Deployment and combat exposure substantially increase the risk for insomnia and other sleep disorders in military personnel. These findings match with the 6-fold increase in the diagnosis of sleep disorders in the VA in recent years. The most prevalent sleep disorder, insomnia, is associated with an increased risk for suicide. Furthermore, disrupted sleep and abnormal cortical activity are common in severe neuropsychiatric conditions affecting veterans such as dementia and schizophrenia. Thus, a better mechanistic understanding of the brain circuitry controlling sleep-wake cycles and cortical oscillations are urgently needed to develop novel treatments for veterans and other vulnerable populations. Accordingly, the broad objective of this research program in mice is to identify new therapeutic targets to correct abnormalities of sleep and cortical electrical activity. We will use an innovative approach in mice which characterizes subgroups of neurons based on their developmental origin and identifies the transcription factors which control their activity in adults, allowing targeted therapies which recalibrate their activity to restore normal sleep and cortical rhythms. We focus on the basal forebrain, a region involved in sleep-wake activity, attention and reward which degenerates in dementia, and on the largest group of neurons in this region which release the inhibitory neurotransmitter, gamma-amino-butyric acid (GABA). We target neurons which express three transcription factors linked to insomnia and other neuropsychiatric disorders common in veterans by genetic and postmortem studies. The roadmap to helping veterans is: We will identify new groups of neurons based on their developmental origin (Aim 1). We will use transgenic mice which allow manipulation of their activity to determine how they affect sleep-wake behavior and cortical oscillations (Aim 2). Finally, we will state-of-the-art genetic techniques to identify the transcription factors which control their activity in adults (Aim 3), allowing us to correct abnormal sleep-wake behavior and cortical electrical activity in neuropsychiatric disorders by designing viral vector based therapies which act on those transcription factors (long-term goal). Forebrain GABAergic neurons are generated in the subpallium, an area of the developing brain implicated in the risk for developing diverse neuropsychiatric disorders affecting veterans. Within the subpallium, different groups of GABAergic neurons are generated by progenitors in the caudal, medial and lateral ganglionic eminences and embryonic preoptic regions. In each region, different transcription factors specify unique groups of neurons. We will use genetically modified mice which express an enzyme, Cre recombinase (Cre), under the control of these transcription factors to identify them and manipulate their activity. Crossing these mouse strains with another mouse strain which expresses a red fluorescent protein in the presence of Cre, in combination with immunostaining will allow us to map their location and phenotype (Aim 1).
In Aim 2 we will study their function by increasing their activity or ablating them using injections of viral vectors which express proteins in the presence of Cre. These experiments will reveal the role of these neurons in sleep-wake behavior and control of cortical electrical activity for the first time and set the stage for translational studies to alter their activity. Finally, in Aim 3, we will begin the first step towards a translational approach by using state-of-the art genetic techniques to modulate the activity of one of these transcription factors, Lhx6, whose expression is altered in a GABAergic cell-type implicated in schizophrenia. We will use a state-of-the-art gene editing technique called Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR), which is currently being tested in clinical trials for various disorders. If successful, as suggested by our strong preliminary data, this project will allow novel translational approaches to study and correct disease-related abnormalities in veterans by manipulating the activity of basal forebrain neurons and genes which regulate sleep-wake behavior and cortical electrical activity.
Sleep disorders are highly prevalent in veterans. A 6-fold increase in the diagnosis of sleep disorders was reported at the VA in recent years. Insomnia is associated with increased risk for suicide in veterans, an area of particular interest for VA. Furthermore, other severe neuropsychiatric disorders affecting veterans, such as schizophrenia or dementia, are associated with abnormalities of cortical electrical activity during wakefulness or specific sleep stages. Current attempts to develop treatments are hampered by a poor understanding of the brain circuitry controlling sleep, wakefulness and cortical activity. This research program in mice uses a novel strategy based on developmental biology to identify and characterize the neurons which control brain arousal and sleep in the basal forebrain, a brain area which degenerates in dementia. State-of-the-art genetic techniques will be used to manipulate the activity of these neurons, an essential first step towards correcting abnormalities of sleep-wake behavior and cortical activity in disorders affecting veterans.
