Score: 213.0, Published: 2024-02-10
DOI: 10.1101/2024.02.09.579589
The coronavirus disease of 2019 (COVID-19) pandemic that has led to more than 700 million confirmed cases and near 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains as an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to the neurological complications both acutely and in long COVID.
Score: 92.0, Published: 2024-02-13
DOI: 10.1101/2024.02.12.579972
In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. Here, we demonstrate using multiple, independent, in vitro and in vivo approaches that the majority ([~]80-90%) of axonal mitochondria in cortical pyramidal neurons (CPNs), lack mitochondrial DNA (mtDNA). Using dynamic, optical imaging analysis of genetically encoded sensors for mitochondrial matrix ATP and pH, we demonstrate that in axons of CPNs, but not in their dendrites, mitochondrial complex V (ATP synthase) functions in a reverse way, consuming ATP and protruding H+ out of the matrix to maintain mitochondrial membrane potential. Our results demonstrate that in mammalian CPNs, axonal mitochondria do not play a major role in ATP supply, despite playing other functions critical to regulating neurotransmission such as Ca2+ buffering.
Score: 33.1, Published: 2024-02-13
DOI: 10.1101/2024.02.13.580198
The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. A growing catalogue of cells in the prenatal brain has revealed remarkable molecular diversity across cortical areas.1,2 Despite this, little is known about how this translates into the patterns of differential cortical expansion observed in humans during the latter stages of gestation. Here we present a new resource, Brain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal developing brain. Built using generative artificial intelligence, Brain is a three-dimensional cellular-resolution digital atlas combining publicly-available serial sections of the postmortem human brain at 21 weeks gestation3 with bulk tissue microarray data, sampled across 29 cortical regions and 5 transient tissue zones.4 Using Brain, we evaluate the molecular signatures of preferentially-expanded cortical regions during human gestation, quantified in utero using magnetic resonance imaging (MRI). We find that differences in the rates of expansion across cortical areas during gestation respect anatomical and evolutionary boundaries between cortical types5 and are founded upon extended periods of upper-layer cortical neuron migration that continue beyond mid-gestation. We identify a set of genes that are upregulated from mid-gestation and highly expressed in rapidly expanding neocortex, which are implicated in genetic disorders with cognitive sequelae. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of expansion across the neocortical sheet during the prenatal epoch. The Brain atlas is available from: https://garedaba.github.io/micro-brain/ and provides a new tool to comprehensively map early brain development across domains, model systems and resolution scales.
Score: 32.7, Published: 2024-02-13
DOI: 10.1101/2024.02.12.579947
The basolateral amygdala (BLA) is essential for assigning positive or negative valence to sensory stimuli. Noxious stimuli that cause pain are encoded by an ensemble of nociceptive BLA projection neurons (BLAnoci ensemble). However, the role of the BLAnoci ensemble in mediating behavior changes and the molecular signatures and downstream targets distinguishing this ensemble remain poorly understood. Here, we show that the same BLAnoci ensemble neurons are required for both acute and chronic neuropathic pain behavior. Using single nucleus RNA-sequencing, we characterized the effect of acute and chronic pain on the BLA and identified enrichment for genes with known functions in axonal and synaptic organization and pain perception. We thus examined the brain-wide targets of the BLAnoci ensemble and uncovered a previously undescribed nociceptive hotspot of the nucleus accumbens shell (NAcSh) that mirrors the stability and specificity of the BLAnoci ensemble and is recruited in chronic pain. Notably, BLAnoci ensemble axons transmit acute and neuropathic nociceptive information to the NAcSh, highlighting this nociceptive amygdala-striatal circuit as a unique pathway for affective-motivational responses across pain states.
Score: 32.4, Published: 2024-02-15
DOI: 10.1101/2024.02.15.580483
Oxytocin is essential in shaping social behavior across the lifespan. While the role of oxytocin signaling in parental care has been widely investigated, little is known about its function in social behavior during early life. This is partly due to the lack of precise technologies for studying the developing brain. Here, we studied the role of oxytocin in pup social behavior under acute separation from and reunion with the mother. We show that the activity of oxytocin neurons was increased by acute maternal separation and returned to baseline after reunion. Behaviorally, maternally separated pups emitted more ultrasonic vocalizations upon reunion, which were further modulated by nipple attachment behavior. These effects were attenuated by blocking the oxytocin receptor during maternal separation. To investigate the role of oxytocin neurons with higher precision, we established a method for transcranial optogenetic silencing of neuronal activity in untethered and freely behaving pups. Using this approach, we found that silencing of oxytocin neurons during maternal separation disrupted vocal behavior during separation and reunion in a sex-specific manner. Our findings reveal an important role of oxytocin in context-dependent vocal communication in pups, offering new insights into the mechanisms of social behavior during early life.
Score: 26.7, Published: 2024-02-12
DOI: 10.1101/2024.02.12.579750
Fast electrical signaling in dendrites is central to neural computations that support adaptive behaviors. Conventional techniques lack temporal and spatial resolution and the ability to track underlying membrane potential dynamics present across the complex three-dimensional dendritic arbor in vivo. Here, we perform fast two-photon imaging of dendritic and somatic membrane potential dynamics in single pyramidal cells in the CA1 region of the mouse hippocampus during awake behavior. We study the dynamics of subthreshold membrane potential and suprathreshold dendritic events throughout the dendritic arbor in vivo by combining voltage imaging with simultaneous local field potential recording, post hoc morphological reconstruction, and a spatial navigation task. We systematically quantify the modulation of local event rates by locomotion in distinct dendritic regions and report an advancing gradient of dendritic theta phase along the basal-tuft axis, then describe a pre-dominant hyperpolarization of the dendritic arbor during sharp-wave ripples. Finally, we find spatial tuning of dendritic representations dynamically reorganizes following place field formation. Our data reveal how the organization of electrical signaling in dendrites maps onto the anatomy of the dendritic tree across behavior, oscillatory network, and functional cell states.
Score: 33.6, Published: 2024-02-08
DOI: 10.1101/2023.10.30.564700
The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinsons disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinsons disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N=22), ON dopaminergic medication (N=18) and ON subthalamic deep brain stimulation (N=8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinsons disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.
Score: 24.7, Published: 2024-02-12
DOI: 10.1101/2024.02.11.579849
The gradual loss of cerebral white matter contributes to cognitive decline during aging. However, microvascular networks that support the metabolic demands of white matter remain poorly defined. We used in vivo deep multi-photon imaging to characterize microvascular networks that perfuse cortical layer 6 and corpus callosum, a highly studied region of white matter in the mouse brain. We show that these deep tissues are exclusively drained by sparse and wide-reaching venules, termed principal cortical venules, which mirror vascular architecture at the human cortical-U fiber interface. During aging, capillary networks draining into deep branches of principal cortical venules are selectively constricted, reduced in density, and diminished in pericyte numbers. This causes hypo-perfusion in deep tissues, and correlates with gliosis and demyelination, whereas superficial tissues become relatively hyper-perfused. Thus, age-related impairment of capillary-venular drainage is a key vascular deficit that contributes to the unique vulnerability of cerebral white matter during brain aging.
Score: 21.7, Published: 2024-02-12
DOI: 10.1101/2024.02.11.579845
Does being awake mean being conscious? This study investigates Mind Blanking (MB), characterized by an "emptiness of mind", comparing it with Mind Wandering (MW) and On-task (ON) states. Using a sustained attention task and electroencephalogram monitoring on 26 participants, behavioral and neurophysiological signatures of MB were examined. MB exhibited a specific pattern of behavioral lapses, as well as decreased fast oscillatory activity and complexity over posterior electrodes compared to MW. Functional connectivity analyses also revealed decreased frontal-posterior connectivity during MB and event-related potentials indicated a disruption in late-stage visual processing, suggesting a lack of conscious access to sensory information during MB. EEG-based neural features enabled trial-level prediction of mental states, furnishing estimates of the fine-grained dynamics of consciousness beyond subjective reports. Overall, these findings challenge the notion of continuous wake consciousness, suggesting that MB represents genuine gaps in our stream of thoughts. SIGNIFICANCE STATEMENTEmploying cutting-edge neurophysiological techniques on high-density EEG recordings, our study unveils unique neurophysiological markers of mind blanking--a phenomenon characterized by lapses in conscious content amidst the flow of consciousness. Distinguished from task-oriented states and mind wandering, this signature sheds light on the elusive nature of mind blanking. Furthermore, we demonstrate the feasibility of decoding consciousness dynamics solely from EEG features, transcending the limitations of intermittent subjective reports. Our findings not only provide a novel framework for investigating the stream of consciousness but also challenge the conventional notion that wakefulness invariably signifies consciousness.
Score: 18.6, Published: 2024-02-14
DOI: 10.1101/2024.02.13.580193
While the neural basis of age-related decline has been extensively studied (1-3), less is known about changes in neural function during the pre-senescent stages of adulthood. Adult neural plasticity is likely a key factor in social insect age polyethism, where individuals perform different tasks as they age and divide labor in an age-dependent manner (4-9). Primarily, workers transition from nursing to foraging tasks (5, 10), become more aggressive, and more readily display alarm behavior (11-16) as they get older. While it is unknown how these behavioral dynamics are neurally regulated, they could partially be generated by altered salience of behaviorally relevant stimuli (4, 6, 7). Here, we investigated how odor coding in the antennal lobe (AL) changes with age in the context of alarm pheromone communication in the clonal raider ant (Ooceraea biroi) (17). Similar to other social insects (11, 12, 16), older ants responded more rapidly to alarm pheromones, the chemical signals for danger. Using whole-AL calcium imaging (18), we then mapped odor representations for five general odorants and two alarm pheromones in young and old ants. Alarm pheromones were represented sparsely at all ages. However, alarm pheromone responses within individual glomeruli changed with age, either increasing or decreasing. Only two glomeruli became sensitized to alarm pheromones with age, while at the same time becoming desensitized to general odorants. Our results suggest that the heightened response to alarm pheromones in older ants occurs via increased sensitivity in these two core glomeruli, illustrating the importance of sensory modulation in social insect division of labor and age-associated behavioral plasticity.