The Center for Psychiatric Neuroscience

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Dr. James P. Shaffery, D. Phil.

	Dr. James P. Shaffery, D. Phil. Associate Professor of Psychiatry and Human Behavior, Head of the Animal Sleep Neurophysiology Laboratory
Key Personnel: Dr. Howard P. Roffwarg, Diplomat, American Board of Sleep Medicine Professor of Psychiatry and Human Behavior Director, UMC Sleep Disorders Center and Division of Sleep Medicine Co-Head of Animal Sleep Neurophysiology Laboratory Jorge Lopez, B.S.

Current Research

Our long-term research goals are to determine the underlying mechanisms that allow rapid eye movement (REM) sleep to function in early life as one part of a genetically programmed set of CNS (central nervous system) processes that, through activity-dependent mechanisms, contributes to maturational development of the brain. This hypothesis is suggested by several characteristics of the REM sleep state: It is more highly represented in the late fetal, neonatal and early infancy periods than in the adult, particularly in species, like humans and other mammals, in which CNS development continues for a time after birth; it decreases to nearly adult levels as the period of maximal brain growth and maturation essentially ceases; and it generates intense neuronal and metabolic activation throughout widespread brain areas, not unlike that seen in the waking state. All this occurs at a phase of development when young animals spend much of their time asleep and cut off from the enabling effects sensory activation is known to have on brain development, the latter which exemplifies the principle of "activity-dependent" brain development. Normal CNS development is directed by routine sensorial experience as well as the additive and complementary activation provided by endogenous REM sleep processes. Though the function of sleep is not fully understood, in support of our REM sleep ontogenetic hypothesis, recent data strongly link REM sleep-related neural activation and CNS synaptic plasticity mechanisms. In terms of this activity-dependent model of CNS development, the REM sleep state is thought to operate synergistically with exogenous, sensory-driven sources of brain activation, so that, together they direct and potentiate normal (usual) brain development.
Increasing our understanding of the mechanisms associated with the hypothesized developmental function of REM sleep may enable prevention and treatment of certain sleep and depression pathologies (see below).

Three main lines of research occupy our efforts to elucidate the function of REMS.

1) A ROLE FOR REM SLEEP IN BRAIN MATURATION
Work on this set of experiments utilizes the developing visual system, during a postnatal critical period, as a model of CNS development, because much is known about how the visual system develops in the critical period, and this enables us to more easily detect the effects of manipulating REM sleep on subsequent development in the visual system. Our earlier data suggests that removal of REM sleep during the critical period prolongs immaturity of the central visual system, leaving it relatively more vulnerable to the effects of abnormal sensory input on the synaptic rearrangement that occurs in this phase of brain development. Our data shows that suppression of REM sleep significantly affects the size of cells found in a primary retinal input nucleus in mid-brain called the lateral geniculate nucleus (LGN). We now seek to demonstrate the direct effects of REMS-related activation on brain development using several methods to increase REMS and test whether this will reverse the previously documented alterations in lateral geniculate nucleus (LGN) cell growth caused by REMS deprivation. We are also investigating the more fundamental and enabling neurophysiological (e.g., brain excitability), neurochemical (e.g., calcium-binding proteins), and neural-signaling (e.g., neurotrophins) mechanisms that possibly mediate the developmental effects of REMS-related activation.

Related Publications
1. Hogan,D., Roffwarg,H.P., and Shaffery,J.P., The effects of 1 week of REM sleep deprivation on parvalbumin and calbindin immunoreactive neruons in central visual pathways of kittens, J. Sleep Res., 10 (2001) 285-296.

2. Shaffery,J.P., Roffwarg,H.P., Speciale,S.G., and Marks,G.A., Ponto-geniculo-occipital-wave suppression amplifies lateral geniculate nucleus cell-size changes in monocularly deprived kittens, Brain Res. Dev. Brain Res., 114 (1999) 109-119.

3. Marks,G.A., Roffwarg,H.P., and Shaffery,J.P., Neuronal activity in the lateral geniculate nucleus associated with ponto-geniculo-occipital waves lacks lamina specificity, Brain Res., 815 (1999) 21-28.

4. Shaffery,J.P., Oksenberg,A., Marks,G.A., Speciale,S.G., Mihailoff,G., and Roffwarg,H.P., REM sleep deprivation in monocularly occluded kittens reduces the size of cells in LGN monocular segment, Sleep, 21 (1998) 837-845.
5. Oksenberg,A., Shaffery,J.P., Marks,G.A., Speciale,S.G., Mihailoff,G., and Roffwarg,H.P., Rapid eye movement sleep deprivation in kittens amplifies LGN cell-size disparity induced by monocular deprivation, Brain Res. Dev. Brain Res., 97 (1996) 51-61.

6. Marks,G.A., Shaffery,J.P., Oksenberg,A., Speciale,S.G., and Roffwarg,H.P., A functional role for REM sleep in brain maturation, Behav. Brain Res., 69 (1995) 1-11.


2) REM SLEEP HAS A ROLE IN DEVELOPMENTAL SYNAPTIC PLASTICITY
Suppression of REM sleep early in life affects synaptic mechanisms and alters developmental synaptic plasticity in visual cortex. These changes can be detected by a post-mortem, in vitro measure that mirrors the recent experience history and ante-mortem state of synaptic plasticity in the living individual. This in vitro measure is a developmentally linked, long-term potentiation (LTP) that can be produced in the visual cortex of young rats. It is usually detectable only during a several-week, postnatal "critical period" of CNS maturation. Our preliminary studies show that deprivation of the REM sleep state in young rats during this late phase of development delays the decline of synaptic plasticity, leading to extension of the critical period for producing developmentally regulated LTP. Our data suggest that REM sleep-controlled activation of visual structures participates in the processes determining the duration of developmental synaptic plasticity in visual cortex. We have subsequently shown that REM sleep suppression in adult rats has no effect on this type of synaptic plasticity, confirming the essential developmental nature of our initial observations in critical period animals.
LTP is an electrophysiological model of synaptic plasticity that is thought to exemplify mechanisms which underlie learning and memory. LTP also models synaptic plasticity processes that occur during brain development. The ability to produce in vitro LTP, in the superficial layers of excised slabs of visual cortex by stimulating the sub-cortical white matter below is developmentally regulated. This is because there is a developmentally specific time-period to which this particular form of LTP is limited. Recently, however, it was shown REM sleep deprivation during the last portion of a postnatal "critical period" of visual system development is capable of extending the period when the developmental form of in vitro LTP can be produced. Our results indicate that REM sleep-related processes occurring in vivo during the REM sleep-deprivation alters the molecular and perhaps genetic makeup of neurons as well as their functional connectivity in visual cortex. These findings further support a role for REMS in brain development.

Related publications

1. Shaffery,J.P. and Roffwarg,H.P., Rapid Eye Movement Sleep (REMS) Deprivation Does Not "Rescue" a Developmentally Regulated Long-term Potentiation (LTP) in Visual Cortex of Mature Rats. Neurosci. Lett., 342 (2003) 196-200.
2. Shaffery,J.P., Sinton,C.M., Bisset,G., Roffwarg,H.P., and Marks,G.A., Rapid Eye Movement Sleep Deprivation Modifies Expression of Long-term Potentiation in Visual Cortex of Immature Rats, Neuroscience, 110 (2002) 431-443.

3) MODELING A NEW ANIMAL PARADIGM OF HUMAN DEPRESSION
Experiments using pharmacological treatments to suppress REM sleep in neonatal rats have shown that this produces behavioral symptoms in adult rats which are somewhat analogous to behavior observed in clinically depressed humans. Pharmacological experiments of this type, however, have many non-specific effects that may account for the behavioral changes. Work in this project is directed at using a non-pharmacological test of this model of human depression by using an instrumental method to suppress REM sleep in young rats. At the same time we specifically test the hypothesis that alterations in several monoaminergic neurotransmitter receptor subtypes, which are implicated in the pathogenesis of, or, adaptive response to human major depressive disorder (MDD), correlate with observable changes in adult behavior in this new rodent model of human depression. Selective suppression of REM sleep by behavioral means, without drug interventions, would confer more certainty upon conclusions regarding 1) the validity of the rodent model of MDD, 2) which neurotransmitter systems (potentially) contribute to the pathogenesis of MDD, and 3) which receptor adaptations enable the (tested) antidepressants that ameliorate depression. A unique aspect of this project is the investigation of each of these neurotransmitter systems in the same model and assessment of the correlations among them. Data from these experiments will ultimately contribute to a better understanding of the functional role of REM sleep in normal CNS development and hopefully to better treatments for patients with major depressive disorder.

Related publication

1. Shaffery, J., Hoffmann, R., and Armitage, R., The neurobiology of depression: perspectives from animal and human sleep studies, Neuroscientist., 9 (2003) 82-98.