The 50 most-cited articles in Journal of Neuroscience, 2023

The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum's broader contributions to cognitive, emotional, and reward processes. The cerebellum's influence on autonomic function further highlights its significance in regulating motivational and emotional states. Perturbations in cerebellar development and function have been implicated in various neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. An increasing appreciation for neuropsychiatric symptoms that arise from cerebellar dysfunction underscores the importance of elucidating the circuit mechanisms that underlie complex interactions between the cerebellum and other brain regions for a comprehensive understanding of complex behavior. By briefly discussing new advances in mapping cerebellar function in affective, cognitive, autonomic, and social processing and reviewing the role of the cerebellum in neuropathology…

Ketamine is a well-characterized NMDA receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a sustained expression of increased synaptic strength. We tested the hypothesis that induction of rapid antidepressant effects requires NMDAR activation, by using behavioral pharmacology, western blot quantification of hippocampal synaptoneurosomal protein levels, and ex vivo hippocampal slice electrophysiology in male mice. We found that ketamine exerts an inverted U-shaped dose-response in antidepressant-sensitive behavioral tests, suggesting that an excessive NMDAR inhibition can prevent ketamine's antidepressant effects. Ketamine's actions to induce antidepressant-like behavioral effects, up-regulation of hippocampal AMPAR subunits GluA1 and GluA2, as well as metaplasticity measured ex vivo using…

The brain is a complex system comprising a myriad of interacting elements, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such intricate systems, offering a framework for integrating multiscale data and complexity. Here, we discuss the application of network science in the study of the brain, addressing topics such as network models and metrics, the connectome, and the role of dynamics in neural networks. We explore the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease, and discuss the potential for collaboration between network science and neuroscience communities. We underscore the importance of fostering interdisciplinary opportunities through funding initiatives, workshops, and conferences, as well as supporting students and postdoctoral fellows with interests in both disciplines. By uniting the network science and neuroscience communities, we can develop novel network-based…

The purpose of our study was to identify the low-dimensional latent components, defined hereafter as motor unit modes, underlying the discharge rates of the motor units in two knee extensors (vastus medialis and lateralis, eight men) and two hand muscles (first dorsal interossei and thenars, seven men and one woman) during submaximal isometric contractions. Factor analysis identified two independent motor unit modes that captured most of the covariance of the motor unit discharge rates. We found divergent distributions of the motor unit modes for the hand and vastii muscles. On average, 75% of the motor units for the thenar muscles and first dorsal interosseus were strongly correlated with the module for the muscle in which they resided. In contrast, we found a continuous distribution of motor unit modes spanning the two vastii muscle modules. The proportion of the muscle-specific motor unit modes was 60% for vastus medialis and 45% for vastus lateralis. The other motor units were either correlated with both muscle modules (shared inputs) or belonged to the module for the other…

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2Areceptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2Areceptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1Aand 5-HT2Creceptors, and with…

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Abstract Visual attention is highly influenced by past experiences. Recent behavioral research has shown that expectations about the spatial location of distractors within a search array are implicitly learned, with expected distractors becoming less interfering. Little is known about the neural mechanism supporting this form of statistical learning. Here we used magnetoencephalography (MEG) to measure human brain activity to test whether proactive mechanisms are involved in the statistical learning of distractor locations. Specifically, we used a new technique called rapid invisible frequency tagging (RIFT) to assess neural excitability in early visual cortex during statistical learning of distractor suppression, while concurrently investigating the modulation of posterior alpha-band activity (8-12 Hz). Male and female human participants performed a visual search task in which a target was occasionally presented alongside a color-singleton distractor. Unbeknown to the participants, the distracting stimuli were presented with different probabilities across the two hemifields. RIFT…

Alzheimer’s disease (AD) is a neurodegenerative disorder with poorly understood etiology. AD has several similarities with other “Western lifestyle” inflammatory diseases, where the gut microbiome and immune pathways have been associated. Previously, we and others have noted the involvement of metabolite-sensing GPCRs and their ligands, short-chain fatty acids (SCFAs), in protection of numerous Western diseases in mouse models, such as Type I diabetes and hypertension. Depletion of GPR43, GPR41, or GPR109A accelerates disease, whereas high SCFA yielding diets protect in mouse models. Here, we extended the concept that metabolite-sensing receptors and SCFAs may be a more common protective mechanism against Western diseases by studying their role in AD pathogenesis in the 5xFAD mouse model. Both male and female mice were included. Depletion of GPR41 and GPR43 accelerated cognitive decline and impaired adult hippocampal neurogenesis in 5xFAD and WT mice. Lack of fiber/SCFAs accelerated a memory deficit, whereas diets supplemented with high acetate and butyrate (HAMSAB) delayed…

Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer's disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 AD and non-AD donors each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimer's brain endothelial cells were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid beta plaques and cerebral amyloid angiopathy (CAA). This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain. Significance Statement: In this work, we show that vascular endothelial cells collected from five different brain regions display surprising variability…

A clear understanding of the neural circuit underlying emotion regulation (ER) is important for both basic and translational research. However, a lack of evidence based on combined neuroimaging and neuromodulation techniques calls into question (1) whether the change of prefrontal-subcortical activity intrinsically and causally contributes to the ER effect; and (2) whether the prefrontal control system directly modulates the subcortical affective system. Accordingly, we combined fMRI recordings with transcranial magnetic stimulation (TMS) to map the causal connections between the PFC and subcortical affective structures (amygdala and insula). A total of 117 human adult participants (57 males and 60 females) were included in the study. The results revealed that TMS-induced ventrolateral PFC (VLPFC) facilitation led to enhanced activity in the VLPFC and ventromedial PFC (VMPFC) as well as attenuated activity in the amygdala and insula during reappraisal but not during nonreappraisal (i.e., baseline). Moreover, the activated VLPFC intensified the prefrontal-subcortical couplings via…

Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic connections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of macrophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 in CX 3 CR1 GFP /+ mice of both sexes led to robust elimination of resident macrophages (∼94%) without significant adverse effects on peripheral leukocytes, cochlear function, and structure. At 1 day (d) post noise exposure of 93 or 90 dB SPL for 2 hours, the degree of hearing loss and synapse loss were comparable in the presence and absence of macrophages. At 30 d after exposure, damaged synapses appeared repaired in the presence of macrophages. However, in the absence of macrophages, such synaptic repair was significantly reduced. Remarkably, on cessation of PLX5622 treatment, macrophages repopulated the…

Parental input is considered a key predictor of language achievement during the first years of life, yet relatively few studies have assessed the effects of parental language input and parent–infant interactions on early brain development. We examined the relationship between measures of parent and child language, obtained from naturalistic home recordings at child ages 6, 10, 14, 18, and 24 months, and estimates of white matter myelination, derived from quantitative MRI at age 2 years (mean = 26.30 months, SD = 1.62, N = 22). Analysis of the white matter focused on dorsal pathways associated with expressive language development and long-term language ability, namely, the left arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF). Frequency of parent–infant conversational turns (CT) uniquely predicted myelin density estimates in both the AF and SLF. Moreover, the effect of CT remained significant while controlling for total adult speech and child speech-related utterances, suggesting a specific role for interactive language experience, rather than simply speech exposure…

Long overlooked in neuroscience research, sex and gender are increasingly included as key variables potentially impacting all levels of neurobehavioral analysis. Still, many neuroscientists do not understand the difference between the terms "sex" and "gender," the complexity and nuance of each, or how to best include them as variables in research designs. This TechSights article outlines rationales for considering the influence of sex and gender across taxa, and provides technical guidance for strengthening the rigor and reproducibility of such analyses. This guidance includes the use of appropriate statistical methods for comparing groups as well as controls for key covariates of sex (e.g., total intracranial volume) and gender (e.g., income, caregiver stress, bias). We also recommend approaches for interpreting and communicating sex- and gender-related findings about the brain, which have often been misconstrued by neuroscientists and the lay public alike.

Healthy brain dynamics can be understood as the emergence of a complex system far from thermodynamic equilibrium. Brain dynamics are temporally irreversible and thus establish a preferred direction in time (i.e., arrow of time). However, little is known about how the time-reversal symmetry of spontaneous brain activity is affected by Alzheimer's disease (AD). We hypothesized that the level of irreversibility would be compromised in AD, signaling a fundamental shift in the collective properties of brain activity toward equilibrium dynamics. We investigated the irreversibility from resting-state fMRI and EEG data in male and female human patients with AD and elderly healthy control subjects (HCs). We quantified the level of irreversibility and, thus, proximity to nonequilibrium dynamics by comparing forward and backward time series through time-shifted correlations. AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels, and at multiple oscillatory frequency bands. At the local level, temporoparietal and frontal regions were affected by…

Rapid detection of a threat or its symbol (e.g., fearful face), whether visible or invisible, is critical for human survival. This function is suggested to be enabled by a subcortical pathway to the amygdala independent of the cortex. However, conclusive electrophysiological evidence in humans is scarce. Here, we explored whether the amygdala can rapidly encode invisible fearful faces. We recorded intracranial electroencephalogram (iEEG) responses in the human (both sexes) amygdala to faces with fearful, happy, and neutral emotions rendered invisible by backward masking. We found that a short-latency intracranial event-related potential (iERP) in the amygdala, beginning 88 ms poststimulus onset, was preferentially evoked by invisible fearful faces relative to invisible happy or neutral faces. The rapid iERP exhibited selectivity to the low spatial frequency (LSF) component of the fearful faces. Time-frequency iEEG analyses further identified a rapid amygdala response preferentially for LSF fearful faces at the low gamma frequency band, beginning 45 ms poststimulus onset. In…

Age-related hearing loss, or presbyacusis, is a common degenerative disorder affecting communication and quality of life for millions of older adults. Multiple pathophysiologic manifestations, along with many cellular and molecular alterations, have been linked to presbyacusis, however, the initial events and causal factors have not been clearly established. Comparisons of the transcriptome in the lateral wall with other cochlear regions in a mouse model of “normal” age-related hearing loss revealed that early pathophysiological alterations in the stria vascularis are associated with increased macrophage activation and a molecular signature indicative of inflammaging, a common form of immune dysfunction. Structure-function correlation analyses in mice across the lifespan showed that the age-dependent increase in macrophage activation in the stria vascularis is associated with a decline in auditory sensitivity. High-resolution imaging analysis of macrophage activation in middle-aged and aged mouse and human cochleas, along with transcriptomic analysis of age-dependent changes in…

The amplitude envelope of speech is crucial for accurate comprehension. Considered a key stage in speech processing, the phase of neural activity in the theta-delta bands (1-10 Hz) tracks the phase of the speech amplitude envelope during listening. However, the mechanisms underlying this envelope representation have been heavily debated. A dominant model posits that envelope tracking reflects entrainment of endogenous low-frequency oscillations to the speech envelope. Alternatively, envelope tracking reflects a series of evoked responses to acoustic landmarks within the envelope. It has proven challenging to distinguish these two mechanisms. To address this, we recorded MEG while participants ( n = 12, 6 female) listened to natural speech, and compared the neural phase patterns to the predictions of two computational models: an oscillatory entrainment model and a model of evoked responses to peaks in the rate of envelope change. Critically, we also presented speech at slowed rates, where the spectro-temporal predictions of the two models diverge. Our analyses revealed transient…

The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic loss in AD, how neurons compensate for this loss and whether this provides cognitive benefits remain almost completely unexplored. In this review, we describe two potential compensatory mechanisms implemented following synaptic loss: the enlargement of the surviving neighboring synapses and the regeneration of synapses. Because dendritic spines, the postsynaptic site of excitatory synapses, are easily visualized using light microscopy, we focus on a range of microscopy approaches to monitor synaptic loss and compensation. Here, we stress the importance of longitudinal dendritic spine imaging, as opposed to fixed-tissue imaging, to gain insights into the temporal dynamics of dendritic spine compensation. We believe that understanding the molecular mechanisms behind these and other forms of synaptic compensation and regeneration will be critical for the development of therapeutics aiming at delaying the onset of…

Abstract To understand how the brain produces behavior, we must elucidate the relationships between neuronal connectivity and function. The medial prefrontal cortex (mPFC) is critical for complex functions including decision-making and mood. mPFC projection neurons collateralize extensively, but the relationships between mPFC neuronal activity and brain-wide connectivity are poorly understood. We performed whole-brain connectivity mapping and fiber photometry to better understand the mPFC circuits that control threat avoidance. Using tissue clearing and light sheet fluorescence microscopy we mapped the brain-wide axon collaterals of populations of mPFC neurons that project to nucleus accumbens (NAc), ventral tegmental area (VTA), or contralateral mPFC (cmPFC) in mice. We present DeepTraCE, for quantifying bulk-labeled axonal projections in images of cleared tissue, and DeepCOUNT, for quantifying cell bodies. Anatomical maps produced with DeepTraCE aligned with known axonal projection patterns and revealed class-specific topographic projections within regions. During threat…

Microglia, the resident immune cells of the CNS, sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically used noninvasive brain stimulation technique, on microglia-mediated synaptic plasticity; 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from microglia in mouse organotypic brain tissue cultures of both sexes, while no significant changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor α (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings,in vivodepletion of microglia abolished rTMS-induced…

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased…

Abstract The meaning of words in natural language depends crucially on context. However, most neuroimaging studies of word meaning use isolated words and isolated sentences with little context. Because the brain may process natural language differently from how it processes simplified stimuli, there is a pressing need to determine whether prior results on word meaning generalize to natural language. fMRI was used to record human brain activity while four subjects (two female) read words in four conditions that vary in context: narratives, isolated sentences, blocks of semantically similar words, and isolated words. We then compared the signal-to-noise ratio (SNR) of evoked brain responses, and we used a voxelwise encoding modeling approach to compare the representation of semantic information across the four conditions. We find four consistent effects of varying context. First, stimuli with more context evoke brain responses with higher SNR across bilateral visual, temporal, parietal, and prefrontal cortices compared to stimuli with little context. Second, increasing context…

Stroke is one of the most common causes of disability, and there are few treatments that can improve recovery after stroke. Therapeutic development has been hindered because of a lack of understanding of precisely how neural circuits are affected by stroke, and how these circuits change to mediate recovery. Indeed, some of the hypotheses for how the CNS changes to mediate recovery, including remapping, redundancy, and diaschisis, date to more than a century ago. Recent technological advances have enabled the interrogation of neural circuits with ever greater temporal and spatial resolution. These techniques are increasingly being applied across animal models of stroke and to human stroke survivors, and are shedding light on the molecular, structural, and functional changes that neural circuits undergo after stroke. Here we review these studies and highlight important mechanisms that underlie impairment and recovery after stroke. We begin by summarizing knowledge about changes in neural activity that occur in the peri-infarct cortex, specifically considering evidence for the…

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Dopamine is a key neurotransmitter in the signaling cascade controlling ocular refractive development, but the exact role and site of action of dopamine D1 receptors (D1Rs) involved in myopia remains unclear. Here, we determine whether retinal D1Rs exclusively mediate the effects of endogenous dopamine and systemically delivered D1R agonist or antagonist in the mouse form deprivation myopia (FDM) model. Male C57BL/6 mice subjected to unilateral FDM or unobstructed vision were divided into the following four groups: one noninjected and three groups that received intraperitoneal injections of a vehicle, D1R agonist SKF38393 (18 and 59 nmol/g), or D1R antagonist SCH39166 (0.1 and 1 nmol/g). The effects of these drugs on FDM were further assessed in Drd1 -knock-out ( Drd1 -KO), retina-specific conditional Drd1 -KO ( Drd1 -CKO) mice, and corresponding wild-type littermates. In the visually unobstructed group, neither SKF38393 nor SCH39166 affected normal refractive development, whereas myopia development was attenuated by SKF38393 and enhanced by SCH39166 injections. In Drd1 -KO or Drd1…

A growing number of social interactions are taking place virtually on videoconferencing platforms. Here, we explore potential effects of virtual interactions on observed behavior, subjective experience, and neural “single-brain” and “interbrain” activity via functional near-infrared spectroscopy neuroimaging. We scanned a total of 36 human dyads (72 participants, 36 males, 36 females) who engaged in three naturalistic tasks (i.e., problem-solving, creative-innovation, socio-emotional task) in either an in-person or virtual (Zoom) condition. We also coded cooperative behavior from audio recordings. We observed reduced conversational turn-taking behavior during the virtual condition. Given that conversational turn-taking was associated with other metrics of positive social interaction (e.g., subjective cooperation and task performance), this measure may be an indicator of prosocial interaction. In addition, we observed altered patterns of averaged and dynamic interbrain coherence in virtual interactions. Interbrain coherence patterns that were characteristic of the virtual condition…

Scientists have long conjectured that the neocortex learns patterns in sensory data to generate top-down predictions of upcoming stimuli. In line with this conjecture, different responses to pattern-matching vs pattern-violating visual stimuli have been observed in both spiking and somatic calcium imaging data. However, it remains unknown whether these pattern-violation signals are different between the distal apical dendrites, which are heavily targeted by top-down signals, and the somata, where bottom-up information is primarily integrated. Furthermore, it is unknown how responses to pattern-violating stimuli evolve over time as an animal gains more experience with them. Here, we address these unanswered questions by analyzing responses of individual somata and dendritic branches of layer 2/3 and layer 5 pyramidal neurons tracked over multiple days in primary visual cortex of awake, behaving female and male mice. We use sequences of Gabor patches with patterns in their orientations to create pattern-matching and pattern-violating stimuli, and two-photon calcium imaging to record…

The auditory steady-state response (ASSR) is a cortical oscillation induced by trains of 40 Hz acoustic stimuli. While the ASSR has been widely used in clinic measurement, the underlying neural mechanism remains poorly understood. In this study, we investigated the contribution of different stages of auditory thalamocortical pathwaymedial geniculate body (MGB), thalamic reticular nucleus (TRN), and auditory cortex (AC)to the generation and regulation of 40 Hz ASSR in C57BL/6 mice of both sexes. We found that the neural response synchronizing to 40 Hz sound stimuli was most prominent in the GABAergic neurons in the granular layer of AC and the ventral division of MGB (MGBv), which were regulated by optogenetic manipulation of TRN neurons. Behavioral experiments confirmed that disrupting TRN activity has a detrimental effect on the ability of mice to discriminate 40 Hz sounds. These findings revealed a thalamocortical mechanism helpful to interpret the results of clinical ASSR examinations. Significance Statement Our study contributes to clarifying the thalamocortical mechanisms…

Individual differences in delay discounting—how much we discount future compared to immediate rewards—are associated with general life outcomes, psychopathology, and obesity. Here, we use machine learning on fMRI activity during an intertemporal choice task to develop a functional brain marker of these individual differences in human adults. Training and cross-validating the marker in one dataset (Study 1,N = 110 male adults) resulted in a significant prediction–outcome correlation (r = 0.49), generalized to predict individual differences in a completely independent dataset (Study 2:N = 145 male and female adults,r = 0.45), and predicted discounting several weeks later. Out-of-sample responses of the functional brain marker, but not discounting behavior itself, differed significantly between overweight and lean individuals in both studies, and predicted fasting-state blood levels of insulin, c-peptide, and leptin in Study 1. Significant predictive weights of the marker were found in cingulate, insula, and frontoparietal areas, among others, suggesting an interplay among regions…

The human visual cortex processes light and dark stimuli with ON and OFF pathways that are differently modulated by luminance contrast. We have previously demonstrated that ON cortical pathways have higher contrast sensitivity than OFF cortical pathways and the difference increases with luminance range (defined as the maximum minus minimum luminance in the scene). Here, we demonstrate that these ON-OFF cortical differences are already present in the human retina and that retinal responses measured with electroretinography are more affected by reductions in luminance range than cortical responses measured with electroencephalography. Moreover, we show that ON-OFF pathway differences measured with electroretinography become more pronounced in myopia, a visual disorder that elongates the eye and blurs vision at far distance. We find that, as the eye axial length increases across subjects, ON retinal pathways become less responsive, slower in response latency, less sensitive, and less effective and slower at driving pupil constriction. Based on these results, we conclude that myopia is…

The ability to extract rhythmic structure is important for the development of language, music, and social communication. Although previous studies show infants' brains entrain to the periodicities of auditory rhythms and even different metrical interpretations (e.g., groups of two vs three beats) of ambiguous rhythms, whether the premature brain tracks beat and meter frequencies has not been explored previously. We used high-resolution electroencephalography while premature infants ( n = 19, 5 male; mean age, 32 ± 2.59 weeks gestational age) heard two auditory rhythms in the incubators. We observed selective enhancement of the neural response at both beat- and meter-related frequencies. Further, neural oscillations at the beat and duple (groups of 2) meter were phase aligned with the envelope of the auditory rhythmic stimuli. Comparing the relative power at beat and meter frequencies across stimuli and frequency revealed evidence for selective enhancement of duple meter. This suggests that even at this early stage of development, neural mechanisms for processing auditory rhythms…

Stress has profound effects on fear extinction, a form of learning that is essential to behavioral therapies for trauma-related and stressor-related disorders. Recent work reveals that acute footshock stress reduces medial prefrontal cortex (mPFC) activity that is critical for extinction learning. Reductions in mPFC activity may be mediated by parvalbumin (PV)-containing interneurons via feedforward inhibition imposed by amygdala afferents. To test this hypothesis, footshock stress-induced Fos expression was characterized in PV+and PV–neurons in the prelimbic (PL) and infralimbic (IL) cortices. Footshock stress increased the proportion of PV+cells expressing Fos in both male and female rats; this effect was more pronounced in IL compared with PL. To determine whether PV+interneurons in the mPFC mediate stress-induced extinction impairments, we chemogenetically silenced these neurons before an immediate extinction procedure in PV-Cre rats. Clozapine-N-oxide (CNO) did not affect conditioned freezing during the extinction procedure. However, CNO exacerbated extinction retrieval in both…

Alzheimer's disease (AD) is associated with changes in large-scale functional brain network organization. Individuals with AD exhibit less segregated resting-state brain networks compared with individuals without dementia. However, declines in brain network segregation are also evident as adult individuals grow older. Determining whether these observations reflect unique or overlapping alterations on the functional connectome of the brain is essential for understanding the impact of AD on network organization and incorporating measures of functional brain network organization toward AD characterization. Relationships between AD dementia severity and participant's age on resting-state brain system segregation were examined in 326 cognitively healthy and 275 cognitively impaired human individuals recruited through the Alzheimer's Disease Neuroimaging Initiative (ADNI) ( N = 601; age range, 55–96 years; 320 females). Greater dementia severity and increasing age were independently associated with lower brain system segregation. Further, dementia versus age relationships with brain…

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2chemoreception). We then studiedScn1aR1407X/+(Dravet syndrome; DS) andScn8aN1768D/+(D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT withpara-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice.…

Abstract Beta activity is thought to play a critical role in sensorimotor processes. However, little is known about how activity in this frequency band develops. Here, we investigated the developmental trajectory of sensorimotor beta activity from infancy to adulthood. We recorded electroencephalography (EEG) from adults, 12-month-olds, and 9-month-olds while they observed and executed grasping movements. We analysed ‘beta burst’ activity using a novel method that combines time-frequency decomposition and principal component analysis (PCA). We then examined the changes in burst rate and waveform motifs along the selected principal components. Our results reveal systematic changes in beta activity during action execution across development. We found a decrease in beta burst rate during movement execution in all age groups, with the greatest decrease observed in adults. Additionally, we identified four principal components that defined waveform motifs that systematically changed throughout the trial. We found that bursts with waveform shapes closer to the median waveform were not…

Abstract Comparing expectation with experience is an important neural computation performed throughout the brain and is a hallmark of predictive processing. Experiments that alter the sensory outcome of an animal’s behavior reveal enhanced neural responses to unexpected self-generated stimuli, indicating that populations of neurons in sensory cortex may reflect prediction errors – mismatches between expectation and experience. However, enhanced neural responses to self-generated stimuli could also arise through non-predictive mechanisms, such as the movement-based facilitation of a neuron’s inherent sound responses. If sensory prediction error neurons exist in sensory cortex, it is unknown whether they manifest as general error responses, or respond with specificity to errors in distinct stimulus dimensions. To answer these questions, we trained mice to expect the outcome of a simple sound-generating behavior and recorded auditory cortex activity as mice heard either the expected sound or sounds that deviated from expectation in one of multiple distinct dimensions. Our data reveal…

Aging is a significant risk factor associated with the progression of CNS neurodegenerative diseases including multiple sclerosis (MS). Microglia, the resident macrophages of the CNS parenchyma, are a major population of immune cells that accumulate in MS lesions. While they normally regulate tissue homeostasis and facilitate the clearance of neurotoxic molecules including oxidized phosphatidylcholines (OxPCs), their transcriptome and neuroprotective functions are reprogrammed by aging. Thus, determining the factors that instigate aging associated microglia dysfunction can lead to new insights for promoting CNS repair and for halting MS disease progression. Through single-cell RNA sequencing (scRNAseq), we identifiedLgals3, which encodes for galectin-3 (Gal3), as an age upregulated gene by microglia responding to OxPC. Consistently, excess Gal3 accumulated in OxPC and lysolecithin-induced focal spinal cord white matter (SCWM) lesions of middle-aged mice compared with young mice. Gal3 was also elevated in mouse experimental autoimmune encephalomyelitis (EAE) lesions and more…

RNA N4-acetylcytidine (ac4C) modification is increasingly recognized as an important layer of gene regulation; however, the involvement of ac4C in pain regulation has not been studied. Here, we report that N-acetyltransferase 10 protein (NAT10; the only known ac4C “writer”) contributes to the induction and development of neuropathic pain in an ac4C-dependent manner. Peripheral nerve injury increases the levels of NAT10 expression and overall ac4C in injured dorsal root ganglia (DRGs). This upregulation is triggered by the activation of upstream transcription factor 1 (USF1), a transcription factor that binds to theNat10promoter. Knock-down or genetic deletion of NAT10 in the DRG abolishes the gain of ac4C sites inSyt9mRNA and the augmentation of SYT9 protein, resulting in a marked antinociceptive effect in nerve-injured male mice. Conversely, mimicking NAT10 upregulation in the absence of injury evokes the elevation ofSyt9ac4C and SYT9 protein and induces the genesis of neuropathic-pain-like behaviors. These findings demonstrate that USF1-governed NAT10 regulates neuropathic pain by…

Abstract Listening in noisy environments requires effort – the active engagement of attention and other cognitive abilities, as well as increased arousal. The ability to separately quantify the contribution of these components is key to understanding the dynamics of effort and how it may change across listening situations and in certain populations. We concurrently measured two types of ocular data in young participants (both sexes) - Pupil dilation (PD) (thought to index arousal aspects of effort) and Microsaccades (MS) (hypothesized to reflect automatic visual exploratory sampling) whilst listeners were performing a speech-in-noise task under high- (HL) and low-(LL) perceptual load conditions. Sentences were manipulated so that the behaviourally relevant information (keywords) appeared at the end (Exp1) or beginning (Exp2) of the sentence, resulting in different temporal demands on focused attention. In line with previous reports, PD effects were associated with increased dilation under load. We observed a sustained difference between HL and LL conditions, consistent with…

Behavioral consequences and neural underpinnings of visuospatial attention have long been investigated. Classical studies using the Posner paradigm have found that visual perception systematically benefits from the use of a spatially informative cue pointing to the to-be-attended spatial location, compared with a noninformative cue. Lateralized α amplitude modulation during visuospatial attention shifts has been suggested to account for such perceptual gain. However, recent studies on spontaneous fluctuations of prestimulus α amplitude have challenged this notion. These studies showed that spontaneous fluctuations of prestimulus α amplitude were associated with the subjective appreciation of stimulus occurrence, while objective accuracy was instead best predicted by the frequency of α oscillations, with faster prestimulus α frequency accounting for better perceptual performance. Here, in male and female humans, by using an informative cue in anticipation of lateralized stimulus presentation, we found that the predictive cue not only modulates preparatory α amplitude but also α…

Abstract To fluidly engage with the world, our brains must simultaneously represent both the scene in front of us and our memory of the immediate surrounding environment (i.e., local visuospatial context). How does the brain’s functional architecture enable sensory and mnemonic representations to closely interface, while also avoiding sensory-mnemonic interference? Here, we asked this question using first-person, head-mounted virtual reality (VR) and fMRI. Using VR, human participants of both sexes learned a set of immersive, real-world visuospatial environments in which we systematically manipulated the extent of visuospatial context associated with a scene image in memory across three learning conditions, spanning from a single field-of-view to a city street. We used individualized, within-subject fMRI to determine which brain areas support memory of the visuospatial context associated with a scene during recall (Exp. 1) and recognition (Exp. 2). Across the whole brain, activity in three patches of cortex was modulated by the amount of known visuospatial context, each located…

Aberrant activation of presynaptic NMDARs in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms responsible for opioid-induced NMDAR hyperactivity remain poorly identified. Here, we show that repeated treatment with morphine or fentanyl reduced monomeric mGluR5 protein levels in the dorsal root ganglion (DRG) but increased levels of mGluR5 monomers and homodimers in the spinal cord in mice and rats of both sexes. Coimmunoprecipitation analysis revealed that monomeric and dimeric mGluR5 in the spinal cord, but not monomeric mGluR5 in the DRG, directly interacted with GluN1. By contrast, mGluR5 did not interact with μ-opioid receptors in the DRG or spinal cord. Repeated morphine treatment markedly increased the mGluR5-GluN1 interaction and protein levels of mGluR5 and GluN1 in spinal synaptosomes. The mGluR5 antagonist MPEP reversed morphine treatment-augmented mGluR5-GluN1 interactions, GluN1 synaptic expression, and dorsal root-evoked monosynaptic EPSCs of dorsal horn neurons. Furthermore, CRISPR-Cas9–induced…

Abstract Astrocytes are key cellular regulators within the brain. The basolateral amygdala (BLA) is implicated in fear memory processing, yet most research has entirely focused on neuronal mechanisms, despite a significant body of work implicating astrocytes in learning and memory. In the present study, we used in vivo fiber photometry to record from amygdalar astrocytes across fear learning, recall, and three separate periods of extinction. We found that BLA astrocytes robustly responded to foot shock during acquisition, that their activity remained remarkably elevated across days in comparison to unshocked control animals, and that their increased activity persisted throughout extinction. Further, we found that astrocytes responded to the initiation and termination of freezing bouts during contextual fear conditioning and recall, and this behavior-locked pattern of activity did not persist throughout the extinction sessions. Importantly, astrocytes do not display these changes while exploring a novel context, suggesting that these observations are context or memory-dependent.…

To understand language, we need to recognize words and combine them into phrases and sentences. During this process, responses to the words themselves are changed. In a step toward understanding how the brain builds sentence structure, the present study concerns the neural readout of this adaptation. We ask whether low-frequency neural readouts associated with words change as a function of being in a sentence. To this end, we analyzed an MEG dataset by Schoffelen et al. (2019) of 102 human participants (51 women) listening to sentences and word lists, the latter lacking any syntactic structure and combinatorial meaning. Using temporal response functions and a cumulative model-fitting approach, we disentangled delta- and theta-band responses to lexical information (word frequency), from responses to sensory and distributional variables. The results suggest that delta-band responses to words are affected by sentence context in time and space, over and above entropy and surprisal. In both conditions, the word frequency response spanned left temporal and posterior frontal areas;…

Abstract Thermoregulatory behavior in homeothermic animals is an innate behavior to defend body core temperature from environmental thermal challenges in coordination with autonomous thermoregulatory responses. In contrast to the progress in understanding the central mechanisms of autonomous thermoregulation, those of behavioral thermoregulation remain poorly understood. We have previously shown that the lateral parabrachial nucleus (LPB) mediates cutaneous thermosensory afferent signaling for thermoregulation. To understand the thermosensory neural network for behavioral thermoregulation, in the present study, we investigated the roles of ascending thermosensory pathways from the LPB in avoidance behavior from innocuous heat and cold in rats. Neuronal tracing revealed two segregated groups of LPB neurons projecting to the median preoptic nucleus (MnPO), a thermoregulatory center (LPB→MnPO neurons), and those projecting to the central amygdaloid nucleus (CeA), a limbic emotion center (LPB→CeA neurons). While LPB→MnPO neurons include separate subgroups activated by heat or cold…

A bstract Behavioural reports of sensory information are biased by stimulus history. The nature and direction of such serial-dependence biases can differ between experimental settings – both attractive and repulsive biases towards previous stimuli have been observed. How and when these biases arise in the human brain remains largely unexplored. They could occur either via a change in sensory processing itself and/or during post-perceptual processes such as maintenance or decision-making. To address this, we analysed behavioural and magnetoencephalographic data from a working-memory task in which participants were sequentially presented with two randomly oriented gratings, one of which was cued for recall at the end of the trial. Behavioural responses showed evidence for two distinct biases: 1) a within-trial repulsive bias away from the previously encoded orientation on the same trial, and 2) a between-trial attractive bias towards the task-relevant orientation on the previous trial. Multivariate classification of stimulus orientation revealed that neural representations during…

Abstract Local translation in neurons is mediated in part by the reactivation of stalled polysomes. Stalled polysomes may be enriched within the pellet of sucrose gradients used to separate polysomes from monosomes. We find that this fraction, isolated from P5 rat brains of both sexes, is enriched in proteins implicated in stalled polysome function, such as the fragile X mental retardation protein (FMRP) and Up-frameshift mutation 1 homolog (UPF1). Cryo-EM analysis of ribosomes in this fraction indicates they are stalled, mainly in the hybrid state. Ribosome profiling of this fraction showed an abundance of footprint reads derived from mRNAs of cytoskeletal proteins implicated in neuronal development and an enrichment of footprint reads on RNA binding proteins. Compared to those usually found in ribosome profiling studies, the footprint reads were more extended on their 3’end and were found in reproducible peaks in the mRNAs. These peaks were enriched in motifs previously associated with mRNAs cross-linked to FMRP in vivo, independently linking the ribosomes in the sedimented pellet…

ABSTRACT Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser-extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and…

Everyday tasks and goal-directed behavior involve the maintenance and continuous updating of information in working memory (WM). WM gating reflects switches between these two core states. Neurobiological considerations suggest that the catecholaminergic and the GABAergic are likely involved in these dynamics. Both of these neurotransmitter systems likely underlie the effects to auricular transcutaneous vagus nerve stimulation (atVNS). We examine the effects of atVNS on WM gating dynamics and their underlying neurophysiological and neurobiological processes in a randomized crossover study design in healthy humans of both sexes. We show that atVNS specifically modulates WM gate closing and thus specifically modulates neural mechanisms enabling the maintenance of information in WM. WM gate opening processes were not affected. atVNS modulates WM gate closing processes through the modulation of EEG alpha band activity. This was the case for clusters of activity in the EEG signal referring to stimulus information, motor response information, and fractions of information carrying…

A sentence is more than the sum of its words: its meaning depends on how they combine with one another. The brain mechanisms underlying such semantic composition remain poorly understood. To shed light on the neural vector code underlying semantic composition, we introduce two hypotheses: (1) the intrinsic dimensionality of the space of neural representations should increase as a sentence unfolds, paralleling the growing complexity of its semantic representation; and (2) this progressive integration should be reflected in ramping and sentence-final signals. To test these predictions, we designed a dataset of closely matched normal and jabberwocky sentences (composed of meaningless pseudo words) and displayed them to deep language models and to 11 human participants (5 men and 6 women) monitored with simultaneous MEG and intracranial EEG. In both deep language models and electrophysiological data, we found that representational dimensionality was higher for meaningful sentences than jabberwocky. Furthermore, multivariate decoding of normal versus jabberwocky confirmed three dynamic…