When faced with danger, human beings respond with a repertoire of defensive behaviors, including freezing and active avoidance. Previous research has revealed a pattern of physiological responses, characterized by heart rate bradycardia, reduced visual exploration, and heightened sympathetic arousal in reaction to avoidable threats, suggesting a state of attentive immobility in humans. However, the electrocortical underpinnings of these behaviors remain largely unexplored. To investigate the visuocortical components of attentive immobility, we recorded parieto-occipital alpha activity, along with eye movements and autonomic responses, while participants awaited either an avoidable, inevitable, or no threat. To test the robustness and generalizability of our findings, we collected data from a total of 101 participants (76 females, 25 males) at two laboratories. Across sites, we observed an enhanced suppression of parieto-occipital alpha activity during avoidable threats, in contrast to inevitable or no threat trials, particularly toward the end of the trial that prompted avoidance responses. This response pattern coincided with heart rate bradycardia, centralization of gaze, and increased sympathetic arousal. Furthermore, our findings expand on previous research by revealing that the amount of alpha suppression, along with centralization of gaze, and heart rate changes predict the speed of motor responses. Collectively, these findings indicate that when individuals encounter avoidable threats, they enter a state of attentive immobility, which enhances perceptual processing and facilitates action preparation. This state appears to reflect freezing-like behavior in humans.

The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anesthetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, suggesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaque V1 and V2 and simultaneously measured behavioral judgments of texture. We generated stimuli along a continuum between naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior compared with V1. The firing of both V1 and V2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the second monkey. We conclude that neural responses supporting texture perception likely continue to develop downstream of V2. Further, combined with neural data recorded while the same two monkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and therefore unlikely to directly reflect the formation of perceptual decisions.

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared with inflammatory pain, the cross talk between nociceptor TLR4 and mu-opioid receptors (MORs), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether (1) antisense knockdown of nociceptor MOR attenuates CIPN, (2) and attenuates the priming associated with CIPN, and (3) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin-induced priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming [the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)], an MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.

Thalamocortical pathways from the rodent ventral posterior (VP) thalamic complex to the somatosensory cerebral cortex areas are a key model in modern neuroscience. However, beyond the intensively studied projection from medial VP (VPM) to the primary somatosensory area (S1), the wiring of these pathways remains poorly characterized. We combined micropopulation tract-tracing and single-cell transfection experiments to map the pathways arising from different portions of the VP complex in male mice. We found that pathways originating from different VP regions show differences in area/lamina arborization pattern and axonal varicosity size. Neurons from the rostral VPM subnucleus innervate trigeminal S1 in point-to-point fashion. In contrast, a caudal VPM subnucleus innervates heavily and topographically second somatosensory area (S2), but not S1. Neurons in a third, intermediate VPM subnucleus innervate through branched axons both S1 and S2, with markedly different laminar patterns in each area. A small anterodorsal subnucleus selectively innervates dysgranular S1. The parvicellular VPM subnucleus selectively targets the insular cortex and adjacent portions of S1 and S2. Neurons in the rostral part of the lateral VP nucleus (VPL) innervate spinal S1, while caudal VPL neurons simultaneously target S1 and S2. Rostral and caudal VP nuclei show complementary patterns of calcium-binding protein expression. In addition to the cortex, neurons in caudal VP subnuclei target the sensorimotor striatum. Our finding of a massive projection from VP to S2 separate from the VP projections to S1 adds critical anatomical evidence to the notion that different somatosensory submodalities are processed in parallel in S1 and S2.

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also indispensable for the blood–brain barrier (BBB), blood–spinal cord barrier, and blood–retinal barrier and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional specifications of pericytes between CNS and peripheral organs have not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This putative cation-transporting ATPase 13A5 (Atp13a5) marker was identified through single-cell transcriptomics, based on its specificity to brain pericytes. We further generated a knock-in model with both tdTomato reporter and Cre recombinase. Using this model to trace the distribution of Atp13a5-positive pericytes in mice, we found that the tdTomato reporter reliably labels the CNS pericytes, including the ones in spinal cord and retina but not peripheral organs. Interestingly, brain pericytes are likely shaped by the developing neural environment, as Atp13a5-positive pericytes start to appear around murine embryonic day 15 (E15) and expand along the cerebrovasculature. Thus, Atp13a5 is a specific marker of CNS pericyte lineage, and this Atp13a5-based model is a reliable tool to explore the heterogeneity of pericytes and BBB functions in health and diseases.

The brain's extracellular matrix (ECM) regulates neuronal plasticity and animal behavior. ECM staining shows a net-like structure around a subset of neurons, a ring-like structure at the nodes of Ranvier, and diffuse staining in the interstitial matrix. However, understanding the structural features of ECM deposition across various neuronal types and subcellular compartments remains limited. To visualize the organization pattern and assembly process of the hyaluronan-scaffolded ECM in the brain, we fused a HaloTag to hyaluronan proteoglycan link protein 1, which links hyaluronan and proteoglycans. Expression or application of the probe in primary rat neuronal cultures enables us to identify spatial and temporal regulation of ECM deposition and heterogeneity in ECM aggregation among neuronal populations. Dual-color birthdating shows the ECM assembly process in culture and in vivo. Sparse expression in mouse brains of either sex reveals detailed ECM architectures around excitatory neurons and developmentally regulated dendritic ECM. Our study uncovers extensive structural features of the brain's ECM, suggesting diverse roles in regulating neuronal plasticity.

We used virus-mediated anterograde and retrograde tracing, optogenetic modulation, immunostaining, in situ hybridization, and patch-clamp recordings in acute brain slices to study the release mechanism and μ-opioid modulation of the dual glutamatergic/GABAergic inputs from the ventral tegmental area and supramammillary nucleus to the granule cells of the dorsal hippocampus of male and female mice. In keeping with previous reports showing that the two transmitters are released by separate active zones within the same terminals, we found that the short-term plasticity and pharmacological modulation of the glutamatergic and GABAergic currents are indistinguishable. We further found that glutamate and GABA release at these synapses are both virtually completely mediated by N- and P/Q-type calcium channels. We then investigated μ-opioid modulation of these synapses and found that activation of μ-opioid receptors (MORs) strongly inhibits the glutamate and GABA release, mostly through inhibition of presynaptic N-type channels. However, the modulation by MORs of these dual synapses is complex, as it likely includes also a disinhibition due to downmodulation of local GABAergic interneurons which make direct axo-axonic contacts with the dual glutamatergic/GABAergic terminals. We discuss how this opioid modulation may enhance LTP at the perforant path inputs, potentially contributing to reinforce memories of drug-associated contexts.

Sleep is known to drive the consolidation of motor memories. During nonrapid eye movement (NREM) sleep, the close temporal proximity between slow oscillations (SOs) and spindles ("nesting" of SO-spindles) is known to be essential for consolidation, likely because it is closely associated with the reactivation of awake task activity. Interestingly, recent work has found that spindles can occur in temporal clusters or "trains." However, it remains unclear how spindle trains are related to the nesting phenomenon. Here, we hypothesized that spindle trains are more likely when SOs co-occur in the prefrontal and motor cortex. We conducted simultaneous neural recordings in the medial prefrontal cortex (mPFC) and primary motor cortex (M1) of male rats training on the reach-to-grasp motor task. We found that intracortically recorded M1 spindles are organized into distinct temporal clusters. Notably, the occurrence of temporally precise SOs between mPFC and M1 was a strong predictor of spindle trains. Moreover, reactivation of awake task patterns is much more persistent during spindle trains in comparison with that during isolated spindles. Together, our work suggests that the precise coupling of SOs across mPFC and M1 may be a potential driver of spindle trains and persistent reactivation of motor memory during NREM sleep.

Neural circuits supporting innate behaviors, such as feeding, exploration, and social interaction, intermingle in the lateral hypothalamus (LH). Although previous studies have shown that individual LH neurons change their firing relative to the baseline during one or more behaviors, the firing rate dynamics of LH populations within behavioral episodes and the coordination of behavior-related LH populations remain largely unknown. Here, using unsupervised graph-based clustering of LH neurons firing rate dynamics in freely behaving male mice, we identified distinct populations of cells whose activity corresponds to feeding, specific times during feeding bouts, or other innate behaviors—social interaction and novel object exploration. Feeding-related cells fired together with a higher probability during slow and fast gamma oscillations (30–60 and 60–90 Hz) than during nonrhythmic epochs. In contrast, the cofiring of neurons signaling other behaviors than feeding was overall similar between slow gamma and nonrhythmic epochs but increased during fast gamma oscillations. These results reveal a neural organization of ethological hierarchies in the LH and point to behavior-specific motivational systems, the dysfunction of which may contribute to mental disorders.

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30–60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS.

GABAergic inhibitory interneurons comprise many subtypes that differ in their molecular, anatomical, and functional properties. In mouse visual cortex, they also differ in their modulation with an animal’s behavioral state, and this state modulation can be predicted from the first principal component (PC) of the gene expression matrix. Here, we ask whether this link between transcriptome and state-dependent processing generalizes across species. To this end, we analysed seven single-cell and single-nucleus RNA sequencing datasets from mouse, human, songbird, and turtle forebrains. Despite homology at the level of cell types, we found clear differences between transcriptomic PCs, with greater dissimilarities between evolutionarily distant species. These dissimilarities arise from two factors: divergence in gene expression within homologous cell types and divergence in cell-type abundance. We also compare the expression of cholinergic receptors, which are thought to causally link transcriptome and state modulation. Several cholinergic receptors predictive of state modulation in mouse interneurons are differentially expressed between species. Circuit modelling and mathematical analyses suggest conditions under which these expression differences could translate into functional differences.

Neuroinflammation can positively influence axon regeneration following injury in the central nervous system. Inflammation promotes the release of neurotrophic molecules and stimulates intrinsic proregenerative molecular machinery in neurons, but the detailed mechanisms driving this effect are not fully understood. We evaluated how microRNAs are regulated in retinal neurons in response to intraocular inflammation to identify their potential role in axon regeneration. We found that miR-383-5p is downregulated in retinal ganglion cells in response to zymosan-induced intraocular inflammation. MiR-383-5p downregulation in neurons is sufficient to promote axon growth in vitro, and the intravitreal injection of a miR-383-5p inhibitor into the eye promotes axon regeneration following optic nerve crush. MiR-383-5p directly targets ciliary neurotrophic factor (CNTF) receptor components, and miR-383-5p inhibition sensitizes adult retinal neurons to the outgrowth-promoting effects of CNTF. Interestingly, we also demonstrate that CNTF treatment is sufficient to reduce miR-383-5p levels in neurons, constituting a positive-feedback module, whereby initial CNTF treatment reduces miR-383-5p levels, which then disinhibits CNTF receptor components to sensitize neurons to the ligand. Additionally, miR-383-5p inhibition derepresses the mitochondrial antioxidant protein peroxiredoxin-3 (PRDX3) which was required for the proregenerative effects associated with miR-383-5p loss-of-function in vitro. We have thus identified a positive-feedback mechanism that facilitates neuronal CNTF sensitivity in neurons and a new molecular signaling module that promotes inflammation-induced axon regeneration.

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration–exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration–exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration–exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

The superior colliculus receives a direct projection from retinal ganglion cells. In primates, it remains unknown if the same ganglion cells also supply the lateral geniculate nucleus. To address this issue, a double-label experiment was performed in two male macaques. The animals fixated a target while injection sites were scouted in the superior colliculus by recording and stimulating with a tetrode. Once suitable sites were identified, cholera toxin subunit B-Alexa Fluor 488 was injected via an adjacent micropipette. In a subsequent acute experiment, cholera toxin subunit B-Alexa Fluor 555 was injected into the lateral geniculate nucleus at matching retinotopic locations. After a brief survival period, ganglion cells were examined in retinal flatmounts. The percentage of double-labeled cells varied locally, depending on the relative efficiency of retrograde transport by each tracer and the precision of retinotopic overlap of injection sites in each target nucleus. In counting boxes with extensive overlap, 76–98% of ganglion cells projecting to the superior colliculus were double labeled. Cells projecting to the superior colliculus constituted 4.0–6.7% of the labeled ganglion cell population. In one particularly large zone, there were 5,746 cells labeled only by CTB-AF555, 561cells double labeled by CTB-AF555 and CTB-AF488, but no cell labeled only by CTB-AF488. These data indicate that retinal input to the macaque superior colliculus arises from a collateral axonal branch supplied by ~5% of the ganglion cells that project to the lateral geniculate nucleus. Surprisingly, there exist no ganglion cells that project exclusively to the SC.

In demanding listening situations, a listener's motivational state may affect their cognitive investment. Here, we aim to delineate how domain-specific sensory processing, domain-general neural alpha power, and pupil size as a proxy for cognitive investment encode influences of motivational state under demanding listening. Participants (male and female) performed an auditory gap-detection task while the pupil size and the magnetoencephalogram were simultaneously recorded. Task demand and a listener's motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect, respectively. Whereas task difficulty impaired performance, reward prospect enhanced it. The pupil size reliably indicated the modulatory impact of an individual's motivational state. At the neural level, the motivational state did not affect auditory sensory processing directly but impacted attentional postprocessing of an auditory event as reflected in the late evoked-response field and alpha-power change. Both pregap pupil dilation and higher parietal alpha power predicted better performance at the single-trial level. The current data support a framework wherein the motivational state acts as an attentional top–down neural means of postprocessing the auditory input in challenging listening situations.

Odor information arrives first in the main olfactory bulb and is then broadcasted to the olfactory cortices and striatum. Downstream regions have unique cellular and connectivity architectures that may generate different coding patterns to the same odors. To reveal region-specific response features, tuning and decoding of single-unit populations, we recorded responses to the same odors under the same conditions across regions, namely, the main olfactory bulb (MOB), the anterior olfactory nucleus (AON), the anterior piriform cortex (aPC), and the olfactory tubercle of the ventral striatum (OT), of awake male mice. We focused on chemically closely related aldehydes that still create distinct percepts. The MOB had the highest decoding accuracy for aldehydes and was the only region encoding chemical similarity. The MOB had the highest fraction of inhibited responses and narrowly tuned odor-excited responses in terms of timing and odor selectivity. Downstream, the interconnected AON and aPC differed in their response patterns to the same stimuli. While odor-excited responses dominated the AON, the aPC had a comparably high fraction of odor-inhibited responses. Both cortices share a main output target that is the MOB. This prompted us to test if the two regions convey also different net outputs. Aldehydes activated AON terminals in the MOB as a bulk signal but inhibited those from the aPC. The differential cortical projection responses generalized to complex odors. In summary, olfactory regions reveal specialized features in their encoding with AON and aPC differing in their local computations, thereby generating inverse net centrifugal and intercortical outputs.

Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We found that in Drosophila melanogaster, a set of neurons, which we call CL062, previously shown to mediate male aggression also mediate female aggression. These neurons elicit aggression acutely and without the presence of a target. Although the same set of actions is elicited in males and females, the overall behavior is sexually dimorphic. The CL062 neurons do not express fruitless, a gene required for sexual dimorphism in flies, and expressed by most other neurons important for controlling fly aggression. Connectomic analysis in a female electron microscopy dataset suggests that these neurons have limited connections with fruitless expressing neurons that have been shown to be important for aggression and signal to different descending neurons. Thus, CL062 is part of a monomorphic circuit for aggression that functions parallel to the known dimorphic circuits.

Key event-related potentials (ERPs) of perceptual decision-making such as centroparietal positivity (CPP) elucidate how evidence is accumulated toward a given choice. Furthermore, this accumulation can be impacted by visual target selection signals such as the N2 contralateral (N2c). How these underlying neural mechanisms of perceptual decision-making are influenced by the spatial congruence of distractors relative to target stimuli remains unclear. Here, we used electroencephalography (EEG) in humans of both sexes to investigate the effect of distractor spatial congruency (same vs different hemifield relative to targets) on perceptual decision-making. We confirmed that responses for perceptual decisions were slower for spatially incongruent versus congruent distractors of high salience. Similarly, markers of target selection (N2c peak amplitude) and evidence accumulation (CPP slope) were found to be lower when distractors were spatially incongruent versus congruent. To evaluate the effects of congruency further, we applied drift diffusion modeling to participant responses, which showed that larger amplitudes of both ERPs were correlated with shorter nondecision times when considering the effect of congruency. The modeling also suggested that congruency's effect on behavior occurred prior to and during evidence accumulation when considering the effects of the N2c peak and CPP slope. These findings point to spatially incongruent distractors, relative to congruent distractors, influencing decisions as early as the initial sensory processing phase and then continuing to exert an effect as evidence is accumulated throughout the decision-making process. Overall, our findings highlight how key electrophysiological signals of perceptual decision-making are influenced by the spatial congruence of target and distractor.

Plasticity in the subcortical motor basal ganglia–thalamo–cerebellar network plays a key role in the acquisition and control of long-term memory for new procedural skills, from the formation of population trajectories controlling trained motor skills in the striatum to the adaptation of sensorimotor maps in the cerebellum. However, recent findings demonstrate the involvement of a wider cortical and subcortical brain network in the consolidation and control of well-trained actions, including a brain region traditionally associated with declarative memory—the hippocampus. Here, we probe which role these subcortical areas play in skilled motor sequence control, from sequence feature selection during planning to their integration during sequence execution. An fMRI dataset (N = 24; 14 females) collected after participants learnt to produce four finger press sequences entirely from memory with high movement and timing accuracy over several days was examined for both changes in BOLD activity and their informational content in subcortical regions of interest. Although there was a widespread activity increase in effector-related striatal, thalamic, and cerebellar regions, in particular during sequence execution, the associated activity did not contain information on the motor sequence identity. In contrast, hippocampal activity increased during planning and predicted the order of the upcoming sequence of movements. Our findings suggest that the hippocampus preorders movements for skilled action sequences, thus contributing to the higher-order control of skilled movements that require flexible retrieval. These findings challenge the traditional taxonomy of episodic and procedural memory and carry implications for the rehabilitation of individuals with neurodegenerative disorders.

Words offer a unique opportunity to separate the processing mechanisms of object subcomponents from those of the whole object, because the phonological or semantic information provided by the word subcomponents (i.e., sublexical information) can conflict with that provided by the whole word (i.e., lexical information). Previous studies have revealed some of the specific brain regions and temporal information involved in sublexical information processing. However, a comprehensive spatiotemporal neural network for sublexical processing remains to be fully elucidated due to the low temporal or spatial resolutions of previous neuroimaging studies. In this study, we recorded stereoelectroencephalography signals with high spatial and temporal resolutions from a large sample of 39 epilepsy patients (both sexes) during a Chinese character oral reading task. We explored the activated brain regions and their connectivity related to three sublexical effects: phonological regularity (whether the whole character's pronunciation aligns with its phonetic radical), phonological consistency (whether characters with the same phonetic radical share the same pronunciation), and semantic transparency (whether the whole character's meaning aligns with its semantic radical). The results revealed that sublexical effects existed in the inferior frontal gyrus, precentral and postcentral gyri, temporal lobe, and middle occipital gyrus. Additionally, connectivity from the middle occipital gyrus to the postcentral gyrus and from postcentral gyrus to the fusiform gyrus was associated with the sublexical effects. These findings provide valuable insights into the spatiotemporal dynamics of sublexical processing and object recognition in the brain.

Systemic study of pathogenic pathways and interrelationships underlying genes associated with Alzheimer's disease (AD) facilitates the identification of new targets for effective treatments. Recently available large-scale multiomics datasets provide opportunities to use computational approaches for such studies. Here, we devised a novel disease gene identification (digID) computational framework that consists of a semi-supervised deep learning classifier to predict AD-associated genes and a protein–protein interaction (PPI) network-based analysis to prioritize the importance of these predicted genes in AD. digID predicted 1,529 AD-associated genes and revealed potentially new AD molecular mechanisms and therapeutic targets including GNAI1 and GNB1, two G-protein subunits that regulate cell signaling, and KNG1, an upstream modulator of CDC42 small G-protein signaling and mediator of inflammation and candidate coregulator of amyloid precursor protein (APP). Analysis of mRNA expression validated their dysregulation in AD brains but further revealed the significant spatial patterns in different brain regions as well as among different subregions of the frontal cortex and hippocampi. Super-resolution STochastic Optical Reconstruction Microscopy (STORM) further demonstrated their subcellular colocalization and molecular interactions with APP in a transgenic mouse model of both sexes with AD-like mutations. These studies support the predictions made by digID while highlighting the importance of concurrent biological validation of computationally identified gene clusters as potential new AD therapeutic targets.

Different people listening to the same story may converge upon a largely shared interpretation while still developing idiosyncratic experiences atop that shared foundation. What linguistic properties support this individualized experience of natural language? Here, we investigate how the "concrete–abstract" axis—the extent to which a word is grounded in sensory experience—relates to within- and across-subject variability in the neural representations of language. Leveraging a dataset of human participants of both sexes who each listened to four auditory stories while undergoing functional magnetic resonance imaging, we demonstrate that neural representations of "concreteness" are both reliable across stories and relatively unique to individuals, while neural representations of "abstractness" are variable both within individuals and across the population. Using natural language processing tools, we show that concrete words exhibit similar neural representations despite spanning larger distances within a high-dimensional semantic space, which potentially reflects an underlying representational signature of sensory experience—namely, imageability—shared by concrete words but absent from abstract words. Our findings situate the concrete–abstract axis as a core dimension that supports both shared and individualized representations of natural language.

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.

A new study from Smithsonian scientists analyzes ant and fungus species, and uncovers the origins of their close partnership

A recent exhibition shows how soldiers sent in votes during the Civil War and World War II, as many Americans would in 2020 following the spread of the Covid-19 pandemic

You’ve got questions. We’ve got experts

The early polygraph machine was considered the most scientific way to detect deception—but that was a myth

Written by the former chief historian of NASA, the book examines the evolution of our cosmic understanding—from early civilizations to the present day

FAO and the World Health Organization (WHO) will continue to work closely on nutrition, food safety and antimicrobial resistance issues, FAO Director-General José Graziano da Silva and WHO Director Margaret [...]

Pope Francis will add his voice to the fight against hunger and malnutrition by addressing the Second International [...]

FAO Director-General José Graziano da Silva today called on countries to put nutrition high on their national and international agendas, and to take a lead role in the upcoming Second [...]

Building on previous efforts, the Kingdom of Morocco will offer technical assistance to the Republic of Guinea through a South-South Cooperation Tripartite Agreement signed today at FAO headquarters by FAO [...]

A recent side event during the Council last week promoted South-South Cooperation (SSC) as a cost-effective means to addressing food insecurity, showcased FAO’s role as a facilitator and voiced the [...]

Santiago, Chile- The declaration of the XXI Specialized Meeting on Family Farming of MERCOSUR (REAF, in Spanish) held last week in Argentina, acknowledged the advances promoted by FAO’s Director General, [...]

The Thomson Reuters Foundation, the corporate charity of the world’s biggest news and information providers, is teaming up with the UN Food and Agriculture Organization (FAO) to improve [...]

Senior staff at FAO yesterday briefed a delegation of five U.S. Senators on FAO’s work on resilience, nutrition, fisheries, climate change, [...]

Rome/New York – Queen Letizia of Spain will join international efforts against hunger and [...]

Better management of the world's ocean resources is crucial to ensuring food global security, [...]

Milan - European governments must help combat [...]

Between last week’s Global Dialogue on Family Farming, a visit from President Evo Morales and the 3Full Article