Louka, C. | Search bioRxiv

bioRxiv2024

A heteromeric nicotinic acetylcholine receptor promotes sleep by relaying GABAergic signals within a locus of motor and sensory integration

Locomotor inactivity and reduced sensory responsiveness are defining attributes of sleep, yet the underlying mechanisms are not well understood. In particular, the molecular and circuit mechanisms by which sleep-regulatory signals from the brain restrict movement and sensation remain largely ill-defined. Here we identify a nicotinic acetylcholine receptor (nAChR) that promotes sleep in Drosophila through its expression in GABAergic neurons of the ventral nerve cord (VNC), a center for motor and sensory systems. Biochemical, genetic, and pharmacological manipulations indicate that a heteromeric nAChR containing the 1 and {beta}1 subunits promotes sleep by coupling cholinergic input to GABA release in the VNC and the likely inhibition of motor neurons, sensory afferents, or both. The functional parallels of the VNC and the mammalian spinal cord suggest that disruptions of analogous inhibitory circuits in humans may impair suppression of behavioral activity and sensory inputs during sleep and contribute to sleep disorders.

neuroscience↗

bioRxiv2022

Obesity promotes breast epithelium DNA damage in BRCA mutation carriers

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population. One Sentence SummaryElevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers

cancer biology↗