Cell-type specific evaluation of globus pallidus pars externa as a translational target to improve sleep and arousal

About This Grant

Significance to VA. Disrupted sleep occurs in many conditions common in Veterans, including VA research priorities such as post-traumatic stress disorder (PTSD), substance abuse, major depression and neurodegenerative disorders. Insomnia is associated with an increased risk for suicide and increases the risk for relapse in opioid use disorder. Furthermore, disrupted sleep and abnormal sleep spindles are common in expensive, hard-to-treat conditions such as dementia and schizophrenia. Increasing evidence suggests that sleep spindles are needed for memory consolidation. Deep sleep is vital in clearing the toxic proteins which are increased by traumatic brain injury and cause neurodegeneration. Accordingly, novel strategies to promote deep restorative sleep are needed for a wide variety of disorders affecting Veterans. Cognitive treatments have utility but exert a relatively modest effect and the most widely used existing pharmacological treatments may disrupt deep restorative sleep and be habit-forming. Thus, alternative treatments are needed. Innovation and Impact. Here, in mice we evaluate for the first time whether deep restorative sleep can be enhanced through cell-type specific modulation of an important basal ganglia structure, the globus pallidus, pars externa (GPe). Our data suggest inhibition of GPe neurons which express the calcium-binding protein parvalbumin (PV+) shortens sleep latency and strongly increases the depth and consolidation of sleep. Our novel data show that another group of neurons which express the transcription factor neuronal PAS domain 1 (Npas1+) regulate sleep spindles, important in memory consolidation. Thus, pharmacological or brain stimulation strategies which inhibit GPe PV+ neurons may be a novel strategy to treat insomnia, whereas inhibition of Npas1+ neurons may promote memory consolidation. Our new data in Aim3 identify a safe natural pharmacological agent which opens potassium channels to inhibit GPe PV+ neurons and promote sleep. Specific Aims. Here, experiments focus on two major, non-overlapping neuronal-types of the GPe, PV+ and Npas1+, which make up 50 % and 30 % of GPe neurons, respectively. Aims 1 and 2 will use state-of-the- art neuromodulatory approaches in genetically-modified mice to test the effects of exciting or inhibiting these neurons on sleep. Aims 1 and 2 will also extend our approach to wild-type mice and identify the downstream neuronal targets. In Aim 3 we will test whether we can enhance sleep via systemic or local application of a safe natural compound which preferentially inhibits GPe PV+ neurons by opening potassium channels. Methodology. All aims investigate the effects of GPe manipulations on sleep and cortical electrical oscillations using electroencephalographic and electromyogram recordings in mice. Aim 1 uses chemogenetics to excite or inhibit GPe PV+ or NPas1+ neurons. Chemogenetics allows a prolonged increase or decrease in neuronal activity through the cell-type specific expression of G-protein activated receptors which respond selectively to an otherwise inert drug. Aim 2 will use closed-loop optogenetics to specifically inhibit (Aim2a) or excite (Aim2b) PV+ or Npas1+ during non-rapid-eye-movement sleep. Optogenetics allows fast and precise manipulation by applying light to neurons expressing light-activated ion channels or pumps. Aim 3 will use a pharmacological approach to inhibit GPe PV+ neurons by opening the potassium channels they express. Path to translation/implementation: Potentially the fastest translational application of this research is to use a pharmacological approach, as in Aim3, to enhance sleep by inhibiting GPe PV+ neurons via opening of the potassium channels they express. Several potassium channel openers, including the natural one we test here are safe and approved for use in humans and proposed as therapeutic agents. Another approach could be to modify existing electrical deep brain stimulation protocols or non-invasive stimulation approaches to target GPe to promote healthy sleep and daytime alertness. Ultimately, in the longer-term, we believe that cell- type specific approaches such as optogenetics or chemogenetics could be applied.