Convergent mechanisms of respiratory dysregulation after seizures and alcohol poisoning

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

Seizures and alcohol poisoning cause significant mortality due to respiratory arrest. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death and causes more years of potential life lost than any other neurological disorder except stroke. Respiratory arrest plays a critical role in SUDEP. Alcohol-related poisonings are the leading cause of acute alcohol-related mortality with an incidence higher than alcohol-related motor vehicle accidents. Respiratory arrest is a central feature of fatal alcohol poisoning. The long-term objective of this proposal is to determine the convergent mechanisms by which seizures and alcohol poisoning affect breathing to enable the rational development of novel treatment strategies. Seizures and alcohol poisoning increase adenosine signaling. Excessive adenosine suppresses breathing. Adenosine inhibits serotonergic and noradrenergic neurons which contribute to respiratory regulation. Our preliminary data indicate that seizures cause adenosine surging in the serotonergic raphe nuclei and that adenosine contributes to the respiratory effects of seizures and alcohol poisoning. These observations form the scientific premise of our overarching hypothesis that adenosinergic inhibition of serotonergic and/or noradrenergic neurons contributes to the effect of seizures and alcohol poisoning on breathing. Our approach utilizes G-protein-coupled receptor-activation-based (GRAB) sensors, a cutting-edge fiber photometry technique, in concert with well-established transgenic manipulations in rodent models. The relationship between respiratory disruption, adenosine signaling, and blood gasses is complicated by the fact that both hypercapnia and hypoxia increase adenosine signaling. In Aim 1, GRAB sensor fiber photometry will be used in artificially ventilated mice to differentiate between (a) adenosine signaling resulting directly from the seizure or alcohol poisoning and (b) adenosine surging that is mediated indirectly by hypercapnia/hypoxia due to respiratory disruption unrelated to adenosine signaling. In Aim 2, GRAB sensor fiber photometry will be used to determine the spatial and temporal characteristics of alterations in adenosinergic, serotonergic and noradrenergic signaling during seizures and alcohol poisoning. In Aim 3, a Cre-LoxP strategy will be used to delete A1 or A2A adenosine receptors in serotonergic and noradrenergic neurons to determine the location and subtype of adenosine receptors that mediate the effect of seizures and alcohol poisoning on breathing. Career Development Summary: This proposal will allow the applicant to reach his career goal of establishing an independent disease-oriented neuroscience research program by initiating a line of inquiry that: (1) topically expands on his prior work, (2) will give him extensive training on a state-of-the-art imaging technique with many other applications, (3) can be taken with the applicant to his next position, and (4) may have a transformative effect on our understanding and treatment of the respiratory sequelae of seizures and alcohol poisoning.