Lezgiyeva K, Liu J, Nguyen K
… +17 more, DeLisle MM, Ko FC, Fullam S, Obeidat AM, Turecek J, Alkislar I, Lehnert BP, Martinez-Garcia RI, Sivakumar R, Choi J, Mazor O, Garibyan L, Sharma N, Emanuel AJ, Malfait AM, Miller RE, Ginty DD
Nociceptors detect damaging stimuli and evoke pain in healthy animals. We conducted an optogenetic activation screen to identify genetically defined nociceptor populations that elicit place aversion and nocifensive behav...Nociceptors detect damaging stimuli and evoke pain in healthy animals. We conducted an optogenetic activation screen to identify genetically defined nociceptor populations that elicit place aversion and nocifensive behaviors in response to stimulation. Smr2- and Bmpr1b-labeled Aδ high-threshold mechanoreceptors (HTMRs) emerged as two of the few nociceptor populations, and we focused on investigating their physiological, morphological, functional, and synaptic properties. These neurons densely innervate skin and other organs, are activated only by intense, potentially damaging stimuli, and are necessary for protective responses to sharp mechanical stimuli. Centrally, Aδ-HTMR projections span multiple spinal segments and terminate across spinal cord laminae, forming strong, monosynaptic connections onto anterolateral tract projection neurons, including antenna cells of the deep dorsal horn. Aδ-HTMRs also engage a local spinal reflex circuit, enabling a remarkably rapid limb withdrawal. Thus, Aδ-HTMRs are myelinated nociceptors with unique properties that can be exploited for the development of new analgesics.
In many neural populations, the computationally relevant signals are posited to be a set of "latent factors"-signals shared across many individual neurons. A given brain area may perform many computations, each associate...In many neural populations, the computationally relevant signals are posited to be a set of "latent factors"-signals shared across many individual neurons. A given brain area may perform many computations, each associated with distinct factors, which can together compose an overall action. The methods for uncovering such structure typically require supervision, which can limit the discovery of novel aspects of activity. Here, we introduce sparse component analysis (SCA), an unsupervised approach. SCA facilitated surprisingly clear parcellations of neural activity across a range of behaviors, when seeking both linear and nonlinear embeddings. We applied SCA to motor cortex activity from reaching and cycling monkeys, single-trial imaging data from C. elegans, and activity from a multitask artificial network. SCA revealed both simple and unexpected instances where the overall population response was built compositionally from sets of factors with distinct computational roles.
Ravichandran P, Bach SV, Phillips RA
… +19 more, Valentine MR, Eagles NJ, Du Y, Del Rosario I, AlGrain HA, Maguire SE, Miller RA, Divecha HR, Tippani M, Montgomery KD, Kleinman JE, Han S, Page SC, Hyde TM, Collado-Torres L, Battle A, Martinowich K, Hicks SC, Maynard KR
The nucleus accumbens (NAc) is a key component of the mesolimbic dopamine system that is implicated in several neuropsychiatric disorders. The NAc contains transcriptomically distinct medium spiny neuron (MSN) subtypes,...The nucleus accumbens (NAc) is a key component of the mesolimbic dopamine system that is implicated in several neuropsychiatric disorders. The NAc contains transcriptomically distinct medium spiny neuron (MSN) subtypes, but their spatial organization remains unclear. We generated a spatiomolecular atlas of the human NAc by integrating paired single-cell and spatial transcriptomics of postmortem NAc tissue. We identified transcriptionally unique cell populations and spatial domains (SpDs), including D1 islands composed of discrete MSN subtypes enriched for dopamine receptor D1 (DRD1) and OPRM1. We demonstrated continuous spatial gene expression gradients across the NAc and evolutionary conservation of spatial features. We also identified SpDs associated with risk for psychiatric and addiction-related traits and spatially mapped risk-associated ligand-receptor interactions. Finally, we predicted enrichment of drug-responsive transcriptional programs in both SpDs and cell types. Collectively, we provide a spatiomolecular framework for understanding the relevance of the human NAc in neuropsychiatric diseases.
Age-related breakdown of the blood-brain barrier (BBB) is associated with cerebrovascular and neurodegenerative diseases, yet its underlying mechanisms remain unclear. Here, we find that BBB leakage begins in midlife and...Age-related breakdown of the blood-brain barrier (BBB) is associated with cerebrovascular and neurodegenerative diseases, yet its underlying mechanisms remain unclear. Here, we find that BBB leakage begins in midlife and is driven primarily by increased endothelial caveolar transcytosis rather than tight junction disruption. AAV-mediated knockdown of caveolin-1 or restoration of Mfsd2a expression reduces endothelial vesicle formation and BBB leakage in aged mice. Transforming growth factor (TGF)-β1, originating from both brain and systemic circulation, increases with aging and directly suppresses Mfsd2a transcription via the Tgfbr2-Smad2/4 signaling in brain microvascular endothelial cells, thereby promoting caveolar transcytosis and BBB leakage. Endothelial-specific Tgfbr2 knockout or pharmacological inhibition of TGF-β signaling reduces endothelial caveolar transcytosis and BBB leakage and attenuates neurological dysfunction in aged mice. These findings identify TGF-β1-induced endothelial transcytosis as a central mechanism underlying age-related BBB breakdown and offer potential therapeutic targets for preserving brain health in age-related neurovascular disorders.
How a visual stimulus is perceived depends on the context provided by other stimuli in the scene. Fu et al. combine imaging, modeling, and innovative closed-loop stimulus generation to identify the brain computations tha...How a visual stimulus is perceived depends on the context provided by other stimuli in the scene. Fu et al. combine imaging, modeling, and innovative closed-loop stimulus generation to identify the brain computations that underlie contextual effects in primary visual cortex (V1) neurons.
In this issue of Neuron, Tian et al. describe a lateral septum GABAergic microcircuit through which systemic administration of the GLP-1 receptor agonist liraglutide, acting via GLP-1 receptor-expressing neurons, inhibit...In this issue of Neuron, Tian et al. describe a lateral septum GABAergic microcircuit through which systemic administration of the GLP-1 receptor agonist liraglutide, acting via GLP-1 receptor-expressing neurons, inhibits alcohol intake in rodent models.
In this issue of Neuron, Etxeberria et al. report that Ptpn6 (SHP-1) restrains TREM2-driven microglial survival and DAM-like activation. Complete loss enhances amyloid containment and protects cortical neurites but trigg...In this issue of Neuron, Etxeberria et al. report that Ptpn6 (SHP-1) restrains TREM2-driven microglial survival and DAM-like activation. Complete loss enhances amyloid containment and protects cortical neurites but triggers white matter degeneration, whereas partial reduction preserves benefit without harm-revealing that the threshold separating protective from detrimental microglial activation is regionally dissociable.
In this issue of Neuron, Hill et al. show that sustained exposure to inflammatory mediators can drive human astrocytes through evolving reactive states, revealing time-dependent transcriptional, epigenetic, and immune-fa...In this issue of Neuron, Hill et al. show that sustained exposure to inflammatory mediators can drive human astrocytes through evolving reactive states, revealing time-dependent transcriptional, epigenetic, and immune-facing programs that remain remarkably plastic after the initiating stimulus is removed.
Navigating dynamic environments often requires the brain to process information from multiple tasks in parallel. Yet, how neural resources are allocated across tasks and reorganized with practice remains unclear. Here, w...Navigating dynamic environments often requires the brain to process information from multiple tasks in parallel. Yet, how neural resources are allocated across tasks and reorganized with practice remains unclear. Here, we combine an original dual-task paradigm in mice with chronic two-photon imaging, optogenetic manipulations, and recurrent neural network models to dissect the underlying cortical dynamics. We show that interference between tasks arises not only from bottlenecks among task-shared neurons but also from reduced activity in non-shared populations. Intriguingly, this reduced activity is associated with rapid coordination between tasks and supports early dual-task success. With training, performance is optimized by a multi-level reorganization, including the recruitment of specialized neurons and progressive segregation of task representations. Network models on the same paradigm implementing these coordination and segregation schemes accelerate dual-task learning, indicating their functional importance. Together, these findings demonstrate how cortical circuits flexibly redistribute and restructure resources to support parallel task processing.
Increasing evidence suggests that higher-order thalamic nuclei are implicated in cognitive behavior. Unlike those in the first-order thalamus, higher-order thalamic neurons have a high propensity to switch from tonic spi...Increasing evidence suggests that higher-order thalamic nuclei are implicated in cognitive behavior. Unlike those in the first-order thalamus, higher-order thalamic neurons have a high propensity to switch from tonic spiking to rapid spike sequences termed bursts. Although bursts have been linked to the augmentation of information transfer in a manner that may support behavior, their role in cognition has never been tested. We show that bursts in the pulvinar, a thalamic node linked to cortical coordination during attention, are attention-modulated and predict behavior. Using neural data from the pulvinar and parietal cortex in macaques performing an attention task, we found that pulvinar bursts were predictive of target detection and reconfigured population codes of spatial location in cortex. Electrical microstimulation of the pulvinar triggered bursts that enhanced target detection and synchronized cortical spiking. These results establish pulvinar bursts as a causal driver of attention, revealing a mechanism by which the higher-order thalamus exerts control over cortical processing and behavior.
Animals efficiently learn to navigate their environment. In the laboratory, naive mice can localize new spatial targets within a handful of trials. It is unclear how such efficiency is possible, as existing models requir...Animals efficiently learn to navigate their environment. In the laboratory, naive mice can localize new spatial targets within a handful of trials. It is unclear how such efficiency is possible, as existing models require far more experience to achieve comparable performance. Taking inspiration from behavior as mice learned to intercept hidden spatial targets, we designed agents that generate structured behavioral trajectories by controlling their speed and angular velocity between anchor points. To rapidly learn good anchors, agents use Bayesian inference on past trajectories to infer the probability that an anchor will be successful and active sampling to refine hypothesized anchors. Agents learn within tens of trials to intercept a hidden target, capturing the evolution of behavioral structure and the upper limits of learning efficiency observed in mice. This algorithm further explains how mice avoid obstacles and rapidly adapt to target switches, and it naturally encompasses both egocentric and allocentric strategies for navigation.
Perceiving the location of nearby objects relative to the body is essential for guiding movement and avoiding danger. Many organisms use touch to estimate object distance, yet how somatosensory circuits extract distance...Perceiving the location of nearby objects relative to the body is essential for guiding movement and avoiding danger. Many organisms use touch to estimate object distance, yet how somatosensory circuits extract distance from tactile inputs remains unclear. Here, we investigate how neurons in the mouse whisker brainstem compute peri-head distance. Using extracellular recordings in awake mice during wall-passing stimulation, we find two coding schemes that tile peri-head space: "proximity," showing monotonically increasing activity as objects approach the face, and "map," showing peaked tuning at specific distances. The map code enables a more precise readout of peri-head distance. Perturbations suggest that long-range internuclear inhibition is important for generating the map code, subtracting heterogeneous peripheral signals from different whiskers or within the same whisker. These findings reveal an underappreciated computational role for brainstem circuits, where inhibition acts as a neural comparator to transform multiplexed peripheral inputs into a stable representation of peri-head distance.
Methods to identify brain areas where neurons are activated in response to stimuli or states typically rely on immediate early gene (IEG) expression. However, variability in IEG expression across subjects and brain areas...Methods to identify brain areas where neurons are activated in response to stimuli or states typically rely on immediate early gene (IEG) expression. However, variability in IEG expression across subjects and brain areas often requires large sample sizes. Further, IEG expression alone cannot determine whether the same or different neurons are activated in response to two distinct stimuli or states. To overcome these challenges, we developed a brain screening method-two-timepoint statistical inference with subtraction (TTP-S)-to identify brain areas on the basis of activity at two timepoints, not one. Applying this approach across 500+ brain areas increases the sensitivity and specificity of screens for engaged brain areas, thereby reducing the required sample size. Coupled with graph theoretical analyses, we use this method to analyze hunger, satiety, food cue presentation, drug treatment, and alcohol consumption, identifying known relevant brain regions and implicating new areas.
Social relationships are best understood not as isolated interactions but as dynamic representations shaped through evaluative processes, interaction-driven learning, motivational value, and memory-based structure. This...Social relationships are best understood not as isolated interactions but as dynamic representations shaped through evaluative processes, interaction-driven learning, motivational value, and memory-based structure. This review synthesizes research across these domains to trace how relationships develop from initial impressions through repeated interactions to stable social bonds and networks. We organize the literature by relationship stage and highlight how overlapping neural systems are differentially engaged as relationships evolve over time. By treating relationships as unfolding processes, we reveal computational principles that become apparent only across time. Building on cognitive map theory, we propose that social relationships are represented as structured relational spaces supporting updating and generalization. We further highlight emerging computational and methodological approaches-including map-based models, naturalistic paradigms, and tools for analyzing dynamic social behavior-that enable the study of relationships across their temporal arc. This framework offers new ways to study the formation, maintenance, and adaptation of social bonds.
Our interaction with the environment shapes how our brain processes sensory information and drives adaptive behavior. This plasticity allows brain adjustments in response to specific sensory experiences. While plasticity...Our interaction with the environment shapes how our brain processes sensory information and drives adaptive behavior. This plasticity allows brain adjustments in response to specific sensory experiences. While plasticity has been consistently detected in visual targets, only limited data exist on its extent in the primary sensory organ, the retina. Here, we show that the zebrafish retina demonstrates plastic transformations in response to visual environment alterations during development. We demonstrate that orientation-selective amacrine cells undergo profound morphological changes in animals previously exposed to distinct visual environments. We further find that the functional orientation-selective retinal output is altered, consistent with the visual environment in which the animals are raised, and that these changes are persistent. Finally, we show that early exposure to different visual environments changes the animals' visuomotor response preference for specifically oriented patterns. Our findings unveil a developmental form of sensory organ plasticity with continuing structural, functional, and behavioral consequences.
Humans can combine symbols to generate new meanings. Here, we studied the regional neural mechanisms that might make this possible. We asked participants to combine two discrete, symbolic features (a shape and a color) t...Humans can combine symbols to generate new meanings. Here, we studied the regional neural mechanisms that might make this possible. We asked participants to combine two discrete, symbolic features (a shape and a color) to make a novel spatial inference. Blood-oxygen-level-dependent (BOLD) data suggested that the hippocampus encoded elementary visual attributes in a high-dimensional, parallel format that permitted flexible individuation. In the ventromedial prefrontal cortex (vmPFC), posterior parietal cortex (PPC), and primary visual cortex (V1), neural patterns for novel stimuli (composites) could be predicted as a linear combination of signals for familiar stimuli (elements). In the vmPFC, this composition occurred in a high-dimensional format, but in PPC and V1, it took place in a low-dimensional, spatial frame of reference that was aligned with the response space. These data offer new insights into the neural circuits underlying compositional generalization.
Lynch CJ, Chang M, Elbau I
… +33 more, Gordon EM, Laumann TO, Du J, Ladwig Z, Lueckel M, Perez DC, Summerville I, Chou J, Johnson M, Ho C, Manfredi N, Nilchian P, Solomonov N, Goldwaser E, Ng T, Moia S, Caballero-Gaudes C, Downar J, Vila-Rodriguez F, Gregory E, Daskalakis ZJ, Blumberger DM, Kay K, Buchanan DM, Williams N, Bhati MT, Clauss J, Zebley B, Victoria LW, Power JD, Grosenick L, Gunning FM, Liston C
Precision functional mapping (PFM) enables the individual-level characterization of brain network organization but requires substantially more and higher-quality fMRI data than is standard. Despite the growing use of PFM...Precision functional mapping (PFM) enables the individual-level characterization of brain network organization but requires substantially more and higher-quality fMRI data than is standard. Despite the growing use of PFM, the objective criteria for data sufficiency and the quality needed to ensure interpretable and replicable individual-level results remain unclear. Here, we introduce the network similarity index (NSI), an objective measure of the extent to which functional connectivity (FC) patterns express the large-scale network structure required for PFM. The NSI captures low-spatial-frequency, coherent network organization and denoising fidelity, and it aligns closely with blinded expert assessments of PFM usability. The NSI also accounts for the variability in the rate at which FC becomes reliable across individuals. This NeuroResource provides an open source framework for NSI-based data quality evaluation and models linking NSI values with expert-judged PFM suitability. This framework can inform expected returns from additional data collection, thus enabling principled decisions about data sufficiency and replication in precision fMRI research.
Alcohol addiction is a chronically relapsing disorder, characterized by compulsive alcohol seeking and taking, the loss of control in limiting intake, and the emergence of hyperkatifeia (a sensitized negative emotional s...Alcohol addiction is a chronically relapsing disorder, characterized by compulsive alcohol seeking and taking, the loss of control in limiting intake, and the emergence of hyperkatifeia (a sensitized negative emotional state) during withdrawal. The hypothesis of this review is that alcohol addiction represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the individual via three stages of the addiction cycle and three respective domains of dysfunction. As addiction develops, the withdrawal/negative affect stage, which mediates the development of a panoply of negative emotional symptoms (termed hyperkatifeia), takes on a more prominent role. Hyperkatifeia then drives compulsive-like drug seeking via negative reinforcement and is mediated by a decrease in the function of brain reward systems that involve key neurotransmitter systems, such as dopamine and opioid peptides, and the recruitment/sensitization of brain stress systems, including corticotropin-releasing factor, dynorphin, hypocretin, ghrelin, norepinephrine, and neuroimmune modulation. These changes are hypothesized to be triggered and maintained by neuroadaptations of the hypothalamic-pituitary-adrenal axis and the sensitization of glucocorticoid receptor signaling. Anti-stress systems, such as neuropeptide Y, nociceptin, endocannabinoids, and oxytocin, may be compromised and contribute to the development and maintenance of hyperkatifeia. Neuroanatomical substrates for hyperkatifeia have a focus on the extended amygdala and elements of the basal ganglia. Neurocircuitry analyses are now identifying cellular and molecular targets for genetic and epigenetic vulnerability within an allostasis framework that shows therapeutic promise for this often-neglected domain of the etiology and perpetuation of alcohol addiction.
In this issue of Neuron, Li and colleagues unveil a circuit-based framework in which parallel insula-prefrontal circuits independently govern stress-induced social fear and novelty preference deficits, and lateral inhibi...In this issue of Neuron, Li and colleagues unveil a circuit-based framework in which parallel insula-prefrontal circuits independently govern stress-induced social fear and novelty preference deficits, and lateral inhibition between these circuits via local parvalbumin interneurons drives their comorbidity.