5 - SLEEP DISORDERS
Immunomodulation, Neuroendocrinology and
Both the neuroendocrine
output arm and the immune stimulus arm of brain-immune communications
affect sleep. Relevant immune factors include the broad family
of immune molecules termed cytokines that include interleukins
(IL), chemokines and other immune products that allow immune
cells to communicate. Cytokines are pleiotropic, both affecting
and originating from many other cells and organs than simply
those of the immune system, and they are key communicator molecules
that affect many aspects of nervous system and neuroendocrine
system function. Resultant sleep alterations induced by cytokines
probably affect the course of and susceptibility to a variety
of diseases including infectious, inflammatory/ autoimmune and
endocrine). Reciprocal interactions between neuroendocrine and
immune factors and sleep include the following:
> Immune molecules
alter sleep architecture.
> Sleep deprivation
alters neuroendocrine and immune responses.
> Immune system
activation and neuroendocrine responses alter sleep.
> Sleep quality
probably affects the course of and susceptibility to infectious
patterns of cytokines produced depend on a combination of host
responses and specific pathogens to which the host is exposed.
Many cytokines affect sleep, each individually in different
ways (e.g. IL-1, -2, -15, -18, TNF, Interferon). Different combinations
of cytokines expressed during infection may have different overall
effects on sleep.
Genetic factors that
determine sleep patterns interact with environmental factors
to contribute to final effects on disease outcome. Genetic host
factors in interaction with environmental factors influence
the set point of neuroendocrine stress response and cytokine
production patterns that interact with cytokine patterns produced
in response to different pathogens/antigens.
Control of complex
phenotypes such as sleep is likely to have the same characteristics
as other complex phenotypes, including behavior or complex illnesses
such as inflammation/arthritis. Thus, it is likely that many
genes, each with small effect (polygenic/multigenic), regulate
different aspects of sleep. Inheritance of sleep phenotypes
could therefore be additive as in other complex phenotypes,
and hence depend not on single genes but on inherited regions
of DNA. Finally, such complex phenotypes often exhibit large
environmental variance. Thus an important area of study will
be to address and dissect gene-environment interactions and
to systematically assess the effect of environmental factors
on genetic factors in sleep phenotypes and disease outcome.
Potential environmental variables that could be examined in
the context of defined genetic backgrounds impacting on sleep
include: 1) relative effects of different neuroendocrine and
neural stress response pathways; 2) effects, pathways and mechanisms
of different pathogen and cytokine exposures; and 3) early developmental
factors (maternal-infant interactions).
In The Last 5 Years
- Progress has been
made in identifying individual and interfacing effects of different
cytokines on sleep architecture and identifying interactions
between the individual components of the hormonal stress response
system (including CRH and cortisol) and the neuronal stress
response system (including sympathetic nervous system responses).
- Progress has included
genetic linkage and segregation analysis of linkage regions
to identify molecules that affect infectious, cytokine, and
sleep interactions. In addition, knock-out animal models and
inbred strains have been used to elucidate the role of individual
immune and endocrine molecules in sleep.
- Short-term sleep
deprivation is associated with complex altered immune responses
but the influence on disease outcome is unclear. There is some
evidence that sleep loss and chronic sleep restriction may be
associated, in addition to cytokines, with other inflammatory
markers (e.g., C-reactive protein) that could impact the development
and severity of cardiovascular disease as well as daytime sleepiness
and fatigue in sleep disorders.
- Identify the effects
of interactions between the neuroendocrine and immune systems
on sleep phenotype and disease outcome in defined genetic models.
These studies should identify the molecular and cellular mechanisms
and neuroanatomical pathways of these interactions and their
effects on sleep architecture, sleep responses to cytokines,
and infectious disease outcome.
- Further define
the role of sleep, sleep deprivation and chronic sleep restriction
on host defense. Human studies are needed to determine the extent
to which sleep disturbance and sleep deprivation are related
to markers of nonspecific inflammatory responses (e.g., leukocytes,
cytokines, c-reactive protein). Studies are needed in transgenic
or knock-out animals, including linkage and segregation studies,
to identify the functional significance to infection resistance
and susceptibility of candidate genes in linkage regions or
of newly discovered cytokines, candidate neurohormones, or other
- Study the biology
of the relationships among cytokines, neuroendocrine function
and sleep, including studies of the relationships of the neuroendocrine
stress response and cytokine induction of sleep in animal models
and human studies. Analysis of gene-environment interactions
and of sleep responses to infectious agents in genetically manipulated
animal models is relevant to the question of how sleep alters
disease susceptibility and outcome. Specific pharmacological
agents (e.g. specific cytokine or neuroendocrine antagonists/agonists)
will be useful to assess the effects of specific neurotransmitters/neurohormones/interleukins/
cytokines on sleep phenotypes.
- Conduct genetic
studies to identify neuroendocrine and immune genes relevant
to sleep phenotypes. Approaches to identify potential candidate
genes of interest could include animal studies utilizing candidate
gene knock-out and transgenic animals, expression microarrays,
and linkage and segregation studies including congenics studies.
Studies in humans and animals could include sequencing of candidate
genes and phenotype characterization of subjects with candidate
gene mutations or of transgenic or knock-out animal models.
- Conduct animal
and human studies to integrate circadian biology and homeostatic
sleep regulation with cytokine biology. This approach could
include both in vitro and in vivo studies.