During wakefulness, the cortical electroencephalogram (EEG) is characterized by low voltage, high-frequency rhythms reflecting active brain processing. In particular, gamma band oscillations (GBO;30-80 Hz or broader, centered on 40 Hz) have been hypothesized to be important in cognition through synchronization of neural assemblies and by providing a temporal framework for spike time-dependent synaptic plasticity. Work from the clinical section of our laboratory and from others has demonstrated GBO abnormalities in prefrontal and primary auditory cortices in schizophrenic patients. Furthermore, GBO deficits are a prominent feature of autism, sleep disorders, coma, and Alzheimers disease. However, relatively little is known about the subcortical control of GBO. Basic science work during previous funding cycles of this grant has focused on one important subcortical region, the basal forebrain (BF), and its control of wakefulness, cortical activation and sleep homeostasis. In particular, we recently found that selective optogenetic stimulation of a particular cell type, BF cortically-projecting, parvalbumin (PV) neurons entrained cortical GBO whereas inhibition impaired GBO and cognition. Thus, the overarching hypothesis to be tested is that BF PV cortically-projecting neurons enhance cortical GBO and cognition, an investigation topic that we see as novel. In this revised application for 4 years of support, each of the specific aims (SA) testing the overarching hypothesis in mice is buttressed by extensive new Preliminary Data. SA1 directly tests the hypothesized role of BF PV neurons in cortical GBO by optogenetic excitation (Channelrhodopsin) and inhibition (ArchT) experiments. SA1 also uses optogenetic excitation combined with unit recording to identify BF PV neurons and their firing patterns in relation to the cortical GBO and behavioral state. We will also determine the spatial topography of cortical activation produced by BF PV excitation using novel high-density EEG recordings. SA2 investigates a molecular mechanism which may enhance cortical GBO during wakefulness, namely, an activity-dependent upregulation of connexin36 proteins which mediate electrical coupling between PV neurons. SA3 will determine the relationship between GBO and behavior by using a simple behavioral task requiring attention, the novel object recognition task. We will determine the effect of sleep deprivation (SD) on GBO and behavior and also test if the inhibition of BF PV neurons will impair cortical GBO and behavioral performance, thus mimicking the effects of SD. The experiments here will use integrated state-of-the-art in vitro, in vivo and behavioral methods to provide optimal understanding of the molecular, cellular and brain connectivity underlying cortical GBO and their implications for behavior, and thereby lay the groundwork for treatments of disorders involving impaired GBO such as schizophrenia and sleep disorders.

Public Health Relevance

This research will help us understand the role of subcortical regions in control of brain oscillations (rhythmic activity);the high frequency oscillations, termd gamma band oscillations, are important for coherence of thought and perception. These oscillations are abnormal in mental disorders, including schizophrenia, where gamma abnormalities have been found to be associated with disordered thinking and hallucinations. By understanding the mechanisms by which cortical gamma band oscillations are controlled by a particular brain cell type, this research will point the way for targeted correction of their abnormalities in mental disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01MH039683-29A1
Application #
8757889
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Shukla, Charu; Basheer, Radhika (2016) Metabolic signals in sleep regulation: recent insights. Nat Sci Sleep 8:9-20
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
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, Youngsoo; Elmenhorst, David; Weisshaupt, Angela et al. (2015) Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain. J Sleep Res 24:549-58
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
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, T; Ramesh, V; Dworak, M et al. (2015) Disrupted sleep-wake regulation in type 1 equilibrative nucleoside transporter knockout mice. Neuroscience 303:211-9
Zielinski, Mark R; Kim, Youngsoo; Karpova, Svetlana A et al. (2014) Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression. Neurosci Lett 580:27-31

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