Dominant models of human lateral prefrontal cortex (LPFC) organization emphasize broad domain-general zones and smooth functional gradients. However, these models rely on group-averaged neuroimaging, which can obscure fi...Dominant models of human lateral prefrontal cortex (LPFC) organization emphasize broad domain-general zones and smooth functional gradients. However, these models rely on group-averaged neuroimaging, which can obscure fine-scale cortical features in highly inter-individually variable regions such as the LPFC. To address this limitation, we collected a new precision fMRI dataset from 10 individuals, each with approximately 2 h of resting-state fMRI and 6 h of task fMRI data. We mapped individual-specific LPFC networks using resting-state data and tested network-level functional preferences using task data. We found that individual LPFC networks showed fragmented and interdigitated organization compared to the group-averaged networks, including novel conserved motifs present across individuals. Task fMRI revealed that distinct yet adjacent networks support domain-specific processes (i.e., language, social cognition, and episodic projection) versus domain-general cognitive control. Sharp functional boundaries were visible at the individual level that could not be observed in group data. These findings uncover previously hidden fine-scale organizational principles present in the LPFC.
Suresh A, Kourdougli N, Nomura T
… +11 more, Buth JE, Miranda-Rottmann S, Sánchez-León CA, Wu MW, Nelson SM, Wall LT, Tran AT, Araya R, Contractor A, Gandal MJ, Portera-Cailliau C
Symptoms of fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell-type-specific mRNA seque...Symptoms of fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell-type-specific mRNA sequencing to profile molecular alterations in cortical excitatory (Camk2) and inhibitory (Pvalb) neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. We uncovered significant genotype-by-cell type interactions for differential gene expression in Camk2a and Pvalb translatomes, and, strikingly, the underlying signaling pathways were often altered in opposite directions. Among the 184 differentially expressed genes that were concordantly dysregulated across both cell types, only Rapgef4 (a.k.a., exchange protein direftly activated by cAMP 2 [Epac2]; upregulated in Fmr1 KO) was also a fragile X messenger ribonucleoprotein (FMRP) target, brain-enriched, and associated with neurodevelopmental disorders. Treatment of Fmr1 KO mice with a specific EPAC2 antagonist restored cortical circuit function and ameliorated multiple behavioral phenotypes. Thus, EPAC2 should be considered a potential therapeutic target for FXS.
Apolipoprotein E4 (APOE4) is the leading genetic risk factor and an increasingly recognized causal contributor to Alzheimer's disease (AD). AD progresses along a temporal, pathological, and clinical continuum spanning pr...Apolipoprotein E4 (APOE4) is the leading genetic risk factor and an increasingly recognized causal contributor to Alzheimer's disease (AD). AD progresses along a temporal, pathological, and clinical continuum spanning preclinical, prodromal, and dementia stages. Across this continuum, APOE4 exerts detrimental effects at distinct times and in different cell types, underscoring the need for a model defining not only how but also when and in which cells these effects occur. In this review, we synthesize current findings and propose a temporal model linking cell-type-specific APOE4 expression to AD progression. In this model, age-associated stress upregulates neuronal APOE4 expression, leading to early neuronal deficits characteristic of preclinical AD. Neuronal APOE4-induced damage subsequently triggers a harmful glial response that, alongside glial APOE4, amplifies neurodegeneration and accelerates the onset of prodromal and dementia AD. This model highlights the temporal and cellular dynamics of APOE4 effects and suggests stage- and cell-type-specific therapeutics targeting APOE4-driven mechanisms across the AD continuum.
Bressan C, Gengatharan A, Rodriguez-Aller R
… +10 more, Richter ML, Snapyan M, Fischer-Sternjak J, Roukerd MR, Rosin N, Cherinet A, Biernaskie J, Habibi E, Götz M, Saghatelyan A
In many tissues, stem cells are found lining fluid-filled cavities, and their neighboring niche cells include cells with beating cilia. However, the role of mechanical forces created by cilia beating on stem cells remain...In many tissues, stem cells are found lining fluid-filled cavities, and their neighboring niche cells include cells with beating cilia. However, the role of mechanical forces created by cilia beating on stem cells remains elusive. We developed an approach to transiently inhibit the cilia beating of ependymal cells (ECs) lining the forebrain ventricle by injecting magnetic bead-coupled antibodies targeting EC cilia and then applying a magnetic field. We show that EC cilia beating enforces neural stem cell (NSC) quiescence through mechano-sensitive polycystin 1/2 (PKD1/2)- and transient receptor potential melastatin 3 (TRPM3)-mediated Ca transients. Only a few hours of EC cilia beating inhibition triggered NSC activation in vivo. CRISPR-Cas9-mediated deletion of TRPM3 or PKD1/2 in NSCs phenocopied the effect of EC cilia beating inhibition, whereas pharmacological activation of TRPM3 rescued NSC quiescence in the absence of cilia beating. Our data reveal that mechanical forces generated by EC cilia beating regulate NSC quiescence/activation dynamics.
Brain activity is highly regulated by GABAergic activity, which can suppress neuronal excitability and synaptic integration. Tonic GABAergic conductances mediated by distinct receptor subtypes can also inhibit neural act...Brain activity is highly regulated by GABAergic activity, which can suppress neuronal excitability and synaptic integration. Tonic GABAergic conductances mediated by distinct receptor subtypes can also inhibit neural activity, although the consequences for dendritic calcium signaling are unclear. Here, we use 2-photon calcium imaging both ex vivo and in awake mice to show that α5-GABARs mediate tonic currents in cortical pyramidal neurons that paradoxically enhance action potential-evoked dendritic calcium influx. Experimental and computational data indicate that the increased calcium influx arises via deinactivation of low-threshold voltage-gated channels. Tonic α5-mediated GABAergic currents and dendritic calcium signals are both enhanced by optogenetic activation of somatostatin-expressing interneurons (SST-INs). In addition, α5-mediated GABAergic facilitation of postsynaptic calcium signaling modulates the short-term plasticity of GABAergic transmission at SST-IN synapses. Our results demonstrate unexpected diversity in the function of both SST-INs and GABAergic signaling to influence dendritic activity and synaptic transmission in the cortex.
While glutamatergic synaptic plasticity is believed to be a fundamental mechanism mediating learning, the behavioral significance of plasticity at cortical GABAergic synapses remains less well understood. Furthermore, de...While glutamatergic synaptic plasticity is believed to be a fundamental mechanism mediating learning, the behavioral significance of plasticity at cortical GABAergic synapses remains less well understood. Furthermore, despite recent discoveries of long-range projections from neocortical GABAergic neurons, details about how they function are also sparse. Here, we combine behavioral optogenetics with patch-clamp electrophysiology to link plasticity at long-range GABAergic synapses with higher-order cognitive functions. Specifically, learning extradimensional rule shifts potentiates callosal GABAergic synapses from prefrontal parvalbumin-expressing (PV) neurons onto corticothalamic neurons. Disrupting this potentiation by inhibiting callosal PV terminals during rule shifts induces perseveration, whereas reinstating this potentiation with subsequent gamma-frequency callosal PV terminal stimulation restores flexible behavior. This shows how a novel plasticity locus can regulate brain circuits underlying normal cognition and pathological states.
Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson's disease (PD). Here, we demonstrate that the non-me...Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson's disease (PD). Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB can function in a non-cell-autonomous manner. In the human brain, GPNMB is widely expressed in neurons and microglia. In induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increase with exposure to apoptotic neurons. In the aSyn fibril-seeded model of PD, iMicroglia-derived GPNMB enhances neuronal aSyn uptake and development of aSyn pathology, including in GPNMB knockout neurons. Conversely, anti-GPNMB antibodies rescue neurons from developing aSyn pathology. Finally, in 1,675 human postmortem cases, GPNMB genotypes conferring higher GPNMB expression are associated with more widespread aSyn pathology. Our data suggest a positive feedback loop, where neurodegeneration triggers increased microglial GPNMB secretion, leading to increased neuronal aSyn pathology and neurodegeneration. Importantly, this cycle can be therapeutically interrupted by anti-GPNMB antibodies.
Jiang M, Li R, Yang X
… +20 more, Ren Z, Yang Z, Azevedo F, Sharma J, Menegas W, Choi S, Yang L, Li M, Su Z, Zhu L, Guo P, He Z, Huang W, Anteraper S, Dai J, Wang L, Yang S, Desimone R, Feng G, Lu Z
Haploinsufficiency of the SHANK3 gene is the primary cause of Phelan-McDermid syndrome (PMS), a severe neurodevelopmental disorder with intellectual disability and autism spectrum disorder. We previously reported that fo...Haploinsufficiency of the SHANK3 gene is the primary cause of Phelan-McDermid syndrome (PMS), a severe neurodevelopmental disorder with intellectual disability and autism spectrum disorder. We previously reported that founder SHANK3 macaques had behaviors reminiscent of some aspects of PMS. However, insights into behavioral, physiological, and cognitive changes were limited due to the small cohort and mosaicism. We therefore generated a larger, F1 generation of heterozygous SHANK3 macaques to conduct more thorough studies. We found sleep disturbances, diminished exploration, atypical social interactions, stereotypical behaviors, and altered brain functional connectivity in SHANK3 macaques. Electroencephalogram recordings revealed a markedly diminished response to auditory stimulation. Cognitively, SHANK3 monkeys did not show major deficits in working memory tests but exhibited an impaired ability to learn and execute a paired-association memory task. We further developed a multi-task array to systemically evaluate autism-related phenotypes, which revealed the heterogeneity of phenotypes and established potential biomarkers for testing therapeutics.
Successful cooperation requires the dynamic integration of social cues. However, the neural mechanisms supporting this complex process remain unknown. Here, we reveal that the primate dorsomedial prefrontal cortex (dmPFC...Successful cooperation requires the dynamic integration of social cues. However, the neural mechanisms supporting this complex process remain unknown. Here, we reveal that the primate dorsomedial prefrontal cortex (dmPFC) implements a gaze-dependent social evidence accumulation process to guide cooperative decisions in freely moving marmoset dyads. A drift-diffusion process in which the partner's action variability is accumulated through social gaze best explains the cooperative actions of the actor. Single-neuron recordings in the dmPFC revealed a direct neural correlate: the slope of predictive ramping activity mapped directly onto the rate of evidence accumulation, while baseline firing, modulated by prior outcomes, mapped onto the initial bias. At the population level, the geometry of dmPFC neural trajectories reflected the strength of social evidence and was linked to cooperative success. Together, these findings establish a multi-level neural mechanism for transforming active sensing into a decision variable, linking a canonical computation to cooperative behavior in a naturalistic setting.
Condrau J, Glück C, Wyss MT
… +16 more, Hösli L, Erlebach E, Zanker HS, von Faber-Castell A, Ravotto L, Eberle G, Allu SR, Esipova TV, Troxler T, Bennett JL, Herwerth M, Wegener S, Saab AS, Vinogradov SA, El Amki M, Weber B
The brain's microvasculature is essential for oxygen and nutrient delivery; however, the mechanisms underlying cerebral capillary repair following injury remain largely elusive. Here, we identify an unrecognized mechanis...The brain's microvasculature is essential for oxygen and nutrient delivery; however, the mechanisms underlying cerebral capillary repair following injury remain largely elusive. Here, we identify an unrecognized mechanism through which brain capillary endothelial cells (ECs) autonomously promote capillary remodeling. Using longitudinal two-photon imaging in mice, we demonstrate that following focal endothelial injury and selective loss of a single EC, neighboring ECs extend their plasma membranes toward each other, rapidly re-establishing capillary continuity and blood flow within 24-48 h. This repair process engages vascular endothelial growth factor receptor 2 (VEGFR2) signaling but occurs independently of perivascular or glial cell involvement. Finally, we reveal regional differences in repair efficacy, with hippocampal capillaries exhibiting a slower and less-efficient response compared with those in the cortex. These findings reveal an intrinsic mechanism that safeguards microvascular integrity and suggest that regional vulnerabilities in endothelial repair could shape brain resilience to injury and disease.
Flexibly responding to sensory cues is fundamental to animal behavior. However, growing evidence suggests that the relevant neural circuits have been incompletely resolved. We trained mice to apply an abstract rule that...Flexibly responding to sensory cues is fundamental to animal behavior. However, growing evidence suggests that the relevant neural circuits have been incompletely resolved. We trained mice to apply an abstract rule that maps identical visual stimuli to opposing actions across contexts and investigated the role of the midbrain reticular formation (MRF) in this process. Large-scale recordings revealed that neurons in the MRF, along with several canonical decision-making areas, maintained persistent representations of task context in pre-stimulus activity. These representations predicted divergent population dynamics, putatively routing stimuli toward context-appropriate actions. The MRF was the only recorded region containing neuronal populations that both predicted lapses in contextual control pre-stimulus and exhibited contextually modulated premotor responses. The MRF also showed task-specific sensory plasticity. Context-coding neurons were aligned with cortical inputs, suggesting a spatial organization. These findings support the hypothesis that the MRF is a key node for setting and implementing abstract contextual states within the distributed circuitry for flexible perceptual decisions.
In natural environments, animals must allocate choices across multiple concurrently available resources when foraging, a complex decision-making process not fully captured by existing models. To understand how rodents le...In natural environments, animals must allocate choices across multiple concurrently available resources when foraging, a complex decision-making process not fully captured by existing models. To understand how rodents learn to navigate this challenge, we developed a novel paradigm in which naive, water-restricted mice freely sampled six options of varying quality arranged around a large (∼2 m) arena. Mice exhibited rapid learning, matching their choices to integrated reward probabilities across six options within tens of minutes. A reinforcement learning model with distinct states for staying vs. leaving an option, as well as a dynamic global learning rate, accurately reproduced behavior. Fiber photometry recordings revealed that dopamine in the nucleus accumbens core (NAcC), but not the dorsomedial striatum (DMS), reflected this learning rate. Moreover, optogenetic manipulation of NAcC dopamine bidirectionally altered learning in quantitative agreement with model predictions. Together, we identified a neural substrate of a learning algorithm enabling efficient multi-option foraging in large spatial environments.
Zhang S, Dong FY, Cai S
… +29 more, Zhou B, Jiang L, Hu LP, Zhu YH, Li H, Yang XM, Cai Z, Yao LL, Wang H, Yao HF, Li J, Li Q, Zhu L, Yang Q, Liu LM, Yu YQ, Zhang JF, Hua R, Zhang XL, Zhu HH, Niu N, Xue J, Jiang C, Sun YW, Han Q, Li DX, Liu DJ, Zhang ZG, Jiang SH
Tumor innervation (TIN) and perineural invasion (PNI) are well-established pathological features of pancreatic ductal adenocarcinoma (PDAC) that drive its aggressiveness and associated pain. Here, we reveal that regenera...Tumor innervation (TIN) and perineural invasion (PNI) are well-established pathological features of pancreatic ductal adenocarcinoma (PDAC) that drive its aggressiveness and associated pain. Here, we reveal that regenerating islet-derived (Reg) proteins, secreted by peritumoral exocrine acinar cells, facilitate TIN and PNI through two paracrine mechanisms. In PDAC cells, Reg proteins drive cancer invasiveness along nerves via autocrine transforming growth factor β (TGF-β) signaling. In neurons, Reg proteins are neurotrophic and potentiate neuronal excitability, resulting in hyperinnervation and pain. Interleukin-22, primarily produced by CD4 T cells, triggers Reg expression. Exostosin-like glycosyltransferase 3 (EXTL3) is the functional receptor for Reg proteins in both cell types. Genetic silencing of Reg or EXTL3 reduces TIN, nerve-cancer proximity, PDAC progression, and pain behavior in mice. Clinically, the Reg-EXTL3-TGF-β axis correlates with increased TIN and PNI severity, poor prognosis, and greater pain. Thus, targeting the Reg-EXTL3 axis may be an attractive strategy for mitigating neural-associated adverse consequences in PDAC.
Zhu Z, Lin W, Xiao L
… +17 more, Qian Z, He T, Wang W, Wang Y, Zhang X, Zhao B, Xie H, Quan X, Zhang Y, Jiang M, Li X, Zhou L, Zhang D, Yu H, Liu Z, Bao L, Jia JM
Adult neuronal survival underlies lifelong brain function, yet its sustaining mechanisms remain unclear. We identify a neurovascular survival axis at intracranial arteries in mice, where superior cervical ganglion (SCG)...Adult neuronal survival underlies lifelong brain function, yet its sustaining mechanisms remain unclear. We identify a neurovascular survival axis at intracranial arteries in mice, where superior cervical ganglion (SCG) sympathetic terminals form synapse-like neurosmooth muscular junctions (NsMJs) with arterial smooth muscle cells (aSMCs) that secrete netrin-4 (Ntn4). Adult aSMC-restricted Ntn4 deletion selectively reduces rostral, intracranial-projecting (cerebrospinal fluid-traced) SCG neurons; the denervation of the intracranial arterial plexus follows soma loss. Local recombinant Ntn4 delivery to the SCG rescues these phenotypes. Ntn4 withdrawal engages a receptor-interacting serine/threonine kinase 1 (RIPK1)/mixed lineage kinase domain-like pseudokinase (MLKL)-linked, caspase-independent, non-inflammatory death program via deleted in colorectal cancer (DCC): unliganded DCC triggers neuronal loss, whereas Dcc knockout preserves vulnerable neurons. Arterial Ntn4 declines from young adulthood and precedes selective neuronal attrition before midlife; aSMC-targeted Ntn4 overexpression prevents this loss. Together, intracranial arteries provide a local, non-cell-autonomous trophic niche that maintains this adult sympathetic subset and becomes compromised as vascular Ntn4 output wanes with age.
The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of AP...The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.
The past decade of transformative advances in neurotechnology portends an exciting future for neuroscience. This NeuroView charts a strategic path to accelerate and integrate research discovery and speed the development...The past decade of transformative advances in neurotechnology portends an exciting future for neuroscience. This NeuroView charts a strategic path to accelerate and integrate research discovery and speed the development of new cures for human brain disorders.
Central nervous system drug delivery centers primarily on strategies aimed at crossing the blood-brain barrier. In a recent study, Gao et al. report that nanoparticles can bypass the blood-brain barrier by hijacking calv...Central nervous system drug delivery centers primarily on strategies aimed at crossing the blood-brain barrier. In a recent study, Gao et al. report that nanoparticles can bypass the blood-brain barrier by hijacking calvarial immune cells and exploiting migration through skull-meninges channels, which enables lesion-targeted, minimally invasive therapeutic delivery to the brain.
In this issue of Neuron, Pezon et al. introduce neural circuit models with flexible connectivity structure that can generate low-dimensional population dynamics with different distributions of single-neuron selectivity,...In this issue of Neuron, Pezon et al. introduce neural circuit models with flexible connectivity structure that can generate low-dimensional population dynamics with different distributions of single-neuron selectivity, from ordered to fully random. This work opens new avenues for inferring circuit structure from neural recordings.
In this issue of Neuron, Yang et al. report cryo-EM structures of the heat-sensing ion channel TRPM3. Leveraging a structure-based virtual screen to identify and optimize novel inhibitors, they demonstrate that a newly d...In this issue of Neuron, Yang et al. report cryo-EM structures of the heat-sensing ion channel TRPM3. Leveraging a structure-based virtual screen to identify and optimize novel inhibitors, they demonstrate that a newly discovered potent and selective TRPM3 antagonist produces analgesia in various rodent pain models.
Circulating levels of the bone-derived hormone osteocalcin maintain GPR37 ventral tegmental area (VTA) GABAergic neurons in a state of readiness. In this issue of Neuron, Liu et al. demonstrate that this bone-to-brain ne...Circulating levels of the bone-derived hormone osteocalcin maintain GPR37 ventral tegmental area (VTA) GABAergic neurons in a state of readiness. In this issue of Neuron, Liu et al. demonstrate that this bone-to-brain neuroendocrine circuit is essential for the rapid detection of and the escape response to visual threats.