Aging affects GABAergic function and calcium homeostasis in the mammalian central clock

Engberink, Anneke H. O. Olde; Gutiérrez, Pablo de Torres; Chiosso, Anna; Das, Ankita; Meijer, Johanna H.; Michel, Stephan

doi:10.3389/fnins.2023.1178457

Cited by 4 publications

References 66 publications

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Alterations of Excitation–Inhibition Balance and Brain Network Dynamics Support Sensory Deprivation Theory in Presbycusis

Su,

Ren,

et al. 2024

Human Brain Mapping

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Sensory deprivation theory is an important hypothesis involving potential pathways between hearing loss and cognitive impairment in patients with presbycusis. The theory suggests that prolonged auditory deprivation in presbycusis, including neural deafferentation, cortical reallocation, and atrophy, causes long‐lasting changes and reorganization in brain structure and function. However, neurophysiological changes underlying the cognition‐ear link have not been explored. In this study, we recruited 98 presbycusis patients and 60 healthy controls and examined the differences between the two groups in gamma‐aminobutyric acid (GABA) and glutamate (Glu) levels in bilateral auditory cortex, excitation–inhibition (E/I) balance (Glu/GABA ratio), dynamic functional network connectivity (dFNC), hearing ability and cognitive performance. Then, correlations with each other were investigated and variables with statistical significance were further analyzed using the PROCESS Macro in SPSS. GABA levels in right auditory cortex and Glu levels in bilateral auditory cortex were lower but E/I balance in right auditory cortex were higher in presbycusis patients compared to healthy controls. Hearing assessments and cognitive performance were worse in presbycusis patients. Three recurring connectivity states were identified after dFNC analysis: State 1 (least frequent, middle‐high dFNC strength with negative functional connectivity), State 2 (high dFNC strength), and State 3 (most frequent, low dFNC strength). The occurrence and dwell time of State 3 were higher, on the other hand, the dwell time of State 2 decreased in patients with presbycusis compared to healthy controls. In patients with presbycusis, worse hearing assessments and cognition were correlated with decreased GABA levels, increased E/I balance, and aberrant dFNC, decreased GABA levels and increased E/I balance were correlated with decreased occurrence and dwell time in State 3. In the mediation model, the fractional windows, as well as dwell time in State 3, mediated the relationship between the E/I balance in right auditory cortex and episodic memory (Auditory Verbal Learning Test, AVLT) in presbycusis. Moreover, in patients with presbycusis, we found that worse hearing loss contribute to lower GABA levels, higher E/I balance, and further impact aberrant dFNC, which caused lower AVLT scores. Overall, the results suggest that a shift in E/I balance in right auditory cortex plays an important role in cognition‐ear link reorganization and provide evidence for sensory deprivation theory, enhancing our understanding the connection between neurophysiological changes and cognitive impairment in presbycusis. In presbycusis patients, E/I balance may serve as a potential neuroimaging marker for exploring and predicting cognitive impairment.

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Alterations of Excitation–Inhibition Balance and Brain Network Dynamics Support Sensory Deprivation Theory in Presbycusis

Su,

Ren,

et al. 2024

Human Brain Mapping

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Functional properties of aged hypothalamic cells

Masliukov

2024

Vitamins and Hormones

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Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome

Wang,

Smale,

Brown

et al. 2024

Preprint

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Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with the possible benefits of a scheduled feeding intervention using theFmr1knockout (KO) mouse model. These mutants displayed clear evidence for sleep and circadian disturbances including delay in the onset of sleep and fragmented activity rhythms with increases in cycle-to-cycle variability. TheFmr1KO mice exhibited deficits in their circadian behavioral response to light with reduced masking, longer time to resetting to shifts in the LD cycle, altered synchronization to a skeleton photoperiod and lower magnitude light-induced phase shifts of activity rhythms. Investigation of the retinal input to the surprachiasmatic nucleus (SCN) with the neurotracer cholera toxin (β subunit) and quantification of the light-evoked cFos expression in the SCN revealed an abnormal retinal innervation of the SCN in theFmr1KO, providing a possible mechanistic explanation for the observed behavioral deficits. Interestingly, disruptions in social and repetitive behavior correlated with sleep duration and fragmentation. Understanding the nature of the deficits, we decided to apply a scheduled feeding regimen (6-hr/18-hr feed/fast cycle) as a circadian-based strategy to boast circadian rhythms independently of light. This intervention significantly improved the activity rhythms and sleep in the mutants. Strikingly, the scheduled feeding ameliorated social interactions and reduced repetitive behaviors as well as the levels of Interferon-gamma and Interleukin-12 in theFmr1KO mutants, suggesting that timed eating may be an effective way to reduce inflammation. Collectively, this work adds support to efforts to develop circadian based interventions to help with symptoms of neurodevelopmental disorders.

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Aging affects GABAergic function and calcium homeostasis in the mammalian central clock

Cited by 4 publications

References 66 publications

Alterations of Excitation–Inhibition Balance and Brain Network Dynamics Support Sensory Deprivation Theory in Presbycusis

Alterations of Excitation–Inhibition Balance and Brain Network Dynamics Support Sensory Deprivation Theory in Presbycusis

Functional properties of aged hypothalamic cells

Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome

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