There is a long history of interplay between the brain sciences and AI in the area of schema theory. Schemas are typically defined as abstract mental structures representing prior knowledge, experiences, and concepts tha...There is a long history of interplay between the brain sciences and AI in the area of schema theory. Schemas are typically defined as abstract mental structures representing prior knowledge, experiences, and concepts that capture how events unfold in different contexts and that alter how we learn new information. Classical models have treated schemas as being distinct from both detail-rich episodic memories and general semantic knowledge. Motivated by learning phenomena in modern generative AI, we propose that earlier connectionist theories that did not articulate any strict division between schemas and other declarative memories should be revived. According to this perspective, schemas are not a distinct set of mnemonic objects in the brain; rather, they are a conceptual tool that scientists use to describe how existing knowledge can exist along a spectrum of abstraction.
In this interview with Neuron, Danilo Bzdok argues that artificial intelligence and big data herald a paradigm shift in neuroscience. Leveraging large language models, researchers can overcome traditional, intuition-driv...In this interview with Neuron, Danilo Bzdok argues that artificial intelligence and big data herald a paradigm shift in neuroscience. Leveraging large language models, researchers can overcome traditional, intuition-driven taxonomies, bridge disciplinary silos, and reconcile today's fragmented knowledge into a unified vision of brain function.
In this issue of Neuron, Goode et al. identify a hippocampus-septum-hypothalamus circuit in which prodynorphin-expressing septal neurons regulate contextual feeding. By transmitting aversive contextual signals, this path...In this issue of Neuron, Goode et al. identify a hippocampus-septum-hypothalamus circuit in which prodynorphin-expressing septal neurons regulate contextual feeding. By transmitting aversive contextual signals, this pathway gates food consumption according to learned environmental context.
Histamine has long been linked to anxiety, yet its effects vary across brain regions and conditions, indicating that its site of action remains unresolved. In this issue of Neuron, Li et al. identify astrocytic H3 recep...Histamine has long been linked to anxiety, yet its effects vary across brain regions and conditions, indicating that its site of action remains unresolved. In this issue of Neuron, Li et al. identify astrocytic H3 receptors in ventral CA1 as key cellular mechanisms, where histaminergic input triggers glial GABA release to suppress anxiety-like behavior.
Gnawing maintains ever-growing rodent incisors, yet the underlying circuit has remained unknown. In this issue of Neuron, Su et al. identify brainstem Sst⁺ neurons linking incisor mechanosensation to jaw motoneurons and...Gnawing maintains ever-growing rodent incisors, yet the underlying circuit has remained unknown. In this issue of Neuron, Su et al. identify brainstem Sst⁺ neurons linking incisor mechanosensation to jaw motoneurons and mesolimbic reward, thereby revealing a self-reinforcing sensorimotor circuit for gnawing.
TDP-43 dysfunction underlies multiple neurodegenerative diseases. In this issue of Neuron, Ye et al. uncover a link between TDP-43 loss of function and altered processing body (P-body) activity and identify the decapping...TDP-43 dysfunction underlies multiple neurodegenerative diseases. In this issue of Neuron, Ye et al. uncover a link between TDP-43 loss of function and altered processing body (P-body) activity and identify the decapping scavenger DCPS as a genetic modifier of neurotoxicity.
Memory processing requires coordinated engagement of neuronal populations across brain networks and over time. How such coordination is organized in the human medial temporal lobe (MTL) remains unclear. Here, we show tha...Memory processing requires coordinated engagement of neuronal populations across brain networks and over time. How such coordination is organized in the human medial temporal lobe (MTL) remains unclear. Here, we show that MTL population activity is dynamically structured by a transient slow-oscillatory architecture that emerges during learning to promote offline consolidation and later recall. Using intracranial recordings that combine single-neuron spiking activity and local field potentials in human participants, we find that mnemonic engagement elicits on-demand slow-oscillatory bursts in the hippocampus. These hippocampal bursts synchronize gamma-band patterns across MTL regions, defining discrete coordination events that pace cross-regional coactivity motifs during learning. These learning-evoked population motifs are selectively reactivated during hippocampal ripples in post-learning rest, and the strength of their reactivation predicts subsequent recall accuracy. Together, these findings identify a multi-scale coordination mechanism that links distributed population activity across learning, consolidation, and recall in humans.
When sensory information is ambiguous, we must interpret current inputs based on a representation constructed from our previous experiences. Although appropriately updating this internal representation to track environme...When sensory information is ambiguous, we must interpret current inputs based on a representation constructed from our previous experiences. Although appropriately updating this internal representation to track environmental changes is essential for behavior, the neural basis of this dynamic integration remains unknown. Using a combination of multi-area single-unit recordings and optogenetic techniques in mice under both behavioral and passive conditions, we find that interactions between the posterior parietal cortex (PPC) and its higher-order thalamic counterpart, the pulvinar (PUL), are necessary to stably maintain representations underlying decision-making based on sensory history. We also identify a mechanism by which shifts in statistical patterns across recent sensory experiences engage inhibitory control of the PUL by the thalamic reticular nucleus (TRN) to facilitate the updating of encoded sensory history. Our results establish a framework in which complementary operations in the thalamus and cortex act in concert to allow internal representations to adaptively track changing conditions.
Successful decision-making requires that external information be interpreted in the context of the body's state. Within the framework of body-brain interaction, deliberately modifying one's autonomic state can shape how...Successful decision-making requires that external information be interpreted in the context of the body's state. Within the framework of body-brain interaction, deliberately modifying one's autonomic state can shape how we evaluate the world, ultimately influencing choices. Yet, it remains unclear whether and how intentional autonomic regulation affects human decision-making. In this study, we tested instructed use of prolonged exhalation, a slow-breathing technique designed to boost parasympathetic activity during risky decision-making. Participants followed distinct breathing protocols while making risky choices, with neural and physiological activity measured using functional magnetic resonance imaging (fMRI) and multichannel monitoring. Prolonged exhalation increased risky choices by enhancing reward sensitivity and elevating cardiac parasympathetic activity. Importantly, individuals with greater parasympathetic upregulation also showed stronger reward-related responses in the ventromedial prefrontal cortex and precuneus. Our work reveals the transformative role of breathing-based interventions, demonstrating that autonomic regulation via breathing can shape value-based decision-making through neuro-cardiac pathways.
Bizzotto M, You SF, Tamborini M
… +13 more, Faggiani E, Morini R, Borreca A, Zhang R, Aladyeva E, Nallapu A, Ferrari C, Harari O, Pozzi D, D'Oliveira Albanus R, Karch CM, Matteoli M, Filipello F
Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Using a maternal immune activation model with polyinosinic:polycytidylic...Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Using a maternal immune activation model with polyinosinic:polycytidylic acid (poly(I:C)), we investigated how maternal infections reshape the progeny hippocampal landscape. Poly(I:C) increased maternal type I interferon (IFN-I), disrupting neuronal transcriptional trajectories and excitatory synapse homeostasis in juvenile offspring. Poly(I:C) offspring microglia exhibited reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of synapse elimination and brain development, accompanied by impaired phagocytosis and suppressed IFN-I-responsive substate. Consistently, a blunted IFN-I signature was observed in postmortem tissues from schizophrenic patients. TREM2 deficiency was associated with aberrant maternal IFN-I and altered neuronal and microglial signatures in poly(I:C) offspring, highlighting its regulatory role in neurodevelopmental pathologies. Blocking maternal IFN-I signaling restored synaptic defects and TREM2 function, suggesting that monitoring IFN-I responses during pregnancy and targeting defective IFN-I cascades in the newborn may represent viable therapeutic approaches to mitigate neurodevelopmental dysfunctions.
Rising media attention regarding consciousness in animals, fetuses, organoids, and AI has led to some rather strong statements. Most of these claims are based on "markers" of consciousness that track the general capacity...Rising media attention regarding consciousness in animals, fetuses, organoids, and AI has led to some rather strong statements. Most of these claims are based on "markers" of consciousness that track the general capacity for information processing rather than subjective experience per se. Accordingly, their relevance for theory arbitration may actually be limited.
Effective decision-making in dynamic environments requires adaptive adjustments of behavioral strategies, particularly in how past experiences inform future choices. To explore the neural basis of this adaptability, we t...Effective decision-making in dynamic environments requires adaptive adjustments of behavioral strategies, particularly in how past experiences inform future choices. To explore the neural basis of this adaptability, we trained mice on two decision-making tasks designed to mimic fast-changing or slow-changing environments. Mice adapted their behavioral strategies accordingly, relying on brief history in the former and integrating longer history in the latter. Two-photon calcium imaging across multiple dorsal cortical areas revealed that the retrosplenial cortex (RSC) displayed a wide range of history-integration timescales that shifted in concert with changes in behavior. This shift in timescales involved population-level reorganization of which neurons encoded longer vs. shorter timescales. Furthermore, optogenetic inactivation of RSC impaired the use of history information in both tasks, supporting its importance in history-based strategies. These findings highlight RSC as a key cortical hub that dynamically adapts its temporal integration of past experiences to support flexible, context-dependent decision-making strategies.
The beneficial effects of sleep on anxiety are established, but the mechanisms remain unclear. We identify a GABAergic circuit from the parafacial zone (PZ) to the lateral parabrachial nucleus (LPB) neurons that project...The beneficial effects of sleep on anxiety are established, but the mechanisms remain unclear. We identify a GABAergic circuit from the parafacial zone (PZ) to the lateral parabrachial nucleus (LPB) neurons that project to the oval bed nucleus of the stria terminalis (ovBNST) as a node for slow-wave sleep (SWS)-mediated anxiolysis. Optogenetic activation of PZ GABAergic neurons following social defeat stress induces time-locked SWS and prevents anxiety. Multi-region Ca recording reveals suppressed activity in LPB and ovBNST during natural and PZ-initiated SWS. The LPB-ovBNST pathway is required to drive wakefulness and anxiety, whereas the LPB-basal forebrain pathway promotes arousal without affecting anxiety. PZ neurons inhibit LPB calcitonin gene-related peptide (CGRP)-expressing neurons, which promote wakefulness and anxiety via ovBNST. This effect specifically requires LPB input to ovBNST corticotropin-releasing hormone (Crh) neurons. Thus, we define a PZ-LPB-ovBNST circuit essential for sleep-related anxiolysis, providing a potential therapeutic target for anxiety disorders.
Li R, Zhang X, Li J
… +17 more, Li H, Wang R, Xue R, Wang H, Wang D, Liu L, Yu X, Cai M, Wang J, Wu Z, Yang Q, Li A, Wang Q, Gu T, Wang S, Zhao G, Dong H
Chronic stress disrupts sleep maintenance, yet its neural basis remains unclear. Here, we demonstrated that mice subjected to chronic social defeat stress exhibit fragmented non-rapid eye movement sleep (NREMs), accompan...Chronic stress disrupts sleep maintenance, yet its neural basis remains unclear. Here, we demonstrated that mice subjected to chronic social defeat stress exhibit fragmented non-rapid eye movement sleep (NREMs), accompanied by reduced density and quality of sleep spindles. Chronic stress enhances the firing and burst activity of ventral tegmental area dopaminergic (VTA) neurons, leading to excessive dopamine release in the medial prefrontal cortex (mPFC). This dopaminergic surge disrupts the continuity of electroencephalogram (EEG) spindles, thereby disturbing the stability of NREMs. Blocking dopamine signaling along the VTA-mPFC pathway during stress exposure or pharmacologically inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated I currents of VTA neurons after chronic stress attenuated sleep fragmentation and restored normal spindle metrics. Our study identifies aberrant VTA burst firing as a critical circuit-level contributor to stress-induced sleep disturbance and proposes a potential mechanistic entry point for dissecting dopamine-dependent regulation of NREMs stability.
Gómez-Deza J, Nebiyou M, El Touny LH
… +19 more, Alkaslasi MR, Zuo Z, Wlaschin JJ, Nadal-Nicolás FM, Stavsky A, Zhang X, Slavutsky AL, Zhang AY, Lloyd EYH, Hayashi PM, Ashby N, Brueck MG, Sohn M, Dale RK, Thomas GM, Li W, Chih-Chien Cheng K, Rocha PP, Le Pichon CE
Neuronal apoptosis is a key feature of neurodegenerative diseases. Considerable efforts have been made to target this pathway; however, the underlying molecular mechanisms remain incompletely understood. Here, we conduct...Neuronal apoptosis is a key feature of neurodegenerative diseases. Considerable efforts have been made to target this pathway; however, the underlying molecular mechanisms remain incompletely understood. Here, we conducted an unbiased, genome-wide CRISPR inhibition screen in human neurons to discover genes required for cell death. We uncover a multitude of targets required for neuronal apoptosis, some known and many previously unidentified. Among them, three stood out as members of a pro-death cascade: dual leucine zipper kinase (DLK or MAP3K12) and the transcription factors JUN and the lesser-known activating transcription factor 2 (ATF2). Through mechanistic studies, we demonstrate that ATF2 phosphorylation by MAP3 kinases is a critical step in neuronal apoptosis. Surprisingly, JUN phosphorylation is not required. Conversion of the MAP3 kinase signal into a pro-apoptotic transcriptional response requires phospho-ATF2 to upregulate JUN. We show that interfering with ATF2 function prevents neuronal apoptosis in vitro and in vivo. Our work posits ATF2 as a promising target for a wide range of neurodegenerative disorders.
Novelty signals guide learning and exploration. Becker et al. show that novelty depends not only on repetition but also on similarity: familiarity generalizes across related stimuli and states, explaining both cortical n...Novelty signals guide learning and exploration. Becker et al. show that novelty depends not only on repetition but also on similarity: familiarity generalizes across related stimuli and states, explaining both cortical novelty responses in mouse V1 and novelty-driven maze exploration behavior.
Active dendrites enrich the repertoire of single-neuron computations. Whereas a lot is known about the function of dendrites in vitro, information about their in vivo properties is limited. A new study uses advanced imag...Active dendrites enrich the repertoire of single-neuron computations. Whereas a lot is known about the function of dendrites in vitro, information about their in vivo properties is limited. A new study uses advanced imaging to study hippocampal CA1 pyramidal neuron dendrites in head-fixed, awake animals.
In this issue of Neuron, Li et al. leverage evolutionary genomics to investigate how animals native to high-altitude environments maintain white matter integrity under chronic hypoxia. They report a fortuitous mutation i...In this issue of Neuron, Li et al. leverage evolutionary genomics to investigate how animals native to high-altitude environments maintain white matter integrity under chronic hypoxia. They report a fortuitous mutation in retinol saturase enriched in mammalian species at high altitude that enhances central nervous system myelination.
Endogenous retroviruses (ERVs) are epigenetically silenced genomic elements whose reactivation can influence host gene regulation. In this issue of Neuron, Chen et al. identify ERV-derived RNA-DNA hybrids that activate n...Endogenous retroviruses (ERVs) are epigenetically silenced genomic elements whose reactivation can influence host gene regulation. In this issue of Neuron, Chen et al. identify ERV-derived RNA-DNA hybrids that activate neuronal C4b, driving microglial synaptic overpruning and autism-like behaviors.
Human ultra-high-field (UHF, ≥7 Tesla) scanners provide increased spatial resolution, advancing functional magnetic resonance imaging (fMRI) research toward the submillimeter scale and enabling fMRI of cortical layers, c...Human ultra-high-field (UHF, ≥7 Tesla) scanners provide increased spatial resolution, advancing functional magnetic resonance imaging (fMRI) research toward the submillimeter scale and enabling fMRI of cortical layers, columns, and other small structures. This offers the potential to non-invasively investigate intracortical circuits and processing mechanisms in the human brain. In this primer, we review applications of 7T, data acquisition and processing challenges, and current open questions. We highlight how the rich information in UHF fMRI challenges traditional analysis tools and the interpretation of high-resolution fMRI data. Because fMRI responses are hemodynamic signals and indirect measures of neural activity, careful consideration of neurovascular coupling is essential when interpreting fMRI data, particularly at high resolution. We discuss the implications of increased resolution for fMRI data acquisition, data processing, and interpretation, with an emphasis on cortical layers.