Laboratory of Neuroscience
Department of Psychiatry, Harvard Medical School
Director: In memoriam: Robert W. McCarley, MD
The Laboratory of Neuroscience, headed by Professor Robert McCarley, MD at the Brockton and West Roxbury Divisions of the VA Boston Healthcare System, is a multidisciplinary laboratory devoted to the understanding of brain mechanisms controlling sleep and their dysfunction in sleep disorders. It is divided into three main sections: Molecular and Biochemical, headed by Associate Professor Radhika Basheer, PhD, In Vitro Electrophysiology, headed by Associate Professor Ritchie Brown, PhD, and Physiology and Behavior, which is headed by Associate Professor Robert Strecker, PhD. These investigators work closely with four scientists at the Assistant Professor/Instructor level, James McKenna, PhD, Lichao Chen, MD, PhD, Michael Christie, PhD, and Anna Kalinchuk, PhD. Funding is provided by grants from the Veterans Administration and the National Institute of Mental Health.
The Laboratory of Neuroscience conducts preclinical basic research focusing on a number of key questions related to sleep and wakefulness:
1) How does the brain wake us up, put us to sleep and switch between different states of sleep? The reciprocal interaction theory of rapid-eye-movement sleep developed by McCarley (1975) and Hobson (1975) has been one of the most influential in our understanding of how slow-wave and rapid-eye-movement sleep alternate during the night. Dysfunction of REM sleep control occurs in several sleep disorders (e.g. narcolepsy).
2) Which brain mechanisms make us sleepy when we stay awake for prolonged periods? Much work in our laboratory in recent years suggests that build-up of adenosine during prolonged wakefulness is responsible for shutting off wake-promoting neurons in the basal forebrain resulting in sleepiness and impaired cognitive performance. Following prolonged wakefulness adenosine receptors are upregulated allowing a further inhibition by adenosine. Blockade of this mechanism by adenosine receptor antagonists such as those found in caffeinated beverages like coffee and tea is their major mode of action (Basheer et al., 2004).
3) Can we develop animal models of human sleep disorders or disruption? Recent work in our laboratory has shown that it is possible to mimic aspects of sleep disruption in rodents using automated devices to perturb sleep and using knockdown of gene expression.
4) What goes wrong in the brain in the sleep disorder narcolepsy? Recent work in several laboratories has convincingly shown that most cases of human narcolepsy are due to a deficiency in the orexin/hypocretin neurotransmitter system. We study the function of this system using in vitro electrophysiological investigation of effects of orexins on brainstem neurons controlling REM sleep and by knockdown of orexin effects using RNA interference. Loss of orexin control of REM sleep and muscle tone results in the symptoms of cataplexy and sleep paralysis seen in narcoleptic patients.
5) What molecular, cellular and neurobehavioral changes are associated with sleep loss/disruption? Our lab examines the effect of sleep deprivation or sleep fragmentation at multiple levels, including genomic and proteomic alterations, neurotransmission changes and neurocognitive consequences.
Section A. Molecular and Biochemical Section
The Molecular and Biochemical section of the Laboratory of Neuroscience is located at the West Roxbury Campus of Boston VA Healthcare System. It is headed by Dr. Radhika Basheer, a molecular biologist by training. The broad objective of her research is to investigate mechanisms involved in the regulation of sleep-wake behavior and sleep homeostasis using the molecular and biochemical methods. The studies involve examining cellular and molecular changes in intracellular signaling pathways, gene expression and proteomics in discreet brain regions that are associated with sleep-wake behavior.
Sleep-wake regulation is a very fundamental process yet least understood at the molecular level. The brain regions and the neurotransmitter systems that are associated with sleep-wake regulation are the subjects of investigation both at cellular and molecular level. Dr Basheer’s lab utilizes multiple techniques such as gene expression studies by RT-PCR and microarrays, manipulation of gene expression using selective pharmacological agents or RNAi, proteomic studies using 1 and 2 dimensional gel electrophoresis and Mass Spectrometry, immunohistochemistry and intracellular imaging, biochemical assays for enzyme activity. These in vitro techniques are combined with in vivo microdialysis/HPLC and sleep recordings to monitor the behavioral states. Three approaches to investigate sleep has been utilized in the studies that include collaborative projects: (i) Effects of Gene manipulations on behavior states (ii) Effect of short term total sleep deprivation (<24h), and (iii) Effect of chronic sleep deprivation (5 days).
Ongoing Projects in the Molecular and Biochemical Section
1) Total sleep deprivation-induced changes in the adenosinergic system in basal forebrain. The work in the last decade, focused on elucidating mechanisms involved in mediating the somnogenic effects of the inhibitory neuromodulator and a well-known metabolic byproduct, adenosine in the wake active area of basal forebrain. The studies performed in rats demonstrated that extracellular adenosine levels increase during sleep deprivation in basal forebrain, as had previously been reported in cats (Porkka-Heiskanen et al., 1997; Basheer et al., 1999). Recent work demonstrated that in basal forebrain, adenosine, acting via the A1 adenosine receptor, activates a signal transduction pathway resulting in increased intracellular calcium that leads to activation of the transcription factor NF-kB in basal forebrain cholinergic neurons (Basheer et al., 2002; Ramesh et al., 2007) (Figure 1, Figure 2). This may ultimately lead to transcription of genes that play a role in the longer-term effects of sleep deprivation (Basheer et al., 2004) (Figure 3). For example, further work from this laboratory has demonstrated that activation of the NF-kB pathway upregulates the levels of adenosine A1 receptor in basal forebrain following 12 and 24 hours of sleep deprivation, consequently increasing the sensitivity of wake-active neurons to the inhibitory effects of adenosine. These studies are supported by a Veterans Administration Merit grant (PI: Radhika Basheer) and NIMH grant (PI: Robert McCarley).
2) Sleep deprivation-induced Nitric Oxide release in basal forebrain and cortex. Dr Basheer’s recent research performed with Dr Anna Kalinchuk includes examining the role of another neuromodulator, nitric oxide, in sleep deprivation-induced increase in extracellular adenosine. Dr Kalinchuk, during her post-doctoral work in the University of Helsinki, has demonstrated that sleep deprivation-induced increase in adenosine in basal forebrain is dependent on an initial increase in nitric oxide which is produced by the inducible nitric oxide synthase in basal forebrain (Kalinchuck et al., 2006;Kalinchuck et al., 2006). An extension of this study is in progress in our laboratory to identify the cellular source of nitric oxide in basal forebrain and in cortical regions following different durations of sleep deprivation.
3) Total sleep deprivation induced genomic and proteomic changes. The advent of microarray and proteomic technology has enhanced the feasibility of screening may genes and proteins in one study. The current project has used these methods to examine changes in the expression of several genes following total sleep deprivation. The characterization is ongoing. Proteomic studies have identified several cytoskeletal and synaptic proteins that change following sleep deprivation indicating dynamic neuronal plasticity during sleep deprivation (Basheer et al., 2005). This project is supported by a Veterans Administration Merit grant (PI: Radhika Basheer).
4) Orexinergic control of Sleep-Wake behavior. The peptide Orexin also known as Hypocretin is synthesized exclusively in a subset of neurons in the perifornical area of posterior hypothalamus and has been shown to be involved in waking. Its deficiency results in a sleep disorder, narcolepsy. In a project funded by the Veterans Administration (PI: Robert McCarley) Dr Lichao Chen is investigating the effects of transiently knocking down the orexin peptide or orexin receptors using RNAi on sleep wake behavior (Chen et al., 2006).
5) Effects of Chronic sleep deprivation on adenosinergic system in basal forebrain and cortex. In collaboration with Dr Robert Strecker and Dr Youngsoo Kim we have begun to examine changes in the A1 receptor mRNA and protein following chronic sleep deprivation. These are the extension of our studies with total sleep deprivation showing an upregulation of A1 receptor in basal forebrain and specific cortical areas suggesting a role of A1 receptor in homeostatic sleep regulation. This work is supported by the Veterans Administration Merit grant (PI: Robert Strecker).
Section B. In Vitro Electrophysiology Section
The In Vitro Electrophysiology Section of the Laboratory of Neuroscience is located at the Brockton Campus of the Boston VA Healthcare System. It is headed by Ritchie E. Brown. The main focus of this investigator´s research program has been to characterize the electrical properties of neurons involved in the control of the sleep-wake cycle and their regulation by neurotransmitters/neuromodulators.
Figure 1: Whole-cell patch-clamp recording from a brainstem neuron in a brain slice maintained in vitro. The recording electrode is visible on the left side.
The changes in brain physiology which occur over the course of the sleep-wake cycle are controlled by a small number of neurotransmitter systems located in the basal forebrain, hypothalamus and brainstem. These neurotransmitter systems precisely regulate each other as well as the function of the rest of the brain through diffuse and widespread projections. In our laboratory, recordings are made directly from neurons involved in behavioral state control using the whole-cell patch-clamp technique in brain slices containing the region of interest (Figure 1). In vitro techniques allow a precise determination of the effects of exogenously applied neurotransmitters on the membrane potential, ionic currents and firing of the neurons. Furthermore, the receptors, signal transduction mechanisms and effector systems involved can be elucidated. Anatomical/Genetic techniques can be used in concert with intracellular recording to determine the neurotransmitter identity, projections and morphology of the recorded cells.
Ongoing Projects in the In Vitro Electrophysiology Section:
1) Characterization of GABAergic neurons important in sleep-wake control. GABA is the major inhibitory neurotransmitter in the brain. Different subpopulations of GABA neurons play
Figure 2: The green fluorescent brain of a GAD67-GFP knock-in mouse (as seen from above).
a crucial role in the control of wakefulness, slow wave and rapid-eye-movement sleep. Furthermore, GABA receptors are the major target of many tranquilizer, anaesthetic and sedative drugs.
In our recent work we have investigated and characterized a novel tool for investigation of GABAergic neurons, the GAD67-GFP knock-in mouse. In these mice a fluorescent jellyfish protein (green fluorescent protein; GFP) is expressed selectively in neurons which release the neurotransmitter gamma-aminobutyric acid (GABA). Thus, we are able to selectively target and record from identified GABAergic neurons in the brainstem and basal forebrain involved in sleep cycle control for the first time. This allows us to determine their intrinsic electrical properties and their responses to neurotransmitters involved in behavioral state control such as the orexins (see next section).
2) Orexinergic control of muscle tone and rapid-eye-movement sleep. The Orexin/Hypocretin system has been recently described in the perifornical area of the lateral/posterior hypothalamus and has generated great interest due to its involvement in the pathogenesis of the disease, narcolepsy. Experimental animals lacking orexins or the type II
Figure 3: GABAergic neurons (green) surrounding serotonin neurons (red) in the dorsal raphe nucleus of the brainstem.
orexin receptor have phenotypes resembling human narcolepsy, with fragmentation of the sleep-wake cycle and periods of behavioral arrest or cataplexy following emotional arousal. Orexins were undetectable in the CSF of many human patients and examination of postmortem narcoleptic brains has provided evidence for degeneration of the orexin neurons. We are currently examining the effects of orexins on brainstem GABA neurons involved in behavioral state control in order to understand how the symptoms of narcolepsy, in particular cataplexy and sleep paralysis, may be generated. This should lead to improved therapies for this disabling disease which has a prevalence of 1 in 2000 individuals. Anatomical tracing techniques in these mice (performed by James T. McKenna) aid our understanding of the brainstem circuitry controlling REM muscle atonia. This work complements work by Lichao Chen who is investigating the consequences of transient, reversible inactivation of the orexin system using the RNAi technique. This work is supported by a Veterans Administration Merit grant (PI Robert McCarley).
3) Electrophysiology of homeostatic sleep regulation. Previous work from this laboratory (see Strecker and Basheer sections) has shown that the neuromodulator adenosine rises in the basal forebrain in association with prolonged wakefulness. Currently, we are focusing on characterizing for the first time the properties of wake promoting GABAergic neurons and testing whether they are inhibited by adenosine. Thus, inhibition of wake-promoting neurons in this area could represent a mechanism underlying sleep homeostasis i.e. why we become more sleepy when we stay awake longer.
4) Ascending mechanisms controlling cortical activation. This project involves characterization of the ascending pathways from the brainstem which control the generation of neuronal oscillations (theta rhythms) associated with wakefulness and REM sleep. Damage to these brainstem pathways in humans results in reversible unconsciousness, vegetative state or coma, states which currently have few therapeutic possibilities.
5) Cellular deficits associated with sleep loss/disruption. Together with Dr. Robert Strecker, we have begun to investigate some of the cellular mechanisms which may underlie the cognitive deficits associated with sleep loss or sleep disruption (as observed in many sleep disorders). In our recent work we found that experimentally induced sleep fragmentation (mimicking that seen in sleep apnea) results in an abolition of hippocampal long-term potentiation, a synaptic phenomenon thought to be crucial for learning and memory formation.
Section C. Physiology and Behavior Section
The Physiology and Behavior Section of the Laboratory of Neuroscience at Harvard Medical School is located at the Brockton Campus of the Boston VA Healthcare System. It is headed by Dr. Robert E. Strecker. This section’s research is focused on investigating the neurophysiological and behavioral changes produced by sleep disruption and by sleep disorders using rodents to model human conditions.
Sleep, an essential part of human life, is needed for optimal health and performance. Sleep disturbance caused by disease (e.g., narcolepsy, sleep apnea) and vocational demands (e.g., shift work, doctors, and emergency/military workers) contributes to decreases in work/school efficiency, and sleepiness is now recognized as a major contributor to accident rates. The two main regulators of wakefulness and sleep are circadian influences and the homeostatic process associated with the duration of prior wakefulness. The circadian process directs the timing of sleep and wakefulness, whereas the homeostatic process regulates the amount of sleep based on the amount of prior wakefulness. Increases in the homeostatic sleep drive are associated with sleepiness, diminished alertness & neurobehavioral function. This diminished function is increasingly being recognized as a major public health and safety issue, and important in diseases such as obstructive sleep apnea (Durmer & Dinges, 2005). The Physiology and Behavior Section investigates the neural substrates of the homeostatic sleep drive, and the behavioral consequences of sleep loss/disruption using rodent models.
Ongoing Projects in the Physiology and Behavior Section:
1) Adenosine: a neurochemical sleep factor thought to mediate the sleepiness associated with prolonged wakefulness. A population of cortically projecting basal forebrain (BF) neurons has long been associated with cortical activation, wakefulness/arousal, and attention/vigilance (refs). Although the cholinergic population of these BF neurons has been the most widely studied, at least two other populations of BF neurons (i.e., GABAergic, and putatively glutamatergic neurons) also play a role in this cortical activation. An inhibition of these BF neurons leads to reduced arousal and vigilance; hence, recent work has attempted to identify the biological processes that inhibit the BF neurons during periods of sleepiness and reduced vigilance. Adenosine, an inhibitory neuromodulator and putative sleep factor, has emerged as a leading neurochemical candidate mediating the inhibition of these wakefulness/vigilance promoting BF neurons.
Adenosine, a byproduct of energy metabolism (adenosine is the “A” in ATP), has been shown to accumulate in the BF and cortex (but not other subcortical regions) during periods of prolonged wakefulness (i.e., when energy demands are high), and to decline during periods of sleep (see Figure 1). Caffeine and theophylline are potent adenosine receptor antagonists, explaining the potent stimulant effects of coffee and tea. As predicted, the application of an adenosine antagonist directly into the BF increases wakefulness, whereas increasing BF adenosine levels via drug application directly into the BF reduces wakefulness. These, and additional findings, support the hypothesis that an elevation of adenosine in the BF is a neurochemical correlate of the sleepiness associated with prolonged wakefulness, and, as such, adenosine may be the mediator of the homeostatic sleep drive. More recent studies by the laboratory have investigated the role of BF adenosine in the excessive daytime sleepiness associated with obstructive sleep apnea and in the cognitive impairments associated with sleep disruption.
2) The neurobiological and behavioral consequences of obstructive sleep apnea using a rat model. Despite an understanding of the causes of obstructive sleep apnea and the availability of treatment options, the investigation of the consequences/symptoms of sleep apnea remains important because up to 85% of patients with sleep apnea are undiagnosed, spending many years with the disorder. In addition, therapy (e.g., CPAP) does not fully resolve the symptoms in many patients. Thus, the consequences of chronic sleep apnea are an important public health concern that has been little investigated, due, in part, to the relative lack of animal models of obstructive sleep apnea. Indeed, the recent finding that intermittent hypoxia, by itself, produces cell death in brain regions associated with cognition (e.g., the hippocampus) underscores the importance of studying the consequences of sleep apnea.
The primary characteristics of sleep apnea are intermittent hypoxia and sleep fragmentation, and are thought to produce symptoms/signs associated with sleep apnea, including excessive daytime sleepiness and various cognitive/attentional impairments. However, it has remained unknown which symptoms/signs of sleep apnea are attributable to sleep fragmentation, and which to intermittent hypoxia, because these characteristics are difficult to separate in humans. The overarching hypothesis guiding the research is that the inhibitory neuromodulator adenosine mediates the sleepiness associated with sleep apnea, whereas the intermittent hypoxia leads to cell death (apoptosis) in brain structures important for learning and memory (e.g., hippocampus and cortex) which, in turn, contributes to the cognitive impairments associated with sleep apnea. The laboratory’s work had previously shown that adenosine, acting via A1 receptors, can inhibit the cortically projecting arousal system found in the BF region to produce the sleepiness associated with short periods of total sleep deprivation. Hence, we predicted (and found) that the sleep fragmentation of sleep apnea would also lead to an elevation of adenosine in the BF.
McKenna et al. (2007) recently described findings supporting the hypothesis that sleep fragmentation is responsible for the excessive daytime sleepiness characteristic of sleep apnea. In his study, rats exposed to experimental sleep fragmentation continued to have almost normal amounts of NREM sleep time over a 24h period (although sleep was severely fragmented). Nonetheless, the following three lines of evidence supported the conclusion that 24h of sleep fragmentation elevated sleepiness in rats: 1) Behavioral measures of sleepiness (e.g., sleep onset latencies were reduced), 2) Electrophysiological measures of sleepiness (e.g., increased NREM delta power and NREM episode duration following 24h of sleep fragmentation), and, 3) Sleep fragmentation-induced elevations of BF adenosine levels closely resembled elevations produced by total sleep deprivation. The combined findings are consistent with the following model: similar to total sleep deprivation, sleep fragmentation leads to an increase of adenosine in the BF which inhibits the activity of wake-promoting BF neurons, leading to decreased cortical activation and a subsequent increase in sleepiness.
3) The neurocognitive consequences of sleep fragmentation in rats. Sleep fragmentation is a common symptom in several clinical disorders including restless leg syndrome depression, posttraumatic stress disorder, narcolepsy, in addition to obstructive sleep apnea. Sleep fragmentation interferes with the architecture of normal sleep, reduces deep sleep, and impairs the restorative/cognitive benefits of sleep via, as yet, unidentified alterations in neural processing. Excessive daytime sleepiness induced by experimental sleep fragmentation in normal humans has been shown to result in significant cognitive impairments, even though total sleep time may not be greatly diminished. In our work, the cognitive impairments produced by sleep fragmentation/disruption are compared to the physiological/biochemical measures in order to understand the neurobiological mechanisms producing the behavioral deficits.
Tartar et al. (2006) demonstrated that 24h of experimental sleep fragmentation in rats impaired spatial learning and memory using a water maze (Fig. 2). This impairment correlated with an absence of hippocampal synaptic plasticity, which is necessary for spatial memory formation (i.e., LTP, long term potentiation was abolished by sleep fragmentation). Two other recent papers demonstrate that sleep disruption in rats produces cognitive impairments that resemble those described in human studies. (Cordova et al., 2006, Fig. 3). McCoy et al. (2007) (Fig. 4) found that rats exposed to 24 h of sleep fragmentation were impaired in attentional set shifting, as shown by their an impaired ability to learn new rules in a behavioral test designed to assess executive function. These findings have broad implications for future work investigating the neural mechanisms underlying the neurocognitive impairments associated with sleep disruption and sleep disorders.
The laboratory has recently begun to study a rat model of chronic sleep restriction. On average, humans need 7 to 9 h of sleep per day to produce optimal rest, health, and daytime performance. However, in our society, many people reduce their sleep due to vocational or other non-medical reasons, a pattern that is called chronic sleep restriction in the experimental literature. Recent experiments reveal that reducing sleep for as little as 2 or 3 h/night for several consecutive days can impair cardiovascular, immune, and endocrine functions, as well as cognitive function and daytime vigilance in man. Indeed, chronic sleep restriction contributes to accident rates and decreases in work/school efficiency. The neurobiological consequences of chronic sleep restriction have been little investigated, due, in part, to the relative lack of animal models of chronic sleep restriction. The laboratory recently established a rat model of chronic sleep restriction, and ongoing research investigates the neurobiological changes that underlie the behavioral and physiological consequences of chronic sleep restriction.
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