The public health and economic impact of circadian and sleep misalignment had grown enormously with the increasingly global and 24 hour nature of our society, and costs are in the billions. In spite of this, however, we know very little about the mechanisms by which sleep and the circadian clock influence memory circuits. Memory formation is bidirectionally sensitive to sleep levels. Sleep in the temporal window following training can enhance formation of memory, while sleep deprivation has negative effects on its formation. In Drosophila, we have a very detailed understanding both of the processes that underlie memory formation and of the circadian clock and sleep circuits. In this proposal we will leverage this knowledge to understand, for the first time at a cellular level, the direct links between memory and sleep/circadian systems.
In Aim 1 we demonstrate that the fly circadian circuit and the fly memory circuits have direct anatomical connections. Further, we show that a circadian neuropeptide which has been associated with arousal is required for normal memory. We hypothesize that these connections provide the pro- arousal function of the circadian clock that helps maintain cognitive function over the course of the day. We will investigate the molecular function of the connections between these peptidergic clock cells and memory circuits and their behavioral role. Understanding connectivity of the clock and associative memory processes at this level will provide us with the ability to develop novel cognitive protection and enhancement strategies.
In Aim 2 we demonstrate that the very process that underlies formation of stable associative memory, concurrent activation of neurons that drive memory consolidation, also drives sleep. This sleep is tightly linked to the learning process and we hypothesize that it is critical for consolidation. We will define the molecular and cellular processes that cause sleep and consolidation in this circuit and investigate the role of concurrently generated sleep in behavior. Understanding this linkage will provide important insight into how manipulation of sleep can be used to enhance memory formation.

Public Health Relevance

The public health and economic impact of circadian and sleep misalignment had grown enormously with the increasingly global and 24 hour nature of our society, and costs are in the billions. In spite of this, however, we know very little about th mechanisms by which sleep and the circadian clock influence memory circuits. Understanding the nature of this gating is therefore critical to both health and safety and the design of rationa and optimal therapeutic approaches for human neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH067284-11
Application #
8654475
Study Section
Special Emphasis Panel (ZRG1-IFCN-Z (02))
Program Officer
Asanuma, Chiiko
Project Start
2002-10-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$404,271
Indirect Cost
$154,271
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Vecsey, Christopher G; Pirez, Nicolas; Griffith, Leslie C (2014) The Drosophila neuropeptides PDF and sNPF have opposing electrophysiological and molecular effects on central neurons. J Neurophysiol 111:1033-45
Griffith, Leslie C (2014) Up all night on a redeye flight. Elife 3:e02087
Chi, Michael W; Griffith, Leslie C; Vecsey, Christopher G (2014) Larval Population Density Alters Adult Sleep in Wild-Type Drosophila melanogaster but Not in Amnesiac Mutant Flies. Brain Sci 4:453-70
Shang, Yuhua; Donelson, Nathan C; Vecsey, Christopher G et al. (2013) Short neuropeptide F is a sleep-promoting inhibitory modulator. Neuron 80:171-83
Pirez, Nicolas; Christmann, Bethany L; Griffith, Leslie C (2013) Daily rhythms in locomotor circuits in Drosophila involve PDF. J Neurophysiol 110:700-8
Griffith, Leslie C (2013) Neuromodulatory control of sleep in Drosophila melanogaster: integration of competing and complementary behaviors. Curr Opin Neurobiol 23:819-23
Ni, Lina; Bronk, Peter; Chang, Elaine C et al. (2013) A gustatory receptor paralogue controls rapid warmth avoidance in Drosophila. Nature 500:580-4
Pulver, Stefan R; Hornstein, Nicholas J; Land, Bruce L et al. (2011) Optogenetics in the teaching laboratory: using channelrhodopsin-2 to study the neural basis of behavior and synaptic physiology in Drosophila. Adv Physiol Educ 35:82-91
Griffith, Leslie C (2011) Circadian biology: the supporting cast takes on a starring role. Curr Biol 21:R313-4
Shang, Yuhua; Haynes, Paula; Pirez, Nicolas et al. (2011) Imaging analysis of clock neurons reveals light buffers the wake-promoting effect of dopamine. Nat Neurosci 14:889-95

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