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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.
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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.
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