B5: Ethanol intoxication in TBI: mechanisms of neuroprotection and neuroglial modulation
PI: F. Roselli
Ethanol intoxication (EI) is a frequent comorbidity of Traumatic Brain Injury (TBI); clinical data have suggested that, paradoxically, it may have protective effects. Experimental confirmation and mechanistic understanding of the interaction between EI and TBI have not been available to date. We have demonstrated that in a weight- drop, concussive murine TBI model, acute EI before TBI results in accelerated and more pronounced neurological recovery, together with a reduced loss of neurons in cortex and hippocampus. We have shown that EI prevents the induction of Immediate Early Genes (IEG) in principal neurons upon TBI as well as the activation of Receptor Tyrosine Kinases (RTK) signaling, in particular of ErbB family receptors on inhibitory interneurons We have used chemiogenetic approaches to show that EI effects are partially mimicked by the inactivation of PV interneurons. In fact, inactivation of Parvalbumin (PV) interneurons is neuroprotective through activity-dependent nuclear calcium signals, and direct activation of principal neurons is sufficient to recapitulate this effect. Furthermore, we have demonstrated that EI has extensive neuroimmunomodulatory effects, including the strong induction of IL-13 in neurons associated with STAT6 phosphorylation.
We now propose to investigate if EI display neuroprotective effects through nuclear calcium signals, hypothesizing it may share a common pathway with PV inactivation. We will also investigate the link between EI-associated neuronal activity and the regulation of the neuroinflammatory response associated with TBI. Finally, further exploring the role of microcircuitry in shaping the vulnerability of principal neurons to TBI, we will use chemiogenetic approaches to activate or inactivate a second class of inhibitory interneurons, the Vasoactive-Intestinal-Peptide (VIP)-positive dis-inhibitory interneurons, and monitor the effects on neuronal survival and gliosis.