Neuroscience[JOURNAL]
Sun
200 papers
Goal-directed hippocampal theta sweeps during memory-guided navigation.
Tang W, Mei X, Harvey RE … +5 more , Carbajal-Leon E, Netzer T, Chang H, Oliva A, Fernandez-Ruiz A
Nat Neurosci · 2026 Jul · PMID 42386948 · Publisher ↗
During navigation, animals continuously sample their environment and plan routes to distant goals. Flexible navigation requires neural dynamics capable of rapidly deploying task-relevant information to direct behavior to...
During navigation, animals continuously sample their environment and plan routes to distant goals. Flexible navigation requires neural dynamics capable of rapidly deploying task-relevant information to direct behavior toward goals. Hippocampal spiking sequences within theta cycles, which sweep along spatial trajectories ahead of the animal, serve as a potential candidate. Previous research identified experience-independent, left-right-alternating theta sweeps as a mechanism for local spatial sampling. However, it remains unclear whether theta sweeps also facilitate trajectory evaluation toward distant, remembered goals. In rats performing goal-directed navigation in an open arena, we identified a distinct form of learning-dependent theta sequences that predicted upcoming goal-directed trajectories. These sequences coordinated with prefrontal cortical activity and were preferentially replayed during sharp-wave ripples. We described a circuit mechanism whereby egocentric goal-direction signals, combined with reduced feedback inhibition, generated goal-directed theta sweeps. Experience-dependent and goal-dependent theta sweeps thus provide a flexible mechanism for goal-directed navigation in open environments.
A Matter of Parameters: Tailored Transcranial Focused Ultrasound Enhances Cortico-Thalamo-Cortical Circuit Resonance.
Kilic U, Carter JR
J Neurosci · 2026 Jul · PMID 42386522 · Full text
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Proactive visual and motor prioritization differentially scale with cue reliability.
Wang 王思思 S, van Ede F
J Neurosci · 2026 Jul · PMID 42386518 · Publisher ↗
Environmental cues enable the brain to anticipate and prepare for upcoming behavior, such as by selectively prioritizing relevant visual representations and associated action plans in working memory in service of an immi...
Environmental cues enable the brain to anticipate and prepare for upcoming behavior, such as by selectively prioritizing relevant visual representations and associated action plans in working memory in service of an imminent task. While it has been demonstrated that neural dynamics of visual and motor prioritization each scale with cue reliability, studies to date tracked either visual or motor prioritization in isolation. It therefore remains unknown whether visual and motor prioritization scale similarly or differently with cue reliability. To fill this gap, we manipulated cue reliability (100%, 80%, 60%) in a visual-motor working-memory task that uniquely enabled us to isolate the neural dynamics associated with visual and motor prioritization in anticipation of an imminent working-memory task. EEG measurements in male and female human volunteers revealed how cue reliability differentially drives visual and motor prioritization. While the strength and timing of visual prioritization were relatively stable across cue reliability levels, motor prioritization profoundly scaled with cue reliability and developed more gradually with lower certainty. These findings show that visual and motor prioritization in working memory are differentially susceptible to the certainty conveyed by environmental cues, and suggest that motor prioritization may be more cautious in nature. To cope with the ever-changing world, the human brain continuously leverages environmental cues to anticipate upcoming behavior, such as by prioritizing relevant visual representations and action plans 'in mind'. Yet, in a volatile world, environmental cues typically vary in the certainty they provide. Building on prior work studying visual or action prioritization in isolation, we uniquely studied how cue certainty shapes both visual and motor prioritization within the same task. We unveil how cue certainty distinctly drives visual and action prioritization, with action prioritization requiring more certainty before deployment, whilst also being deployed more gradually at lower certainty. Thus, prioritization of potential actions is distinct from-and more cautious than-prioritization of the visual representations that guide these actions.
Connectomic evidence that ordered activity drives neuromuscular network formation.
Meirovitch Y, Kang K, Draft RW … +13 more , Pavarino EC, Echeverri MFH, Yang F, Turney SG, Berger DR, Peleg A, Montero-Crespo M, Wu Y, Schalek RL, Lu J, Livet J, Tapia JC, Lichtman JW
Nat Neurosci · 2026 Jun · PMID 42380673 · Publisher ↗
We reconstructed complete connectomes between motor neurons and muscle fibers in small mouse muscles from birth through successive stages of postnatal development, when synaptic reorganization is most prominent. During d...
We reconstructed complete connectomes between motor neurons and muscle fibers in small mouse muscles from birth through successive stages of postnatal development, when synaptic reorganization is most prominent. During development, marked reductions in axonal branching produced an approximately 6.5-fold decrease in the number of axons innervating each neuromuscular junction (NMJ), culminating in single innervation of all NMJs. Surprisingly, many neonatal muscle fibers also had more than one NMJ site. Most, but not all, of these supernumerary NMJs were eliminated. The few multiNMJ fibers that remained in adults had two widely separated junctions innervated by axons that exerted similar contractile forces and therefore had similar activity patterns. Unexpectedly, the muscle connectome further showed that both the loss of axons from individual NMJs and the elimination of entire NMJs related to the recruitment order of the innervating axonal cohort, and that this relationship reflected a rank-ordered pattern of axonal co-innervation. These observations argue that both local intrajunctional and long-distance interjunctional synaptic competition are activity-mediated and that the structure of mature neural circuits arises from the activity patterns of developing circuits.
Erratum: Yao et al., "Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death".
J Neurosci · 2026 Jun · PMID 42379883 · Publisher ↗
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Erratum: L'Episcopo et al., "Plasticity of Subventricular Zone Neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) Mouse Model of Parkinson's Disease Involves Cross Talk between Inflammatory and Wnt/β-Catenin Signaling Pathways: Functional Consequences for Neuroprotection and Repair".
J Neurosci · 2026 Jun · PMID 42379882 · Publisher ↗
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Combined maternal separation and limited bedding-nesting increase goal tracking, delay discounting, and impulsive action, and moderate sign-tracking-perseverance associations in male rats.
Cifuentes J, Arias-Higuera M, Acevedo-Triana C … +3 more , Hylin MJ, Pozzo-Miller L, Hurtado-Parrado C
BMC Neurosci · 2026 Jun · PMID 42374171 · Full text
BACKGROUND: Extensive research with rodent models has shown detrimental effects of early-life adversity (ELA) on behavioral (e.g., impulsive behavior, anxiety, and depression) and neurobiological processes (e.g., alterat...
BACKGROUND: Extensive research with rodent models has shown detrimental effects of early-life adversity (ELA) on behavioral (e.g., impulsive behavior, anxiety, and depression) and neurobiological processes (e.g., alterations of neuroendocrine processes and maturation of brain areas). However, heterogeneous methodologies, including types and variations of ELA manipulations could have contributed to inconsistent findings across studies. Recent research indicates that the combination of the two most widely implemented rodent ELA protocols, Maternal Separation (MS) and Limited Bedding/Nesting (LBN), produces consistent and robust behavioral effects. We assessed the effects of combined MS-LBN on four processes linked to both ELA and behavioral disorders in later stages of life: incentive salience of reward cues, and impulsive choice, action, and persistence/perseverance. METHODS: Sixteen male Sprague Dawley rats were divided in groups of combined MS-LBN during postnatal days 2-21 and without ELA. They were exposed to an Autoshaping Pavlovian conditioning task (AUT), a delay-discounting task (DDT), and acquisition and extinction of a multiple schedule of reinforcement with long and short Variable Intervals (VI) across a span of 18 weeks. RESULTS: Compared to the No-ELA group, ELA rats displayed higher goal-tracking during the AUT (higher nose-poking in the food-delivery location), higher impulsive choice during test and 7-week re-test of the DDT (preference for the smaller-sooner reinforcer over the larger-later), and less efficient responding during the long-interval schedule of reinforcement (more unnecessary responses per pellet). Associations between autoshaping and reinforcement-schedule performance were identified, with ELA moderating the relationship between sign tracking and efficiency during training and persistence/perseverance during extinction. CONCLUSIONS: Combined MS-LBN was associated with task-specific changes in reward-related and impulsive behavior in male rats. These complex patterns of disruptions across behavioral processes adds further support to the notion that combined ELA protocols are promising robust models of adverse rearing in humans, which often entails multiple stressors. CLINICAL TRIAL NUMBER: Not applicable.
Noninvasive decoding of typed sentences from human brain activity.
Lévy J, Zhang M, Pinet S … +4 more , Rapin J, Banville H, d'Ascoli S, King JR
Nat Neurosci · 2026 Jun · PMID 42374156 · Publisher ↗
Modern neuroprostheses can now restore communication in patients who have lost the ability to speak or move. However, implanting these invasive devices comes with risks inherent to neurosurgery. Here we introduce a nonin...
Modern neuroprostheses can now restore communication in patients who have lost the ability to speak or move. However, implanting these invasive devices comes with risks inherent to neurosurgery. Here we introduce a noninvasive method to decode the production of sentences from brain activity and demonstrate its efficacy in a cohort of 35 healthy volunteers. For this, we present Brain2Qwerty, a new deep learning architecture trained to decode sentences from either electro- or magnetoencephalography, while participants typed briefly memorized sentences on a QWERTY keyboard. With magnetoencephalography, Brain2Qwerty reaches, on average, a character error rate of 29% and substantially outperforms electroencephalography (character error rate: 65%). For the best participants, the model achieves a character error rate of 18%, and can perfectly decode a variety of sentences outside of the training set. Overall, these results narrow the gap between invasive and noninvasive methods and thus open the path for developing safe brain-computer interfaces for noncommunicating patients.
Representations of subsecond duration-based timing by complex spike synchrony in cerebellar Purkinje neurons.
Goldstein SA, Brown ST, Raman IM
J Neurosci · 2026 Jun · PMID 42373549 · Publisher ↗
The cerebellum contributes to associative motor learning and sensorimotor coordination in part by tracking subsecond time intervals between behaviorally relevant events, raising the question of how duration, or absolute...
The cerebellum contributes to associative motor learning and sensorimotor coordination in part by tracking subsecond time intervals between behaviorally relevant events, raising the question of how duration, or absolute time, is encoded. Here, we investigated whether information about duration is present in Purkinje cell complex spikes during repetitive sensory stimuli. Crus 1 Purkinje cells expressing the fast calcium indicator GCaMP8f were imaged at high speed (250 fps), allowing detection of complex spike-associated calcium signals from hundreds of Purkinje cell dendrites simultaneously, with 4-ms temporal resolution, in awake head-fixed mice of both sexes. Air puffs were applied to the whisker pad in stimulus trains that varied in the mean and variance of interstimulus intervals (ISIs, 100-900 ms). In responsive cells, the mean probability of complex spike firing increased about fivefold ∼35 ms post-puff, primarily owing to well-timed spiking after the stimulus rather than an increase in spike rate. The maximal response probability, and in some cells also the response latency, varied linearly with ISI. The values of both variables were consistent for each ISI, regardless of the attributes of the stimulus train, suggesting that they carried information about absolute, rather than relative, durations between stimulus pairs. Because each puff evoked only one or zero complex spikes per Purkinje cell, the dependence of spike probability on ISI emerged as a trial-by-trial dependence of the degree of synchronous firing on ISI, suggesting that subsecond absolute timing of somatosensory signals may be represented by complex spike synchrony across populations of Purkinje cells. The cerebellum regulates motor behaviors that require tracking time intervals briefer than one second. Here, we tested how the complex spikes of cerebellar Purkinje cells may encode the interval duration between somatosensory stimuli. We find that at least two attributes of complex spiking vary linearly with the interval between pairs of stimuli, namely, firing likelihood and firing latency. Because of their low spiking probability, however, individual Purkinje neurons cannot accurately report timing information about single stimulus pairs. Nevertheless, the number and latency of complex spikes fired synchronously across the Purkinje cell population changed consistently with the absolute interval between somatosensory stimuli. These data thus demonstrate one way in which neurons may represent time.
The extended language network: Language-responsive brain areas whose contributions to language remain to be discovered.
Wolna A, Wright A, Casto C … +3 more , Hutchinson S, Lipkin B, Fedorenko E
J Neurosci · 2026 Jun · PMID 42373548 · Publisher ↗
Although language neuroscience has largely focused on 'core' left frontal and temporal brain areas and their right-hemisphere homotopes, numerous other areas-cortical and subcortical-have been implicated in linguistic pr...
Although language neuroscience has largely focused on 'core' left frontal and temporal brain areas and their right-hemisphere homotopes, numerous other areas-cortical and subcortical-have been implicated in linguistic processing. However, these areas' contributions to language remain unclear given that the evidence for their recruitment comes from diverse paradigms, many of which conflate language processing with perceptual, motor, or task-related cognitive processes. Using fMRI data from 772 participants (438 females, 334 males) performing an extensively validated language 'localizer' paradigm that isolates language processing from other processes, we a) delineate a comprehensive set of areas that respond reliably to language across written and auditory modalities, and b) evaluate these areas' selectivity for language relative to a demanding non-linguistic task. In line with prior claims, many areas outside the core fronto-temporal network respond during language processing, and most of them show selectivity for language relative to general task demands. These language-selective areas of the extended language network include areas around the temporal poles, in the medial frontal cortex, in the hippocampus, and in the cerebellum, among others. Although distributed across many parts of the brain, the extended language-selective network still only comprises a small fraction (<5%) of the grey matter volume, challenging the view that the entire brain processes language. These newly identified language-selective areas can now be systematically characterized to decipher their contributions to language processing, including testing whether these contributions differ from those of the core language areas. Language processing consistently recruits a left-lateralized fronto-temporal brain network, but language tasks often additionally engage areas outside this core system. In an fMRI dataset of 772 participants performing a validated language localizer task, we identified 17 brain areas outside the core fronto-temporal network that respond to both auditory and written language. Most of these areas show selectivity for language, including regions in the temporal poles, medial frontal cortex, hippocampus, and cerebellum. Despite its large number of components, this extended language network still only takes up a small fraction of the grey matter volume, challenging the view that the entire brain processes language. These findings lay the foundation for systematic characterization of these newly identified non-canonical language areas.
Identification of polyamine metabolism-related gene signatures for prognostic and immunological stratification in glioma.
Hu M, Xu L, Hua X … +2 more , Zhang C, Li H
Neuroscience · 2026 Jun · PMID 42373010 · Publisher ↗
Polyamine metabolism plays an essential role in glioma progression and the tumor microenvironment (TME). However, its prognostic and immunotherapeutic significance remains incompletely understood. We integrated transcrip...
Polyamine metabolism plays an essential role in glioma progression and the tumor microenvironment (TME). However, its prognostic and immunotherapeutic significance remains incompletely understood. We integrated transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) to construct a prognostic risk model via Least Absolute Shrinkage and Selection Operator (LASSO) regression. This model was externally validated using the GSE108474 and GSE43378 cohorts. Multivariable Cox regression was employed to identify key prognostic predictors, while consensus clustering was applied to stratify patients into distinct molecular subtypes. A robust 19-gene signature was established to calculate risk scores, effectively categorizing patients into high- and low-risk groups with significantly divergent survival outcomes. From this signature, five genes were identified as independent prognostic factors via multivariable Cox analysis. Ultimately, three prioritized core candidate biomarkers (AGMAT, PSMC5, and SMS) were extracted, among which SMS exhibited exceptionally high individual diagnostic efficacy. Furthermore, consensus clustering delineated two distinct subgroups (C1 and C2). The C1 subtype exhibited a less immune-infiltrated phenotype but higher PD-L1 expression and elevated TIDE scores, indicating stronger immune evasion and poorer survival. In contrast, the C2 subtype was characterized by robust immune cell infiltration, a more favorable prognosis, and a superior computationally predicted response to immunotherapy. In conclusion, our polyamine metabolism-related gene signature may serve as a promising candidate biomarker for evaluating clinical outcomes and computationally estimated immunotherapy efficacy in glioma. While this risk model and molecular subtyping framework offer novel insights for therapeutic stratification, prospective clinical validation is required.
Age- and sex-dependent effects of single prolonged stress on behavioral, hematological, and oxidative stress parameters in C57BL/6J mice.
Balatskyi V, Demianchuk O, Gospodaryov D … +2 more , Abrat O, Bayliak M
Neuroscience · 2026 Jun · PMID 42373009 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a pathological condition associated with the experience of traumatic stress. This study investigated the age- and sex-specific effects of single prolonged stress (SPS), a validate...
Post-traumatic stress disorder (PTSD) is a pathological condition associated with the experience of traumatic stress. This study investigated the age- and sex-specific effects of single prolonged stress (SPS), a validated rodent PTSD model, on behavioral, hematological, and oxidative stress parameters in C57BL/6J mice. Young adult (∼2.5 months) and middle-aged (10-12 months) male and female mice were subjected to SPS that included restraint, forced swimming, predator sound exposure, and ether anesthesia. Young adult SPS-treated males and females exhibited anxiety-related behavior in the open field test, which was accompanied by an elevated blood leukocyte count. Additionally, young SPS-treated males had lipid peroxidation in the diencephalon-midbrain region. Young adult females subjected to SPS showed impairment of spatial memory in the T-maze, higher hemoglobin levels, and lower plasma paraoxonase activity. In middle-aged males and females, SPS led to lower blood leukocyte levels. In addition, middle-aged SPS males showed impaired spatial memory, higher plasma protein levels, lower blood glucose, and lower NAD(P)H:quinone oxidoreductase 1 (NQO1) activity in the cerebral cortex. In middle-aged females, SPS exposure led to lower hemoglobin levels, higher plasma myeloperoxidase activity, and elevated plasma glucose levels. Age-related shifts were also evident in control mice, with older animals showing elevated baseline leukocyte counts, anxiety-like behavior, and decreased antioxidant defenses (NQO1 and glutathione-S-transferase, only in females) and higher lipid peroxides (only in males) in the diencephalon-midbrain compared to young adult ones. Overall, our results suggest that SPS induces age- and sex-dependent alterations.
Thoracic paravertebral nerve block combined with general anesthesia for patients undergoing minimally invasive vertebroplasty: effects on pain and lumbar function.
Luo D, Zhang X, Cheng X … +1 more , Cheng H
Int J Neurosci · 2026 Jul · PMID 42366690 · Publisher ↗
OBJECTIVE: This work was conducted to evaluate the effects of thoracic paravertebral nerve block (TPVB) combined with general anesthesia (GA) on pain and lumbar function in patients undergoing minimally invasive vertebro...
OBJECTIVE: This work was conducted to evaluate the effects of thoracic paravertebral nerve block (TPVB) combined with general anesthesia (GA) on pain and lumbar function in patients undergoing minimally invasive vertebroplasty. METHODS: One hundred patients scheduled for minimally invasive vertebroplasty were randomly allocated to a GA group (GA alone, = 50) or a TPVB + GA group (TPVB combined with GA, = 50). Mean arterial pressure (MAP) and heart rate (HR) were recorded preoperatively (T), at puncture (T), at bone cement injection (T), and at the end of surgery (T). Operative time, intraoperative blood loss, and anesthetic consumption were compared. Pain was assessed using the visual analogue scale (VAS) on postoperative days 1, 3, and 7. Lumbar function was evaluated using the Oswestry Disability Index (ODI) preoperatively, 1 week postoperatively, and 1 month postoperatively. Adverse events were also recorded. RESULTS: Significant group, time, and interaction effects were observed for MAP, HR, VAS, and ODI (all < 0.05). Compared with the GA group, the TPVB + GA group showed lower MAP and HR at T-T, reduced blood loss and anesthetic use, lower VAS scores, improved ODI scores, and fewer adverse events (all < 0.05). CONCLUSION: TPVB combined with GA stabilizes perioperative hemodynamics, alleviates pain, and promotes recovery of lumbar function.
Glycine as a potential neuroprotective adjuvant to reduce cisplatin-induced brain inflammation in mice.
Kazmi HMO, Suleman MU, Maqsood SI … +10 more , Khan SA, Khadam I, Khattak SM, Khalil U, Mursaleen M, Jami MMW, Javed S, Ullah N, Ikram M, Alqumbaey M
BMC Neurosci · 2026 Jun · PMID 42366339 · Full text
BACKGROUND: Cisplatin-induced neurotoxicity is driven in part by neuroinflammation and oxidative injury in vulnerable brain regions. Glycine has anti-inflammatory and antioxidant properties that may offer neuroprotection...
BACKGROUND: Cisplatin-induced neurotoxicity is driven in part by neuroinflammation and oxidative injury in vulnerable brain regions. Glycine has anti-inflammatory and antioxidant properties that may offer neuroprotection against chemotherapy-related brain damage. METHODS: Twenty-five adult male BALB/c mice were randomized into five groups (n = 5/group) Group 1 received cisplatin for 14 days; Group 2 received cisplatin plus glycine for 14 days; Group 3 received cisplatin for 28 days; Group 4 received cisplatin for 14 days followed by glycine for 14 days; and Group 5 received cisplatin for 28 days with glycine introduced from day 14 to day 28. Cisplatin was administered intraperitoneally at 3 mg/kg every fourth day, and glycine was given subcutaneously at 1 g/kg daily. The primary outcome was serum TNF-α measured by ELISA. Secondary outcomes were neuronal integrity and optical density in the hippocampus and frontal cortex assessed by Nissl staining. Data were analyzed using one-way ANOVA with Tukey post-hoc testing. RESULTS: Serum TNF-α levels differed significantly among groups (F = 230.422, p < 0.001). Mean TNF-α concentrations were 150.0 pg/mL in Group 1, 130.2 pg/mL in Group 2, 201.4 pg/mL in Group 3, 159.4 pg/mL in Group 4, and 171.0 pg/mL in Group 5. Prolonged cisplatin exposure (Group 3) produced the highest TNF-α levels, whereas concurrent glycine administration during the 14-day regimen (Group 2) resulted in the lowest levels. Compared with the 28-day cisplatin group, both delayed glycine treatment (Group 4) and glycine introduced during the second half of cisplatin exposure (Group 5) were associated with lower TNF-α concentrations. Histological analysis demonstrated reduced Nissl staining intensity and neuronal preservation in cisplatin-only groups, particularly Group 3, whereas glycine-treated groups showed better preservation of neuronal architecture and optical density in the hippocampus and frontal cortex. CONCLUSION: Glycine attenuated cisplatin-induced neuroinflammation and preserved neuronal integrity in the hippocampus and frontal cortex of mice. These findings support further preclinical evaluation of glycine as a low-cost adjuvant strategy to reduce chemotherapy-associated neurotoxicity.
Striatal control of amygdalar acetylcholine release during salience-associated processing.
Chen A, Li Y, Zhu H … +12 more , Cui X, Gu H, Pan Y, Weng Y, Ye Q, Guan W, Sun Q, Li B, Xiao L, Xu F, Deng H, Xiao X
Nat Neurosci · 2026 Jun · PMID 42362886 · Publisher ↗
Acetylcholine (ACh) signaling in the basolateral amygdala (BLA) has been implicated in salience-related processing and associative learning, yet the circuit mechanisms that regulate its dynamics remain poorly understood....
Acetylcholine (ACh) signaling in the basolateral amygdala (BLA) has been implicated in salience-related processing and associative learning, yet the circuit mechanisms that regulate its dynamics remain poorly understood. Here we show that BLA ACh dynamically represented salience. In the mouse nucleus accumbens (NAc), D1-expressing medium spiny neurons (MSNs) selectively promote, whereas D2-expressing MSNs selectively suppress, ACh release in the BLA but not in the cortex or hippocampus. NAc D1 and D2 MSNs regulate BLA ACh by disinhibiting and inhibiting cholinergic neurons in the substantia innominata (SI), respectively. Axon terminals of D1 and D2 MSNs in the SI exhibit differential responses to salient stimuli and modulate BLA ACh dynamics. Closed-loop optogenetic manipulations of NAc D1 and D2 projections to the SI have opposing effects on associative learning. Our findings uncover an unconventional role of striatal MSNs in modulating behavioral significance through the regulation of salience-related amygdalar ACh activity.
Mitochondrial stress response drives microglial senescence.
Peruzzotti-Jametti L, Pluchino S
Nat Neurosci · 2026 Jun · PMID 42362885 · Publisher ↗
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Conditioned accumbal dopamine transients forecast individual preference for drug versus natural rewards and compulsive behavior.
Pascoli V, Python L, Hiver A … +9 more , van Zessen R, Chaudun F, Hinz J, Flakowski J, Girard B, Reva M, Bellone C, Esmaeili V, Lüscher C
Nat Neurosci · 2026 Jun · PMID 42362884 · Publisher ↗
Addicted individuals prefer drug rewards over natural rewards. Dysregulated dopamine (DA) signaling in the nucleus accumbens is thought to trigger this phenomenon, but there is little supporting evidence. Using a genetic...
Addicted individuals prefer drug rewards over natural rewards. Dysregulated dopamine (DA) signaling in the nucleus accumbens is thought to trigger this phenomenon, but there is little supporting evidence. Using a genetically encoded sensor, we monitored DA dynamics in mice in an operant associative task with natural (fat solution) or artificial (cocaine or optogenetic DA self-stimulation) rewards. During learning, DA transients emerged at predictive cues for both reward types, vanished at natural reward delivery, but persisted at artificial reward delivery. In choice sessions, animals' preferences varied from exclusive natural reward to exclusive artificial reward. Individual preferences were predicted by cue-evoked DA response magnitudes. Revaluation of reward contingencies shifted reward-type preference and DA signaling accordingly, but not in mice showing compulsive drug seeking, indicating impaired value updating in these mice. These results support a model in which DA drives adaptive reward seeking, with persistent cue-associated DA signaling underpinning addiction vulnerability.
The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
Perez J MJ, Lam A, Weissleder C … +11 more , Bertoli F, Raji H, Bosch M, Nemazanyy I, Kalb S, Kehili M, Hirschberg I, Brunetti D, Heckenbach I, Scheibye-Knudsen M, Deleidi M
Nat Neurosci · 2026 Jun · PMID 42362883 · Publisher ↗
Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR activation in glial cells...
Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPR activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPR in neurodegenerative disease pathogenesis.
Interpretable abstractions of artificial neural networks predict behavior and neural activity during human information gathering.
D'Ambrogio S, Grohn J, Khalighinejad N … +3 more , Mattar MG, Hunt L, Rushworth MFS
Nat Neurosci · 2026 Jun · PMID 42362882 · Publisher ↗
Humans and other animals are driven to acquire information about opportunities in their environments, yet how they evaluate what is worth learning remains unclear. Here we combine artificial neural networks with symbolic...
Humans and other animals are driven to acquire information about opportunities in their environments, yet how they evaluate what is worth learning remains unclear. Here we combine artificial neural networks with symbolic regression to extract an expressive yet interpretable model that specifies how human participants evaluate decision-relevant information during choice. The recovered function depends primarily on the relative evidence accumulated across options rather than absolute uncertainty about each, revealing that participants seek information symmetry across alternatives rather than minimizing uncertainty option by option. This account outperforms standard models of uncertainty-based exploration and generalizes to an independent dataset. Using ultrahigh-field (7T) functional magnetic resonance imaging optimized for midbrain and brainstem, we simultaneously measured activity across five neuromodulatory nuclei and two cortical regions. Ventral tegmental area activity showed opposed coding of information and selection values, a pattern suited to arbitrating between sampling and choosing, and anterior cingulate cortex and anterior insula tracked value-of-information computations.
Cortical and thalamic afferent connectomes distinguish ACC subregions of the macaque brain.
Dc M, Tm L, Jl F
J Neurosci · 2026 Jun · PMID 42362380 · Publisher ↗
In humans and nonhuman primates, the anterior cingulate cortex (ACC) is an interface between "interoceptive" and "exteroceptive" domains. The ACC contains discrete subdivisions that are distinct in cytoarchitecture, conn...
In humans and nonhuman primates, the anterior cingulate cortex (ACC) is an interface between "interoceptive" and "exteroceptive" domains. The ACC contains discrete subdivisions that are distinct in cytoarchitecture, connectivity, and function. The subgenual ACC (sgACC) is a key area for arousal state modulation. Importantly, the sgACC is dysregulated in major depression and a target for neuromodulation therapies, including deep brain stimulation. In contrast, the perigenual ACC (pgACC) is important for cognitive functions, including social decision-making. Understanding the major sources of afferent input to the sgACC and pgACC is essential for elucidating functional modulation, including in major depression. We took a mesoscopic, 'connectomic' approach to examine the balance of projections to ACC subdivisions from two sources of glutamatergic input: the prefrontal cortex (PFC) and insula, and the thalamus (n=6 macaques). Using retrograde tracer injections into ACC subdivisions in male macaques, and unbiased statistical clustering, we revealed that the ACC subdivisions are under the influence of strikingly different "heavily-weighted" (HW) inputs from PFC and thalamus. Only one cortical region, area 10m, has HW projections to both sgACC and pgACC, suggesting an integrative role. Additionally, the pgACC sends "top-down" inputs to the sgACC, without significant "bottom-up" return input. Finally, ACC and thalamus-ACC circuits are hierarchically organized, governed by cortical granularity and thalamo-cortical connectivity. Agranular cortices and their associated thalamic nuclei formed most inputs to the sgACC. In contrast, pgACC receives a balanced set of afferents from agranular, dysgranular, and granular cortices, coupled with inputs from broader thalamic regions associated with these cortices. The ACC contains discrete subdivisions based on cytoarchitecture and connectivity, which serve unique functional roles. The sgACC and pgACC subdivisions receive many similar inputs based on neuroimaging work. Here, we leverage higher resolution retrograde tract-tracing in macaques to examine the relative weights and relationships of multiple cortical and thalamic afferents to each region. Using unbiased analyses of labeled cells, we conclude that the balance of afferent inputs shifts from a connectome dominated by agranular cortices and their thalamic partners in sgACC, to a more balanced afferent connectome in pgACC, represented by agranular, dysgranular, and granular cortices and their broader thalamic partners. These results facilitate interpretation of functional studies, and bridge understanding of the connectional basis of psychiatric disorders.
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