bioRxiv Science⌕ Search

Biology subjects

Marcotulli, D.

Publications and source records attributed to Marcotulli, D..

2 recordsLinked to original sources

Adolescent chronic sleep restriction promotes alcohol drinking in adulthood: evidence from epidemiological and preclinical data.

Epidemiological investigations have indicated that insufficient sleep is prevalent among adolescents, posing a globally underestimated health risk. Sleep fragmentation and sleep loss during adolescence have been linked to concurrent emotional dysregulation and an increase in impulsive, risk-taking behaviors, including a higher likelihood of substance abuse. Among the most widely used substances, alcohol stands as the primary risk factor for deaths and disability among individuals aged 15-49 worldwide. While the association between sleep loss and alcohol consumption during adolescence is well documented, the extent to which prior exposure to sleep loss in adolescence contributes to heightened alcohol use later in adulthood remains less clearly delineated. Here, we analyzed longitudinal epidemiological data spanning 9 years, from adolescence to adulthood, including 5497 participants of the Avon Longitudinal Study of Parents And Children cohort. Sleep and alcohol measures collected from interviews and questionnaires at 15 and 24 years of age were analyzed with multivariable linear regression and a cross-lagged autoregressive path model. Additionally, we employed a controlled preclinical experimental setting to investigate the causal relationship underlying the associations found in the human study and to assess comorbid behavioral alterations. Preclinical data were collected by sleep restricting Marchigian Sardinian alcohol preferring rats (msP, n=40) during adolescence and measuring voluntary alcohol drinking concurrently and in adulthood. Polysomnography was used to validate the efficacy of the sleep restriction procedure. Behavioral tests were used to assess anxiety, risky behavior, and despair. In humans, after adjusting for covariates, we found a cross-sectional association between all sleep parameters and alcohol consumption at 15 years of age but not at 24 years. Notably, alcohol consumption (Alcohol Use Disorder Identification Test for Consumption) at 24 years was predicted by insufficient sleep at 15 years whilst alcohol drinking at 15 years could not predict sleep problems at 24. In msP rats, adolescent chronic sleep restriction escalated alcohol consumption and led to increased propensity for risk-taking behavior in adolescence and adulthood. Our findings demonstrate that adolescent insufficient sleep causally contributes to higher adult alcohol consumption, potentially by promoting risky behavior.

neuroscience↗

Levetiracetam inhibits SV2A-synaptotagmin interaction at synapses that lack SV2B

Epilepsy remains a difficult-to-treat neurological disorder prompting the need for new therapies that work via alternate mechanisms. Levetiracetam (LEV) is the first in a series of anti-epilepsy drugs that target presynaptic functioning. LEV binds the synaptic vesicle protein SV2A, and has been shown to decrease neurotransmitter release in hippocampal slices. The molecular basis of LEV action is unknown, however, and direct effects of LEV on SV2A function remain to be determined. SV2A is the most widely expressed paralog of a three-gene family (SV2A, B, C) that is variably co-expressed throughout the CNS. All three SV2s bind the calcium sensor protein synaptotagmin and SV2 plays a crucial role in synaptotagmin stability and trafficking. Here we addressed the action of LEV at the cellular and molecular level asking whether the presence of non-LEV binding SV2 paralogs influences drug action and whether LEV impacts SV2As role in synaptotagmin function. We report that LEV altered short-term synaptic plasticity in isolated neurons from SV2B knockout but not wild-type mice, mimicking the loss of SV2 function. Similarly, LEV reduced SV2A binding to synaptotagmin only in the absence of SV2B. Furthermore, LEV reduced and slowed the internalization of synaptotagmin in neurons cultured from SV2B KO but not WT mice. Taken together, these findings suggest that LEV alters synaptic release probability by disrupting SV2s regulation of synaptotagmin selectively in neurons that express only SV2A. Neurons that meet this requirement include most inhibitory neurons and the granule cells of the dentate gyrus, two classes of neuron implicated in epilepsy.

pharmacology and toxicology↗