Pacinians are also highly active during a wide variety of natural behaviors, including walking, grooming, digging, and climbing. Pacinians in the hindlimb are sensitive enough to be activated by forelimb- or upper-body-dominant behaviors. Finally, we find that Pacinian LTMRs have diverse tuning and sensitivity. Our findings suggest a Pacinian population code for the representation of vibro-tactile features generated by self-initiated movements and low-amplitude environmental vibrations emanating from distant locations.

Linking cortical surface area to computational properties in human visual perception.

Cortical structure and function are closely linked, shaping the neural basis of human behavior. This study explores how cortical surface area (SA), a structural feature, influences computational properties in human visual perception. Using a combination of psychophysical, neuroimaging, and computational modeling approaches, we find that variations in SA across the parietal and frontal cortices are linked to distinct behavioral patterns in a motion perception task. These differences in behavior correspond to specific parameters within a divisive normalization model, indicating a unique contribution of SA to the spatial organization of cortical circuitry. This work highlights the importance of cortical architecture in modifying computational processes that underlie perception, enhancing our understanding of how structural differences can influence neural function and behavior.

Circuit-motivated generalized affine models characterize stimulus-dependent visual cortical shared variability.

Correlated variability in the visual cortex is modulated by stimulus properties. The stimulus dependence of correlated variability impacts stimulus coding and is indicative of circuit structure. An affine model combining a multiplicative factor and an additive offset has been proposed to explain how correlated variability in primary visual cortex (V1) depends on stimulus orientations. However, whether the affine model could be extended to explain modulations by other stimulus variables or variability shared between two brain areas is unknown. Motivated by a simple neural circuit mechanism, we modified the affine model to better explain the contrast dependence of neural variability shared within either primary or secondary visual cortex (V1 or V2) as well as the orientation dependence of neural variability shared between V1 and V2. Our results bridge neural circuit mechanisms and statistical models and provide a parsimonious explanation for the stimulus dependence of correlated variability within and between visual areas.

CCR3 knockdown attenuates prolonged underwater operations-induced cognitive impairment via alleviating microglia-mediated neuroinflammation.

Maintaining cognitive integrity is crucial during underwater operations, which can significantly impact work performance and risk severe accidents. However, the cognitive effects of underwater operations and their underlying mechanism remain elusive, posing great challenges to the medical protection of professionals concerned. Here, we found that a single underwater operation session affects cognition in a time-dependent model. Prolonged exposure elicits significant cognitive impairment and hippocampal dysfunction, accompanied by increased neuroinflammation. Furthermore, RNA sequencing (RNA-seq) analysis revealed the involvement of neuroinflammation and highlighted the critical role of CCR3. Knockdown of CCR3 significantly rescued cognitive impairment and hippocampal dysfunction and reversed the upregulation of pro-inflammatory cytokines, by switching the activated microglia from a pro-inflammatory to a neuroprotective phenotype. Taken together, these results highlighted the time-dependent effects of a single underwater operation session on cognitive function. Knocking down CCR3 can attenuate neuroinflammation by regulating polarization of activated microglia, thereby alleviating prolonged underwater operations-induced cognitive impairment.

Homeostasis of mRNA concentrations through coupling transcription, export, and degradation.

Many experiments showed that eukaryotic cells maintain a constant mRNA concentration upon various perturbations by actively regulating mRNA production and degradation rates, known as mRNA buffering. However, the underlying mechanism is still unknown. In this work, we unveil a mechanistic model of mRNA buffering: the releasing-shuttling (RS) model. The model incorporates two crucial proteins, X and Y, which play several roles, including transcription, decay, and export factors, in the different stages of mRNA metabolism. The RS model predicts the constant mRNA concentration under genome-wide genetic perturbations and cell volume changes, the slowed-down mRNA degradation after Pol II depletion, and the temporal transcription dynamics after exonuclease depletion, in agreement with multiple experiments. Finally, we present a list of X and Y candidates and propose an experimental method to identify X. Our work uncovers potentially universal pathways coupling transcription, export, and degradation that help cells maintain mRNA homeostasis.

Perceptual awareness of near-threshold tones scales gradually with auditory cortex activity and pupil dilation.

Negative-going responses in sensory cortex co-vary with perceptual awareness of sensory stimuli. Given that this awareness negativity has also been observed for undetected stimuli, some have challenged its role for perception. To address this question, we combined magnetoencephalography, electroencephalography, and pupillometry to study how sustained attention and response criterion affect the auditory awareness negativity. Participants first detected distractor sounds and denied hearing task-irrelevant near-threshold tones, which evoked neither awareness negativity nor pupil dilation. These same tones evoked both responses when task-relevant, stronger for hit but also present for miss trials. Participants then rated their perception on a six-point scale to test whether response criterion explains the presence of these responses for miss trials. Decreasing perception ratings were associated with gradually reduced evoked responses, consistent with signal detection theory. These results support the concept of an awareness negativity that is modulated by attention but does not require a non-linear threshold mechanism.

Distinct role of central predictive mechanisms in tactile suppression.

Tactile sensitivity on a limb is reduced during movement. This tactile suppression results presumably from central predictive mechanisms that downregulate sensations caused during voluntary action. Suppression also occurs during passive movements, indicating a role for peripheral mechanisms, questioning the predictive nature of suppression. Yet, predictions existing beyond the motor domain (non-motor predictions) can also modulate tactile suppression. This study aimed to disentangle central motor predictive and peripheral feedback mechanisms while accounting for non-motor predictions. Participants detected tactile stimuli on their limb shortly before it moved in an active or passive manner. Passive movements were either fully (100%) or partially (50%) predictable. We found tactile suppression during both active and passive movements irrespective of whether the passive movements were predictable. Importantly, tactile suppression was stronger in active than passive movements highlighting the specific role of central predictive mechanisms.

Oleic acid released by sensory neurons inhibits TRPV1-mediated thermal hypersensitivity via GPR40.

Noxious stimuli activate nociceptive sensory neurons, causing action potential firing and the release of diverse signaling molecules. Several peptides have already been identified to be released by sensory neurons and shown to modulate inflammatory responses and inflammatory pain. However, it is still unclear whether lipid mediators can be released upon sensory neuron activation to modulate intercellular communication. Here, we analyzed the lipid secretome of capsaicin-stimulated nociceptive neurons with LC-HRMS, revealing that oleic acid is strongly released from sensory neurons by capsaicin. We further demonstrated that oleic acid inhibits capsaicin-induced calcium transients in sensory neurons and reverses bradykinin-induced TRPV1 sensitization by a calcineurin (CaN) and GPR40 (FFAR1) dependent pathway. Additionally, oleic acid alleviated zymosan-mediated thermal hypersensitivity via the GPR40, suggesting that the capsaicin-mediated oleic acid release from sensory neurons acts as a protective and feedback mechanism, preventing sensory neurons from nociceptive overstimulation via the GPR40/CaN/TRPV1-axis.