GPR37 has been recognized as a negative regulator of oligodendrocyte myelination. However, its role in demyelination recovery remains unclear. To examine the function of GPR37 in remyelination, we compared wild-type and...GPR37 has been recognized as a negative regulator of oligodendrocyte myelination. However, its role in demyelination recovery remains unclear. To examine the function of GPR37 in remyelination, we compared wild-type and GPR37-deficient mice of either sex after focal (lysolecithin) or global (cuprizone) toxin-induced demyelination, as well as immune-mediated demyelination (experimental autoimmune encephalomyelitis, EAE). We found that the absence of GPR37 resulted in enhanced recovery in all three models. In focal demyelination, we observed that, while the initial lesioned area was similar in size between genotypes, two weeks after induction of demyelination, the remyelinated area was markedly larger and lesion size was reduced in null mice compared to wild-type animals. Unlike local demyelination, which induced similar demyelination in both genotypes, cuprizone induced much faster and more severe demyelination in the mutant's corpus callosum. However, we observed a significant increase in remyelination in the mutant mice compared to their wild-type counterparts. After immune-mediated demyelination, the clinical scores of null mice were lower than those of wild-type animals from day 16 post-induction of EAE. Similar results were obtained in mice lacking GPR37 specifically in oligodendrocytes, indicating that faster recovery after EAE is cell autonomous. Our study suggests that GPR37 is both myelin-protective and negatively regulates remyelination in the adult brain. Furthermore, our findings demonstrate that GPR37 exhibits context-dependent functions across distinct demyelinating disease models. Myelination by oligodendrocytes is essential for the normal function of the central nervous system. However, in conditions where demyelination occurs, such as multiple sclerosis (MS) and other white matter disorders, the restoration of the myelin sheath through remyelination becomes essential for neurological recovery. In this study, we investigate the role of GPR37, a G protein-coupled receptor abundant in oligodendrocytes that negatively regulates myelination, during recovery following demyelination. By utilizing both toxin-induced and immune-mediated models of demyelination, we found that the absence of GPR37 enhances remyelination. This suggests that GPR37 could serve as a potential therapeutic target to promote remyelination in conditions such as MS, and other neurological and psychiatric disorders associated with white matter abnormalities.
Mosaic mutations in the X-linked cell adhesion molecule Protocadherin 19 (PCDH19) lead to epilepsy with cognitive impairment, whereas complete absence of functional protein, although possibly linked to autistic features,...Mosaic mutations in the X-linked cell adhesion molecule Protocadherin 19 (PCDH19) lead to epilepsy with cognitive impairment, whereas complete absence of functional protein, although possibly linked to autistic features, does not elicit any seizures. It is believed that mosaic expression of PCDH19 leads to defective neuronal communication, but whether further roles beyond cell adhesion are critical for PCDH19 function in the cortex is currently unknown. We confirm that the proteolytic processing of PCDH19, previously described in hippocampal neurons, also takes place in mouse cortical neurons in vivo and show that nuclear transport of its intracellular domain is mediated by importins. RNAseq analysis further indicates that the intracellular domain of PCDH19 leads to broad transcriptomic changes. Finally, we use electroporation to provide the first in vivo data about the role of this cleaved intracellular domain in upper layer cortical neurons of male and female mice, where it reduces spine density through an increase in gene expression without affecting overall dendritic morphology. Our results suggest that PCDH19 could act as an activity sensor in a synapse to nucleus signalling pathway involved in synaptic homeostasis. We investigate non-adhesive functions of the epilepsy-linked cell adhesion protein PCDH19 and uncover a signalling role for its intracellular domain in cortical neurons. Beyond its established function in cell adhesion, we show that proteolytic cleavage of PCDH19 and nuclear import of its intracellular fragment leads to transcriptomic changes that impact dendritic spine density through the upregulation of genes. These findings suggest that PCDH19 may act as a synaptic activity sensor, linking membrane dynamics to nuclear responses in the regulation of synaptic homeostasis.
Anjos-Santos A, Bianchi PC, Favoretto CA
… +3 more, Bezerra F, Paiva RVN, Cruz FC
Neuroscience
· 2026 Jun · PMID 42303084
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Exposure to environments associated with ethanol use can trigger craving and reinstatement of seeking behavior after extinction. The hippocampus integrates contextual information with motivational and emotional outputs,...Exposure to environments associated with ethanol use can trigger craving and reinstatement of seeking behavior after extinction. The hippocampus integrates contextual information with motivational and emotional outputs, encoding drug-related memories, but intrahippocampal functional organization during ethanol context renewal remains poorly characterized. Here, we investigated the role of the dorsal and ventral hippocampus and its functional connectivity and neuronal composition during reinstatement of ethanol-seeking behavior. Adult male C57BL/6 mice self-administered Ethanol + Saccharin or Saccharin (control) in Context A, underwent extinction in Context B, and were tested in Context A versus B. Next, we quantified Fos (neuronal activation marker) expression in dorsal (CA1, CA2, CA3, and Dentate Gyrus - DG) and ventral (vSUB) hippocampus and assessed the coordinated activity among subregions by correlation-based network analysis. Finally, we determined the phenotype (co-labeling with GABA and glutamate markers) of Fos-labeled neuronal populations involved in the context-induced reinstatement of ethanol seeking. Reexposure to context A, but not context B, reinstated ethanol-seeking behavior and increased Fos expression in CA2. Reexposure to context B increased Fos expression in DG. Network topology identified a dynamic functional intrahippocampal connection, highlighting CA2 as a central hub during ethanol context renewal. Finally, despite low overall activation, we observed that activated neuronal populations were predominantly excitatory and a proportionally greater recruitment of GABAergic neurons. Our data indicate that hippocampal activation patterns and connectivity dynamically reorganize during context-induced ethanol seeking, supporting its role in relapse-related memory processes.
AIM: To compare the clinical efficacy and safety of cryopreserved autologous bone flaps versus titanium plates for cranioplasty in patients with cranial defects. METHODS: Sixty patients with cranial defects admitted to o...AIM: To compare the clinical efficacy and safety of cryopreserved autologous bone flaps versus titanium plates for cranioplasty in patients with cranial defects. METHODS: Sixty patients with cranial defects admitted to our hospital from January 2021 to June 2024 were retrospectively selected. They were assigned to the autologous bone group ( = 30, cranioplasty with cryopreserved autologous bone flaps) and the titanium plate group ( = 30, cranioplasty with titanium plates) according to the reconstruction material. The perioperative indicators, outcome for cranioplasty, neurological function recovery, incidence of complications, and treatment costs were compared between the two groups. RESULTS: The autologous bone group exhibited significantly better outcomes for cranioplasty at 3 and 6 months postoperatively than the titanium plate group ( < 0.05). At 6 months postoperatively, the autologous bone group exhibited significantly higher NIHSS scores than the titanium plate group ( < 0.05). The intracranial pressure levels were significantly lower at all postoperative time points in the autologous bone group than in the titanium plate group ( < 0.05). The autologous bone group demonstrated faster recovery of inflammatory indicators, lower overall incidence of complications (6.67% vs. 30.00%) (=4.588, = 0.032), and lower hospitalization costs and material expenses than the titanium plate group ( < 0.05). CONCLUSION: Cryopreservation of autologous bone flaps for cranioplasty is associated with improved bone healing, better neurological recovery, reduced complication rates, and lower medical costs. However, these observational findings require further validation through prospective randomized controlled trials. Nevertheless, the current evidence supports the potential clinical application of this technique when feasible.
Zhu K, Liu Y, Min JH
… +20 more, Joshua V, Lin J, Li Y, Kreutzmann JC, Guo Y, Xia W, Mohammadi E, Pieber M, Suerth V, Xia Y, Andrusivova Z, Hugnot JP, Kanatani S, Uhlén P, Lundeberg J, Li X, Fancy SPJ, Sarlus H, Harris RA, Lund H
Adult language learning varies widely among individuals, with some learners quickly acquiring knowledge and skills while others struggle with specific components or overall proficiency despite similar exposure. This vari...Adult language learning varies widely among individuals, with some learners quickly acquiring knowledge and skills while others struggle with specific components or overall proficiency despite similar exposure. This variability, once linked to frontotemporal language regions, is increasingly seen as originating from distributed networks involved in attention, control, and memory. The role and organization of these networks in explaining these differences remain unclear. We hypothesized that intrinsic multi-network connectivity underpins these variations, revealing potential neuromarkers of interactions among systems beyond language regions. We tested this in 101 healthy adults (72 females and 29 males) using multimodal neuroimaging before seven days of artificial language training across six tasks targeting auditory and speech categories, words, morphosyntax, and sentence structures. We identified one general component shared across tasks and five task-specific ones. Using cross-validated predictive modeling and graph-theoretic metrics, we found that the general component's learning outcome (LO) and rate (LR) were primarily driven by the dorsal attention and frontoparietal networks. Their local efficiency was a strong predictor, highlighting local resilience and mesoscale segregation. Local connectivity dominated in association cortical networks, while global integration occurred in subcortical regions, reflecting a balance between segregation and integration influences learning. Only task-specific word learning was predictable, relying on default-mode and frontoparietal hubs. Single-modality predictions were weaker, emphasizing the value of multimodal approaches. These findings suggest that the intrinsic network topology underlies individual success in language learning, supporting a multiple-system model in which attention, default, and subcortical networks work together to shape learning trajectories and advance mechanistic understanding. Adult learners vary greatly in how effectively and successfully they learn a new language, but the neural basis for this variability remains unclear. Using multimodal MRI data collected before training and connectome-based graph-theoretic measures, we demonstrate that intrinsic brain network topology predicts both a general language-learning factor and learning speed across six artificial-language-learning tasks in 101 adults. The strongest predictive features were found in the dorsal attention and frontoparietal control networks, with nodal local efficiency emerging as the most consistent marker. A cortical-subcortical dissociation in local-efficiency and global-integration properties may underlie these individual differences. These findings highlight potential network-level neuromarkers for predicting adult language learning success beyond language areas.
A central question in cognitive neuroscience is how the brain implements abstract computations that must generalize across superficially different inputs. Language provides a strong test case: the same grammatical operat...A central question in cognitive neuroscience is how the brain implements abstract computations that must generalize across superficially different inputs. Language provides a strong test case: the same grammatical operation, such as pluralization, can be realized through distinct rules and forms across languages. Whether such transformations rely on language-specific neural systems or on abstract mechanisms that generalize across linguistic contexts remains unresolved. Crucially, these transformations must be computed online and integrated into speech planning within a tightly constrained time window. Using magnetoencephalography, we tracked the millisecond dynamics of grammatical word-form transformations during seminaturalistic phrase completion in humans of both sexes. Highly proficient Spanish-English bilinguals produced singular and plural noun forms in both languages in a design that fully orthogonalized semantic number, phonological changes, grammatical inflection, and produced language. Adjusting words to fit their grammatical context engaged a left-lateralized frontotemporal network beginning ∼100 ms after cue onset. Multivariate decoding revealed that the neural patterns supporting this computation generalized across languages, across different surface plural forms, and to pseudowords, demonstrating that abstractly equivalent operations are instantiated in the same neural substrates despite differences in linguistic form. Together, these findings provide time-resolved neural evidence for a language-general computational mechanism, showing that the brain implements grammatical transformations as abstract, generative operations. More broadly, they show how bilingualism can be used to probe general principles of neural organization, revealing how abstract computations may be shared and reused across representational systems.
Neuroscience
· 2026 Jun · PMID 42297095
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This study evaluated the effects of maternal consumption of crude and refined Brazil nut oil (Bertholletia excelsa) during gestation and lactation on reflex maturation and cognitive development in male and female rat off...This study evaluated the effects of maternal consumption of crude and refined Brazil nut oil (Bertholletia excelsa) during gestation and lactation on reflex maturation and cognitive development in male and female rat offspring. Pregnant females were assigned to three groups: control (water), crude oil, and refined oil (3000 mg/kg, orally). Reflex ontogeny was assessed from postnatal day 1 to 21, and behavioral performance was evaluated using the Open Field Test, object recognition test, and Morris water maze. Fatty acid profiles of maternal milk and offspring brain tissue were also analyzed. Maternal supplementation with crude oil promoted earlier maturation of sensorimotor reflexes, particularly in female offspring, indicating enhanced early neurodevelopment. In contrast, refined oil supplementation significantly improved short- and long-term memory, demonstrated by increased exploration of novel objects and superior spatial memory performance, with stronger effects in females. Only offspring from the refined oil group showed significant locomotor habituation in the Open Field Test, suggesting improved non-associative learning. Lipid analyses revealed higher levels of monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) in maternal milk and offspring brain tissue from the refined oil group, nutrients associated with synaptic plasticity, neurogenesis, and reduced neuroinflammation. Conversely, the crude oil, richer in medium-chain saturated fatty acids, may explain the accelerated reflex maturation observed. Overall, maternal intake of Brazil nut oil modulated neurodevelopment and cognition in a sex dependent manner. Refined oil enhanced cognitive function, whereas crude oil primarily stimulated early reflex maturation, highlighting the importance of maternal lipid quality for optimal early-life neurological development.
Taniguchi S, Dijkstra BW, D'Cruz N
… +2 more, Nieuwboer A, Gilat M
Neuroscience
· 2026 Jun · PMID 42297094
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Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that has been related to abnormal functional connectivity across motor, cognitive, and limbic networks. However, it remains unclear how directi...Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that has been related to abnormal functional connectivity across motor, cognitive, and limbic networks. However, it remains unclear how directional (i.e., effective) connectivity between various networks is altered by an actual FOG-related motor imagery task. Twenty-four individuals with PD (11 freezers and 13 non-freezers) and 15 healthy controls underwent functional MRI. Participants performed a motor imagery task while observing two videos: (1) a person with PD engaged in typical walking, and (2) a person with PD experiencing a FOG-episode. We performed between-group comparisons of the task-related changes using dynamic causal modeling (DCM) analysis and the parametric empirical Bayes framework, followed by correlation analysis. DCM analysis revealed that task-dependent changes in effective connectivity during FOG imagery differed significantly in two limbic to cognitive network connections in freezers compared with non-freezers. Specifically, freezers showed greater changes in connectivity from the hippocampus to anterior part of middle frontal gyrus (posterior probability > 0.95), which was associated with a higher freezing ratio (Spearman's rho = 0.952, p < 0.01). We also found lower changes in connectivity from anterior insula to supramarginal gyrus (posterior probability > 0.95), which was not correlated with FOG measures. Motor imagery of FOG altered effective connectivity from limbic to cognitive regions in freezers versus non-freezers. The positive modulatory effects on connectivity from the hippocampus to middle frontal gyrus in freezers could represent a greater limbic FOG-related episodic memory response or a failed suppression of these responses in freezers.
Yi D, Lang X, Li J
… +7 more, Cui H, Ye Y, Ling Y, Zhou Y, Chen S, Wang Y, Wen P
Int J Neurosci
· 2026 Jun · PMID 42295140
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This study aimed to examine the effects of sericin on diabetic cognitive impairment (DCI) in rats based on neuroinflammation. SD rats were first fed with a high sugar and high fat diet for 4 weeks, and then injected with...This study aimed to examine the effects of sericin on diabetic cognitive impairment (DCI) in rats based on neuroinflammation. SD rats were first fed with a high sugar and high fat diet for 4 weeks, and then injected with 50 mg/kg streptozotocin intraperitoneally to establish a diabetic model. The diabetic rats were randomly divided into 3 groups and treated with distilled water ( = 10), 500 mg/kg ( = 10) or 1000 mg/kg ( = 20) sericin, respectively, by gavage once a day for 8 weeks. Before the end of the trial, 10 rats in the 1000 mg/kg sericin group were injected with 10 μg EX527, a Sirtuin-1 (SIRT1) inhibitor, into the lateral ventricles once every other day for 5 times. Treated with sericin significantly reduced fasting blood glucose and improved DCI in rats. Sericin significantly inhibited neuroinflammation and microglial activation, reduced the expression of NOD-like receptor protein 3 (NLRP3) and thioredoxin-interacting protein (TXNIP) proteins, and reduced cell apoptosis, while increasing the expression of SIRT1 protein in the hippocampus of diabetic rats. After inhibiting SIRT1 with EX527, the above effect of sericin on DCI rats was weakened. These results indicated that sericin may block DCI progression in rats by inhibiting TXNIP/NLRP3 neuroinflammation and neuronal apoptosis through SIRT1.
Zhou X, Wang J, Yang X
… +4 more, Huang J, Fan H, Wang S, Si F
Neuroscience
· 2026 Jun · PMID 42289225
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Type 2 diabetes mellitus (T2DM) is frequently complicated by cognitive impairments. We aim to investigate white matter microstructural changes in T2DM with mild cognitive impairments(T2DM-MCI). Sixteen T2DM-MCI patients,...Type 2 diabetes mellitus (T2DM) is frequently complicated by cognitive impairments. We aim to investigate white matter microstructural changes in T2DM with mild cognitive impairments(T2DM-MCI). Sixteen T2DM-MCI patients, thirty-six T2DM with normal cognition (T2DM-NC), and twenty-nine healthy controls (HCs) were enrolled in this study. Neurite Orientation Dispersion and Density Imaging (NODDI) and cognitive assessment were obtained from all participants. White matter microstructural alterations in T2DM-MCI were evaluated with NODDI. Furthermore, correction analysis was performed to assess the relationship between white matter microstructural alterations and cognitive performance. Compared with HC, T2DM-MCI and T2DM-NC showed lower neurite density index (NDI), higher orientation dispersion index (ODI) and free water fraction (FWF) in multiple white matter fibers such as inferior fronto-occipital fasciculus, superior thalamic radiation and corticospinal tract. T2DM-MCI also showed increased ODI and FWF compared with T2DM-NC. In addition, white matter microstructural changes showed significant correlation with cognitive scores and blood glucose level in the T2DM-MCI group. White matter microstructural alterations correlated with cognitive impairments in T2DM-MCI, deepening our understanding of the neural basis of early cognitive impairment in T2DM.
Iloglu Z, Li M, Gkini V
… +7 more, Bespalov M, Le Joncour V, Yamada S, Filppu P, Heikinheimo O, Laakkonen P, Namba T
Neuroscience
· 2026 Jun · PMID 42289224
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Polybrene, also known as a common name hexadimethrine bromide, is a reagent widely used to improve the transduction efficiency of viral vectors. Although polybrene has been used for studying glioblastoma cells, its cytot...Polybrene, also known as a common name hexadimethrine bromide, is a reagent widely used to improve the transduction efficiency of viral vectors. Although polybrene has been used for studying glioblastoma cells, its cytotoxicity on these cells has not been systematically addressed. Glioblastoma is one of the most aggressive types of brain tumors, associated with poor patient prognosis due to its high cellular heterogeneity and resistance to treatment. Glioblastoma is known to consist of multiple subtypes, which represent distinct molecular and cellular characteristics of glioblastoma cells. Due to such differences in their characters, each glioblastoma cell subtype exhibits distinct sensitivity to chemicals. In this study, we show that polybrene reduces cell viability more strongly in neural progenitor cell-like (NPC-like) glioblastoma cells than in mesenchymal-like (MES-like) cells, with increased sensitivity also observed in non-MES-like cell states. This effect in NPC-like cells suggests a possible involvement of calcineurin, a calcium/calmodulin-dependent phosphatase, since inhibition of calcineurin using FK-506 or cyclosporine A (CsA) rescues polybrene-induced cell death.Our findings suggest that polybrene sensitivity scoring could provide a rapid and affordable method for glioblastoma subtype prediction and highlight calcineurin involvement as a potential subtype-associated specific pathway in glioblastoma.
Erickson N, Ihnatovych I, Szabados A
… +2 more, Szigeti K, Kabbani N
BMC Neurosci
· 2026 Jun · PMID 42288732
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The CHRNA7 gene, located on chromosome 15q13.3, encodes the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit and lies within a genomic region characterized by high recombination rates and associations with multiple...The CHRNA7 gene, located on chromosome 15q13.3, encodes the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit and lies within a genomic region characterized by high recombination rates and associations with multiple neuropsychiatric disorders. Within this region, the human specific gene CHRFAM7A arose through partial duplication, rearrangement, and fusion between CHRNA7 and FAM7A. The direct CHRFAM7A allele has been shown to negatively regulate α7 nAChR function. The inverted allele (CHRFAM7AΔ2bp), harboring a two-base pair deletion in exon 6, is linked to schizophrenia, bipolar disorder, and other psychiatric conditions. In this study, we investigated how the presence of the CHRFAM7AΔ2bp allele alters the cellular proteome. Using high-throughput proteomic analysis by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), we characterized protein expression in neuronal progenitors differentiated from isogenic human induced pluripotent stem cell (iPSC) lines representing CHRFAM7AΔ2bp and CHRFAM7A-null genotypes. Comparative analysis identified 129 differentially expressed proteins enriched in pathways related to extracellular matrix organization, collagen biosynthesis, and cell adhesion. Functional assays further demonstrated differences in matrix adhesion between CHRFAM7A-null and CHRFAM7AΔ2bp-derived progenitors. These results suggest that the CHRFAM7AΔ2bp variant influences cellular structure through modulation of adhesion matrix-interaction proteins. This work provides insight into molecular mechanisms that may underlie increased neurodisease vulnerability associated with this genotype.
Neuroscience
· 2026 Jun · PMID 42288186
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The social behavior neural network (SBNN) is a circuit composed of reciprocally connected limbic structures that regulate social behaviors, including aggression. Although both males and females of many species display a...The social behavior neural network (SBNN) is a circuit composed of reciprocally connected limbic structures that regulate social behaviors, including aggression. Although both males and females of many species display a range of agonistic behaviors in response to social encounters, studies of the neural circuitry underlying these behaviors have focused almost exclusively on males. In the present study, we investigated sex differences in the neural circuitry activated in response to social interactions in Syrian hamsters (Mesocricetus auratus). We employed c-Fos immunohistochemistry to quantify neuronal activation following agonistic encounters between same-sex male and female dyads during a resident-intruder test. Animals were tested in their home cage either alone (n = 7 per sex) or with a same-sex, non-aggressive intruder (n = 7 per sex) for 10 min. Social interactions were characterized almost exclusively by aggressive interactions with aggression occurring more frequently in females than in males. Our data revealed substantial sex differences in the neuronal activation of the SBNN in response to these encounters. In some regions, neuronal activity changed in opposite directions in males and females compared to controls (e.g., posterior lateral septum), while in others, there was a change in neuronal activation in only one sex (e.g., medial amygdala). These findings support the hypothesis that the neural circuitry activated in response to social interactions including aggression exhibit marked sexual differentiation.
Farrokhi AM, Moshrefi F, Karimian-Sani-Varjovi H
… +4 more, Seddighfar M, Liang J, Li Y, Haghparast A
Neuroscience
· 2026 Jun · PMID 42288185
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Relapse to opioid use, driven by the retrieval of powerful drug-associated memories, remains a major clinical obstacle. The neurophysiological mechanisms within the prelimbic cortex (PrL)-ventral tegmental area (VTA) cir...Relapse to opioid use, driven by the retrieval of powerful drug-associated memories, remains a major clinical obstacle. The neurophysiological mechanisms within the prelimbic cortex (PrL)-ventral tegmental area (VTA) circuit that govern this reinstatement of drug-seeking are poorly defined. This study aimed to identify the specific electrophysiological signatures of morphine-primed reinstatement by analyzing local field potential (LFP) activity and PrL-VTA coherence in a rat model of conditioned place preference (CPP). Following conditioning, morphine-treated rats exhibited decreased beta power in the PrL, while the VTA showed a broad increase in power across theta, alpha, beta, and gamma frequencies. These oscillatory changes largely persisted after extinction. The findings reveal distinct neural state during relapse. Morphine-primed reinstatement was uniquely marked by a specific reduction in VTA beta power. Furthermore, the PrL showed opposing changes in low- and high-frequency bands, characterized by increased delta and theta power alongside decreased high-gamma power. Most notably, a widespread alteration in the PrL-VTA circuit emerged, involving higher delta, alpha, and high-gamma coherence, but lower theta and low-gamma coherence. These results suggest that the retrieval of opioid-associated memories is not simply a return to a pre-extinction state but is governed by a distinct neurophysiological pattern. Specifically, the reorganization of information flow between the PrL and VTA emerges as a critical biomarker for the reinstatement of addiction memory. These signatures offer new insights into the circuit-level dynamics of relapse and may help inform the development of future therapeutic interventions.
Neuroscience
· 2026 Jun · PMID 42288184
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Amyloid-β (Aβ) accumulation in the brain is a defining pathological feature of Alzheimer's disease (AD). Cerebral Aβ burden is regulated not only by central production and degradation but also by its transport and cleara...Amyloid-β (Aβ) accumulation in the brain is a defining pathological feature of Alzheimer's disease (AD). Cerebral Aβ burden is regulated not only by central production and degradation but also by its transport and clearance in the peripheral circulation. Blood-borne Aβ carriers provide a potential peripheral route for reducing brain Aβ levels by strengthening the brain-to-blood concentration gradient, representing a therapeutic strategy that does not require direct penetration of the blood-brain barrier. This review summarizes advances in blood-borne Aβ carriers and discusses their potential therapeutic applications in AD. Key carriers include human serum albumin (HSA), transthyretin (TTR), α-macroglobulin (αM), soluble low-density lipoprotein receptor-related protein 1 (sLRP1), apolipoproteins, red blood cells (RBC), monocytes and platelets, all of which participate in Aβ binding, transport from the brain to peripheral organs, and subsequent clearance. Structural abnormalities or functional dysregulation of these carriers may impair peripheral Aβ metabolism and promote cerebral Aβ deposition. Because blood-based therapeutic strategies are clinically feasible, may improve patient compliance, and do not require direct blood-brain barrier penetration, targeting circulating Aβ carriers has attracted increasing attention as a potential therapeutic approach for AD. This review further summarizes the classification and functional mechanisms of major blood-borne Aβ carriers, analyzes related intervention strategies and current limitations, and highlights future directions, including multi-target combination therapy and precision medicine. These discussions may provide a theoretical basis for developing AD treatments that target blood-borne Aβ transport and clearance.
The basal ganglia (BG) are central to voluntary action, yet how they organize complex behavior remains unclear. Using a novel operant counting task, we trained mice to perform a specific number of lever presses to obtain...The basal ganglia (BG) are central to voluntary action, yet how they organize complex behavior remains unclear. Using a novel operant counting task, we trained mice to perform a specific number of lever presses to obtain a reward, enabling quantification of continuous kinematics and discrete actions. Stimulation of direct pathway and indirect pathway neurons (dSPNs and iSPNs) exert bidirectional and dissociable influences on both movement steering and press count: activation of dSPNs steers mice contraversively and extends press sequences, whereas activation of iSPNs steers mice ipsiversively and prematurely terminates press sequences. Calcium imaging reveals dSPNs and iSPNs that tracked physical approach or count progress, with ramping activity patterns consistent with accumulation and discharge dynamics. The difference between dSPN and iSPN population activity scales with proximity to spatial and numerical goals. These findings show that the BG implement a push-pull controller to integrate kinematics and action counting to steer progress toward goals.