Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 1, 2024
Language: Английский
Aging Cell, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 2, 2025
ABSTRACT With advancing age, significant changes occur in the female reproductive system, most notable of which is decline oocyte quality, a key factor affecting fertility. However, mechanisms underlying aging remain poorly understood. In this study, we obtained oocytes from aged and young mice performed single‐cell transcriptome sequencing, comparing our findings with existing proteomic analyses. Our analysis revealed that one primary characteristics disruption calcium ion homeostasis. Specifically, identified two genes involved process, Calb1 Rpl23 . Experimental validation demonstrated knockdown CALB1 led to reduced levels endoplasmic reticulum mitochondria, resulting mitochondrial dysfunction meiotic defects. Further experiments suggested RPL23 may function as downstream gene CALB1, its caused dysfunction, excessive accumulation reactive oxygen species (ROS), spindle assembly Notably, overexpression these partially rescued maternal age‐related defective phenotypes, underscoring their crucial roles aging. This study provides comprehensive understanding specific mouse at resolution, supported by experimental validation, offers new directions potential targets for future research into health issues.
Language: Английский
Citations
2
Biological Psychiatry, Journal Year: 2024, Volume and Issue: unknown
Published: June 1, 2024
Language: Английский
Citations
11
Neurobiology of Stress, Journal Year: 2024, Volume and Issue: 30, P. 100628 - 100628
Published: March 15, 2024
Uncontrollable stress exposure impairs working memory and reduces the firing of dorsolateral prefrontal cortex (dlPFC) "Delay cells", involving high levels norepinephrine dopamine release. Previous work has focused on catecholamine actions dlPFC pyramidal cells, but inhibitory interneurons may contribute as well. The current study combined immunohistochemistry multi-scale microscopy with iontophoretic physiology behavioral analyses to examine effects beta1-noradrenergic receptors (β1-ARs) neurons in layer III dlPFC. We found β1-AR robustly expressed different classes labeled by calcium-binding proteins calbindin (CB), calretinin (CR), parvalbumin (PV). Immunoelectron confirmed expression plasma membrane PV-expressing dendrites. PV can be identified fast-spiking (FS) physiological recordings, thus were studied macaques performing a task. Iontophoresis agonist had mixed effect, increasing subset decreasing others, likely reflecting loss entire microcircuit. This overall contributes impaired during stress, pretreatment selective antagonist, nebivolol, prevented stress-induced deficits. Thus, antagonists helpful treating stress-related disorders.
Language: Английский
Citations
6
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: June 16, 2024
Abstract Marmosets and macaques are common non-human primate models of cognition, but evidence suggests that marmosets perform more poorly appear distractible during cognitive tasks. The dorsolateral prefrontal cortex (dlPFC) plays a key role in regulating attention, prior research dopaminergic modulation inhibitory parvalbumin (PV) neurons could contribute to distractibility performance. Thus, we compared the two species using visual fixation task with distractors, performed molecular anatomical analyses dlPFC, linked functional microcircuitry performance computational modeling. We found than macaques, marmoset dlPFC PV contain higher levels dopamine-1 receptor (D1R) transcripts, similar mice, D1R protein. model suggested expression may increase by suppressing microcircuits, e.g., when dopamine is released salient stimuli.
Language: Английский
Citations
4
Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 8, 2025
Abstract Aging rhesus macaques provide a unique model for learning how age and inflammation drive early‐stage pathology in sporadic Alzheimer's disease, testing potential therapeutics. Unlike mice, aging have extensive association cortices inflammatory signaling similar to humans, are apolipoprotein E ε4 homozygotes, naturally develop tau amyloid with marked cognitive deficits. Importantly, monkeys the opportunity study early‐stage, soluble hyperphosphorylated (p‐tau), including p‐tau217. As p‐tau is rapidly dephosphorylated post mortem , it not captured human brains except biopsy material. However, new macaque data show that toxic neurons capable of seeding across cortical circuits. Extensive evidence indicates age‐related contributes calcium dysregulation, which drives hyperphosphorylation beta generation. Pharmacological studies aged suggest inhibiting restoring regulation can reduce minimal side effects, appropriate preventive Highlights window into early stage, phosphorylated (p‐tau). Inflammation advancing leads p‐tau, (Aβ). Macaque research shows undergoes transsynaptic cortex. traps precursor protein–containing endosomes, may increase Aβ vicious cycles. Restoring cortex reduced p‐tau217 levels macaques.
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 6, 2025
Abstract Expression of the N-methyl-D-aspartate receptor, particularly when containing GluN2B subunit (NMDAR-GluN2B) varies across prefrontal cortex (PFC). In humans, subgenual cingulate (SGC) contains among highest levels NMDAR-GluN2B expression, while dorsolateral (dlPFC) exhibits a more moderate level expression. are commonly associated with ionotropic synaptic function and plasticity, essential to neurotransmission underlying working memory in macaque dlPFC layer III circuits afflicted schizophrenia. However, can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked neurodegenerative processes. The SGC is an early site tau pathology sporadic Alzheimer’s Disease (sAD), which mirrors its high Additionally, hyperactive depression, treated NMDAR antagonists. Given clinical relevance dlPFC, current study used immunoelectron microscopy (immunoEM) quantitatively compare expression patterns excitatory inhibitory neuron dendrites rhesus dlPFC. We larger population dendritic shafts spines putative pyramidal neurons as compared had higher proportion NMDAR-GluN2B. contrast, from both areas, was far frequently observed over These findings provide insight into varying cortical vulnerability alterations excitability forces. Scope Statement receptors that contribute second messenger signaling events. induce diverse array neuronal part due variation composition subcellular localization receptor humans. This highly expressed cingulate, area mood emotion, moderately cortex, cognitive Extrasynaptic NMDAR, often contain subunit, have been detrimental cellular events like neurodegeneration. Here, using resolution electron macaques, we evidence prominent than cortex. Conversely, consistent their contribution firing during memory. help illuminate propensity tonic hyperactivity major depression neurodegeneration disease, explain how rapid acting antidepressants exert therapeutic action neural circuits.
Language: Английский
Citations
0
medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: March 27, 2025
Type 2 diabetes (T2DM) is associated with brain abnormalities and cognitive dysfunction, including increased risk for Alzheimer's disease. However, the mechanisms of T2DM-related dementia remain poorly understood. We obtained retrospective data from Mayo Clinic Study Aging 271 individuals T2DM 542 demographically matched non-diabetic controls (age 51-89, 62% male). identified regions significant gray matter atrophy in group then determined which genes were significantly expressed these using imaging transcriptomics. selected 15 candidate involved insulin signaling, lipid metabolism, amyloid processing, N-methyl-D-aspartate-mediated neurotransmission, calcium signaling. The demonstrated default mode, frontal-parietal, sensorimotor networks (p < 0.05 cluster threshold corrected false discovery rate, FDR). IRS1, AKT1, PPARG, PRKAG2 , GRIN2B same (R > 0.10, p 0.03, FDR corrected). Bayesian network analysis indicated directional paths among all 5 as well Clinical Dementia Rating score. Directional altered (Structural Hamming Distance = 12, 0.004), PPARG expression becoming more important context pathophysiology. Alterations transcriptome patterns occurred absence deficit or accumulation, potentially representing an early biomarker dementia.
Language: Английский
Citations
0
Frontiers in Neuroanatomy, Journal Year: 2025, Volume and Issue: 19
Published: April 4, 2025
Expression of the N-methyl-D-aspartate receptor, particularly when containing GluN2B subunit (NMDAR-GluN2B), varies across prefrontal cortex (PFC). In humans, subgenual cingulate (SGC) contains among highest levels NMDAR-GluN2B expression, while dorsolateral (dlPFC) exhibits a more moderate level expression. are commonly associated with ionotropic synaptic function and plasticity essential to neurotransmission underlying working memory in macaque dlPFC layer III circuits, which humans afflicted schizophrenia. However, can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked neurodegenerative processes. The SGC is an early site tau pathology sporadic Alzheimer’s disease (sAD), mirrors its high Additionally, hyperactive depression, treated NMDAR antagonists. Given clinical relevance dlPFC, current study used immunoelectron microscopy (immunoEM) quantitatively compare expression patterns excitatory inhibitory neuron dendrites rhesus dlPFC. We larger population putative pyramidal neurons as compared had higher proportion NMDAR-GluN2B. contrast, from both areas, was far frequently observed over These findings provide insight into varying cortical vulnerability alterations excitability forces.
Language: Английский
Citations
0
Neuron, Journal Year: 2025, Volume and Issue: 113(10), P. 1548 - 1561.e8
Published: May 1, 2025
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: June 14, 2024
Summary Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer’s disease, have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) brain, where it blocks NMDA α7-nicotinic receptors (nic-α7Rs). These essential for neurotransmission dlPFC, suggesting that KYNA may cause higher cognitive these disorders. The current study found its synthetic enzyme, KAT II, greatly expanded expression primate dlPFC both glia neurons. Local application of onto neurons markedly reduced the delay-related firing needed working memory via actions at nic-α7Rs, while inhibition II enhanced neuronal aged macaques. Systemic administration agents reduce production similarly improved performance monkeys, a therapeutic avenue treatment
Language: Английский
Citations
1