The 50 most-cited articles in Journal of Neuroscience, 2022

evidence that mTOR activation in microglia would benefit β-Amyloid (Aβ)-related AD pathologies, as it upregulates Trem2, a key receptor for Aβ plaque uptake. Inhibition of mTOR pathway with rapamycin, a well-established immunosuppressant, downregulated Trem2 in microglia and reduced Aβ plaque clearance indicating that mTOR inactivation may be detrimental in Aβ-associated AD patients. This finding will have a significant public health impact and benefit, regarding the usage of rapamycin in AD patients, which we believe will aggravate the Aβ-related AD pathologies.

Physical exercise improves motor performance in individuals with Parkinson9s disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in ex vivo corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise…

The physiological underpinnings of the necessity of sleep remain uncertain. Recent evidence suggests that sleep increases the convection of cerebrospinal fluid (CSF) and promotes the export of interstitial solutes, thus providing a framework to explain why all vertebrate species require sleep. Cardiovascular, respiratory and vasomotor brain pulsations have each been shown to drive CSF flow along perivascular spaces, yet it is unknown how such pulsations may change during sleep in humans. To investigate these pulsation phenomena in relation to sleep, we simultaneously recorded fast fMRI, magnetic resonance encephalography (MREG), and electroencephalography (EEG) signals in a group of healthy volunteers. We quantified sleep-related changes in the signal frequency distributions by spectral entropy analysis and calculated the strength of the physiological (vasomotor, respiratory, and cardiac) brain pulsations by power sum analysis in 15 subjects (age 26.5 ± 4.2 years, 6 females). Finally, we identified spatial similarities between EEG slow oscillation (0.2–2 Hz) power and MREG…

Abstract Oxytocin (OT) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of OT neurons and their quantitative relationship with OT receptor (OTR) expression presents challenges to understanding circuit specific OT functions. Here, we establish a whole-brain distribution and anatomical connectivity map of OT neurons, and their relationship with OTR expression using cell type specific viral tools and high-resolution 3D mapping methods. We utilize a flatmap to describe OT neuronal expression in four hypothalamic domains including under-characterized OT neurons in the tuberal nucleus. OT neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, OT neurons in the supraoptic (SO) and accessory nuclei have limited central projection to a small subset of the nine circuits. Surprisingly, quantitative comparison between OT output and OTR expression showed no…

Abstract The human dorsolateral prefrontal cortex (DLPFC, approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along with rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography and resting-state functional magnetic resonance imaging were employed to map out the patterns of connectivity from each DLPFC subregions. Structural connectivity demonstrated graded intra-regional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that he dorsal-rostral subregions was restricted to connect to other frontal and limbic areas, whereas the ventral-caudal…

Classical models have traditionally focused on the left posterior inferior frontal gyrus (Broca's area) as a key region for motor planning of speech production. However, converging evidence suggests that it is not critical for either speech motor planning or execution. Alternative cortical areas supporting high-level speech motor planning have yet to be defined. In this review, we focus on the precentral gyrus, whose role in speech production is often thought to be limited to lower-level articulatory muscle control. In particular, we highlight neurosurgical investigations that have shed light on a cortical region anatomically located near the midpoint of the precentral gyrus, hence called the middle precentral gyrus (midPrCG). The midPrCG is functionally located between dorsal hand and ventral orofacial cortical representations and exhibits unique sensorimotor and multisensory functions relevant for speech processing. This includes motor control of the larynx, auditory processing, as well as a role in reading and writing. Furthermore, direct electrical stimulation of midPrCG can…

The neuroscience of music and music-based interventions (MBIs) is a fascinating but challenging research field. While music is a ubiquitous component of every human society, MBIs may encompass listening to music, performing music, music-based movement, undergoing music education and training, or receiving treatment from music therapists. Unraveling the brain circuits activated and influenced by MBIs may help us gain better understanding of the therapeutic and educational values of MBIs by gathering strong research evidence. However, the complexity and variety of MBIs impose unique research challenges. This article reviews the recent endeavor led by the National Institutes of Health to support evidence-based research of MBIs and their impact on health and diseases. It also highlights fundamental challenges and strategies of MBI research with emphases on the utilization of animal models, human brain imaging and stimulation technologies, behavior and motion capturing tools, and computational approaches. It concludes with suggestions of basic requirements when studying MBIs and…

Both the cerebellum and the basal ganglia are known for their roles in motor control and motivated behavior. These two systems have been classically considered as independent structures that coordinate their contributions to behavior via separate cortico-thalamic loops. However, recent evidence demonstrates the presence of a rich set of direct connections between these two regions. Although there is strong evidence for connections in both directions, for brevity we limit our discussion to the better-characterized connections from the cerebellum to the basal ganglia. We review two sets of such connections: disynaptic projections through the thalamus and direct monosynaptic projections to the midbrain dopaminergic nuclei, the VTA and the SNc. In each case, we review the evidence for these pathways from anatomic tracing and physiological recordings, and discuss their potential functional roles. We present evidence that the disynaptic pathway through the thalamus is involved in motor coordination, and that its dysfunction contributes to motor deficits, such as dystonia. We then discuss…

ABSTRACT Human brain activity generates electroencephalographic (EEG) oscillations that characterize specific behavioral and vigilance states. The frequency of these oscillations is typically sufficient to distinguish a given state, however theta oscillations (4-8 Hz) have instead been found in near-opposite conditions of drowsiness during sleep deprivation and alert cognitive control. While the latter has been extensively studied and is often referred to as “frontal midline theta”, the former has been investigated far less but is considered to be a marker for local sleep during wake. In this study we investigated to what extent theta oscillations differed during cognitive tasks and sleep deprivation. We measured high-density EEG in 18 young healthy adults performing 6 tasks under 3 levels of sleep deprivation. We found both cognitive load and sleep deprivation increased theta power in medial prefrontal cortical areas, however sleep deprivation caused additional increases in theta in many other, predominantly frontal, areas. The sources of sleep deprivation theta were…

Abstract Research into the nature of 1/ f -like, non-oscillatory electrophysiological activity has grown exponentially in recent years in cognitive neuroscience. The shape of this activity has been linked to the balance between excitatory and inhibitory neural circuits, which is thought to be important for information processing. However, to date, it is not known whether the presentation of a stimulus induces changes in the parameters of 1/ f activity, which are separable from the emergence of event-related potentials (ERPs). Here, we analyze event-related broadband changes in scalp-recorded EEG both before and after removing ERPs to demonstrate their confounding effect, and to establish whether there are genuine stimulus-induced changes in 1/ f . Using data from a passive and an active auditory task (n=23), we found that the shape of the post-event spectra differed significantly from the pre-event spectra even after removing the frequency-content of ERPs. Further, a significant portion of this difference could be accounted for by a rotational shift in 1/ f activity, manifesting as…

Abstract We aimed to investigate a potentially sexually dimorphic role of Calcitonin Gene-Related Peptide (CGRP) in mouse and rat models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 (IL-6) signaling, CGRP receptor antagonists, olcegepant and CGRP 8-37 , both given intrathecally, blocked and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury (SNI) model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient effects in males. This…

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D; N = 628, ages 8–21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organization reported by others. In sensorimotor areas, T1w/T2w ratio measures start…

The control of contraction strength is a key part of movement control. In primates, both corticospinal and reticulospinal cells provide input to motoneurons. Corticospinal discharge is known to correlate with force, but there are no previous reports of how reticular formation (RF) activity modulates with different contractions. Here we trained two female macaque monkeys (body weight, 5.9–6.9 kg) to pull a handle that could be loaded with 0.5–6 kg weights and recorded from identified pyramidal tract neurons (PTNs) in primary motor cortex and RF cells during task performance. Population-averaged firing rate increased monotonically with higher force for the RF, but showed a complex profile with little net modulation for PTNs. This reflected a more heterogeneous profile of rate modulation across the PTN population, leading to cancellation in the average. Linear discriminant analysis classified the force based on the time course of rate modulation equally well for PTNs and RF cells. Peak firing rate had significant linear correlation with force for 43 of 92 PTNs (46.7%) and 21 of 46 RF…

Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for Neuroscience. As of 2022, there were hundreds of clinical trials recruiting participants for testing the therapeutic effects of psychedelics. Emerging evidence suggests that psychedelic drugs may exert some of their long-lasting therapeutic effects by inducing structural and functional neural plasticity. Herein, basic and clinical research attempting to elucidate the mechanisms of these compounds is showcased. Topics covered include psychedelic receptor binding sites, effects of psychedelics on gene expression, and on dendrites, and psychedelic effects on microcircuitry and brain-wide circuits. We describe unmet clinical needs and the current state of translation to the clinic for psychedelics, as…

Abstract A standard view of human language processing is that comprehenders build richly structured mental representations of natural language utterances, word by word, using computationally costly memory operations supported by domain-general working memory resources. However, three core claims of this view have been questioned, with some prior work arguing that (1) rich word-by-word structure building is not a core function of the language comprehension system, (2) apparent working memory costs are underlyingly driven by word predictability ( surprisal ), and/or (3) language comprehension relies primarily on domain-general rather than domain-specific working memory resources. In this work, we simultaneously evaluate all three of these claims using naturalistic comprehension in fMRI. In each participant, we functionally localize (a) a language-selective network and (b) a ‘multiple-demand’ network that supports working memory across domains, and we analyze the responses in these two networks of interest during naturalistic story listening with respect to a range of theory-driven…

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n= 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n= 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n= 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area…

A surprising finding of recent studies in mouse is the dominance of widespread movement-related activity throughout the brain, including in early sensory areas. In awake subjects, failing to account for movement risks misattributing movement-related activity to other (e.g., sensory or cognitive) processes. In this article, we (1) review task designs for separating task-related and movement-related activity, (2) review three “case studies” in whichnotconsidering movement would have resulted in critically different interpretations of neuronal function, and (3) discuss functional couplings that may prevent us from ever fully isolating sensory, motor, and cognitive-related activity. Our main thesis is that neural signals related to movement are ubiquitous, and therefore ought to be considered first and foremost when attempting to correlate neuronal activity with task-related processes.

Traumatic brain injury (TBI) is associated with an increased risk of cognitive, psychiatric, and neurodegenerative complications that may develop after injury. Increased microglial reactivity following TBI may underlie chronic neuroinflammation, neuropathology, and exaggerated responses to immune challenges. Therefore, the goal of this study was to force turnover of trauma-associated microglia that develop after diffuse TBI and determine whether this alleviated chronic inflammation, improved functional recovery and attenuated reduced immune reactivity to lipopolysaccharide (LPS) challenge. Male mice received a midline fluid percussion injury (mFPI) and 7 d later were subjected to a forced microglia turnover paradigm using CSF1R antagonism (PLX5622). At 30 d postinjury (dpi), cortical gene expression, dendritic complexity, myelin content, neuronal connectivity, cognition, and immune reactivity were assessed. Myriad neuropathology-related genes were increased 30 dpi in the cortex, and 90% of these gene changes were reversed by microglial turnover. Reduced neuronal connectivity was…

A bstract Touch is critical for our ability to manipulate objects, as evidenced by the deficits incurred when touch is absent. To restore the sense of touch via electrical stimulation of the peripheral nerves requires that we understand how the parameters of stimulation shape the evoked sensation. To this end, we investigated the sensory consequences of changing the frequency of pulse trains (PF) delivered to the peripheral nerves of humans chronically implanted with multi-channel nerve cuff electrodes. We found that increases in PF led to systematic increases in perceived frequency, up to about 50 Hz, at which point further changes in PF had little to no impact on sensory quality. Above this transition frequency, ratings of perceived frequency levelled off, the ability to discriminate changes in PF was abolished, and verbal descriptors selected to characterize the sensation changed abruptly. We conclude that the quality of electrically evoked tactile sensations can be shaped by imposing temporal patterns on a fixed neural population, but this temporal patterning can only be…

Abstract How variable is the functionally-defined structure of early visual areas in human cortex and how much variability is shared between twins? Here we quantify individual differences in the best understood functionally-defined regions of cortex: V1, V2, V3. The Human Connectome Project 7T Retinotopy Dataset includes retinotopic measurements from 181 subjects, including many twins. We trained four “anatomists” to manually define V1-V3 using retinotopic features. These definitions were more accurate than automated anatomical templates and showed that surface areas for these maps varied more than three-fold across individuals. This three-fold variation was little changed when normalizing visual area size by the surface area of the entire cerebral cortex. In addition to varying in size, we find that visual areas vary in how they sample the visual field. Specifically, the cortical magnification function differed substantially among individuals, with the relative amount of cortex devoted to central vision varying by more than a factor of 2. To complement the variability analysis, we…

Abstract Human childhood is characterized by dramatic changes in the mind and brain. However, little is known about the large-scale intrinsic cortical network changes that occur during childhood due to methodological challenges in scanning young children. Here, we overcome this barrier by using sophisticated acquisition and analysis tools to investigate functional network development in children between the ages of 4 and 10 years ( n = 92). At multiple spatial scales, age is positively associated with brain network segregation. At the system level, age was associated with segregation of systems involved in attention from those involved in abstract cognition, and with integration among attentional and perceptual systems. Associations between age and functional connectivity are most pronounced in visual and medial prefrontal cortex, the two ends of a gradient from perceptual, externally oriented cortex to abstract, internally oriented cortex. These findings suggest that both ends of the sensory-association gradient may develop early, in contrast to the classical theories that cortical…

Understanding the unique functions of different subregions of primate prefrontal cortex has been a longstanding goal in cognitive neuroscience. Yet, the anatomy and function of one of its largest subregions (the frontopolar cortex) remain enigmatic and underspecified. Our Society for Neuroscience minisymposiumPrimate Frontopolar Cortex: From Circuits to Complex Behaviorswill comprise a range of new anatomic and functional approaches that have helped to clarify the basic circuit anatomy of the frontal pole, its functional involvement during performance of cognitively demanding behavioral paradigms in monkeys and humans, and its clinical potential as a target for noninvasive brain stimulation in patients with brain disorders. This review consolidates knowledge about the anatomy and connectivity of frontopolar cortex and provides an integrative summary of its function in primates. We aim to answer the question: what, if anything, does frontopolar cortex contribute to goal-directed cognition and action?

Abstract Neuroimaging, neuropsychological, and psychophysical evidence indicates that concept retrieval selectively engages specific sensory and motor brain systems involved in the acquisition of the retrieved concept. However, it remains unclear which supramodal cortical regions contribute to this process and what kind of information they represent. Here, we used representational similarity analysis of two large fMRI data sets, with a searchlight approach, to generate a detailed map of human brain regions where the semantic similarity structure across individual lexical concepts can be reliably detected. We hypothesized that heteromodal cortical areas typically associated with the “default mode network” encode multimodal experiential information about concepts, consistent with their proposed role as cortical integration hubs. In two studies involving different sets of concepts and different participants (both sexes), we found a distributed, bihemispheric network engaged in concept representation, composed of high-level association areas in the anterior, lateral, and ventral…

The estrous cycle is a potent modulator of neuron physiology. In rodents, in vivo ventral tegmental area (VTA) dopamine (DA) activity has been shown to fluctuate across the estrous cycle. Although the behavioral effect of fluctuating sex steroids on the reward circuit is well studied in response to drugs of abuse, few studies have focused on the molecular adaptations in the context of stress and motivated social behaviors. We hypothesized that estradiol fluctuations across the estrous cycle acts on the dopaminergic activity of the VTA to alter excitability and stress response. We used whole-cell slice electrophysiology of VTA DA neurons in naturally cycling, adult female C57BL/6J mice to characterize the effects of the estrous cycle and the role of 17β-estradiol on neuronal activity. We show that the estrous phase alters the effect of 17β-estradiol on excitability in the VTA. Behaviorally, the estrous phase during a series of acute variable social stressors modulates subsequent reward-related behaviors. Pharmacological inhibition of estrogen receptors in the VTA before stress during…

The ability to comprehend phrases is an essential integrative property of the brain. Here, we evaluate the neural processes that enable the transition from single-word processing to a minimal compositional scheme. Previous research has reported conflicting timing effects of composition, and disagreement persists with respect to inferior frontal and posterior temporal contributions. To address these issues, 19 patients (10 male, 9 female) implanted with penetrating depth or surface subdural intracranial electrodes, heard auditory recordings of adjective-noun, pseudoword-noun, and adjective-pseudoword phrases and judged whether the phrase matched a picture. Stimulus-dependent alterations in broadband gamma activity, low-frequency power, and phase-locking values across the language-dominant left hemisphere were derived. This revealed a mosaic located on the lower bank of the posterior superior temporal sulcus (pSTS), in which closely neighboring cortical sites displayed exclusive sensitivity to either lexicality or phrase structure, but not both. Distinct timings were found for effects…

Abstract Although there is mounting evidence that input from the dorsal visual pathway is crucial for object processes in the ventral pathway, the specific functional contributions of dorsal cortex to these processes remain poorly understood. Here, we hypothesized that dorsal cortex computes the spatial relations among an object’s parts – a processes crucial for forming global shape percepts – and transmits this information to the ventral pathway to support object categorization. Using fMRI with human participants (females and males), we discovered regions in the intraparietal sulcus (IPS) that were selectively involved in computing object-centered part relations. These regions exhibited task-dependent functional and effective connectivity with ventral cortex, and were distinct from other dorsal regions, such as those representing allocentric relations, 3D shape, and tools. In a subsequent experiment, we found that the multivariate response of posterior IPS, defined on the basis of part-relations, could be used to decode object category at levels comparable to ventral object…

Abstract Neural responses to visual stimuli exhibit complex temporal dynamics, including sub-additive temporal summation, response reduction with repeated or sustained stimuli (adaptation), and slower dynamics at low contrast. These phenomena are often studied independently. Here, we demonstrate these phenomena within the same experiment and model the underlying neural computations with a single computational model. We extracted time-varying responses from electrocorticographic (ECoG) recordings from patients presented with stimuli that varied in contrast, duration, and inter-stimulus interval (ISI). Aggregating data across patients yielded 98 electrodes with robust visual responses, covering both earlier (V1-V3) and higher-order (V3a/b, LO, TO, IPS) retinotopic maps. In all regions, the temporal dynamics of neural responses exhibit several non-linear features: peak response amplitude saturates with high contrast and longer stimulus durations; the response to a second stimulus is suppressed for short ISIs and recovers for longer ISIs; response latency decreases with increasing…

Visual processing is strongly influenced by recent stimulus history, a phenomenon termed adaptation. Prominent theories cast adaptation as a consequence of optimized encoding of visual information by exploiting the temporal statistics of the world. However, this would require the visual system to track the history of individual briefly experienced events, within a stream of visual input, to build up statistical representations over longer timescales. Here, using an openly available dataset from the Allen Brain Observatory, we show that neurons in the early visual cortex of the mouse indeed maintain long-term traces of individual past stimuli that persist despite the presentation of several intervening stimuli, leading to long-term and stimulus-specific adaptation over dozens of seconds. Long-term adaptation was selectively expressed in cortical, but not in thalamic, neurons, which only showed short-term adaptation. Early visual cortex thus maintains concurrent stimulus-specific memory traces of past input, enabling the visual system to build up a statistical representation of the…

Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59…

The fetal brains experience rapid and complex development in utero during the second and third trimesters. In utero MRI of the fetal brain in this period enables us to quantify normal fetal brain development in the spatiotemporal domain. In this study, we established a high-quality spatiotemporal atlas between 23 and 38 weeks gestational age (GA) from 90 healthy Chinese human fetuses of both sexes using a pairwise and groupwise registration pipeline. We quantified the fetal cortical morphology indices and characterized their spatiotemporal developmental pattern. The cortical thickness exhibited a biphasic pattern that first increased and then decreased; the curvature fitted well into the Gompertz growth model; sulcal depth increased linearly, while surface area expanded exponentially. The cortical thickness and curvature trajectories consistently pointed to a characteristic time point around GA of 31 weeks. The characteristic GA and growth rate obtained from individual cortical regions suggested a central-to-peripheral developmental gradient, with the earliest development in the…

Abstract Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in the cortex during non-rapid eye movement sleep (NREM). Recently, cortical ripples in humans have been shown to enfold the replay of neuron firing patterns during cued recall. Here, using intracranial recordings from 18 patients (12 female), we show that cortical ripples also occur during NREM in humans, with similar density, oscillation frequency (∼90 Hz), duration, and amplitude to waking. Ripples occurred in all cortical regions with similar characteristics, unrelated to putative hippocampal connectivity, and were less dense and robust in higher association areas. Putative pyramidal and interneuron spiking phase-locked to cortical ripples during NREM, with phase delays consistent with ripple generation through pyramidal-interneuron feedback. Cortical ripples were smaller in amplitude than hippocampal ripples, but were similar in density, frequency, and duration. Cortical ripples during NREM typically occurred just prior to the upstate…

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of…

Abstract Although previous studies point to qualitative similarities between working memory (WM) and attention, the degree to which these two constructs rely on shared neural mechanisms remains unknown. Focusing on one such potentially shared mechanism, we tested the hypothesis that selecting an item within WM utilizes similar neural mechanisms as selecting a visible item via a shift of attention. We used fMRI and machine learning to decode both the selection among items visually available and the selection among items stored in WM in human subjects (both sexes). Patterns of activity in visual, parietal, and to a lesser extent frontal cortex predicted the locations of the selected items. Critically, these patterns were strikingly interchangeable; classifiers trained on data during attentional selection predicted selection from WM, and classifiers trained on data during selection from memory predicted attentional selection. Using models of voxel receptive fields, we visualized topographic population activity that revealed gain enhancements at the locations of the externally and…

Consolidation of memory is believed to involve offline replay of neural activity. While amply demonstrated in rodents, evidence for replay in humans, particularly regarding motor memory, is less compelling. To determine whether replay occurs after motor learning, we sought to record from motor cortex during a novel motor task and subsequent overnight sleep. A 36-year-old man with tetraplegia secondary to cervical spinal cord injury enrolled in the ongoing BrainGate brain–computer interface pilot clinical trial had two 96-channel intracortical microelectrode arrays placed chronically into left precentral gyrus. Single- and multi-unit activity was recorded while he played a color/sound sequence matching memory game. Intended movements were decoded from motor cortical neuronal activity by a real-time steady-state Kalman filter that allowed the participant to control a neurally driven cursor on the screen. Intracortical neural activity from precentral gyrus and 2-lead scalp EEG were recorded overnight as he slept. When decoded using the same steady-state Kalman filter parameters,…

Abstract Prior studies on emotion regulation identified a set of brain regions specialized for generating and controlling affect. Researchers generally agree that when up- and down-regulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating areas. However, the assumption that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We call this assumption the ‘affective dial hypothesis.’ Our study tested this hypothesis by examining the overlap between the sets of regions activated during up-regulation and those deactivated during down-regulation in a large number of participants (N=105). We found that up- and down-regulation both recruit regulatory regions such as the inferior frontal gyrus and dorsal anterior cingulate gyrus but act on distinct affect-generating regions. While up-regulation increases BOLD signal in regions associated with emotion such as the amygdala, anterior insula, striatum and anterior cingulate gyrus as well as in regions associated with sympathetic vascular…

Axons differ in their growth potential: whereas during development, axons rapidly grow to their targets, in the adult mammalian, CNS axons have lost their ability to grow and therefore fail to regenerate. Recent progress has enabled a better understanding of how developmental mechanisms direct axon regeneration. Focusing on neuronal polarization, where one neurite is singled out to become the axon, has uncovered the mechanisms initiating axon growth and growth restraint. This has helped to define the processes that need to be reactivated to induce axon regeneration: microtubule stabilization and actin dynamics. The molecular machinery underlying axon growth and axon regeneration is remarkably similar and includes the Rho-GTPases Cdc42, Rac-1, and RhoA, as well as the actin regulators cofilin and Myosin II. Importantly, neuron-intrinsic growth inhibitors in the adult nervous system, including the voltage-gated calcium channel subunit α2δ2 and the presynaptic active zone protein Munc13, restrain dynamics while the components driving axon growth remain largely present. The identified…

Dorsal raphe (DR) 5-HT neurons regulate sleep–wake transitions. Previous studies demonstrated that single-unit activity of DR 5-HT neurons is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and ceases during rapid eye movement (REM) sleep. However, characteristics of the population-level activity of DR 5-HT neurons, which influence the entire brain, are largely unknown. Here, we measured population activities of 5-HT neurons in the male and female mouse DR across the sleep–wake cycle by ratiometric fiber photometry. We found a slow oscillatory activity of compound intracellular Ca2+ signals during NREM sleep. The trough of the concave 5-HT activity increased across sleep progression, but 5-HT activity always returned to that seen during the wake period. When the trough reached a minimum and remained there, REM sleep was initiated. We also found a unique coupling of the oscillatory 5-HT activity and wideband EEG power fluctuation. Furthermore, optogenetic activation of 5-HT neurons during NREM sleep triggered a high EMG power and induced wakefulness,…

How do we come to sense that a hand in view belongs to our own body or not? Previous studies have suggested that the integration of vision and somatosensation in the frontoparietal areas plays a critical role in the sense of body ownership (i.e., the multisensory perception of limbs and body parts as our own). However, little is known about how these areas implement the multisensory integration process at the computational level and whether activity predicts illusion elicitation in individual participants on a trial-by-trial basis. To address these questions, we used functional magnetic resonance imaging and a rubber hand illusion-detection task and fitted the registered neural responses to a Bayesian causal inference model of body ownership. Thirty healthy human participants (male and female) performed 12 s trials with varying degrees of asynchronously delivered visual and tactile stimuli of a rubber hand (in view) and a (hidden) real hand. After the 12 s period, participants had to judge whether the rubber hand felt like their own. As hypothesized, activity in the premotor and…

The olfactory sense of the domestic dog is widely recognized as being highly sensitive with a diverse function; however, little is known about the structure of its olfactory system. This study examined a cohort of mixed-sex mesaticephalic canines and used diffusion tensor imaging (DTI), an MRI technique, to map connections from the olfactory bulb to other cortical regions of the brain. The results were validated using the Klingler dissection method. An extensive pathway composed of five white matter tracts connecting to the occipital lobe, cortical spinal tract, limbic system, piriform lobe, and entorhinal pathway was identified. This is the first documentation of a direct connection between the olfactory bulb and occipital lobe in any species and is a step toward further understanding how the dog integrates olfactory stimuli into their cognitive function. SIGNIFICANCE STATEMENT The highly sensitive olfactory system of the domestic dog is largely unexplored. We applied diffusion tractography and dissection techniques to evaluate the white matter connections associated with the…

Oxytocin (OXT) neurons in paraventricular nucleus of hypothalamus (PVN) are involved in modulating multiple functions, including social, maternal, feeding, and emotional related behaviors. PVN OXT neurons are canonically classified into magnocellular (Magno) and parvocellular (Parvo) subtypes. However, morpho-electric properties and the diversity of PVN OXT neurons are not well investigated. In this study, we profiled the morpho-electric properties of PVN OXT neurons by combining transgenic mice, electrophysiological recording, morphologic reconstruction, and unsupervised clustering analyses. Total 224 PVN OXT neurons from 23 mice were recorded and used for analyses in this study, and 29 morpho-electric parameters were measured. Magno and Parvo OXT neurons have prominent differences in their morpho-electric features, and PVN OXT neurons in male and female mice share similar neuronal properties. Some morpho-electric features of PVN OXT neurons, especially Magno neurons, exhibit significant diverse changes along the rostral–caudal axis. Furthermore, we find that PVN OXT neurons are…

ABSTRACT Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the ATXN3 gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutant ATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions, the cerebellum and brainstem. The most significant disease-associated module through weighted gene co-expression network analysis revealed dysfunction in SCA3 oligodendrocyte…

Sensory driven activity during early life is critical for setting up the proper connectivity of the sensory cortices. We ask here whether social play behavior, a particular form of social interaction that is highly abundant during postweaning development, is equally important for setting up connections in the developing prefrontal cortex (PFC). Young male rats were deprived from social play with peers during the period in life when social play behavior normally peaks [postnatal day 21–42] (SPD rats), followed by resocialization until adulthood. We recorded synaptic currents in layer 5 cells in slices from medial PFC of adult SPD and control rats and observed that inhibitory synaptic currents were reduced in SPD slices, while excitatory synaptic currents were unaffected. This was associated with a decrease in perisomatic inhibitory synapses from parvalbumin-positive GABAergic cells. In parallel experiments, adult SPD rats achieved more reversals in a probabilistic reversal learning (PRL) task, which depends on the integrity of the PFC, by using a more simplified cognitive strategy…

Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination ofin vivocircuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic (EMG) recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mice. Further, optogenetic studies demonstrate a causal link between such neuronal…

Reaction time is accelerated if a loud (startling) sound accompanies the cue—the “StartReact” effect. Animal studies revealed a reticulospinal substrate for the startle reflex; StartReact may similarly involve the reticulospinal tract, but this is currently uncertain. Here we trained two female macaque monkeys to perform elbow flexion/extension movements following a visual cue. The cue was sometimes accompanied by a loud sound, generating a StartReact effect in electromyogram response latency, as seen in humans. Extracellular recordings were made from antidromically identified corticospinal neurons in primary motor cortex (M1), from the reticular formation (RF), and from the spinal cord (SC; C5–C8 segments). After loud sound, task-related activity was suppressed in M1 (latency, 70–200 ms after cue), but was initially enhanced (70–80 ms) and then suppressed (140–210 ms) in RF. SC activity was unchanged. In a computational model, we simulated a motoneuron pool receiving input from different proportions of the average M1 and RF activity recorded experimentally. Motoneuron firing…

Astrocytes release functional mitochondria (Mt) that play regulatory and prosurvival functions on entering adjacent cells. We recently demonstrated that these released Mts could enter microglia to promote their reparative/prophagocytic phenotype that assists in hematoma cleanup and neurological recovery after intracerebral hemorrhage (ICH). However, the relevance of astrocytic Mt transfer into neurons in protecting brain after ICH is unclear. Here, we found that ICH causes a robust increase in superoxide generation and elevated oxidative damage that coincides with loss of the mitochondrial enzyme manganese superoxide dismutase (Mn-SOD). The damaging effect of ICH was reversed by intravenous transplantation of astrocytic Mt, which on entering the brain (and neurons), restored Mn-SOD levels and reduced neurological deficits in male mice subjected to ICH. Using an in vitro ICH-like injury model in cultured neurons, we established that astrocytic Mt on entering neurons prevented reactive oxygen species-induced oxidative stress and neuronal death by restoring neuronal Mn-SOD levels while…

Abstract Inhibitory microcircuits play an essential role in regulating cortical responses to sensory stimuli. Interneurons that inhibit dendritic or somatic integration in pyramidal neurons act as gatekeepers for neural activity, synaptic plasticity and the formation of sensory representations. Conversely, interneurons that specifically inhibit other interneurons can open gates through disinhibition. In the rodent piriform cortex, relief of dendritic inhibition permits long-term potentiation (LTP) of the recurrent synapses between pyramidal neurons (PNs) thought to underlie ensemble odor representations. We used an optogenetic approach to identify the inhibitory interneurons and disinhibitory circuits that regulate LTP. We focused on three prominent inhibitory neuron classes-somatostatin (SST), parvalbumin (PV), and vasoactive intestinal polypeptide (VIP) interneurons. We find that LTP is gated by the inactivation SST or PV interneurons or by activation of VIP interneurons. Further, activation of VIP interneurons strongly inhibits putative SST-cells during LTP induction, but only…

How do people limit awareness of unwanted memories? When such memories intrude, a control process engages the right DLPFC (rDLPFC) to inhibit hippocampal activity and stop retrieval. It remains unknown how the need for control is detected, and whether control operates proactively to prevent unwelcome memories from being retrieved, or responds reactively, to counteract intrusions. We hypothesized that dorsal ACC (dACC) detects the emergence of an unwanted trace in awareness and transmits the need for inhibitory control to rDLPFC. During a memory suppression task, we measured in humans (both sexes) trial-by-trial variations in the theta power and N2 amplitude of dACC, two EEG markers that are thought to reflect the need for control. With simultaneous EEG-fMRI recordings, we tracked interactions among dACC, rDLPFC, and hippocampus during suppression. We found a clear role of dACC in detecting the need for memory control and upregulating prefrontal inhibition. Importantly, we identified distinct early (300–450 ms) and late (500–700 ms) dACC contributions, suggesting both proactive…

ABSTRACT The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift co-operatively or competitively remains unclear. Cortical inputs have also been implicated in the shift towards automaticity, but it is unknown if they mirror their downstream striatal targets across this transition. We addressed these questions using a five-step heterogeneous action sequencing task in rats that is optimally performed by automated chains of actions. By optimising automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly the medial prefrontal cortex was not involved, however the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial…

Traumatic brain injury (TBI) is associated with chronic psychiatric complications and increased risk for development of neurodegenerative pathology. Aged individuals account for most TBI-related hospitalizations and deaths. Nonetheless, neurobiological mechanisms that underlie worsened functional outcomes after TBI in the elderly remain unclear. Therefore, this study aimed to identify pathways that govern differential responses to TBI with age. Here, adult (2 months of age) and aged (16–18 months of age) male C57BL/6 mice were subjected to diffuse brain injury (midline fluid percussion), and cognition, gliosis, and neuroinflammation were determined 7 or 30 d postinjury (dpi). Cognitive impairment was evident 7 dpi, independent of age. There was enhanced morphologic restructuring of microglia and astrocytes 7 dpi in the cortex and hippocampus of aged mice compared with adults. Transcriptional analysis revealed robust age-dependent amplification of cytokine/chemokine, complement, innate immune, and interferon-associated inflammatory gene expression in the cortex 7 dpi. Ingenuity…

The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area (AHA) did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine; Dex). By contrast, fragmentation persisted under high sleep pressure produced by sleep deprivation (SD), mice had a high…