The broad objective of this research program is to use a mouse model to understand the cellular mechanisms underlying alterations in sleep spindles in schizophrenia (Sz), a disease which is highly prevalent in the VA and which consumes ~40 % of the VA mental healthcare budget. Recent studies in Sz patients have provided consistent evidence for abnormalities in the number and intrinsic frequency of sleep spindles, a waxing and waning electroencephalographic (EEG) pattern observed during light non-REM (NREM) sleep. However, human studies are limited in their ability to decipher the underlying cellular mechanisms. Thus, here we propose to use state-of-the-art optogenetic techniques in mice to investigate the underlying neurobiology. Previous basic science work suggested that sleep spindles require the activity of GABAergic neurons in the thalamic reticular nucleus (TRN), most of which contain the calcium binding protein, parvalbumin (PV). Postmortem findings in Sz indicate reductions in the activity of cortical GABAergic neurons containing PV. Since TRN PV neurons are derived from the same developmental pathway, a plausible and so far untested hypothesis is that sleep spindle abnormalities are due to downregulation of the activity of TRN PV neurons. Recent studies in Sz patients using the hypnotic, eszopiclone, which targets the a3-subunit-containing GABAA receptors expressed by TRN neurons, ameliorates sleep & sleep spindle abnormalities and improves memory consolidation. Thus, if successful, our experiments in mice could lead to novel therapies to correct Sz spindle abnormalities based on the manipulation of the activity of TRN PV neurons and thereby improve cognition, a core impairment in Sz. Our experiments have specific predictions that shed light on the role of TRN PV neurons in the cellular mechanisms of spindles. We test the effect on TRN PV neurons and cortical EEG using optogenetic stimulation with Channelrhodopsin2 (ChR2) (gain of function for spindles and NREM sleep) and inhibition using the proton pump ArchT (loss of function for spindles and NREM sleep). Experiments in Specific Aim (SA) 1 will test if bilateral ChR2 stimulation will elici sleep spindles and increase NREM sleep, thereby also reducing auditory sensory transmission during NREM episodes. Unit recordings will show identified TRN PV neurons will fire in bursts associated with spindles. Experiments in SA 2 will test if bilateral optical inhibition of TRN PV neurons will reduce spindles and NREM sleep, modeling spindle abnormalities in Sz. Experiments in SA 3 will investigate an important and so far poorly investigated input pathway to TRN, arising in the basal forebrain. We will test if optical excitation of the basal forebrain GABA/PV input to TRN will reduce sleep spindles in vivo and inhibit TRN PV neurons in vitro, thereby testing the functional role of this anatomically documented pathway, with predicted inhibition of TRN PV neurons producing spindle reduction. In vitro experiments will test our hypothesis of mediation of effects on TRN PV neurons by GABAA receptors containing an a3-subunit, mimicking the a3-subunit effect of eszopiclone. Finally in SA 4 we will test if bilateral optogenetic manipulation of TRN PV neurons will alter memory recall in the Novel Object Recognition Task, thus mimicking the cognitive deficits seen in Sz. We predict Chr2 will improve and Arch T will impair performance.

Public Health Relevance

The broad objective of this research program is to understand the cellular mechanisms underlying alterations in sleep spindles in schizophrenia (Sz), a disease which is highly prevalent in the VA and which consumes ~40 % of the VA mental healthcare budget. Recent studies in Sz patients have provided consistent evidence for abnormalities in the number and intrinsic frequency of sleep spindles, a waxing and waning electroencephalographic (EEG) pattern, together with associated cognitive problems. However the cellular mechanisms underlying spindles are poorly understood, thereby hindering development of pharmacologic treatments. Our research will test a model of Sz abnormalities related to the downregulation of the activity of a particular type of thalamic reticular neuron found to be abnormal elsewhere in Sz, the GABA parvalbumin- containing neuron. We will also investigate a PV neuron GABA receptor likely responsible for the pharmacologic improvement of spindle and cognitive deficits in Sz to aid pharmacologic development.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001356-08
Application #
9605193
Study Section
Neurobiology R (NURR)
Project Start
2011-10-01
Project End
2019-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
8
Fiscal Year
2019
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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Yang, Chun; McKenna, James T; Brown, Ritchie E (2017) Intrinsic membrane properties and cholinergic modulation of mouse basal forebrain glutamatergic neurons in vitro. Neuroscience 352:249-261
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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
McNally, James M; McCarley, Robert W (2016) Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities. Curr Opin Psychiatry 29:202-10
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
Brown, Ritchie E; McKenna, James T (2015) Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal. Front Neurol 6:135
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
Lin, Shih-Chieh; Brown, Ritchie E; Hussain Shuler, Marshall G et al. (2015) Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition. J Neurosci 35:13896-903

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