Publications by authors named "Mark N Wu"

41 Publications

Personality and Insomnia Symptoms in Older Adults: The Baltimore Longitudinal Study of Aging.

Sleep 2021 Apr 1. Epub 2021 Apr 1.

Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Study Objective: To examine associations of personality dimensions and facets with insomnia symptoms in a community sample of older adults.

Methods: We studied 1,049 participants aged 60-97 years in the Baltimore Longitudinal Study of Aging. Personality was assessed by the Revised NEO Personality Inventory (NEO-PI-R), and insomnia symptom severity was measured by the Women's Health Initiative Insomnia Rating Scale (WHIIRS).

Results: Adjusting for demographic characteristics, higher neuroticism, lower conscientiousness, and lower extraversion were associated with greater insomnia symptom severity. These associations remained significant for neuroticism and conscientiousness when further adjusting for depressive symptoms and comorbidities. Higher scores on neuroticism facets Anxiety, Angry Hostility, and Depression, and lower scores on conscientiousness facets Competence, Order, and Achievement-Striving and on agreeableness facet Altruism were associated with greater insomnia symptom severity in fully adjusted models. Results were similar among cognitively normal older adults (N=966), except higher scores on extraversion facets Warmth and Assertiveness associated with lower insomnia symptom severity, and agreeableness facet Altruism was unassociated.

Conclusion: Among older adults, insomnia symptoms appear partially related to personality, with persons higher in neuroticism experiencing greater insomnia symptom severity, and those higher in conscientiousness experiencing lower insomnia symptom severity. Exploring facets of the Big Five dimensions may provide additional insight regarding the etiology and resolution of sleep disturbance, and some of these associations may differ based on cognitive status. Future studies should investigate the hypothesis that sleep impairment mediates part of the association between specific personality traits and health-related outcomes.
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http://dx.doi.org/10.1093/sleep/zsab082DOI Listing
April 2021

Astroglial Calcium Signaling Encodes Sleep Need in Drosophila.

Curr Biol 2021 Jan 12;31(1):150-162.e7. Epub 2020 Nov 12.

Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address:

Sleep is under homeostatic control, whereby increasing wakefulness generates sleep need and triggers sleep drive. However, the molecular and cellular pathways by which sleep need is encoded are poorly understood. In addition, the mechanisms underlying both how and when sleep need is transformed to sleep drive are unknown. Here, using ex vivo and in vivo imaging, we show in Drosophila that astroglial Ca signaling increases with sleep need. We demonstrate that this signaling is dependent on a specific L-type Ca channel and is necessary for homeostatic sleep rebound. Thermogenetically increasing Ca in astrocytes induces persistent sleep behavior, and we exploit this phenotype to conduct a genetic screen for genes required for the homeostatic regulation of sleep. From this large-scale screen, we identify TyrRII, a monoaminergic receptor required in astrocytes for sleep homeostasis. TyrRII levels rise following sleep deprivation in a Ca-dependent manner, promoting further increases in astrocytic Ca and resulting in a positive-feedback loop. Moreover, our findings suggest that astrocytes then transmit this sleep need to a sleep drive circuit by upregulating and releasing the interleukin-1 analog Spätzle, which then acts on Toll receptors on R5 neurons. These findings define astroglial Ca signaling mechanisms encoding sleep need and reveal dynamic properties of the sleep homeostatic control system.
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http://dx.doi.org/10.1016/j.cub.2020.10.012DOI Listing
January 2021

Characterization of mWake expression in the murine brain.

J Comp Neurol 2021 Jun 10;529(8):1954-1987. Epub 2020 Nov 10.

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

Structure-function analyses of the mammalian brain have historically relied on anatomically-based approaches. In these investigations, physical, chemical, or electrolytic lesions of anatomical structures are applied, and the resulting behavioral or physiological responses assayed. An alternative approach is to focus on the expression pattern of a molecule whose function has been characterized and then use genetic intersectional methods to optogenetically or chemogenetically manipulate distinct circuits. We previously identified WIDE AWAKE (WAKE) in Drosophila, a clock output molecule that mediates the temporal regulation of sleep onset and sleep maintenance. More recently, we have studied the mouse homolog, mWAKE/ANKFN1, and our data suggest that its basic role in the circadian regulation of arousal is conserved. Here, we perform a systematic analysis of the expression pattern of mWake mRNA, protein, and cells throughout the adult mouse brain. We find that mWAKE labels neurons in a restricted, but distributed manner, in multiple regions of the hypothalamus (including the suprachiasmatic nucleus, dorsomedial hypothalamus, and tuberomammillary nucleus region), the limbic system, sensory processing nuclei, and additional specific brainstem, subcortical, and cortical areas. Interestingly, mWAKE is also observed in non-neuronal ependymal cells. In addition, to describe the molecular identities and clustering of mWake cells, we provide detailed analyses of single cell RNA sequencing data from the hypothalamus, a region with particularly significant mWAKE expression. These findings lay the groundwork for future studies into the potential role of mWAKE cells in the rhythmic control of diverse behaviors and physiological processes.
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http://dx.doi.org/10.1002/cne.25066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009828PMC
June 2021

MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII.

J Clin Invest 2020 09;130(9):4663-4678

Division of Cardiology.

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.
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http://dx.doi.org/10.1172/JCI133181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456244PMC
September 2020

Neural circuit mechanisms encoding motivational states in Drosophila.

Curr Opin Neurobiol 2020 10 18;64:135-142. Epub 2020 Jun 18.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Animals engage in motivated behaviors, such as feeding and mating behaviors, to ensure their own survival and the survival of their species. However, the neural circuits mediating the generation and persistence of these motivational drives remain poorly understood. Here we review recent studies on the circuit mechanisms underlying motivational states in Drosophila, with a focus on feeding, courtship, and aggression. These studies shed light on the molecular and cellular mechanisms by, which key drive neurons receive relevant input signals, integrate information, and decide on a specific behavioral output. We also discuss conceptual models for integrating these circuit mechanisms, distinguishing between those for homeostatically-regulated versus non-homeostatically-regulated motivated behaviors. We suggest that the ability to trigger persistence of a motivated behavior may be a feature of integrator or apex/command neurons.
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http://dx.doi.org/10.1016/j.conb.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669672PMC
October 2020

TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca.

Nat Commun 2020 05 29;11(1):2679. Epub 2020 May 29.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4 triggers increased intracellular Ca through a Ca/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca responses, the importance of tightly regulated Ca dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41467-020-16411-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260201PMC
May 2020

Sleep: Slow Waves Quiet the Fly's Mind.

Curr Biol 2019 11;29(21):R1129-R1131

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Slow-wave sleep is a marker of sleep need, but its presence and function in non-mammalian species have been controversial. A new study finds sleep-dependent slow wave oscillations in the fruit fly, which act to inhibit sensory input during sleep.
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http://dx.doi.org/10.1016/j.cub.2019.09.010DOI Listing
November 2019

Semaphorin 2b Regulates Sleep-Circuit Formation in the Drosophila Central Brain.

Neuron 2019 10 26;104(2):322-337.e14. Epub 2019 Sep 26.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

The fan-shaped body (FB) neuropil in the Drosophila brain central complex (CX) controls a variety of adult behaviors, including navigation and sleep. How neuronal processes are organized into precise layers and columns in the FB and how alterations in FB neural-circuit wiring affect animal behaviors are unknown. We report here that secreted semaphorin 2b (Sema-2b) acts through its transmembrane receptor Plexin B (PlexB) to locally attract neural processes to specific FB laminae. Aberrant Sema-2b/PlexB signaling leads to select disruptions in neural lamination, and these disruptions result in the formation of ectopic inhibitory connections between subsets of FB neurons. These structural alternations and connectivity defects are associated with changes in fly sleep and arousal, emphasizing the importance of lamination-mediated neural wiring in a central brain region critical for normal sleep behavior.
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http://dx.doi.org/10.1016/j.neuron.2019.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227428PMC
October 2019

Sleep Duration and Cognition in a Nationally Representative Sample of U.S. Older Adults.

Am J Geriatr Psychiatry 2019 12 4;27(12):1386-1396. Epub 2019 Jul 4.

Department of Psychiatry and Behavioral Sciences (APS), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Mental Health (APS), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; Johns Hopkins University Center on Aging and Health (APS), Baltimore, MD.

Objective: Excessive and insufficient sleep have been associated with cognitive dysfunction in older adults in U.S. and non-U.S.

Studies: However, the U.S. studies were not in nationally representative samples. The authors investigated the association between sleep duration and cognitive performance in a nationally representative sample of U.S. older adults.

Participants: The authors studied 1,496 survey participants aged 60 years or older from the National Health and Nutrition Examination Survey 2013-2014 dataset.

Measurements: Our primary predictor was weekday (or workday) nighttime sleep duration, categorized as 2-4, 5, 6, 7 (reference), 8, 9, and 10 hours or more. The authors studied five cognitive outcomes: Consortium to Establish a Registry for Alzheimer's Disease Word Learning (CERAD-WL) immediate recall, CERAD-WL delayed recall, Animal Fluency Test (AFT), Digital Symbol Substitution Test (DSST), and subjective cognitive problems (SCP).

Results: After adjusting for age, sex, race, education, depressive symptoms, and sedative-hypnotic use, sleep duration of 10 hours or more was significantly associated with lower scores on CERAD-WL immediate recall, CERAD-WL delayed recall, AFT, and DSST, and greater odds of SCP; sleep duration of 8 hours or more was associated with lower CERAD-WL delayed recall scores: 8, 9, and 10 hours or more. After adjustment, there were no significant associations of shorter sleep duration with cognition.

Conclusion: In U.S. adults aged 60 years or older, long nighttime weekday or workday sleep duration is associated with poorer verbal memory, semantic fluency, working memory, and processing speed in addition to greater odds of self-reported cognitive problems. Long sleep duration may be a marker of fragmented sleep or neurodegeneration in U.S. older adults.
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http://dx.doi.org/10.1016/j.jagp.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842702PMC
December 2019

Morning and Evening Circadian Pacemakers Independently Drive Premotor Centers via a Specific Dopamine Relay.

Neuron 2019 05 10;102(4):843-857.e4. Epub 2019 Apr 10.

Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address:

Many animals exhibit morning and evening peaks of locomotor behavior. In Drosophila, two corresponding circadian neural oscillators-M (morning) cells and E (evening) cells-exhibit a corresponding morning or evening neural activity peak. Yet we know little of the neural circuitry by which distinct circadian oscillators produce specific outputs to precisely control behavioral episodes. Here, we show that ring neurons of the ellipsoid body (EB-RNs) display spontaneous morning and evening neural activity peaks in vivo: these peaks coincide with the bouts of locomotor activity and result from independent activation by M and E pacemakers. Further, M and E cells regulate EB-RNs via identified PPM3 dopaminergic neurons, which project to the EB and are normally co-active with EB-RNs. These in vivo findings establish the fundamental elements of a circadian neuronal output pathway: distinct circadian oscillators independently drive a common pre-motor center through the agency of specific dopaminergic interneurons.
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http://dx.doi.org/10.1016/j.neuron.2019.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533154PMC
May 2019

Clock-Generated Temporal Codes Determine Synaptic Plasticity to Control Sleep.

Cell 2018 11 11;175(5):1213-1227.e18. Epub 2018 Oct 11.

Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address:

Neurons use two main schemes to encode information: rate coding (frequency of firing) and temporal coding (timing or pattern of firing). While the importance of rate coding is well established, it remains controversial whether temporal codes alone are sufficient for controlling behavior. Moreover, the molecular mechanisms underlying the generation of specific temporal codes are enigmatic. Here, we show in Drosophila clock neurons that distinct temporal spike patterns, dissociated from changes in firing rate, encode time-dependent arousal and regulate sleep. From a large-scale genetic screen, we identify the molecular pathways mediating the circadian-dependent changes in ionic flux and spike morphology that rhythmically modulate spike timing. Remarkably, the daytime spiking pattern alone is sufficient to drive plasticity in downstream arousal neurons, leading to increased firing of these cells. These findings demonstrate a causal role for temporal coding in behavior and define a form of synaptic plasticity triggered solely by temporal spike patterns.
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http://dx.doi.org/10.1016/j.cell.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239908PMC
November 2018

Excessive daytime sleepiness and napping in cognitively normal adults: associations with subsequent amyloid deposition measured by PiB PET.

Sleep 2018 10;41(10)

National Institute on Aging Intramural Research Program, Baltimore, MD.

Study Objectives: To determine the association of excessive daytime sleepiness (EDS) and napping with subsequent brain β-amyloid (Aβ) deposition in cognitively normal persons.

Methods: We studied 124 community-dwelling participants in the Baltimore Longitudinal Study of Aging Neuroimaging Substudy who completed self-report measures of EDS and napping at our study baseline and underwent [11C] Pittsburgh compound B positron emission tomography (PiB PET) scans of the brain, an average ±standard deviation of 15.7 ± 3.4 years later (range 6.9 to 24.6). Scans with a cortical distribution volume ratio of >1.06 were considered Aβ-positive.

Results: Participants were aged 60.1 ± 9.8 years (range 36.2 to 82.7) at study baseline; 24.4% had EDS and 28.5% napped. In unadjusted analyses, compared with participants without EDS, those with EDS had more than 3 times the odds of being Aβ+ at follow-up (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.44, 7.90, p = 0.005), and 2.75 times the odds after adjustment for age, age2, sex, education, and body mass index (OR = 2.75, 95% CI: 1.09, 6.95, p = 0.033). There was a trend-level unadjusted association between napping and Aβ status (OR = 2.01, 95% CI: 0.90, 4.50, p = 0.091) that became nonsignificant after adjustment (OR = 1.86, 95% CI: 0.73, 4.75, p = 0.194).

Conclusions: EDS is associated with more than 2.5 times the odds of Aβ deposition an average of 15.7 years later. If common EDS causes (e.g., sleep-disordered breathing, insufficient sleep) are associated with temporally distal AD biomarkers, this could have important implications for AD prevention.
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http://dx.doi.org/10.1093/sleep/zsy152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187104PMC
October 2018

A Genetic Toolkit for Dissecting Dopamine Circuit Function in Drosophila.

Cell Rep 2018 Apr;23(2):652-665

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

The neuromodulator dopamine (DA) plays a key role in motor control, motivated behaviors, and higher-order cognitive processes. Dissecting how these DA neural networks tune the activity of local neural circuits to regulate behavior requires tools for manipulating small groups of DA neurons. To address this need, we assembled a genetic toolkit that allows for an exquisite level of control over the DA neural network in Drosophila. To further refine targeting of specific DA neurons, we also created reagents that allow for the conversion of any existing GAL4 line into Split GAL4 or GAL80 lines. We demonstrated how this toolkit can be used with recently developed computational methods to rapidly generate additional reagents for manipulating small subsets or individual DA neurons. Finally, we used the toolkit to reveal a dynamic interaction between a small subset of DA neurons and rearing conditions in a social space behavioral assay.
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http://dx.doi.org/10.1016/j.celrep.2018.03.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962273PMC
April 2018

Time for Bed: Genetic Mechanisms Mediating the Circadian Regulation of Sleep.

Trends Genet 2018 05 24;34(5):379-388. Epub 2018 Jan 24.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Sleep is an evolutionarily conserved behavior that is increasingly recognized as important for human health. While its precise function remains controversial, sleep has been suggested to play a key role in a variety of biological phenomena ranging from synaptic plasticity to metabolic clearance. Although it is clear that sleep is regulated by the circadian clock, how this occurs remains enigmatic. Here we examine the genetic mechanisms by which the circadian clock regulates sleep, drawing on recent work in fruit flies, zebrafish, mice, and humans. These studies reveal that central and local clocks utilize diverse mechanisms to regulate different aspects of sleep, and a better understanding of this multilayered regulation may lead to a better understanding of the functions of sleep.
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http://dx.doi.org/10.1016/j.tig.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910202PMC
May 2018

Sleep: Setting the 'Circadian' Alarm Clock.

Curr Biol 2018 01;28(1):R26-R28

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

How the circadian clock regulates downstream behaviors, such as sleep, remains poorly understood. A new study reveals that clock-dependent downscaling of GABA sensitivity of arousal neurons promotes wakefulness at dawn.
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http://dx.doi.org/10.1016/j.cub.2017.11.011DOI Listing
January 2018

Sleep Disturbance, Cognitive Decline, and Dementia: A Review.

Semin Neurol 2017 08 24;37(4):395-406. Epub 2017 Aug 24.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1055/s-0037-1604351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910033PMC
August 2017

The laminar organization of the ellipsoid body is semaphorin-dependent and prevents the formation of ectopic synaptic connections.

Elife 2017 06 20;6. Epub 2017 Jun 20.

The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, United States.

The ellipsoid body (EB) in the brain is a central complex (CX) substructure that harbors circumferentially laminated ring (R) neuron axons and mediates multifaceted sensory integration and motor coordination functions. However, what regulates R axon lamination and how lamination affects R neuron function remain unknown. We show here that the EB is sequentially innervated by small-field and large-field neurons and that early developing EB neurons play an important regulatory role in EB laminae formation. The transmembrane proteins semaphorin-1a (Sema-1a) and plexin A function together to regulate R axon lamination. R neurons recruit both GABA and GABA-A receptors to their axon terminals in the EB, and optogenetic stimulation coupled with electrophysiological recordings show that Sema-1a-dependent R axon lamination is required for preventing the spread of synaptic inhibition between adjacent EB lamina. These results provide direct evidence that EB lamination is critical for local pre-synaptic inhibitory circuit organization.
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http://dx.doi.org/10.7554/eLife.25328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511011PMC
June 2017

APOE Genotype and Nonrespiratory Sleep Parameters in Cognitively Intact Older Adults.

Sleep 2017 08;40(8)

Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD.

Study Objectives: The apolipoprotein E (APOE) Ɛ4 allele increases Alzheimer's disease (AD) risk and has been linked to a greater risk of sleep-disordered breathing. We investigated the association of APOE genotype with nonrespiratory sleep parameters.

Methods: We studied 1264 cognitively normal participants in the Baltimore Longitudinal Study of Aging (mean = 57.5 ± 16.1 years, range 19.9-92.0, 48.2% women, 19.8% African American) with APOE genotyping and self-reported sleep duration (≥9, 7 or 8, ≤6 hours), difficulty falling/staying asleep, and napping. We compared Ɛ4 carriers with all noncarriers and compared persons at reduced (Ɛ2/Ɛ2 or Ɛ2/Ɛ3) or elevated AD risk (≥1 Ɛ4 allele) with those neutral for AD risk (Ɛ3/Ɛ3).

Results: In fully adjusted models, those with ≥1 Ɛ4 allele had a greater odds of being in a shorter sleep duration category compared to all noncarriers (odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.06, 1.88) and Ɛ3/Ɛ3 carriers (OR = 1.43, 95% CI 1.06, 1.92). Compared to Ɛ3/Ɛ3 carriers, Ɛ2/Ɛ2 or Ɛ2/Ɛ3 carriers had a lower odds of reporting napping (OR = 0.64, 95% CI 0.43, 0.96). Among participants aged ≥50 years, sleep duration findings remained and Ɛ4 carriers had a greater odds of trouble falling/staying asleep than noncarriers (OR = 1.49, 95% CI 1.02, 2.17). We found some evidence for stronger associations of Ɛ4 with sleep duration among African Americans.

Conclusions: Self-reported sleep duration, napping, and trouble falling/staying asleep differ by APOE genotype. Studies are needed to examine whether APOE promotes AD by degrading sleep and to clarify the role of race in these associations.
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http://dx.doi.org/10.1093/sleep/zsx076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804995PMC
August 2017

Branch-specific plasticity of a bifunctional dopamine circuit encodes protein hunger.

Science 2017 05;356(6337):534-539

Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.

Free-living animals must not only regulate the amount of food they consume but also choose which types of food to ingest. The shifting of food preference driven by nutrient-specific hunger can be essential for survival, yet little is known about the underlying mechanisms. We identified a dopamine circuit that encodes protein-specific hunger in The activity of these neurons increased after substantial protein deprivation. Activation of this circuit simultaneously promoted protein intake and restricted sugar consumption, via signaling to distinct downstream neurons. Protein starvation triggered branch-specific plastic changes in these dopaminergic neurons, thus enabling sustained protein consumption. These studies reveal a crucial circuit mechanism by which animals adjust their dietary strategy to maintain protein homeostasis.
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http://dx.doi.org/10.1126/science.aal3245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513152PMC
May 2017

An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks.

Curr Biol 2017 Jan 22;27(1):128-136. Epub 2016 Dec 22.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light but resistant to temperature shifts that entrain peripheral clocks [1-5]. The SCN expresses many functionally important neuropeptides, including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks and organizes circadian behavior [5-16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17, 18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip mice under light-dark cycles and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1- and Vip-deficient mice and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1 and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions.
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http://dx.doi.org/10.1016/j.cub.2016.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269403PMC
January 2017

Sleep Drive Is Encoded by Neural Plastic Changes in a Dedicated Circuit.

Cell 2016 Jun 19;165(6):1347-1360. Epub 2016 May 19.

Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address:

Prolonged wakefulness leads to an increased pressure for sleep, but how this homeostatic drive is generated and subsequently persists is unclear. Here, from a neural circuit screen in Drosophila, we identify a subset of ellipsoid body (EB) neurons whose activation generates sleep drive. Patch-clamp analysis indicates these EB neurons are highly sensitive to sleep loss, switching from spiking to burst-firing modes. Functional imaging and translational profiling experiments reveal that elevated sleep need triggers reversible increases in cytosolic Ca(2+) levels, NMDA receptor expression, and structural markers of synaptic strength, suggesting these EB neurons undergo "sleep-need"-dependent plasticity. Strikingly, the synaptic plasticity of these EB neurons is both necessary and sufficient for generating sleep drive, indicating that sleep pressure is encoded by plastic changes within this circuit. These studies define an integrator circuit for sleep homeostasis and provide a mechanism explaining the generation and persistence of sleep drive.
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http://dx.doi.org/10.1016/j.cell.2016.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892967PMC
June 2016

Sleep Duration and Subsequent Cortical Thinning in Cognitively Normal Older Adults.

Sleep 2016 05 1;39(5):1121-8. Epub 2016 May 1.

Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD.

Study Objectives: To determine the association between self-reported sleep duration and cortical thinning among older adults.

Methods: We studied 122 cognitively normal participants in the Baltimore Longitudinal Study of Aging with a mean age = 66.6 y (range, 51-84) at baseline sleep assessment and 69.5 y (range, 56-86) at initial magnetic resonance imaging (MRI) scan. Participants reported average sleep duration and completed a mean of 7.6 1.5-T MRI scans (range, 3-11), with mean follow-up from initial scan of 8.0 y (range, 2.0-11.8).

Results: In analyses adjusted for age, sex, education, race, and interval between sleep assessment and initial MRI scan, participants reporting > 7 h sleep at baseline had thinner cortex in the inferior occipital gyrus and sulcus of the left hemisphere at initial MRI scan than those reporting 7 h (cluster P < 0.05). In adjusted longitudinal analyses, compared to those reporting 7 h of sleep, participants reporting < 7 h exhibited higher rates of subsequent thinning in the superior temporal sulcus and gyrus, inferior and middle frontal gyrus, and superior frontal sulcus of the left hemisphere, and in the superior frontal gyrus of the right hemisphere; those reporting > 7 h of sleep had higher rates of thinning in the superior frontal and middle frontal gyrus of the left hemisphere (cluster P < 0.05 for all). In sensitivity analyses, adjustment for apolipoprotein E (APOE) e4 genotype reduced or eliminated some effects but revealed others. When reports of < 7 h of sleep were compared to reports of 7 or 8 h combined, there were no significant associations with cortical thinning.

Conclusions: Among cognitively normal older adults, sleep durations of < 7 h and > 7 h may increase the rate of subsequent frontotemporal gray matter atrophy. Additional studies, including those that use objective sleep measures and investigate mechanisms linking sleep duration to gray matter loss, are needed.
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http://dx.doi.org/10.5665/sleep.5768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835311PMC
May 2016

Drosophila models of neurologic disease.

Exp Neurol 2015 Dec;274(Pt A):1-3

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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http://dx.doi.org/10.1016/j.expneurol.2015.10.004DOI Listing
December 2015

Sleep interacts with aβ to modulate intrinsic neuronal excitability.

Curr Biol 2015 Mar 5;25(6):702-712. Epub 2015 Mar 5.

Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address:

Background: Emerging data suggest an important relationship between sleep and Alzheimer's disease (AD), but how poor sleep promotes the development of AD remains unclear.

Results: Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ-induced hyperexcitability and suggest that defects in specific K(+) currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan.

Conclusions: Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD.
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http://dx.doi.org/10.1016/j.cub.2015.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366315PMC
March 2015

Objectively Measured Sleep and β-amyloid Burden in Older Adults: A Pilot Study.

SAGE Open Med 2014 Aug;2

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD.

Background/aims: Although disturbed sleep is associated with cognitive deficits, the association between sleep disturbance and Alzheimer's disease (AD) pathology is unclear. In this pilot study, we examined the extent to which sleep duration, sleep quality, and sleep-disordered breathing (SDB) are associated with β-amyloid (Aβ) deposition in the brains of living humans.

Methods: We studied 13 older adults (8 with normal cognition and 5 with mild cognitive impairment (MCI)). Participants completed neuropsychological testing, polysomnography and Aβ imaging with [C]-Pittsburgh compound B.

Results: Among participants with MCI, higher apnea-hypopnea index and oxygen desaturation index were associated with greater Aβ deposition, globally and regionally in the precuneus. There were no significant associations between SDB and Aβ deposition among cognitively normal participants. There were no significant associations between sleep duration or sleep fragmentation and Aβ deposition.

Conclusion: These preliminary results suggest that, among older adults with MCI, greater SDB severity is associated with greater Aβ deposition.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304392PMC
http://dx.doi.org/10.1177/2050312114546520DOI Listing
August 2014

Improved and expanded Q-system reagents for genetic manipulations.

Nat Methods 2015 Mar 12;12(3):219-22, 5 p following 222. Epub 2015 Jan 12.

The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The Q system is a repressible binary expression system for transgenic manipulations in living organisms. Through protein engineering and in vivo functional tests, we report here variants of the Q-system transcriptional activator, including QF2, for driving strong and ubiquitous expression in all Drosophila tissues. Our QF2, Gal4QF and LexAQF chimeric transcriptional activators substantially enrich the toolkit available for transgenic regulation in Drosophila melanogaster.
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http://dx.doi.org/10.1038/nmeth.3250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344399PMC
March 2015

Regulation of synaptic development and function by the Drosophila PDZ protein Dyschronic.

Development 2014 Dec 30;141(23):4548-57. Epub 2014 Oct 30.

Department of Neuroscience, The Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA

Synaptic scaffold proteins control the localization of ion channels and receptors, and facilitate molecular associations between signaling components that modulate synaptic transmission and plasticity. Here, we define novel roles for a recently described scaffold protein, Dsychronic (DYSC), at the Drosophila larval neuromuscular junction. DYSC is the Drosophila homolog of whirlin/DFNB31, a PDZ domain protein linked to Usher syndrome, the most common form of human deaf-blindness. We show that DYSC is expressed presynaptically and is often localized adjacent to the active zone, the site of neurotransmitter release. Loss of DYSC results in marked alterations in synaptic morphology and cytoskeletal organization. Moreover, active zones are frequently enlarged and misshapen in dysc mutants. Electrophysiological analyses further demonstrate that dysc mutants exhibit substantial increases in both evoked and spontaneous synaptic transmission. We have previously shown that DYSC binds to and regulates the expression of the Slowpoke (SLO) BK potassium channel. Consistent with this, slo mutant larvae exhibit similar alterations in synapse morphology, active zone size and neurotransmission, and simultaneous loss of dysc and slo does not enhance these phenotypes, suggesting that dysc and slo act in a common genetic pathway to modulate synaptic development and output. Our data expand our understanding of the neuronal functions of DYSC and uncover non-canonical roles for the SLO potassium channel at Drosophila synapses.
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http://dx.doi.org/10.1242/dev.109538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302934PMC
December 2014

Impact of sleep on the risk of cognitive decline and dementia.

Curr Opin Psychiatry 2014 Nov;27(6):478-83

aDepartment of Mental Health, Johns Hopkins Bloomberg School of Public Health bDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine cDepartments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland dDepartments of Psychiatry, Neurology, and Epidemiology and Biostatistics, University of California, San Francisco and San Francisco VA Medical Center, San Francisco, California, USA.

Purpose Of Review: Trouble falling or staying asleep, poor sleep quality, and short or long sleep duration are gaining attention as potential risk factors for cognitive decline and dementia, including Alzheimer's disease. Sleep-disordered breathing has also been linked to these outcomes. Here, we review recent observational and experimental studies investigating the effect of poor sleep on cognitive outcomes and Alzheimer's disease, and discuss possible mechanisms.

Recent Findings: Observational studies with self-report and objective sleep measures (e.g. wrist actigraphy, polysomnography) support links between disturbed sleep and cognitive decline. Several recently published studies demonstrate associations between sleep variables and measures of Alzheimer's disease pathology, including cerebrospinal fluid measures of Aβ and PET measures of Aβ deposition. In addition, experimental studies suggest that sleep loss alters cerebrospinal fluid Aβ dynamics, decrements in slow-wave sleep may decrease the clearance of Aβ from the brain, and hypoxemia characteristic of sleep-disordered breathing increases Aβ production.

Summary: Findings indicate that poor sleep is a risk factor for cognitive decline and Alzheimer's disease. Although mechanisms underlying these associations are not yet clear, healthy sleep appears to play an important role in maintaining brain health with age, and may play a key role in Alzheimer's disease prevention.
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http://dx.doi.org/10.1097/YCO.0000000000000106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323377PMC
November 2014

WIDE AWAKE mediates the circadian timing of sleep onset.

Neuron 2014 Apr 13;82(1):151-66. Epub 2014 Mar 13.

Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address:

How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep.
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http://dx.doi.org/10.1016/j.neuron.2014.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982794PMC
April 2014