Nature reviews. Neuroscience, Год журнала: 2025, Номер unknown
Опубликована: Май 16, 2025
Язык: Английский
Cell Reports, Год журнала: 2025, Номер 44(2), С. 115300 - 115300
Опубликована: Фев. 1, 2025
The dentate gyrus of the hippocampus is important for many cognitive functions, including learning, memory, and mood. Here, we present transcriptome-wide spatial gene expression maps human investigate age-associated changes across lifespan. Genes associated with neurogenesis extracellular matrix are enriched in infants decline throughout development maturation. Following infancy, inhibitory neuron markers increase, cellular proliferation decrease. We also identify spatio-molecular signatures that support existing evidence protracted maturation granule cells during adulthood increases neuroinflammation-related expression. Our findings notion hippocampal neurogenic niche undergoes major following infancy molecular regulators brain aging glial- neuropil-enriched tissue.
Язык: Английский
Процитировано
2
The EMBO Journal, Год журнала: 2024, Номер unknown
Опубликована: Окт. 4, 2024
Abstract Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated age-related neurodegenerative disorders such as Parkinson’s Alzheimer’s disease. While decreases throughout the lifespan of short-lived model organisms, it remains unknown whether a decline occurs aging mammalian brain—a question fundamental importance for understanding cell type- region-specific susceptibility to neurodegeneration. Here, we define longitudinal dynamics basal macroautophagy across neuronal non-neuronal types within intact mouse brain vivo. Quantitative profiling reporter cohorts from young geriatric ages reveals cell- tissue-specific alterations between distinct subregions populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia interneurons. We also find that healthy is hallmarked by dynamic accumulation differentially acidified lysosomes several neural subsets. Our findings argue against any widespread mitophagic activity, instead demonstrating fluctuations trajectory, with strong implications ongoing theragnostic development.
Язык: Английский
Процитировано
9
Brain Sciences, Год журнала: 2024, Номер 14(4), С. 327 - 327
Опубликована: Март 28, 2024
Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function an energy substrate signal molecule, recent research revealed lactate to serve epigenetic regulator the brain. However, molecular mechanisms by which regulates spatial memory role prevention of disorders remain unclear. Herein, we injected L-lactate (10 μmol/kg/d for 6 d) into mouse’s hippocampus, followed Morris water maze (MWM) test analyses. Improved performances were observed mice with lactate. Besides, upregulated expression synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), growth associated protein 43 (GAP43) hippocampal tissues HT22 cells, suggesting potential transmission formation. The facilitative monocarboxylate transporter 2 (MCT2), neuron-specific transporter, this process was confirmed, MCT2 antagonists attenuated lactate-induced upregulation proteins. Moreover, induced lactylation, post-translational modification, could be suppressed inhibition. RNA sequencing lactated-injected comprehensive gene profile influenced lactate, significant changes genes transcriptional progress. These data demonstrate that injection enhances mice, potentially through induction playing crucial these Our findings shed light on multi-faceted regulation, opening new avenues therapeutic interventions targeting disorders.
Язык: Английский
Процитировано
7
eLife, Год журнала: 2025, Номер 13
Опубликована: Янв. 31, 2025
Non-linear summation of synaptic inputs to the dendrites pyramidal neurons has been proposed increase computation capacity through coincidence detection, signal amplification, and additional logic operations such as XOR. Supralinear dendritic integration documented extensively in principal neurons, mediated by several voltage-dependent conductances. It also reported parvalbumin-positive hippocampal basket cells, innervated feedback excitatory synapses. Whether other interneurons, which support feed-forward or inhibition neuron dendrites, exhibit local non-linear excitation is not known. Here, we use patch-clamp electrophysiology, two-photon calcium imaging glutamate uncaging, show that supralinear near-synchronous spatially clustered glutamate-receptor depolarization occurs NDNF-positive neurogliaform cells oriens-lacunosum moleculare interneurons mouse hippocampus. was detected via recordings somatic depolarizations elicited uncaging on fragments, and, concurrent transients. Supralinearity abolished blocking NMDA receptors (NMDARs) but resisted blockade voltage-gated sodium channels. Blocking L-type channels signalling only had a minor effect voltage supralinearity. Dendritic boosting signals argues for previously unappreciated computational complexity dendrite-projecting inhibitory
Язык: Английский
Процитировано
1
Phytotherapy Research, Год журнала: 2024, Номер 38(6), С. 2619 - 2640
Опубликована: Март 15, 2024
Abstract Salidroside, a principal bioactive component of Rhodiola crenulata , is neuroprotective across wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected transient 2 h middle artery occlusion (MCAO), received intraperitoneal vehicle or ± intracerebroventricular HSC70 inhibitor VER155008 TrkB ANA‐12 for up 7 days. MRI, behavioural tests, immunofluorescent staining western blotting measured effects salidroside. Reverse virtual docking enzymatic assays assessed interaction with purified recombinant HSC70. Salidroside dose‐dependently decreased infarct volumes neurological deficits, maximal by 50 mg/kg/day. This dose also improved performance beam balance Morris water maze tests. significantly increased BrdU + /nestin /DCX /NeuN − BDNF cells the peri‐infarct cortex, less effect striatum no significant subventricular zone. was predicted bind ATPase HSC70‐dependent luciferase activities, but it did not activate HSP70. immunoreactivity concentrated cortex unchanged However, prevented salidroside‐dependent increases neurogenesis, cortex. protein p‐TrkB/TrkB ratio ischemic brain, changes ANA‐12, respectively. Additionally, blocked directly activates HSC70, thereby stimulating neuroprotection via BDNF/TrkB signalling MCAO. similar activators might provide clinical therapies stroke.
Язык: Английский
Процитировано
6
Trends in Pharmacological Sciences, Год журнала: 2024, Номер 45(7), С. 586 - 601
Опубликована: Май 18, 2024
Alzheimer's disease (AD) and schizophrenia (SCZ) represent two major neuropathological conditions with a high burden. Despite their distinct etiologies, patients suffering from AD or SCZ share common burden of disrupted memory functions unattended by current therapies. Recent preclinical analyses highlight cell-type-specific contributions parvalbumin interneurons (PVIs), particularly the plasticity cellular excitability, towards intact neuronal network function (cell-to-network plasticity) performance. Here we argue that deficits PVI cell-to-network may underlie in SCZ, explore therapeutic avenues: targeting PVI-specific neuromodulation, including neuropeptides, recruitment synchrony gamma frequency range (40 Hz) external stimulation. We finally propose these approaches be merged under consideration recent insights into human brain physiology.
Язык: Английский
Процитировано
6
Annual Review of Neuroscience, Год журнала: 2024, Номер 47(1), С. 187 - 209
Опубликована: Апрель 25, 2024
The hippocampus is critical for memory and spatial navigation. ability to map novel environments, as well more abstract conceptual relationships, fundamental the cognitive flexibility that humans other animals require survive in a dynamic world. In this review, we survey recent advances our understanding of how implemented anatomically functionally by hippocampal circuitry, during both active exploration (online) rest (offline). We discuss advantages limitations spike timing–dependent plasticity recently discovered behavioral timescale synaptic supporting distinct learning modes hippocampus. Finally, suggest complementary roles these types explaining many-shot single-shot rules could work together support maps.
Язык: Английский
Процитировано
4
The Journal of Physiology, Год журнала: 2024, Номер unknown
Опубликована: Июль 21, 2024
Abstract The synaptic vesicle (SV) cycle ensures the release of neurotransmitters and replenishment SVs to sustain neuronal activity. Multiple endocytosis sorting pathways contribute recapture SV membrane proteins after fusion. Adaptor protein (AP) complexes are among critical components retrieval machinery. canonical clathrin adaptor AP2 most across many populations. An alternative AP1/AP3‐dependent process mediates formation a subset that differ from vesicles in molecular composition respond preferentially during higher frequency firing. Furthermore, recent studies show vesicular transporters for different depend extent on AP3 pathway this affects properties respective neurotransmitters. This review focuses current understanding AP‐dependent functional diversity SVs. We also discuss contribution these regulation neurotransmitter image
Язык: Английский
Процитировано
4
Journal of Clinical Investigation, Год журнала: 2024, Номер 134(19)
Опубликована: Июль 26, 2024
Patients with autism spectrum disorder (ASD) frequently experience sleep disturbance. Genetic mutations in Neuroligin-3 (NLG3) genes are highly correlative ASD and However, the cellular neural circuit bases of this correlation remain elusive. Here, we find conditional knockout NLG3 (NLG3-CKO) medial septum (MS) impairs social memory reduces sleep. MS causes hyperactivity MS-GABA neurons during avoidance wakefulness. Activation MSGABA induces deficits loss C57BL/6 mice. In contrast, inactivation these ameliorates NLG3-CKO Sleep deprivation leads to deficits, while isolation loss, both resulting a reduction expression an increase activity GABAergic from Furthermore, MS-GABA-innervated CA2 specifically regulate without impacting sleep, whereas MSGABA-innervating preoptic area selectively control affecting behavior. Together, findings demonstrate that hyperactive impair disrupt MS, achieve modality specificity through their divergent downstream targets.
Язык: Английский
Процитировано
4
iScience, Год журнала: 2024, Номер 27(2), С. 108824 - 108824
Опубликована: Янв. 9, 2024
Highlights•The vHPC-NAc circuit encodes contexts associated with food reward•vHPC cholecystokinin (CCK) interneurons inhibit vCA1→NAc projecting pyramidal cells•Silencing CCK in a reward context increased activity of improved the encoding contextual memorySummaryAssociating rewards depends on hippocampal circuits, local inhibitory positioned to play an important role shaping activity. Here, we demonstrate that context-reward memory requires ventral hippocampus (vHPC) nucleus accumbens (NAc) is gated by interneurons. In sucrose conditioned place preference (CPP) task, optogenetically inhibiting terminals impaired acquisition preference. Transsynaptic rabies tracing revealed neurons were monosynaptically innervated Using intersectional genetic targeting interneurons, ex vivo optogenetic activation GABAergic transmission onto neurons, while inhibition cFos these projection neurons. Notably, interneuron during CPP learning time spent sucrose-associated location, suggesting enhanced place-reward memory. Our findings reveal previously unknown microcircuit crucial for modulating strength learning.Graphical abstract
Язык: Английский
Процитировано
3