Age-associated changes to neuronal dynamics involve a disruption of excitatory/inhibitory balance in C. elegans DOI Creative Commons
Gregory S. Wirak, Jeremy Florman, Mark J. Alkema

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: June 15, 2022

In the aging brain, many of alterations underlying cognitive and behavioral decline remain opaque. Caenorhabditis elegans offers a powerful model for research, with simple, well-studied nervous system to further our understanding cellular modifications functional accompanying senescence. We perform multi-neuronal imaging across aged C. system, measuring an age-associated breakdown in system-wide organization. At single-cell resolution, we detect shifts activity dynamics toward higher frequencies. addition, measure specific loss inhibitory signaling that occurs early process alters systems' critical excitatory/inhibitory balance. These effects are recapitulated mutation calcium channel subunit UNC-2/CaV2α. find manipulation GABA can partially ameliorate or accelerate aging. The also mitigated by disruption insulin pathway, known increase longevity, reduction caspase activation. Data from mammals consistent findings, suggesting conserved shift balance age leads global neuronal decline.

Language: Английский

Ageing and Cognition DOI
Sydney M. A. Juan, Paul A. Adlard

Sub-cellular biochemistry/Subcellular biochemistry, Journal Year: 2019, Volume and Issue: unknown, P. 107 - 122

Published: Jan. 1, 2019

Language: Английский

Citations

91
The aging mouse brain: cognition, connectivity and calcium DOI Creative Commons
Carola I. Radulescu, Veronika Cerar, Peter Haslehurst

et al.

Cell Calcium, Journal Year: 2021, Volume and Issue: 94, P. 102358 - 102358

Published: Jan. 23, 2021

Aging is a complex process that differentially impacts multiple cognitive, sensory, neuronal and molecular processes. Technological innovations now allow for parallel investigation of circuit function, structure composition in the brain awake behaving adult mice. Thus, mice have become critical tool to better understand how aging brain. However, more granular systems-based approach, which considers impact age on key features relating neural processing, required. Here, we review evidence probing mouse We focus range processes including cognitive abilities, sensory systems, synaptic plasticity calcium regulation. Across many find prominent age-related dysregulation even before 12 months age, suggesting emerging alterations can manifest by late adulthood. also reports some are remarkably resilient aging. The suggests does not drive parallel, linear all but instead earlier, severely, than others. propose capturing fine-scale vulnerability resilience may provide opportunities rejuvenation aged

Language: Английский

Citations

71
Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging DOI Creative Commons
Felipe Cabral‐Miranda,

Giovanni Tamburini,

Gabriela Martínez

et al.

The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(22)

Published: Oct. 31, 2022

Language: Английский

Citations

45
Decoding the nexus: branched-chain amino acids and their connection with sleep, circadian rhythms, and cardiometabolic health DOI Creative Commons
Hui Li, Laurent Seugnet

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(5), P. 1350 - 1363

Published: June 3, 2024

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and, either directly or indirectly, overall body health, encompassing metabolic and cardiovascular well-being. Given the heightened activity of brain, there exists a considerable demand nutrients in comparison to other organs. Among these, branched-chain amino acids, comprising leucine, isoleucine, valine, display distinctive significance, from their contribution protein structure involvement metabolism, especially cerebral processes. first acids that are released into circulation post-food intake, assume pivotal role regulation synthesis, modulating insulin secretion acid sensing pathway target rapamycin. Branched-chain key players influencing brain’s uptake monoamine precursors, competing shared transporter. Beyond these contribute cycles γ-aminobutyric glutamate, well energy metabolism. Notably, they impact GABAergic neurons excitation/inhibition balance. rhythmicity plasma concentrations, observed over 24-hour conserved rodent models, is under circadian clock control. mechanisms underlying those rhythms physiological consequences disruption not fully understood. Disturbed sleep, obesity, diabetes, diseases can elevate concentrations modify oscillatory dynamics. driving effects currently focal point ongoing research efforts, since normalizing levels has ability alleviate severity pathologies. In this context, Drosophila model, though underutilized, holds promise shedding new light on mechanisms. Initial findings indicate its potential introduce novel concepts, particularly elucidating intricate connections between clock, sleep/wake, Consequently, use transport emerge critical components orchestrators web interactions across multiple organs throughout sleep/wake cycle. They could represent one so far elusive connecting sleep patterns paving way therapeutic interventions.

Language: Английский

Citations

10
Sex- and age-related changes in GABA signaling components in the human cortex DOI Creative Commons

Madhavi Pandya,

Thulani H. Palpagama,

Clinton Turner

et al.

Biology of Sex Differences, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 14, 2019

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in nervous system. Previous studies have shown fluctuations expression levels of GABA signaling components—glutamic decarboxylase (GAD), receptor (GABAR) subunit, and transporter (GAT)—with increasing age between sexes; however, this limited knowledge highly based on animal models that produce inconsistent findings. This study first analysis age- sex-specific changes GAD, GABAA/BR subunits, GAT human sensory motor cortices; superior (STG), middle (MTG), inferior temporal gyrus (ITG); cerebellum. Utilizing Western blotting, we found GABAergic system relatively robust against sex age-related differences all brain regions examined. However, observed several sex-dependent GABAAR subunit STG along with age-dependent GAD level alteration. No significant were α1, α2, α5, β3, γ2 STG. significantly higher α3 young males compared to old males. We a difference α1 expression: presenting women across stages life Older females showed lower β3 These might influence neurotransmission lead sex- age-specific disease susceptibility progression.

Language: Английский

Citations

75
Critical periods of brain development DOI
J. Miguel Cisneros-Franco, Patrice Voss, Maryse E. Thomas

et al.

Handbook of clinical neurology, Journal Year: 2020, Volume and Issue: unknown, P. 75 - 88

Published: Jan. 1, 2020

Language: Английский

Citations

52
Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study DOI Creative Commons
Laura Michiels, Aline Delva, June van Aalst

et al.

NeuroImage, Journal Year: 2021, Volume and Issue: 232, P. 117877 - 117877

Published: Feb. 24, 2021

11C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as vivo proxy of density. There are discrepancies postmortem data on stability density with healthy aging. In this study, aging sex potential modifiers binding were investigated volunteers over 7 adult decades, assuming that the number SV2A vesicles per synapse is not influenced by age or sex. 80 underwent PET structural T1 T2 MR imaging. Grey matter changes firstly evaluated voxel-based morphometry (VBM). Parametric standardized uptake value ratio (SUVR) images calculated using centrum semiovale reference tissue. To correct for atrophy-related partial volume effects, region-based voxel-wise type correction (PVC) was applied FreeSurfer. The correlations volume-of-interest (VOI)-based approach, without PVC assess contribution underlying morphology upon Full results available 78 participants (19–85y; 33 M/45 F). VBM grey concentration most predominant perisylvian frontal regions. After PVC, no significantly decreased SUVR found analysis, whereas VOI-based analysis showed slight decrease caudate nucleus (−1.7% decade, p= 0.0025) only. association between SUVR, nor an interaction parameter. vivo, does support cortical aging, subcortically small effect observed. addition, detected, which allows pooling datasets both sexes.

Language: Английский

Citations

49
Cerebral Hypoxia: Its Role in Age-Related Chronic and Acute Cognitive Dysfunction DOI Open Access
Brina Snyder,

Stephanie M. Simone,

Tania Giovannetti

et al.

Anesthesia & Analgesia, Journal Year: 2021, Volume and Issue: unknown

Published: March 29, 2021

Postoperative cognitive dysfunction (POCD) has been reported with widely varying frequency but appears to be strongly associated aging. Outside of the surgical arena, chronic and acute cerebral hypoxia may exist as a result respiratory, cardiovascular, or anemic conditions. Hypoxia extensively implicated in impairment. Furthermore, disease states both accompany progress Perioperative is likely underdiagnosed, its contribution POCD underappreciated. Herein, we discuss various processes forms which contribute POCD. outline hypoxia-related mechanisms, such hypoxia-inducible factor activation, ischemia, cerebrovascular reserve, excitotoxicity, neuroinflammation, impairment how these mechanisms interact Finally, opportunities prevent manage related hypoxia.

Language: Английский

Citations

48
Molecular Basis of Late-Life Depression DOI Open Access

Chien-Yi Kuo,

Chieh‐Hsin Lin, Hsien‐Yuan Lane

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7421 - 7421

Published: July 10, 2021

Late-life depression (LLD), compared to at a young age, is more likely have poor prognosis and high risk of progression dementia. A recent systemic review meta-analysis the present antidepressants for LLD showed that treatment response rate was 48% remission only 33.7%, thus implying need improve with other approaches in future. Recently, agents modulating glutamatergic system been tested mental disorders such as schizophrenia, dementia, depressive disorder. Ketamine, noncompetitive NMDA receptor (NMDAR) antagonist, requires evidence from randomized clinical trials (RCTs) prove its efficacy safety treating LLD. The metabotropic receptors (mGluRs) are family G-protein-coupled receptors, inhibition Group II mGluRs subtypes (mGlu2 mGlu3) found be effective ketamine exerting rapid antidepressant activity some animal studies. Inflammation has thought contribute long time. cytokine levels not increase age but also decrease serotonin. Regarding LLD, interleukin 6 (IL-6) tumor necrosis factor α (TNF-α) released vivo reduced serotonin level. Brain-derived neurotrophic (BDNF), growth modulator tropomyosin kinase (Trk) tyrosine probably declines quantitatively age. Recent studies suggest BDNF/TrkB decrement may learning deficits memory impairment. In process aging, physiological changes combination geriatric diseases vascular result poorer comparison young-age depression. Treatments generally unsatisfactory. Novel treatments anti-inflammatory or NMDAR agonists/antagonists require Last least, which share common pathways interrelate reciprocally, great concern. If it possible enhance LDD, dementia can prevented delated.

Language: Английский

Citations

41
A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain DOI Creative Commons
Manan Bhatt,

Laure Gauthier-Manuel,

Erika Lazzarin

et al.

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: April 13, 2023

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in central nervous system (CNS). Its homeostasis maintained by neuronal and glial GABA transporters (GATs). The four GATs identified humans are GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11), betaine/GABA transporter-1 BGT-1 (SLC6A12) which all members of solute carrier 6 (SLC6) family sodium-dependent transporters. While has been investigated extensively, other less studied their role CNS not clearly defined. Altered GABAergic neurotransmission involved different diseases, but importance remained understudied limits drug targeting. In this review, well-studied transporter compared with less-studied aim to leverage knowledge on shed new light open questions concerning BGT-1. most recent structure, functions, expression, localization discussed along specific as targets for neurological neurodegenerative disorders. We review discuss data binding sites Na + , Cl − substrates, inhibitors building cryo-EM structure highlight molecular determinants functions. two proteins looking at transport coupling mechanism, well structural kinetic models. Furthermore, we information selective together pharmacophore hypothesis substrates.

Language: Английский

Citations

17