Achieving complex goals often requires breaking them down into simpler subgoals. In this issue of Neuron, Grossman et al. show that people structure their behavior hierarchically when pursuing goals, and they reveal cand...Achieving complex goals often requires breaking them down into simpler subgoals. In this issue of Neuron, Grossman et al. show that people structure their behavior hierarchically when pursuing goals, and they reveal candidate brain computations that support this planning.
Visual pop-out reflects feature-dependent surround modulation in primary visual cortex (V1). In this issue of Neuron, Hendricks et al. reveal that co-tuned pyramidal cells selectively engage somatostatin interneurons (SS...Visual pop-out reflects feature-dependent surround modulation in primary visual cortex (V1). In this issue of Neuron, Hendricks et al. reveal that co-tuned pyramidal cells selectively engage somatostatin interneurons (SSTs) via like-to-like excitation, switching cortical circuits into a suppressed state that supports orientation-based figure-ground segmentation.
GABA receptors are critical in insect neurotransmission. How insecticides act on these receptors in pest insects and in beneficial insects like honeybees remains underexplored. Here, Labouré et al. reveal how insecticide...GABA receptors are critical in insect neurotransmission. How insecticides act on these receptors in pest insects and in beneficial insects like honeybees remains underexplored. Here, Labouré et al. reveal how insecticides modulate honeybee GABA receptors, facilitating design of safer pesticides.
In this issue of Neuron, Grimm et al. describe the Jarvis voltage indicator, which demonstrates that scanless parallel two-photon excitation enables robust, high-speed voltage imaging in vivo, overturning prior assumptio...In this issue of Neuron, Grimm et al. describe the Jarvis voltage indicator, which demonstrates that scanless parallel two-photon excitation enables robust, high-speed voltage imaging in vivo, overturning prior assumptions about the incompatibility of rhodopsin-based indicators with two-photon microscopy.
The exquisite acuity of mammalian hearing relies on cochlear amplification provided by sensory outer hair cells (OHCs), downstream of mechanoelectrical transduction of sound. In OHCs, transduction is initiated by deflect...The exquisite acuity of mammalian hearing relies on cochlear amplification provided by sensory outer hair cells (OHCs), downstream of mechanoelectrical transduction of sound. In OHCs, transduction is initiated by deflection of stereocilia conveyed through tethering to the tectorial membrane (TM) via an incompletely characterized protein complex, the TM attachment crowns (TM-ACs). We identify Tmem145, a G protein-coupled receptor (GPCR)-related "Golgi-dynamics-domain-seven-transmembrane (GOST)" protein, as the core element of TM-ACs. Tmem145 localized to the tips of the tallest row of stereocilia, precisely matching the localization of previously known components of TM-ACs, tubby, and stereocilin. Genetic ablation in mice resulted in loss of tubby and stereocilin from OHC stereocilia, disconnection of the hair bundle from the TM, and profound hearing loss with a lack of cochlear amplification. Tmem145 binds cytosolic tubby and anchors secreted stereocilin, likely through its extracellular Golgi-like domain. This architecture suggests a general role of Tmem145-related proteins as organizers of transmembrane anchor complexes.
The hippocampus contains a multisensory cognitive map that incorporates spatial cues from across the senses, such as vision and olfaction. However, how primary sensory information transforms along pathways to the hippoca...The hippocampus contains a multisensory cognitive map that incorporates spatial cues from across the senses, such as vision and olfaction. However, how primary sensory information transforms along pathways to the hippocampus into this single, combined map is largely unknown. Specifically, does the hippocampus generate or inherit the multisensory map of space? Here, we used multisensory virtual reality and large-scale functional imaging to determine whether and how the main input regions to hippocampus, the lateral and medial entorhinal cortices (LECs and MECs, respectively), map olfactory, and visual sensory spaces in navigating mice. We discovered that, unlike multisensory mapping in the hippocampus, LEC preferentially maps olfactory space, whereas MEC preferentially maps visual space, regardless of the behavioral relevance of the spaces. This establishes the existence of largely independent brain maps for different sensory spaces, suggesting that the hippocampus builds the cognitive map by combining modality-specific maps from pre-synaptic cortical regions.
Human cognition relies on two modes: a perceptually coupled mode where mental states are driven by sensory input and a perceptually decoupled mode featuring self-generated mental content. Imagined states that evoke menta...Human cognition relies on two modes: a perceptually coupled mode where mental states are driven by sensory input and a perceptually decoupled mode featuring self-generated mental content. Imagined states that evoke mental imagery are thought to be supported primarily by reinstated activity in sensory cortex, but transmodal systems are also implicated in imagery-related processes like mind-wandering, recollection, and imagining the future. During a precision fMRI experiment, participants imagined different scenarios in the scanner, then rated their mental states using multi-dimensional experience sampling. Thinking involving scenes evoked activity within parts of the canonical default network, while imagining speech evoked activity within the language network. In each domain, imagining-related activity overlapped with activity evoked by viewing scenes or listening to speech, respectively; however, this overlap was predominantly within transmodal association networks, rather than adjacent unimodal sensory networks. We conclude that the engagement of transmodal networks supports self-generated mental states involving different forms of mental imagery.
Over the last three decades, dogma-breaking studies have refuted the brain's assumed immune isolation. Echoing Ramón y Cajal metaphor of neurons as "butterflies," I propose viewing the brain as a neuroimmune garden, with...Over the last three decades, dogma-breaking studies have refuted the brain's assumed immune isolation. Echoing Ramón y Cajal metaphor of neurons as "butterflies," I propose viewing the brain as a neuroimmune garden, with neurons sustained by immune-cell nectar, supporting maintenance, plasticity, protection, and repair.
Ali M, Timsina J, Xu Y
… +35 more, Chen Y, Gong K, Western D, Heo G, Liu M, Budde J, Pottier C, Schindler SE, Morris JC, Holtzman DM, Puerta R, Cano A, Boada M, Fernandez MV, Ruiz A, Aguilar M, Alvarez I, Pastor P, Perlmutter JS, Campbell MC, Kotzbauer PT, Oh HS, Wilson EN, Guen YL, Knight Alzheimer Disease Research Center (Knight-ADRC), Alzheimer Disease Neuroimaging Initiative (ADNI), Fundació ACE Alzheimer Center Barcelona (FACE), Barcelona-1, Stanford Alzheimer Disease Research Center (Stanford-ADRC), Global Neurodegeneration Proteomics Consortium (GNPC), Tarawneh R, Wyss-Coray T, Sung YJ, Ibanez L, Cruchaga C
Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), share overlapping clinical and pathological features. We...Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), share overlapping clinical and pathological features. We analyzed cerebrospinal fluid (CSF) and plasma proteomes from 2,705 and 3,009 samples, respectively, across these NDs, identifying disease-specific and shared molecular signatures. CSF showed more disease-associated proteins than plasma, with AD and DLB exhibiting the strongest cross-tissue similarity. Pathway analyses revealed shared dysregulation of immune-related processes in CSF and plasma across the NDs, as well as disease-specific impairment of glycosylation and apoptotic pathways in AD; ATF4 and PERK signaling in PD; fibroblast growth factor receptor (FGFR) and interleukin signaling in DLB; and glycoprotein hormones disruption in FTD. We developed disease-specific predictive models showing high accuracy (area under the curve [AUC]: 0.81-0.95 in CSF and 0.80-0.89 in plasma). These findings reveal distinct and convergent mechanisms across NDs, highlighting potential biomarkers and pathways for diagnostic and therapeutic strategies in neurodegeneration.
Hill EJ, Sojka C, Sampson MM
… +11 more, Kebede N, Wang HV, Showrin S, King AT, Sing AD, Chang J, Emory Brain Organoid Hub, Faundez V, Sampson TR, Venneti S, Sloan SA
Astrocytes adapt to injury and disease by entering reactive states with altered gene expression, morphology, and function, but we know little about how these states evolve over time in the human setting. Using human cort...Astrocytes adapt to injury and disease by entering reactive states with altered gene expression, morphology, and function, but we know little about how these states evolve over time in the human setting. Using human cortical organoids and primary fetal cortical tissue, we mapped the temporal dynamics of inflammatory astrocytes. Brief and prolonged exposure to inflammatory cytokines elicited distinct time-dependent transcriptomic and chromatin accessibility signatures. Astrocytes that experienced either acute or chronic cytokine exposure reverted to a quiescent genomic state within days of cytokine withdrawal. Unexpectedly, only chronic inflammation revealed induction of major histocompatibility complex class II (MHC class II) expression in astrocytes. We validated MHC class II expression and surface localization in organotypic fetal cortical slices and human pathological sections. We also found evidence that delayed MHC class II emergence reflects progressive activation of interferon-linked signaling in astrocytes. Through co-immunoprecipitation of MHC class II complexes from cytokine-treated astrocytes, we demonstrate the presence of MHC class II-presented peptides, which include neuronal debris.
Ellingford R, Harris SS, Kehring M
… +19 more, Rajani RM, Lam FKW, Graykowski D, Bӧken D, Welikovitch LA, Khasnavis A, Laban R, Heslegrave A, Yaman U, Mate de Gerando A, Bond SA, Wray S, Salih DA, Dupret D, Dolan RJ, Klenerman D, Zetterberg H, Hyman BT, Busche MA
Memory-based cognition relies on the integrity of cortico-hippocampal circuits, which are compromised in Alzheimer's disease (AD) as β-amyloid (Aβ) and tau accumulate. However, the mechanisms linking this pathology to ci...Memory-based cognition relies on the integrity of cortico-hippocampal circuits, which are compromised in Alzheimer's disease (AD) as β-amyloid (Aβ) and tau accumulate. However, the mechanisms linking this pathology to circuit dysfunction remain unclear. In mouse models, using in vivo two-photon and Neuropixels recordings, we show that Aβ-tau pathology promotes both region- and layer-specific impairments, involving reduced burst firing in superficial cortical layers and CA1 and reduced mean firing of excitatory and inhibitory neurons in deep cortical layers and CA1. Exposure to Aβ primed the susceptibility of neuronal populations to tau-induced impairment. Combined Aβ-tau reduced synaptic NMDA receptor (NMDAR) density in both mouse and human tissue, while Aβ-tau co-reduction restored NMDARs and firing patterns and improved contextual memory. NMDAR antagonism in healthy mice phenocopied regional and laminar deficits. Our findings implicate synaptic NMDAR hypofunction as a reversible mechanism linking Aβ-tau synergy to cortico-hippocampal dysfunction in AD.
Multiciliated choroid plexus epithelial cells (CPECs) are responsible for cerebrospinal fluid (CSF) production and are exposed to mechanical stimuli derived from CSF flow and intercellular contacts. However, their mechan...Multiciliated choroid plexus epithelial cells (CPECs) are responsible for cerebrospinal fluid (CSF) production and are exposed to mechanical stimuli derived from CSF flow and intercellular contacts. However, their mechanotransduction mechanisms remain poorly understood. Here, we show that the mechanically activated ion channel Piezo1 is prominently expressed in apical and lateral membranes of mature CPECs, mediates mechanically evoked currents and Ca influx in response to both fluid flow and pharmacological activation by Yoda1, and maintains the Ca homeostasis in a cell-cell contact-dependent manner. Either knockout or overexpression of Piezo1 in CPECs led to severe hydrocephalus in mice, reduced CSF flow, disrupted ciliary maintenance, and altered expression of cilia-related genes. Piezo1-mediated Ca homeostasis regulates ciliogenesis of primary cultured CPECs. These findings establish Piezo1 as a critical mechanotransducer in CPECs for controlling the homeostasis of Ca signaling, ciliogenesis and CSF, and its mechanopathological linkage to hydrocephalus.
PIEZO proteins form evolutionarily conserved mechanically activated ion channels, and the prototype mouse PIEZO1 (mPIEZO1) is cation selective. However, the evolutionary conservation and adaptation of the structure-funct...PIEZO proteins form evolutionarily conserved mechanically activated ion channels, and the prototype mouse PIEZO1 (mPIEZO1) is cation selective. However, the evolutionary conservation and adaptation of the structure-function properties of PIEZOs remain poorly understood. Here, we discover that Drosophila PIEZO (dPIEZO) exhibits unusual ion selectivity for both Cl and Ca. Its cryoelectron microscopy (cryo-EM) structure adopts the characteristic three-bladed, propeller-shaped architecture of mPIEZO1 but in a distinct conformational state. We identify that the lateral-plug domain (Arg1385-Ala1397) and key residues, such as His1391 and Arg1396, determine the distinct ion selectivity of dPIEZO. His1391 is evolutionarily conserved from insects to mammals and mediates pH-dependent tuning of the ion selectivity of dPIEZO. Evolving Arg1396 to His in mammalian PIEZO1 might functionally change the lateral-plug domain from a selectivity filter to a pluggable gate. Together, these findings shed light on the evolutionary conservation, adaptation, and regulation of the structure-function properties of PIEZO channels.
CNS vascular endothelial cells (ECs) exhibit a distinctive gene expression program that is foundational for the blood-brain barrier (BBB). Previous research identified candidate cis-regulatory elements (CREs) that were h...CNS vascular endothelial cells (ECs) exhibit a distinctive gene expression program that is foundational for the blood-brain barrier (BBB). Previous research identified candidate cis-regulatory elements (CREs) that were hypothesized to control this program. In this work, transgenic mice and recombinant adeno-associated virus (rAAV) vectors have been used to interrogate these candidate CREs in vivo. These experiments show that an 850 bp genomic DNA segment ∼60 kb 5' of Slc2a1 possesses enhancer activity that is (1) specific for BBB+ CNS ECs and (2) both necessary and sufficient for BBB+ EC gene expression. A screen of >8,000 genomic DNA segments from CNS EC-specific CRE candidates reveals several hundred with enhancer activity. Transcription factors ERG and LEF1 are shown to occupy sites in brain ECs that are highly enriched in candidate and experimentally validated CREs, lending strong support to a model in which canonical Wnt signaling activates the BBB program via LEF1.
Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds that protect disease-affected or damaged healthy cell types. Here, we gene...Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds that protect disease-affected or damaged healthy cell types. Here, we generated 20,000 human retinal organoids with green fluorescent protein (GFP)-labeled cone photoreceptors. Since degeneration of cones is a leading cause of blindness, we induced cone death and screened 2,707 compounds with known targets for those that saved cones or those that further damaged cones. We identified inhibitors of casein kinase 1 (CK1) that protected cones, heat shock protein 90 (HSP90) inhibitors that saved cones in the short term but damaged them in the longer term, and broad histone deacetylase (HDAC) inhibition by many compounds that significantly damaged cones. Finally, we confirmed the protective effects of identified compounds in a mouse model of photoreceptor degeneration. This work provides a database for cone-damaging compounds and describes compounds and targets that can be starting points to develop neuroprotection for cones in diseases such as macular degeneration.
Stress-induced analgesia (SIA) is a crucial adaptive response. The central amygdala (CeA) has been implicated in this process, yet its underlying cellular mechanisms remain elusive. Here, we show that a subset of somatos...Stress-induced analgesia (SIA) is a crucial adaptive response. The central amygdala (CeA) has been implicated in this process, yet its underlying cellular mechanisms remain elusive. Here, we show that a subset of somatostatin-expressing CeA neurons (CeA) in mice selectively represent nociception and that acute stress suppresses their responses to noxious stimuli. Interestingly, this stress-induced suppression is selective to the representation of nociception rather than a general alteration in response to salience. Moreover, corticotropin-releasing hormone-expressing CeA neurons (CeA), the primary local inhibitory input to CeA, exhibit diverse activation patterns in response to acute stress. Inhibition of CeA during, but not after, acute stress significantly reduces SIA, indicating a state-dependent role of CeA in modulating nociception. Furthermore, CeA-projecting neurons in the dorsal raphe nucleus are persistently activated during stress and mediate SIA through activating CeA serotonin (5-HT) 2A receptors. Together, our results define the circuit basis through which the CeA contributes to SIA.
Alcohol use disorder (AUD) lacks effective brain-targeted treatments. Here, using mouse models, we show that glucagon-like peptide-1 receptor (GLP-1R) signaling in the dorsal lateral septum (dLS) regulates alcohol consum...Alcohol use disorder (AUD) lacks effective brain-targeted treatments. Here, using mouse models, we show that glucagon-like peptide-1 receptor (GLP-1R) signaling in the dorsal lateral septum (dLS) regulates alcohol consumption and reward. Systemic administration of the GLP-1R agonist liraglutide decreased alcohol intake and ethanol-evoked dopamine release in the nucleus accumbens, requiring GLP-1R expression in the dLS. Alcohol consumption suppressed dLS neuronal activity, whereas liraglutide prevented alcohol-induced suppression of transient calcium dynamics. Inactivation of these neurons increased alcohol consumption and abolished the behavioral effects of liraglutide, whereas chemogenetic activation suppressed alcohol-directed behavior. Circuit-level analysis identified a local inhibitory projection from dLS neurons to estrogen receptor 1-expressing neurons in the ventral lateral septum (vLS neurons), and targeted manipulation of this circuit confirmed its role in regulating alcohol intake. Together, these findings delineate a septal inhibitory circuit through which GLP-1R signaling modulates alcohol-related behaviors and highlight the dLS as a therapeutic target for AUD.
Cholinergic neurons exhibit distinct firing patterns underlying diverse physiological and pathological states, but the mechanisms governing their dynamic switching, particularly in negative emotional contexts, remain unc...Cholinergic neurons exhibit distinct firing patterns underlying diverse physiological and pathological states, but the mechanisms governing their dynamic switching, particularly in negative emotional contexts, remain unclear. Here, we demonstrate that medial habenula cholinergic (MHb) neurons transition from tonic to burst firing during nicotine withdrawal, driving anxiety-like behaviors in mice. Integrating transcriptomics, electrophysiology, and genetic manipulation, we identified the RNA-binding protein pumilio 1 (Pum1) as a critical brake on this switch. Pum1 binds Cacna1g mRNA (encoding Cav3.1) at nucleotides 6,498-6,501, promoting its decay. MHb neurons comprise two subpopulations: burst-firing Pum1 and tonic-firing Pum1 neurons. Withdrawal downregulates Pum1, derepressing Cav3.1 to induce pathological bursting. Genetic or pharmacological suppression of Cav3.1, or Pum1 overexpression, rescues burst firing and anxiety-like behaviors. Our study unveils MHb neurons' burst firing as a causal driver of anxiety and reveals the Pum1-Cav3.1 axis as a master regulator of firing plasticity, offering a potential targeted therapeutic strategy for cholinergic dysfunction-related disorders.
Methamphetamine (METH) use disorder (MUD) is characterized by high relapse rates driven by craving, yet the underlying neural mechanisms remain unclear. Here, we reveal the temporal and circuit-specific contributions of...Methamphetamine (METH) use disorder (MUD) is characterized by high relapse rates driven by craving, yet the underlying neural mechanisms remain unclear. Here, we reveal the temporal and circuit-specific contributions of somatostatin (SST) and parvalbumin (PV) interneurons (INs) in the prelimbic cortex (PL) in the incubation of METH craving. SST INs mediated drug seeking during early withdrawal (day 1) via lateral hypothalamus (LH) GABAergic inputs, while PV INs drove seeking following prolonged withdrawal (day 15) via anteromedial thalamus (AM) glutamatergic inputs. Single-cell RNA sequencing (scRNA-seq) revealed upregulated KCNC2 (encoding the Kv3.2 potassium channel) in both subtypes, with specific protein modifications. Selective KCNC2 knockdown in SST or PV INs significantly suppressed drug seeking during early or prolonged withdrawal, respectively. These findings uncover the distinct contributions of PL IN subtypes to the incubation of craving and identify KCNC2 as a potential phase-specific therapeutic target in MUD.
Etxeberria A, Lee SH, Kuhn JA
… +25 more, Callow M, Novikova G, Fortin JP, Choy MK, Xie L, Imperio J, Vito S, Tsai MC, Lock J, Taraborrelli L, Haag SM, Chen H, Ge M, Ngu H, Foreman O, Stark K, Friedman BA, Haley B, Hansen DV, Meilandt WJ, Easton A, Martin S, Murthy A, Costa M, Bohlen CJ
Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary...Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased neuritic dystrophy around amyloid plaques in the TauPS2APP model of Alzheimer's disease. However, deletion also dysregulated homeostasis in normal white matter and exacerbated neurodegeneration in disease. Heterozygous deletion revealed a differential gene-dosage sensitivity for beneficial and detrimental effects, exhibiting reduced neuritic damage near plaques without white-matter harm. Single-cell RNA sequencing uncovered multiple disease-associated microglia (DAM)-like transcriptional states, with Lgals3 microglia emerging alongside neurodegeneration after Ptpn6 deletion. In all, these findings reveal both the protective and latent degenerative potential of microglia held in check by Ptpn6.