The broad objective of this proposal is to understand the cellular mechanisms which control sleepiness. Sleep deprivation (SD) and insomnia are experienced by ~40% of military personnel immediately after deployment and SD is a well-known risk factor that adversely affects the mental health of veterans. The basal forebrain (BF) is an important brain region for controlling the increased propensity for sleep after SD i.e. sleep homeostasis. Previous grant cycles investigated how sleep homeostasis is mediated by inhibition of BF wake-promoting neurons via increases in the extracellular concentration of adenosine (ADex), and investigated the role of extracellular adenosine triphosphate (ATPex) as a source of ADex. However, the circuit and neurotransmitter basis for these increases in ATPex and ADex has remained unresolved. At least three types of cortically-projecting, wake-active neurons coexist within BF: cholinergic (ChAT+), parvalbumin expressing GABAergic (PV+) and glutamatergic (vGluT2+). Selective lesion studies of BF ChAT+ neurons suggested that they are required for SD-induced increases in ADex and for sleep homeostasis. However, irreversible lesions may cause degenerative changes which go beyond loss of ChAT+ neurons. Thus, it is important to test the role of ChAT+ neurons using reversible stimulation or inactivation experiments. Furthermore, the need for intact ChAT+ neurons could reflect either ATPex/ADex release from ChAT+ neurons themselves and/or ChAT+ modulation of neighboring, non-cholinergic neurons. Thus, in this application we will use our novel methodology of optodialysis (Zant et al., 2016) to combine reversible, neuronal-subtype-specific optogenetic manipulations with simultaneous in vivo microdialysis to measure neurochemical changes in the presence and absence of selective antagonists for particular neurotransmitter receptors to delineate functional interactions between neuronal subtypes. Recent reports showed that optogenetic stimulation of vGluT2+ neurons excited ChAT+ neurons whereas PV+ neurons had only a weak influence on ChAT+ neurons. Furthermore, BF glutamate receptor activation enhanced acetylcholine (ACh) release in cortex and increased ADex levels in BF. These findings provide the basis for our hypothesis that local positive feedback between BF ChAT+ and vGluT2+ but not PV+ neurons leads to the ATPex/ADex increases which underlie the homeostatic sleep response.
Three specific aims (SA) are proposed towards this goal: We will examine the role of cholinergic, parvalbumin expressing GABAergic, and glutamatergic neurons in sleep homeostasis using optogenetic stimulation and inhibition (SA1) and BF increases of ATPex and ADex using optodialysis (SA2). Using in vitro electrophysiology and in vivo optodialysis, SA3 will examine the hypothesis that a local positive feedback between cholinergic and glutamatergic neurons leads to BF ATPex/ADex increases during SD. Successful completion of these studies will provide insight into the cellular and neurochemical mechanisms underlying the homeostatic sleep response. Thereby, facilitating the development of therapeutic measures to reduce the deleterious effects of sleep loss in military personnel, veterans and people with sleep disorders.

Public Health Relevance

Acute and chronic sleep deprivation is an unavoidable condition faced by soldiers that often leads to longer- term sleep problems in the post-war veteran population. Sleep problems often coincide and contribute to other health problems for active duty soldiers and veterans, complicating their return from deployment and elevating their risk for a number of serious physical and mental health ailments, including post-traumatic stress disorder (PTSD) and depression. On one hand sleep disturbances are considered as resultant core features of PTSD/depression. On the other hand sleep disturbance is a well-known risk factor that adversely affects mental health. Therefore, as proposed in this project, we believe that for therapeutic interventions, it is critical to understand all aspects of sleep biology that change in the brain in response to sleep loss. Here we investigate the homeostatic sleep mechanisms that underlie excessive sleepiness and performance decrement after periods of sleep deprivation.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001404-06
Application #
9397955
Study Section
Neurobiology R (NURR)
Project Start
2011-10-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Boston Health Care System
Department
Type
DUNS #
034432265
City
Boston
State
MA
Country
United States
Zip Code
02130
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Zant, Janneke C; Kim, Tae; Prokai, Laszlo et al. (2016) Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study. J Neurosci 36:2057-67
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Kalinchuk, Anna V; Porkka-Heiskanen, Tarja; McCarley, Robert W et al. (2015) Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis. Eur J Neurosci 41:182-95
Kim, T; Ramesh, V; Dworak, M et al. (2015) Disrupted sleep-wake regulation in type 1 equilibrative nucleoside transporter knockout mice. Neuroscience 303:211-9
Kim, Tae; Thankachan, Stephen; McKenna, James T et al. (2015) Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc Natl Acad Sci U S A 112:3535-40
Yang, Chun; McKenna, James T; Zant, Janneke C et al. (2014) Cholinergic neurons excite cortically projecting basal forebrain GABAergic neurons. J Neurosci 34:2832-44

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