Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) ex vivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.

The central nervous system (CNS) is increasingly recognized as a critical modulator in the oncogenesis of glioblastoma multiforme (GBM), with interactions between cancer and local neuronal circuits frequently leading to epilepsy; however, the relative contributions of these factors remain unclear. Here, we report a coordinated intratumor shift among distinct cancer subtypes within progenitor-like families of epileptic GBM patients, revealing an accumulation of oligodendrocyte progenitor (OPC)-like subpopulations at the cancer-neuron interface along with heightened electrical signaling activity in the surrounding neuronal networks. The OPC-like cells associated with epilepsy express KCND2, which encodes the voltage-gated K channel K4.2, enhancing neuronal excitability via accumulation of extracellular K, as demonstrated in patient-derived ex vivo slices, xenografting models, and engineering organoids. Together, we uncovered the essential local circuitry, cellular components, and molecular mechanisms facilitating cancer-neuron interaction at peritumor borders. KCND2 plays a crucial role in mediating nervous system-cancer electrical communication, suggesting potential targets for intervention.

Merging information across sensory modalities is key to forming robust percepts, yet how the brain achieves this feat remains unclear. Recent studies report cross-modal influences in the primary sensory cortex, suggesting possible multisensory integration in the early stages of cortical processing. We test several hypotheses about the function of auditory influences on mouse primary somatosensory cortex (S1) using in vivo two-photon calcium imaging. We found sound-evoked spiking activity in an extremely small fraction of cells, and this sparse activity did not encode auditory stimulus identity. Moreover, S1 did not encode information about specific audio-tactile feature conjunctions. Auditory and audio-tactile stimulus encoding remained unchanged after both passive experience and reinforcement. These results suggest that while primary sensory cortex is plastic within its own modality, the influence of other modalities is remarkably stable and stimulus nonspecific.

Aging has a detrimental impact on white matter, resulting in reduced volume, compromised structural integrity of myelinated axons, and an increase in white matter hyperintensities. These changes are closely linked to cognitive decline and neurological disabilities. The deterioration of myelin and its diminished ability to regenerate as we age further contribute to the progression of neurodegenerative disorders. Understanding these changes is crucial for devising effective disease prevention strategies. Here, we will discuss the structural alterations in white matter that occur with aging and examine the cellular and molecular mechanisms driving these aging-related transformations. We highlight how the progressive disruption of white matter may initiate a self-perpetuating cycle of inflammation and neural damage.

Social creatures must attend to threat signals from conspecifics and respond appropriately, both behaviorally and physiologically. In this work, we show in mice a threat-sensitive immune mechanism that orchestrates psychological processes and is amenable to social modulation. Repeated encounters with socially cued threats triggered meningeal neutrophil (MN) priming preferentially in males. MN activity was correlated with attenuated defensive responses to cues. Canonical neutrophil-specific activation marker CD177 was upregulated after social threat cueing, and its genetic ablation abrogated male behavioral phenotypes. CD177 signals favored meningeal T helper (Th)1-like immune bias, which blunted neural response to threatening stimuli by enhancing intrinsic GABAergic inhibition within the prelimbic cortex via interferon-gamma (IFN-γ). MN signaling was sensitized by negative emotional states and governed by socially dependent androgen release. This male-biased hormone/neutrophil regulatory axis is seemingly conserved in humans. Our findings provide insights into how immune responses influence behavioral threat responses, suggesting a possible neuroimmune basis of emotional regulation.

Horizontal cells provide feedback inhibition to cone axon terminals via an unidentified synaptic mechanism. In this issue of Neuron, Morikawa and colleagues demonstrate that the electrogenic bicarbonate transporter (Slc4a5), which regulates pH, plays a crucial role at this feedback synapse.

New work by Mark Wu's group in this issue of Neuron indicates that a neural population within the lateral amygdala, defined by the expression of mWAKE, functions as a crucial circadian oscillator to drive circadian rhythms in anxiety and touch sensitivity.

Glioblastoma (GBM) is an incurable disease with high intratumoral heterogeneity. Bioinformatic studies have examined transcriptional heterogeneity with differing conclusions. Here, we characterize GBM heterogeneity and highlight critical phenotypic and hierarchical roles for quiescent cancer stem cells (qCSCs). Unsupervised single-cell transcriptomic analysis of patient-derived xenografts (PDXs) delineates six GBM transcriptional states with unique tumor exclusive gene signatures, five of which display congruence with central nervous system (CNS) cell lineages. We employ a surrogate tumor evolution assay by serial xenograft transplantation to demonstrate faithful preservation of somatic mutations, transcriptome, and qCSCs. PDX chemotherapy results in CSC resistance and expansion, also seen in recurrent patient GBM. In aggregate, these novel GBM transcriptional signatures exclusively identify tumor cells and define the hierarchical landscape as stable biologically discernible cell types that allow capture of their evolution upon recurrence, emphasizing the importance of CSCs and demonstrating general relevance to all GBM.

Redox-mediated posttranslational modification, as exemplified by protein S-nitrosylation, modulates protein activity and function in both health and disease. Here, we review recent findings that show how normal aging, infection/inflammation, trauma, environmental toxins, and diseases associated with protein aggregation can each trigger excessive nitrosative stress, resulting in aberrant protein S-nitrosylation and hence dysfunctional protein networks. These redox reactions contribute to the etiology of multiple neurodegenerative disorders as well as systemic diseases. In the CNS, aberrant S-nitrosylation reactions of single proteins or, in many cases, interconnected networks of proteins lead to dysfunctional pathways affecting endoplasmic reticulum (ER) stress, inflammatory signaling, autophagy/mitophagy, the ubiquitin-proteasome system, transcriptional and enzymatic machinery, and mitochondrial metabolism. Aberrant protein S-nitrosylation and transnitrosylation (transfer of nitric oxide [NO]-related species from one protein to another) trigger protein aggregation, neuronal bioenergetic compromise, and microglial phagocytosis, all of which contribute to the synapse loss that underlies cognitive decline in Alzheimer's disease and related dementias.

Interoception, the sensation and perception of internal bodily states, should be conceptualized through specialized modalities like cardioception, pulmoception, gastroception, and uroception. This NeuroView emphasizes cardioception, exploring heart-brain interactions, cardiac reflexes, and their influence on mental states and behavior.

Corticothalamic projections to sensorimotor thalamic nuclei show modest firing rates and serve to modulate the activity of thalamic relay neurons. By contrast, here we find that high-order corticothalamic projections from the prelimbic (PL) cortex to the anterior paraventricular thalamic nucleus (aPVT) maintain high-frequency activity and evoke strong synaptic excitation of aPVT neurons in rats. In a significant fraction of aPVT cells, such high-frequency excitation of PL-aPVT projections leads to a rapid decay of action potential amplitudes, followed by a depolarization block (DB) that strongly limits aPVT maximum firing rates, thereby regulating both defensive and appetitive behaviors in a frequency-dependent manner. Strong inhibitory inputs from the anteroventral portion of the thalamic reticular nucleus (avTRN) inhibit the firing rate of aPVT neurons during periods of high-spike fidelity but restore it during prominent DB, suggesting that avTRN activity can modulate the effects of PL inputs on aPVT firing rates to ultimately control motivated behaviors.

Technological advances allow neurophysiologists to explore the brain during natural behaviors, revealing new functional principles and challenging old ones. In this issue of Neuron, Li and colleagues show that the traditional parcellation of the marmoset frontal cortex does not apply to naturalistic conversations.

Pathologic α-synuclein (α-syn) aggregates from the gastrointestinal (GI) tract may contribute to Parkinson's disease (PD). Xiang et al. report in Neuron that enteric nervous system-specific expression of asparaginyl endopeptidase (AEP)-truncated α-syn and tau spreads to the brain, synergistically causing PD-related neurodegeneration and neurobehavioral deficits.

In the current issues of Neuron and Cell Reports, Libé-Philippot et al. and Assendorp et al. identify interactions between human-specific SRGAP2C, synaptic regulator SRGAP2A, and neurodevelopmental disorder-associated proteins SYNGAP1 and CTNND2 that slow synaptic maturation in human neurons.

Behavior in naturalistic scenarios occurs in diverse environments. Adaptive strategies rely on multiple neural circuits and competing decision systems. However, past studies of rodent decision making have largely measured behavior in simple environments. To fill this gap, we recorded neural ensembles from hippocampus (HC), dorsolateral striatum (DLS), and dorsomedial prefrontal cortex (dmPFC) while rats foraged for food under changing rules in environments with varying topological complexity. Environmental complexity increased behavioral variability, lengthened HC nonlocal sequences, and modulated action caching. We found contrasting representations between DLS and HC, supporting a competition between decision systems. dmPFC activity was indicative of setting this balance, in particular predicting the extent of HC non-local coding. Inactivating mPFC impaired short-term behavioral adaptation and produced long-term deficits in balancing decision systems. Our findings reveal the dynamic nature of decision-making systems and how environmental complexity modulates their engagement with implications for behavior in naturalistic environments.

Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.

To understand a visual scene, observers need to both recognize objects and encode relational structure. For example, a scene comprising three apples requires the observer to encode concepts of "apple" and "three." In the primate brain, these functions rely on dual (ventral and dorsal) processing streams. Object recognition in primates has been successfully modeled with deep neural networks, but how scene structure (including numerosity) is encoded remains poorly understood. Here, we built a deep learning model, based on the dual-stream architecture of the primate brain, which is able to count items "zero-shot"-even if the objects themselves are unfamiliar. Our dual-stream network forms spatial response fields and lognormal number codes that resemble those observed in the macaque posterior parietal cortex. The dual-stream network also makes successful predictions about human counting behavior. Our results provide evidence for an enactive theory of the role of the posterior parietal cortex in visual scene understanding.

Characterizing the functional organization of cerebral cortex is a fundamental step in understanding how different kinds of information are processed in the brain. However, it is still unclear how these areas are organized during naturalistic visual and auditory stimulation. Here, we used high-resolution functional MRI data from 176 human subjects to map the macro-architecture of the entire cerebral cortex based on responses to a 60-min audiovisual movie stimulus. A data-driven clustering approach revealed a map of 24 functional areas/networks, each explicitly linked to a specific aspect of sensory or cognitive processing. Novel features of this map included an extended scene-selective network in the lateral prefrontal cortex, separate clusters responsive to human-object and human-human interaction, and a push-pull interaction between three executive control (domain-general) networks and domain-specific regions of the visual, auditory, and language cortex. Our cortical parcellation provides a comprehensive and unified map of functionally defined areas in the human cerebral cortex.