Dual Orexin Antagonist Treatment to Prevent the Neurobehavioral Sequelae of TBI
Abstract
The central hypothesis here is that following TBI, treatment with a sleep aid namely a dual orexin antagonist will mitigate the development of neurobehavioral sequelae of TBI by: a) normalizing sleep and its homeostatic drive/sleep pressure, and b) enhancing GABAergic inhibition in brain regions relevant for sleep disturbances, seizures and mood/anxiety disorders namely the thalamus, hippocampus and amygdala. Specific Aims: Aim 1: To perform CCI or sham injury followed by 2-month long EEG recordings for sleep and epileptiform activity during treatment with a dual orexin antagonist (DORA) ACT462206 or a vehicle. Aim 2: To perform behavioral testing including tail suspension for a depression phenotype, fear conditioning for PTSD phenotype and Morris Water Maze for spatial learning and memory in CCI or sham injury groups towards the end of 2-month-long daily treatment with ACT-462206 or a respective vehicle. Aim 3: To perform patch-clamp electrophysiology to record cellular and network excitability measures focusing on thalamic reticular neurons (important for sleep slow-wave or delta activity generation), dentate granule cells and CA1 pyramidal neurons (important for epilepsy) and pyramidal neurons in basolateral amygdala (mood disorders) at the end of 2-month long DORA (ACT462206) or vehicle treatment. Aim 4: To perform EEG recordings and behavioral experiments as in Aim 1 and 2 following CCI after treatment with an orexin receptor-2 agonist YNT185 as a comparative study.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2024
- Accession Number
- AD1227968
Entities
People
- Matganti Rama
Organizations
- University of Wisconsin–Madison