The 50 most-cited articles in Journal of Neuroscience, 2019

The term "salience network" refers to a suite of brain regions whose cortical hubs are the anterior cingulate and ventral anterior insular (i.e., frontoinsular) cortices. This network, which also includes nodes in the amygdala, hypothalamus, ventral striatum, thalamus, and specific brainstem nuclei, coactivates in response to diverse experimental tasks and conditions, suggesting a domain-general function. In the 12 years since its initial description, the salience network has been extensively studied, using diverse methods, concepts, and mammalian species, including healthy and diseased humans across the lifespan. Despite this large and growing body of research, the essential functions of the salience network remain uncertain. In this paper, which makes no attempt to comprehensively review this literature, I describe the circumstances surrounding the initial discovery, conceptualization, and naming of the salience network, highlighting aspects that may be unfamiliar to many readers. I then discuss some of the key advances provided by subsequent research and conclude by posing a few…

Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood–brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain…

Extracellular vesicles (EVs) include exosomes and microvesicles and have been shown to have roles in the CNS ranging from the removal of unwanted biomolecules to intercellular communication to the spread of pathogenic proteins associated with neurodegenerative diseases. EVs carry protein, lipid, and genetic cargo, and research over more than a decade has shown that they contain the misfolded forms of proteins associated with Alzheimer's, Parkinson's, and the prion diseases. Altered genetic cargo, usually in the form of miRNAs, have also been identified in EVs patients with these diseases, suggesting that EVs may be a source of disease biomarkers. Whether EVs play a key role in the pathogenesis of neurological diseases remains to be firmly established because most current research is performed using cell culture and transgenic animal models. If EVs are identified as a key pathological contributor to neurological conditions, they will form a novel target for therapeutic intervention. This Dual Perspectives article will discuss the current understanding of the role of EVs in…

Beta oscillations (∼13 to 30 Hz) have been observed during many perceptual, cognitive, and motor processes in a plethora of brain recording studies. Although the function of beta oscillations (hereafter "beta" for short) is unlikely to be explained by any single monolithic description, we here discuss several convergent findings. In prefrontal cortex (PFC), increased beta appears at the end of a trial when working memory information needs to be erased. A similar "clear-out" function might apply during the stopping of action and the stopping of long-term memory retrieval (stopping thoughts), where increased prefrontal beta is also observed. A different apparent role for beta in PFC occurs during the delay period of working memory tasks: it might serve to maintain the current contents and/or to prevent interference from distraction. We confront the challenge of relating these observations to the large literature on beta recorded from sensorimotor cortex. Potentially, the clear-out of working memory in PFC has its counterpart in the postmovement clear-out of the motor plan in…

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome, which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut–brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFAs), key bioactive microbial metabolites, are the missing link along the gut–brain axis and might be able to modulate recovery after experimental stroke. SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFAs induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in spine and synapse densities. RNA sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional remodeling. Further analyses confirmed a substantial impact of SCFAs on microglial…

The landscape of gender in education and the workforce has shifted over the past decades: women have made gains in representation, equitable pay, and recognition through awards, grants, and publications. Despite overall change, differences persist in the fields of science, technology, engineering, and mathematics (STEM). This Viewpoints article on gender disparities in STEM offers an overarching perspective by addressing what the issues are, why the issues may emerge, and how the issues may be solved. In Part 1, recent data on gaps in representation, compensation, and recognition (awards, grants, publications) are reviewed, highlighting differences across subfields (e.g., computer science vs biology) and across career trajectories (e.g., bachelor's degrees vs senior faculty). In Part 2, evidence on leading explanations for these gaps, including explanations centered on abilities, preferences, and explicit and implicit bias, is presented. Particular attention is paid to implicit bias: mental processes that exist largely outside of conscious awareness and control in both male and…

The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.

The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded…

Mitochondria play many important biological roles, including ATP production, lipid biogenesis, ROS regulation, and calcium clearance. In neurons, the mitochondrion is an essential organelle for metabolism and calcium homeostasis. Moreover, mitochondria are extremely dynamic and able to divide, fuse, and move along microtubule tracks to ensure their distribution to the neuronal periphery. Mitochondrial dysfunction and altered mitochondrial dynamics are observed in a wide range of conditions, from impaired neuronal development to various neurodegenerative diseases. Novel imaging techniques and genetic tools provide unprecedented access to the physiological roles of mitochondria by visualizing mitochondrial trafficking, morphological dynamics, ATP generation, and ultrastructure. Recent studies using these new techniques have unveiled the influence of mitochondria on axon branching, synaptic function, calcium regulation with the ER, glial cell function, neurogenesis, and neuronal repair. This review provides an overview of the crucial roles played by mitochondria in the CNS in…

Recent proposals suggest that sleep may be a factor associated with accumulation of two core pathological features of Alzheimer9s disease (AD): tau and β-amyloid (Aβ). Here we combined PET measures of Aβ and tau, electroencephalogram sleep recordings, and retrospective sleep evaluations to investigate the potential utility of sleep measures in predicting in vivo AD pathology in male and female older adults. Regression analyses revealed that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. Aβ burden was not associated with coupling impairment but instead predicted the diminished amplitude of <1 Hz slow-wave-activity, results that were statistically dissociable from each other. Additionally, comparisons of AD pathology and retrospective, self-reported changes in sleep duration demonstrated that changes in sleep across the lifespan can predict late-life Aβ and tau burden. Thus, quantitative and qualitative features of human sleep represent potential noninvasive, cost-effective, and scalable biomarkers (current and…

Neurotransmission is sustained by endocytosis and refilling of synaptic vesicles (SVs) locally within the presynapse. Until recently, a consensus formed that after exocytosis, SVs are recovered by either fusion pore closure (kiss-and-run) or clathrin-mediated endocytosis directly from the plasma membrane. However, recent data have revealed that SV formation is more complex than previously envisaged. For example, two additional recycling pathways have been discovered, ultrafast endocytosis and activity-dependent bulk endocytosis, in which SVs are regenerated from the internalized membrane and synaptic endosomes. Furthermore, these diverse modes of endocytosis appear to influence both the molecular composition and subsequent physiological role of individual SVs. In addition, previously unknown complexity in SV refilling and reclustering has been revealed. This review presents a modern view of the SV life cycle and discusses how neuronal subtype, physiological temperature, and individual activity patterns can recruit different endocytic modes to generate new SVs and sculpt subsequent…

Music ranks among the greatest human pleasures. It consistently engages the reward system, and converging evidence implies it exploits predictions to do so. Both prediction confirmations and errors are essential for understanding one's environment, and music offers many of each as it manipulates interacting patterns across multiple timescales. Learning models suggest that a balance of these outcomes (i.e., intermediate complexity) optimizes the reduction of uncertainty to rewarding and pleasurable effect. Yet evidence of a similar pattern in music is mixed, hampered by arbitrary measures of complexity. In the present studies, we applied a well-validated information-theoretic model of auditory expectation to systematically measure two key aspects of musical complexity: predictability (operationalized as information content [IC]), and uncertainty (entropy). In Study 1, we evaluated how these properties affect musical preferences in 43 male and female participants; in Study 2, we replicated Study 1 in an independent sample of 27 people and assessed the contribution of veridical…

The locus coeruleus (LC) is a seemingly singular and compact neuromodulatory nucleus that is a prominent component of disparate theories of brain function due to its broad noradrenergic projections throughout the CNS. As a diffuse neuromodulatory system, noradrenaline affects learning and decision making, control of sleep and wakefulness, sensory salience including pain, and the physiology of correlated forebrain activity (ensembles and networks) and brain hemodynamic responses. However, our understanding of the LC is undergoing a dramatic shift due to the application of state-of-the-art methods that reveal a nucleus of many modules that provide targeted neuromodulation. Here, we review the evidence supporting a modular LC based on multiple levels of observation (developmental, genetic, molecular, anatomical, and neurophysiological). We suggest that the concept of the LC as a singular nucleus and, alongside it, the role of the LC in diverse theories of brain function must be reconsidered.

Abstract Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer’s disease. We test the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [ 11 C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 humans (13 females/15 males) with clinical diagnosis of probable Alzheimer’s disease or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy humans (8 females/6 males). Source-based ‘inflammetry’ was used to extract principal components of [ 11 C]PK11195 PET signal variance across all participants. rs-fMRI data were pre-processed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal co-variance between neuroinflammation and brain connectivity profiles, in relation to group and cognitive status. Patients showed significantly higher [ 11…

The recent shift in sociopolitical debates and growing liberalization of cannabis use across the globe has raised concern regarding its impact on vulnerable populations, such as pregnant women and adolescents. Epidemiological studies have long demonstrated a relationship between developmental cannabis exposure and later mental health symptoms. This relationship is especially strong in people with particular genetic polymorphisms, suggesting that cannabis use interacts with genotype to increase mental health risk. Seminal animal research directly linked prenatal and adolescent exposure to delta-9-tetrahydrocannabinol, the major psychoactive component of cannabis, with protracted effects on adult neural systems relevant to psychiatric and substance use disorders. In this article, we discuss some recent advances in understanding the long-term molecular, epigenetic, electrophysiological, and behavioral consequences of prenatal, perinatal, and adolescent exposure to cannabis/delta-9-tetrahydrocannabinol. Insights are provided from both animal and human studies, including in vivo…

An integral part of human language is the capacity to extract meaning from spoken and written words, but the precise relationship between brain representations of information perceived by listening versus reading is unclear. Prior neuroimaging studies have shown that semantic information in spoken language is represented in multiple regions in the human cerebral cortex, while amodal semantic information appears to be represented in a few broad brain regions. However, previous studies were too insensitive to determine whether semantic representations were shared at a fine level of detail rather than merely at a coarse scale. We used fMRI to record brain activity in two separate experiments while participants listened to or read several hours of the same narrative stories, and then created voxelwise encoding models to characterize semantic selectivity in each voxel and in each individual participant. We find that semantic tuning during listening and reading are highly correlated in most semantically selective regions of cortex, and models estimated using one modality accurately…

Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various CNS diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Here, we investigated the important functions of circRNA TLK1 (circTLK1) in this process. The levels of circTLK1 were significantly increased in brain tissues in a mouse model of focal cerebral ischemia and reperfusion. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. Furthermore, circTLK1 functioned as an endogenous miR-335-3p sponge to inhibit miR-335-3p activity, resulting in the increase of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly (ADP-ribose) polymerase expression and a subsequent exacerbation of neuronal injury. Clinical studies confirmed increased levels of circTLK1 in the plasma of patients with acute ischemic stroke (59 males and 12 females). Our findings reveal a detrimental role of circTLK1 in ischemic brain injury. SIGNIFICANCE STATEMENT The extent of neuronal injury…

Humans excel at understanding speech even in adverse conditions such as background noise. Speech processing may be aided by cortical activity in the delta and theta frequency bands, which have been found to track the speech envelope. However, the rhythm of non-speech sounds is tracked by cortical activity as well. It therefore remains unclear which aspects of neural speech tracking represent the processing of acoustic features, related to the clarity of speech, and which aspects reflect higher-level linguistic processing related to speech comprehension. Here we disambiguate the roles of cortical tracking for speech clarity and comprehension through recording EEG responses to native and foreign language in different levels of background noise, for which clarity and comprehension vary independently. We then use a both a decoding and an encoding approach to relate clarity and comprehension to the neural responses. We find that cortical tracking in the theta frequency band is mainly correlated to clarity, whereas the delta band contributes most to speech comprehension. Moreover, we…

17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70–80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenousin vivoE2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore,in vitrostudies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect…

It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer9s disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of coculturing WT neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that overexpress BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured WT neurons. Double-mutant 5xF:pGB mice displayed improvements in cognitive tasks compared with 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of…

Migraine is the second leading cause for disability worldwide and the most common neurological disorder. It is also three times more common in women; reasons for this sex difference are not known. Using preclinical behavioral models of migraine, we show that application of calcitonin gene-related peptide (CGRP) to the rat dura mater produces cutaneous periorbital hypersensitivity. Surprisingly, this response was observed only in females; dural CGRP at doses from 1 pg to 3.8 μg produce no responses in males. In females, dural CGRP causes priming to a pH 7.0 solution after animals recover from the initial CGRP-induced allodynia. Dural application of interleukin-6 causes acute responses in males and females but only causes priming to subthreshold dural CGRP (0.1 pg) in females. Intracisternal application of BDNF also causes similar acute hypersensitivity responses in males and females but only priming to subthreshold dural CGRP (0.1 pg) in females. Females were additionally primed to a subthreshold dose of the NO-donor sodium nitroprusside (0.1 mg/kg) following dural CGRP. Finally, the…

Sleep loss increases the experience of pain. However, the brain mechanisms underlying altered pain processing following sleep deprivation are unknown. Moreover, it remains unclear whether ecologically modest night-to-night changes in sleep, within an individual, confer consequential day-to-day changes in experienced pain. Here, we demonstrate that acute sleep deprivation amplifies pain reactivity within human (male and female) primary somatosensory cortex yet blunts pain reactivity in higher-order valuation and decision-making regions of the striatum and insula cortex. Consistent with this altered neural signature, we further show that sleep deprivation expands the temperature range for classifying a stimulus as painful, specifically through a lowering of pain thresholds. Moreover, the degree of amplified reactivity within somatosensory cortex following sleep deprivation significantly predicts this expansion of experienced pain across individuals. Finally, outside of the laboratory setting, we similarly show that even modest nightly changes in sleep quality (increases and decreases)…

Large-scale functional connectome formation and reorganization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated before birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules, and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function. SIGNIFICANCE STATEMENTThe fetal…

Abstract The neurophysiological basis of motor processes and their control is of tremendous interest to basic researchers and clinicians alike. Notably, both movement initiation and cancellation are accompanied by prominent field potential changes in the β-frequency band (15-29Hz). In trial-averages, movement initiation is indexed by β-band desynchronization over sensorimotor sites, while movement cancellation is signified by β-power increases over (pre)frontal areas. However, averaging misrepresents the true nature of the β-signal. As recent work has highlighted, raw β-band activity is characterized by short-lasting, burst-like events, rather than by steady modulations. To investigate how such β-bursts relate to movement initiation and cancellation in humans, we investigated scalp-recorded β-band activity in 234 healthy subjects performing the Stop-signal task. Four observations were made: First, both movement initiation and cancellation were indexed by systematic, localized changes in β-bursting. While β-bursting at bilateral sensorimotor sites steadily declined during movement…

The discovery of a G-protein-coupled receptor for lactate named hydroxycarboxylic acid receptor 1 (HCAR1) in neurons has pointed to additional nonmetabolic effects of lactate for regulating neuronal network activity. In this study, we characterized the intracellular pathways engaged by HCAR1 activation, using mouse primary cortical neurons from wild-type (WT) and HCAR1 knock-out (KO) mice from both sexes. Using whole-cell patch clamp, we found that the activation of HCAR1 with 3-chloro-5-hydroxybenzoic acid (3Cl-HBA) decreased miniature EPSC frequency, increased paired-pulse ratio, decreased firing frequency, and modulated membrane intrinsic properties. Using fast calcium imaging, we show that HCAR1 agonists 3,5-dihydroxybenzoic acid, 3Cl-HBA, and lactate decreased by 40% spontaneous calcium spiking activity of primary cortical neurons from WT but not from HCAR1 KO mice. Notably, in neurons lacking HCAR1, the basal activity was increased compared with WT. HCAR1 mediates its effect in neurons through a Giα-protein. We observed that the adenylyl cyclase–cAMP–protein kinase A axis is…

Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer9s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the β cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, whereas RNA sequencing analysis excluded a transcriptional…

Persistent endoplasmic reticulum (ER) stress in neurons is associated with activation of inflammatory cells and subsequent neuroinflammation following traumatic brain injury (TBI); however, the underlying mechanism remains elusive. We found that induction of neuronal-ER stress, which was mostly characterized by an increase in phosphorylation of a protein kinase R-like ER kinase (PERK) leads to release of excess interferon (IFN)β due to atypical activation of the neuronal-STING signaling pathway. IFNβ enforced activation and polarization of the primary microglial cells to inflammatory M1 phenotype with the secretion of a proinflammatory chemokine CXCL10 due to activation of STAT1 signaling. The secreted CXCL10, in turn, stimulated the T-cell infiltration by serving as the ligand and chemoattractant for CXCR3+T-helper 1 (Th1) cells. The activation of microglial cells and infiltration of Th1 cells resulted in white matter injury, characterized by impaired myelin basic protein and neurofilament NF200, the reduced thickness of corpus callosum and external capsule, and decline of mature…

The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of β-amyloid (Aβ). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aβ degradation capacity. Human CSF from APOE ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE ε3/ε3 carriers. Enhancing ABCA1…

The accumulation of misfolded proteins is a common pathological feature of many neurodegenerative disorders, including synucleinopathies such as Parkinson9s disease (PD), which is characterized by the presence of α-synuclein (α-syn)-containing Lewy bodies. However, although recent studies have investigated α-syn accumulation and propagation in neurons, the molecular mechanisms underlying α-syn transmission have been largely unexplored. Here, we examined a monogenic form of synucleinopathy caused by loss-of-function mutations in lysosomal ATP13A2/PARK9. These studies revealed that lysosomal exocytosis regulates intracellular levels of α-syn in human neurons. Loss of PARK9 function in patient-derived dopaminergic neurons disrupted lysosomal Ca2+ homeostasis, reduced lysosomal Ca2+ storage, increased cytosolic Ca2+, and impaired lysosomal exocytosis. Importantly, this dysfunction in lysosomal exocytosis impaired α-syn secretion from both axons and soma, promoting α-syn accumulation. However, activation of the lysosomal Ca2+ channel transient receptor potential mucolipin 1 (TRPML1) was…

Abstract Although the EEG slow wave of sleep is typically considered to be a hallmark of Non Rapid Eye Movement (NREM) sleep, recent work in mice has shown that slow waves can also occur in REM sleep. Here we investigated the presence and cortical distribution of low-frequency (1-4 Hz) oscillations in human REM sleep by analyzing high-density EEG sleep recordings obtained in 28 healthy subjects. We identified two clusters of low-frequency oscillations with distinctive properties: 1) a fronto-central cluster characterized by ∼2.5-3.0 Hz, relatively large, notched delta waves (so-called ‘sawtooth waves’) that tended to occur in bursts, were associated with increased gamma activity and rapid eye movements, and upon source modeling, displayed an occipito-temporal and a fronto-central component; and 2) a medial occipital cluster characterized by more isolated, slower (<2 Hz) and smaller waves that were not associated with rapid eye movements, displayed a negative correlation with gamma activity and were also found in NREM sleep. Thus, low-frequency oscillations are an integral part of…

Abstract In principle, selective attention is the net result of target selection and distractor suppression. The way in which both mechanisms are implemented neurally has remained contested. Neural oscillatory power in the alpha frequency band (~10 Hz) has been implicated in the selection of to-be-attended targets, but there is lack of empirical evidence for its involvement in the suppression of to-be-ignored distractors. Here, we use electroencephalography (EEG) recordings of N = 33 human participants (males and females) to test the pre-registered hypothesis that alpha power directly relates to distractor suppression and thus operates independently from target selection. In an auditory spatial pitch discrimination task, we modulated the location (left vs right) of either a target or a distractor tone sequence, while fixing the other in the front. When the distractor was fixed in the front, alpha power relatively decreased contralaterally to the target and increased ipsilaterally. Most importantly, when the target was fixed in the front, alpha lateralization reversed in direction…

Abstract Apolipoprotein E (ApoE) mediates clearance of circulating lipoproteins from blood by binding to ApoE receptors. Humans express three genetic variants, ApoE2, ApoE3, and ApoE4, that exhibit distinct ApoE receptor binding properties. In brain, ApoE is abundantly produced by activated astrocytes and microglia, and three variants differentially affect Alzheimer’s disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to the disease. A role for ApoE4 in driving microglial dysregulation and impeding Aβ clearance in AD is well documented, but the direct effects of three variants on neurons are poorly understood. Extending previous studies, we here demonstrate that ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades which among others enhance synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD…

Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA…

Abstract It is well known that attention can facilitate performance by top-down biasing processing of task-relevant information in advance. Recent findings from behavioral studies suggest that distractor inhibition is not under similar direct control, but strongly dependent on expectations derived from previous experience. Yet, how expectations about distracting information influence distractor inhibition at the neural level remains unclear. The current study addressed this outstanding question in three experiments in which search displays with repeating distractor or target locations across trials allowed observers to learn which location to selectively suppress or boost. Behavioral findings demonstrated that both distractor and target location learning resulted in more efficient search, as indexed by faster response times. Crucially, benefits of distractor learning were observed without target location foreknowledge, unaffected by the number of possible target locations, and could not be explained by priming alone. To determine how distractor location expectations facilitated…

Cognitive control is necessary for goal-directed behavior, yet people treat cognitive control demand as a cost, which discounts the value of rewards in a similar manner as other costs, such as delay or risk. It is unclear, however, whether the subjective value (SV) of cognitive effort is encoded in the same putatively domain-general brain valuation network implicated in other cost domains, or instead engages a distinct frontoparietal network, as implied by recent studies. Here, we provide rigorous evidence that the valuation network, with core foci in the ventromedial prefrontal cortex and ventral striatum, also encodes SV during cognitive effort-based decision-making in healthy, male and female adult humans. We doubly dissociate this network from frontoparietal regions that are instead recruited as a function of decision difficulty. We show that the domain-general valuation network jointly and independently encodes both reward benefits and cognitive effort costs. We also demonstrate that cognitive effort SV signals predict choice and are influenced by state and trait motivation,…

Speech perception involves the integration of sensory input with expectations based on the context of that speech. Much debate surrounds the issue of whether or not prior knowledge feeds back to affect early auditory encoding in the lower levels of the speech processing hierarchy, or whether perception can be best explained as a purely feedforward process. Although there has been compelling evidence on both sides of this debate, experiments involving naturalistic speech stimuli to address these questions have been lacking. Here, we use a recently introduced method for quantifying the semantic context of speech and relate it to a commonly used method for indexing low-level auditory encoding of speech. The relationship between these measures is taken to be an indication of how semantic context leading up to a word influences how its low-level acoustic and phonetic features are processed. We record EEG from human participants (both male and female) listening to continuous natural speech and find that the early cortical tracking of a word9s speech envelope is enhanced by its semantic…

Electrocorticogram (ECoG), obtained by low-pass filtering the brain signal recorded from a macroelectrode placed on the cortex, is extensively used to find the seizure focus in drug-resistant epilepsy and is of growing importance in cognitive and brain–machine-interfacing studies. To accurately estimate the epileptogenic cortex or to make inferences about cognitive processes, it is important to determine the “spatial spread” of ECoG (i.e., the extent of cortical tissue that contributes to its activity). However, the ECoG spread is currently unknown; even the spread of local field potential (LFP) obtained from microelectrodes is debated, with estimates ranging from a few hundred micrometers to several millimeters. Spatial spread can be estimated by measuring the receptive field (RF) and multiplying by the cortical magnification factor, but this method overestimates the spread because RF size gets inflated due to several factors. This issue can be partially addressed using a model that compares the RFs of two measures, such as LFP and multi-unit activity (MUA). To use this approach…

Abstract Background Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse. Methods In collaboration with the genetics company 23andMe, Inc., we performed several genome-wide association studies ( GWAS ) on measures of impulsive personality traits (the short version of the UPPSP Impulsive Behavior Scale, and the Barratt Impulsiveness Scale [BIS-11]) and drug experimentation (the number of drug classes an individual has tried in their lifetime) in up to 22,861 male and female adult research participants of European ancestry. Results Impulsive personality traits and drug experimentation showed SNP-heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with the UPPSP Sensation Seeking subscale ( P = 8.3 × 10 -9 , rs139528938) and showed a suggestive association with drug experimentation ( P = 3.0 × 10 -7 , rs2163971; r 2 = 0.68 with rs139528938); CADM2 has been previously associated with measures…

Abstract How does the brain represent the reliability of its sensory evidence? Here, we test whether sensory uncertainty is encoded in cortical population activity as the width of a probability distribution – a hypothesis that lies at the heart of Bayesian models of neural coding. We probe the neural representation of uncertainty by capitalizing on a well-known behavioral bias called serial dependence. Human observers of either sex reported the orientation of stimuli presented in sequence, while activity in visual cortex was measured with fMRI. We decoded probability distributions from population-level activity and found that serial dependence effects in behavior are consistent with a statistically advantageous sensory integration strategy, in which uncertain sensory information is given less weight. More fundamentally, our results suggest that probability distributions decoded from human visual cortex reflect the sensory uncertainty that observers rely on in their decisions, providing critical evidence for Bayesian theories of perception.

Chronic social defeat (CSD) in male mice can produce anxiety and aberrant socialization. Animals susceptible to CSD show activation of microglia, which have elevated levels of oxidative stress markers. We hypothesized that microglia and reactive oxygen species (ROS) production contribute to the CSD stress-induced changes in affective behavior. First, we selectively depleted microglia (99%) by administering the CSF1R (colony-stimulating factor 1 receptor) antagonist PLX5622 before and during the 14 d CSD procedure. Microglia-depleted mice in contrast to nondepleted mice were protected from the stress effects measured by light/dark and social interaction tests. ROS production, measured histochemically following dihydroethidium administration, was elevated by CSD, and the production was reduced to basal levels in mice lacking microglia. The deleterious stress effects were also blocked in nondepleted mice by continuous intracerebral administration of N-acetylcysteine (NAC), a ROS inhibitor. In a second experiment, at the end of the CSD period, PLX5622 was discontinued to allow…

Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo. Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5–43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal…

ATM (ataxia-telangiectasia mutated) is a PI3K-like kinase best known for its role in the DNA damage response (DDR), especially after double-strand breaks. Mutations in the ATM gene result in a condition known as ataxia-telangiectasia (A-T) that is characterized by cancer predisposition, radiosensitivity, neurodegeneration, sterility, and acquired immune deficiency. We show here that the innate immune system is not spared in A-T. ATM-deficient microglia adopt an active phenotype that includes the overproduction of proinflammatory cytokines that are toxic to cultured neurons and likely contribute to A-T neurodegeneration. Causatively, ATM dysfunction results in the accumulation of DNA in the cytoplasm of microglia as well as a variety of other cell types. In microglia, cytoplasmic DNA primes an antiviral response via the DNA sensor, STING (stimulator of interferon genes). The importance of this response pathway is supported by our finding that inhibition of STING blocks the overproduction of neurotoxic cytokines. Cytosolic DNA also activates the AIM2 (absent in melanoma 2) containing…

Chemotherapy-induced peripheral neuropathy (CIPN) remains a pressing clinical problem; however, our understanding of sexual dimorphism in CIPN remains unclear. Emerging studies indicate a sex-dimorphic role of Toll-like receptor 4 (TLR4) in driving neuropathic pain. In this study, we examined the role of TLR9 in CIPN induced by paclitaxel in WT and Tlr9 mutant mice of both sexes. Baseline pain sensitivity was not affected in either Tlr9 mutant male or female mice. Intraplantar and intrathecal injection of the TLR9 agonist ODN 1826 induced mechanical allodynia in both sexes of WT and Tlr4 KO mice but failed to do so in Tlr9 mutant mice. Moreover, Trpv1 KO or C-fiber blockade by resiniferatoxin failed to affect intraplantar ODN 1826-induced mechanical allodynia. Interestingly, the development of paclitaxel-evoked mechanical allodynia was attenuated by TLR9 antagonism or Tlr9 mutation only in male mice. Paclitaxel-induced CIPN caused macrophage infiltration to DRGs in both sexes, and this infiltration was not affected by Tlr9 mutation. Paclitaxel treatment also upregulated TNF and…

Contextual fear memory becomes less context-specific over time, a phenomenon referred to as contextual fear generalization. Overgeneralization of contextual fear memory is a core symptom of post-traumatic stress disorder (PTSD), but circuit mechanisms underlying the generalization remain unclear. We show here that neural projections from the anterior cingulate cortex (ACC) to ventral hippocampus (vHPC) mediate contextual fear generalization in male mice. Retrieval of contextual fear in a novel context at a remote time point activated cells in the ACC and vHPC, as indicated by significantly increased C-fos+ cells. Using chemogenetic or photogenetic manipulations, we observed that silencing the activity of ACC or vHPC neurons reduced contextual fear generalization at the remote time point, whereas stimulating the activity of ACC or vHPC neurons facilitated contextual fear generalization at a recent time point. We found that ACC neurons projected to the vHPC unidirectionally, and importantly, silencing the activity of projection fibers from the ACC to vHPC inhibited contextual fear…

In the mammalian brain, the insula is the primary cortical substrate involved in the perception of taste. Recent imaging studies in rodents have identified a “gustotopic” organization in the insula, whereby distinct insula regions are selectively responsive to one of the five basic tastes. However, numerous studies in monkeys have reported that gustatory cortical neurons are broadly-tuned to multiple tastes, and tastes are not represented in discrete spatial locations. Neuroimaging studies in humans have thus far been unable to discern between these two models, though this may be because of the relatively low spatial resolution used in taste studies to date. In the present study, we examined the spatial representation of taste within the human brain using ultra-high resolution functional magnetic resonance imaging (MRI) at high magnetic field strength (7-tesla). During scanning, male and female participants tasted sweet, salty, sour, and tasteless liquids, delivered via a custom-built MRI-compatible tastant-delivery system. Our univariate analyses revealed that all tastes (vs…

Abstract Refractory focal neocortical epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1 , was codon-optimized for human expression and mutated to accelerate the channels’ recovery from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a non-integrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled pre-clinical trial, the EKC lentivector robustly reduced seizure frequency in a rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. This demonstration of efficacy in a clinically relevant setting, combined with the…

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) are focal malformations of cortical development (FMCDs) that are highly associated with intractable epilepsy. TSC and FCD are mTORopathies caused by a spectrum of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway genes leading to differential activation of mTOR signaling. However, whether the degree of mTOR hyperactivity influences disease severity remains unclear. Here, we examined the effects of differential mTOR hyperactivity levels on epilepsy and associated neuropathology in a mouse model of TSC and FCD. Constitutively active Rheb (RhebCA), the canonical activator of mTOR complex 1 (mTORC1), was expressed in mouse embryos of either sex viain uteroelectroporation at low, intermediate, and high concentrations to induce different mTORC1 activity levels in developing cortical neurons. We found that RhebCAexpression induced mTORC1 hyperactivation and increased neuronal soma size and misplacement in a dose-dependent manner. No seizures were detected in the low RhebCAmice, whereas the…

Humans have bred different lineages of domestic dogs for different tasks such as hunting, herding, guarding, or companionship. These behavioral differences must be the result of underlying neural differences, but surprisingly, this topic has gone largely unexplored. The current study examined whether and how selective breeding by humans has altered the gross organization of the brain in dogs. We assessed regional volumetric variation in MRI studies of 62 male and female dogs of 33 breeds. Neuroanatomical variation is plainly visible across breeds. This variation is distributed nonrandomly across the brain. A whole-brain, data-driven independent components analysis established that specific regional subnetworks covary significantly with each other. Variation in these networks is not simply the result of variation in total brain size, total body size, or skull shape. Furthermore, the anatomy of these networks correlates significantly with different behavioral specialization(s) such as sight hunting, scent hunting, guarding, and companionship. Importantly, a phylogenetic analysis…

Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial…

Differently from other myeloid cells, microglia derive exclusively from precursors originating within the yolk sac and migrate to the CNS under development, without any contribution from fetal liver or postnatal hematopoiesis. Consistent with their unique ontology, microglia may express specific physiological markers, which have been partly described in recent years. Here we wondered whether profiles distinguishing microglia from peripheral macrophages vary with age and under pathology. To this goal, we profiled transcriptomes of microglia throughout the lifespan and included a parallel comparison with peripheral macrophages under physiological and neuroinflammatory settings using age- and sex-matched wild-type and bone marrow chimera mouse models. This comprehensive approach demonstrated that the phenotypic differentiation between microglia and peripheral macrophages is age-dependent and that peripheral macrophages do express some of the most commonly described microglia-specific markers early during development, such as Fcrls, P2ry12, Tmem119, and Trem2. Further, during chronic…