EDITORIAL
published: 13 March 2014
doi: 10.3389/fnint.2014.00026
INTEGRATIVE NEUROSCIENCE
Beyond the borders: the gates and fences of neuroimmune
interaction
Javier Velázquez-Moctezuma , Emilio Domínguez-Salazar and Beatriz Gómez-González *
Area of Neurosciences, Biology of Reproduction Department, CBS, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Mexico City, Mexico
*Correspondence: [email protected]
Edited by:
Sidney A. Simon, Duke University, USA
Keywords: neuroimmunomodulation, neuroimmunology, neuroendocrinology, brain barriers, neuroimmunoendocrinology
Historically, in most organisms the nervous, immune, and the
endocrine systems have been studied as independent components. However, during the last decades, growing evidence supports the notion that these are three parts of a unique system,
the neuro-immune-endocrine system (Besedosky and Rey, 2007).
Both clinical observations and experimental data obtained from
animals reveal a close relationship among the three components
of the system. This is the theme of this Research Topic.
The literature contains a large number of reports concerning the relationship between two of the three components:
neuro-immune, neuro-endocrine, and immune-endocrine. More
recently, the third component of the triad has been added to
the study of stress (Baumann and Turpin, 2010) and depression
(Hernández et al., 2013). A similar situation has been reported for
neuro-immune mechanisms in which an endocrine component is
now disclosed, e.g., irritable bowel syndrome (Stasi et al., 2012).
Thus, if we consider that the neuro-immune-endocrine system
is just one complex regulatory system, then the understanding
of the interactions among the three systems can lead us to analyze many pathological states, which have usually been studied as
a single disequilibrium of one of these three components, such
as rheumathoid arthritis (del Rey et al., 2010), and depression
(Hernández et al., 2013).
As part of their independent study, the three systems were
characterized as having highly specialized signaling molecules
that constituted a fence against mutual interaction; neurotransmitters were described for neural communication, hormones
for endocrine communication and cytokines and chemokines
for immune signaling. However, as the characterization of both
the signaling molecules and the receptor systems progressed,
the fences transformed into gates for direct neuro-immuneendocrine communication; receptors for neural derived signals
were found in both the endocrine and immune systems. Cytokine
production was described inside the central nervous system and
the hormones were shown to signal both the neural and immune
cells. The only fences left were the barriers precluding direct
contact between the cellular and molecular components of the
three systems, particularly the brain barriers. Those barriers were
shown to have localized fences that allowed selective interaction among the cellular and molecular components of the three
systems in a highly regulated manner.
This Research Topic includes original reports, reviews and
minireviews regarding the description of the gates and fences in
neuro-immune-endocrine interactions. It contains four sections;
in the first section three papers describe the gates and fences for
Frontiers in Integrative Neuroscience
neuroimmune interactions directly at the central nervous system. Stolp et al. (2013) describe the changes in neuro-immune
interactions through the brain barriers during early development
and ageing. Hurtado-Alvarado et al. (2013) present evidence on
the role of pericytes, a blood-brain barrier cellular component,
in the regulation of the immune response in the brain under
both physiological and pathological conditions. Chavarría and
Cárdenas (2013) review the influence of neurons and glial cells
on the immune response once immune cells have trespassed
the brain barriers, molecules promoting an immuno-modulatory
environment in the brain are described.
The second section includes two reviews emphasizing the
role of hormones on neuro-immune interactions. Quintanar and
Guzmán-Soto (2013) describe the role of hypothalamic neurohormones in peripheral immune responses, including the clinical
relevance of those hormones. Monasterio et al. (2013) discuss the
participation of prolactin and progesterone in the regulation of
immune responses in the central nervous system of pregnant and
lactating females.
The third section contains three papers that describe interactions between the brain and gut. Montiel-Castro et al. (2013)
describe the role of the immune system in the cross-talk between
the gut microbiota and the brain, focusing in the description of the regulatory effects of microbiota on brain physiology
and behavior. Campos-Rodríguez et al. (2013) present evidence
regarding the role of stress hormones on the intestinal immune
response, both at the cellular and molecular levels. Garzoni et al.
(2013) review the neuro-immune mechanisms mediating the
development of antenatal intestinal inflammatory response, with
special emphasis on the role of the cholinergic anti-inflammatory
pathway in the generation of necrotizing enterocolitis.
Finally, the fourth section includes two papers discussing the
alteration in neuro-immuno-endocrine interactions in disease.
The paper by Meraz-Ríos et al. (2013) discusses the role of inflammatory signals in the exacerbation of the hallmark pathophysiological changes in Alzheimer’s disease. In addition, they also
discuss the outcomes of the use of anti-inflammatory drugs and
immunotherapy to prevent and/or reduce neuroinflammation in
patients suffering Alzheimer’s disease. Finally, León-Cabrera et al.
(2013) describe the relationship among leptin levels, inflammatory mediators and metabolic changes in the Mexican population,
aiming to establish a profile of neuro-immune-endocrine factors
ensuing the generation of metabolic syndrome.
All the papers included in this volume are just a sample of the
large amount of research that should be done in the forward years
www.frontiersin.org
March 2014 | Volume 8 | Article 26 | 1
Hindawi Publishing Corporation
Clinical and Developmental Immunology
Volume 2013, Article ID 801341, 14 pages
http://dx.doi.org/10.1155/2013/801341
Review Article
Sleep Loss as a Factor to Induce Cellular and Molecular
Inflammatory Variations
Gabriela Hurtado-Alvarado,1 Lenin Pavón,2 Stephanie Ariadne Castillo-García,1
María Eugenia Hernández,2 Emilio Domínguez-Salazar,1
Javier Velázquez-Moctezuma,1 and Beatriz Gómez-González1
1
Area of Neurosciences, Department of Biology of Reproduction, CBS, Universidad Autónoma Metropolitana,
Unidad Iztapalapa, Avenida San Rafael Atlixco No. 186, Colonia Vicentina, Iztapalapa, 09340 Mexico City, Mexico
2
Department of Psychoimmunology, National Institute of Psychiatry, “Ramón de la Fuente”, Calzada México-Xochimilco 101,
Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, DF, Mexico
Correspondence should be addressed to Beatriz Gómez-González; [email protected]
Received 26 July 2013; Revised 19 October 2013; Accepted 21 October 2013
Academic Editor: Marco Antonio Velasco-Velázquez
Copyright © 2013 Gabriela Hurtado-Alvarado et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical and experimental studies in
humans and animal models have shown that immune function is impaired when sleep loss is experienced. Sleep loss exerts a strong
regulatory influence on peripheral levels of inflammatory mediators of the immune response. An increasing number of research
projects support the existence of reciprocal regulation between sleep and low-intensity inflammatory response. Recent studies show
that sleep deficient humans and rodents exhibit a proinflammatory component; therefore, sleep loss is considered as a risk factor for
developing cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer’s disease, and multiple sclerosis).
Circulating levels of proinflammatory mediators depend on the intensity and duration of the method employed to induce sleep
loss. Recognizing the fact that the concentration of proinflammatory mediators is different between acute and chronic sleep-loss
may expand the understanding of the relationship between sleep and the immune response. The aim of this review is to integrate
data from recent published reports (2002–2013) on the effects of sleep loss on the immune response. This review may allow readers
to have an integrated view of the mechanisms involved in central and peripheral deficits induced by sleep loss.
1. Introduction
Sleep is a vital phenomenon, classically divided into two
distinct phases: sleep with rapid eye movements (REM)
and sleep without rapid eye movements (non-REM) [1]. In
humans, three stages of non-REM sleep have been characterized by electroencephalography (EEG); these include lowfrequency slow wave sleep (SWS) with EEG synchronization,
light sleep, and an intermediate sleep stage 2. In contrast,
REM sleep is characterized by EEG activity similar to that of
waking and by the loss of muscle tone [2, 3]. Both phases,
REM sleep and non-REM sleep, alternate throughout total
sleep time [2, 3]. REM sleep is amply studied because it is
considered important for learning, memory consolidation,
neurogenesis, and regulation of the blood-brain barrier
function [4–8], while non-REM sleep is related to hormonal
release (e.g., growth hormone secretion), the decline in the
thermal set point, and is characterized by a reduction of cardiovascular parameters (e.g., lowering of blood pressure) [9,
10]. Although sleep constitutes a considerable portion of the
mammalian lifetime [2], specific sleep function still remains
controversial. Many hypotheses have been proposed, including tissue repair, thermoregulation, homeostatic restoration,
memory consolidation processes, and preservation of neuroimmune-endocrine integrity [10, 11].
The paramount role of sleep in the physiology of animal
models and humans is evident by the effects of sleep loss.
Serious physiological consequences of sleep loss include
REVIEW ARTICLE
published: 10 January 2014
doi: 10.3389/fnint.2013.00080
Pericytes: brain-immune interface modulators
Gabriela Hurtado-Alvarado, Adrian M. Cabañas-Morales and Beatriz Gómez-Gónzalez*
Area of Neurosciences, Department of Biology of Reproduction, Unidad Iztapalapa, Universidad Autónoma Metropolitana, Mexico City, Mexico
Edited by:
Sidney A. Simon, Duke University,
USA
Reviewed by:
Patrizia Casaccia, University of
Medicine and Dentistry, USA
Antonio Pereira, Federal University of
Rio Grande do Norte, Brazil
*Correspondence:
Beatriz Gómez-Gónzalez, Area of
Neurosciences, Department Biology
of Reproduction, Unidad Iztapalapa,
Universidad Autónoma Metropolitana,
Avenida San Rafael Atlixco No. 186,
Colonia Vicentina, Iztapalapa, Mexico
City 09340, Mexico
e-mail: [email protected];
[email protected]
The premise that the central nervous system is immune-privileged arose from the fact that
direct contact between immune and nervous cells is hindered by the blood–brain barrier.
However, the blood–brain barrier also comprises the interface between the immune and
nervous systems by secreting chemo-attractant molecules and by modulating immune
cell entry into the brain. The majority of published studies on the blood–brain barrier
focus on endothelial cells (ECs), which are a critical component, but not the only one;
other cellular components include astroglia, microglia, and pericytes. Pericytes are poorly
studied in comparison with astrocytes or ECs; they are mesenchymal cells that can modify
their ultrastructure and gene expression in response to changes in the central nervous
system microenvironment. Pericytes have a unique synergistic relationship with brain ECs
in the regulation of capillary permeability through secretion of cytokines, chemokines,
nitric oxide, matrix metalloproteinases, and by means of capillary contraction. Those
pericyte manifestations are related to changes in blood–brain barrier permeability by an
increase in endocytosis-mediated transport and by tight junction disruption. In addition,
recent reports demonstrate that pericytes control the migration of leukocytes in response
to inflammatory mediators by up-regulating the expression of adhesion molecules and
releasing chemo-attractants; however, under physiological conditions they appear to be
immune-suppressors. Better understanding of the immune properties of pericytes and
their participation in the effects of brain infections, neurodegenerative diseases, and sleep
loss will be achieved by analyzing pericyte ultrastructure, capillary coverage, and protein
expression. That knowledge may provide a mechanism by which pericytes participate in
the maintenance of the proper function of the brain-immune interface.
Keywords: pericytes, blood–brain barrier, immune response, inflammation, cytokines, REM sleep loss, brain
endothelial cell, tight junction disruption
INTRODUCTION
The brain must respond to blood-borne signals but has no direct
access to them (Persidsky et al., 2006; Saper, 2010). Likewise,
the immune system does not contact directly the brain milieu;
they interact through the brain-immune interface, the blood–
brain barrier. The interface is comprised by endothelial cells
(ECs), astrocytes, microglia, pericytes, and extracellular matrix
components (basal lamina and glycocalyx; Risau, 1991; Ballabh
et al., 2004; Ueno, 2007; Gómez-González et al., 2012). ECs limit
blood-borne macromolecules or cells from crossing into the brain
through junction complexes that fasten together adjacent cell
membranes. In addition, transcellular trafficking of molecules
is limited by the minimal expression of endocytosis and the
presence of specialized carrier systems (Zlokovic, 2008; Abbott
et al., 2010). Although ECs provide the physical and chemical
barrier function per se, all elements are crucial for the development and maintenance of the blood–brain barrier, allowing
it to be the interface between peripheral systems and the brain
(Zlokovic, 2008).
Pericytes have been increasingly implicated in the regulation
of local blood-flow in brain regions with increased synaptic activity, a phenomenon known as neurovascular coupling (reviewed in
Hamilton et al., 2010); furthermore, they have also been involved
in the regulation of the blood–brain barrier permeability to
Frontiers in Integrative Neuroscience
circulating molecules (Armulik et al., 2010). Better understanding of the immune properties of pericytes and their participation
in the changes observed during brain infections and neurodegenerative diseases will provide a mechanism by which pericytes
participate in the maintenance of the proper function of the
brain-immune interface, the blood–brain barrier. Here we present
recent evidence depicting the new roles of pericytes in regulating
blood–brain barrier function under normal and pathological conditions and hypothesize its potential role in the regulation of the
blood–brain barrier after chronic sleep loss.
PERICYTES AS BLOOD–BRAIN BARRIER COMPONENTS
Pericytes are smooth muscle-derived cells that play a crucial
role in keeping brain homeostasis given their presence at the
blood–brain barrier and particularly their active role in what
is known as the neurovascular unit (Zlokovic, 2008; GómezGonzález et al., 2012). Rouget (1874), for the first time, described
a population of branched cells with contractile properties that
surrounded ECs. Fifty years later, these mesenchymal cells were
renamed “pericytes” by Zimmerman in concordance with their
anatomical location: abluminal to ECs and luminal to parenchymal cells (Kim et al., 2006; Sá-Pereira et al., 2012). Anatomically,
pericytes have projections that wrap around capillaries and are
embedded within the basal lamina. The diversity in pericyte
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“fnint-07-00080” — 2014/1/9 — 20:30 — page 1 — #1
January 2014 | Volume 7 | Article 80 | 1
Acta Neuropathol (2010) 119:303–315
DOI 10.1007/s00401-009-0590-4
ORIGINAL PAPER
Prenatal stress alters microglial development and distribution
in postnatal rat brain
Beatriz Gómez-González Æ Alfonso Escobar
Received: 15 April 2009 / Revised: 28 August 2009 / Accepted: 4 September 2009 / Published online: 16 September 2009
Ó Springer-Verlag 2009
Abstract Stress affects microglial function and viability
during adulthood and early postnatal life; however, it is
unknown whether stress to the pregnant dam might alter
offspring microglia. The effects of prenatal stress on microglial development and distribution in the postnatal brain
were studied using Wistar rats. Prenatal stress consisting of
20 min of forced swimming occurred on embryonic days
10–20. On postnatal days 1 and 10, stressed and control
pups were killed. Microglia were identified using Griffonia
simplicifolia lectin and quantified in the whole encephalon.
In addition, plasma corticosterone was measured in dams at
embryonic day 20, and in pups on postnatal days 1 and 10.
At postnatal day 1, there was an increase in number of
ramified microglia in the parietal, entorhinal and frontal
cortices, septum, basal ganglia, thalamus, medulla oblongata and internal capsule in the stressed pups as compared
to controls, but also there was a reduction of amoeboid
microglia and the total number of microglia in the corpus
callosum. By postnatal day 10, there were no differences in
the morphologic type or the distribution of microglia
between the prenatal stress and control groups, except in
the corpus callosum; where prenatal stress decreased the
number of ramified microglia. The stress procedure was
effective in producing plasma rise in corticosterone levels
of pregnant rats at embryonic day 20 when compared to
B. Gómez-González (&) A. Escobar
Department of Cell Biology and Physiology,
Instituto de Investigaciones Biomédicas,
Universidad Nacional Autónoma de México,
Ciudad Universitaria, 04510 Mexico D.F., Mexico
e-mail: [email protected]
B. Gómez-González
Facultad de Psicologı́a, Universidad Nacional Autónoma de
México, Mexico D.F., Mexico
same age controls. Prenatal stress reduced the number of
immature microglia and promoted an accelerated microglial differentiation into a ramified form. These findings
may be related to an increase in plasma corticosterone in
the pregnant dam.
Keywords In utero stress Amoeboid microglia Ramified microglia Corticosterone
Introduction
The origin of microglia is one of the most controversial
issues on glial research. Several hypotheses have been
proposed in relation to the origin of microglia; microglia
have been considered to be of mesodermal, neuroectodermal (similar to astrocytes and oligodendrocytes) or
monocytic origin [10, 28]. Consensus opinion currently
holds that microglia derive from the embryonic mesoderm
[10]; specifically, microglia are thought to derive from
peripheral blood monocytes that infiltrate the central nervous system via local blood vessels during embryonic and
early postnatal life [32, 42, 51]. In the rat, microglia are
first seen between embryonic days 12–14 [51]. During
early phases of neural development, microglia are amoeboid. As development progresses, microglia acquire a
mature ramified form [28, 32]. At birth, amoeboid
microglia concentrate in three colonies in the rat forebrain:
the corpus callosum, internal capsule and ventral part of the
external capsule [16, 30, 33]. From those reservoirs,
amoeboid microglia migrate to all remaining neuroanatomic sites during the later embryonic stages and the first 3
postnatal weeks [11]. In the early postnatal rat, ramified
microglia with short stout processes are the predominant
form in the neocortex and hippocampus, and there is
123
Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Issue: Neuroimmunomodulation in Health and Disease
Role of sleep in the regulation of the immune system and
the pituitary hormones
Beatriz Gómez-González,∗ Emilio Domı́nguez-Salazar,∗ Gabriela Hurtado-Alvarado,
Enrique Esqueda-Leon, Rafael Santana-Miranda, Jose Angel Rojas-Zamorano,
and Javier Velázquez-Moctezuma
Department of Biology of Reproduction and Sleep Disorders Clinic, Universidad Autónoma Metropolitana-Iztapalapa, Mexico
City, Federal District, Mexico
Address for correspondence: Javier Velázquez-Moctezuma, M.D., PhD., Area of Neurosciences, Department of Biology of
Reproduction, CBS, Universidad Autónoma Metropolitana-Iztapalapa, Av. San Rafael Atlixco No. 186, Col Vicentina,
Iztapalapa, Mexico City, DF, Mexico 09340. [email protected]
Sleep is characterized by a reduced response to external stimuli and a particular form of electroencephalographic
(EEG) activity. Sleep is divided into two stages: REM sleep, characterized by muscle atonia, rapid eye movements,
and EEG activity similar to wakefulness, and non-REM sleep, characterized by slow EEG activity. Around 80% of
total sleep time is non-REM. Although it has been intensely studied for decades, the function (or functions) of sleep
remains elusive. Sleep is a highly regulated state; some brain regions and several hormones and cytokines participate
in sleep regulation. This mini-review focuses on how pituitary hormones and cytokines regulate or affect sleep
and how sleep modifies the plasma concentration of hormones as well as cytokines. Also, we review the effects of
hypophysectomy and some autoimmune diseases on sleep pattern. Finally, we propose that one of the functions of
sleep is to maintain the integrity of the neuro–immune–endocrine system.
Keywords: sleep; cytokines; pituitary gland; hormones; autoimmune diseases; sleep loss; sleep function
Introduction
Sleep is a widespread phenomenon among vertebrates; it is characterized by the adoption of a
species-specific posture, by increases in sensory
thresholds, immobility, and by the generation of
hallmark patterns of electroencephalographic activity.1 In mammals, sleep is divided into two stages:
rapid eye movement (REM) sleep and non-REM
sleep. During REM sleep, a high-frequency and
low-voltage electrical brain activity is observed, accompanied by rapid eye movements and absence
of muscle tone in skeletal muscles. On the other
hand, non-REM sleep, composed of both light and
slow-wave sleep, is characterized by the presence of
high-voltage and low-frequency electroencephalographic activity, diminished muscle tone, and slow
∗
These authors contributed equally to the work reported.
eye movements.2,3 Humans sleep around one-third
of their lifetime, and other mammals, such as rodents, sleep almost two-thirds of their lifetime.
Sleep is an active process that requires the synchronous activation and deactivation of many nervous centers located in the hypothalamus and brain
stem, whose activity directly modifies the cortical
electrical activity. At the central nervous system
level, REM sleep is characterized by a decreased
release of noradrenalin and serotonin and by increases in acetylcholine release by the REM-sleep
generators in the pons; in the hypothalamus, histaminergic and orexinergic neurons are silent during REM sleep compared with wakefulness.4 Meanwhile, non-REM sleep is characterized by almost
full suppression of acetylcholine release and a progressive reduction in noradrenalin and serotonin
concentration.5 In addition to the changes observed
in neurotransmitter content, a tight reciprocal relationship between sleep and the endocrine system
doi: 10.1111/j.1749-6632.2012.06616.x
c 2012 New York Academy of Sciences.
Ann. N.Y. Acad. Sci. 1261 (2012) 97–106 97
Send Orders for Reprints to [email protected]
Current Neurovascular Research, 2013, 10, 197-207
197
REM Sleep Loss and Recovery Regulates Blood-Brain Barrier Function
Beatriz Gómez-González#,*, Gabriela Hurtado-Alvarado#, Enrique Esqueda-León, Rafael SantanaMiranda, José Ángel Rojas-Zamorano and Javier Velázquez-Moctezuma
Area of Neurosciences, Department of Biology of Reproduction, CBS, Universidad Autónoma Metropolitana-Iztapalapa,
Mexico City, Mexico
Abstract: The functions of rapid eye movement (REM) sleep have remained elusive since more than 50 years. Previous
reports have identified several independent processes affected by the loss and subsequent recovery of REM sleep
(hippocampal neurogenesis, brain stem neuronal cell death, and neurotransmitter content in several brain regions);
however, a common underlying mechanism has not been found. We propose that altered brain homeostasis secondary to
blood-brain barrier breakdown may explain all those changes induced by REM sleep loss. Therefore, the present report
aimed to study the consequences of REM sleep restriction upon blood-brain barrier permeability to Evans blue. REM
sleep restriction was induced by the multiple platform technique; male rats were REM sleep restricted 20h daily (with 4h
sleep opportunity) during 10 days; control groups included large platform and intact rats. To study blood-brain barrier
permeability Evans blue was intracardially administered; stained brains were sliced and photographed for optical density
quantification. An independent experiment was carried out to elucidate the mechanism of blood-brain breakdown by
transmission electron microscopy. REM sleep restriction increased blood-brain barrier permeability to Evans blue in the
whole brain as compared to both control groups. Brief periods of sleep recovery rapidly and effectively restored the severe
alteration of blood-brain barrier function by reducing blood-to-brain transfer of Evans blue. The mechanism of bloodbrain barrier breakdown involved increased caveolae formation at brain endothelial cells. In conclusion, our data suggest
that REM sleep regulates the physical barrier properties of the blood-brain barrier.
Keywords: BBB, EEG, REM sleep restriction, REM sleep function, transmission electron microscopy.
INTRODUCTION
Sleep is a widespread phenomenon among vertebrates; it
is characterized by a rapidly reversible immobility, reduced
awareness to environmental stimuli, acquisition of species’
specific postures, and distinctive brain electrical activity [1].
In mammals, sleep is divided into two major stages, rapid
eye-movement sleep (REM) and non-REM sleep. REM sleep
is characterized by fast desynchronized electroencephalographic (EEG) activity and muscle atonia, while nonREM sleep is characterized by slow wave EEG activity and
slight muscle tone reduction [2]. Although highly studied
since more than 50 years, the function of sleep remains
elusive; pioneer works proved that sleep is important to
preserve life, because chronic sleep loss induced progressive
health deterioration until death of the experimental animals
[3, 4]. Therefore, sleep function is hypothesized to preserve
the integrity of the systems controlling the constancy of the
internal milleu (the endocrine and immune systems) [5]; in
particular Korth [6] suggested that sleep could maintain the
function of the system that keeps brain homeostasis, the
blood-brain barrier, but until now no evidence has been
given to support such sleep function.
The blood-brain barrier is constituted by endothelial
cells, pericytes, astroglia and microglia, whose functions
include selective transport of molecules from blood-to-brain
and vice versa, metabolism of blood- and brain-borne
molecules, as well as protection to the brain from potentially
neurotoxic blood-borne molecules (e.g. glutamate and
albumin) [7]. Proper blood-brain barrier function is needed
to guarantee normal physiology of both neuronal and glial
cells, indeed direct neural exposure to blood-borne proteins
may induce apoptosis and glial reactivity [8-10]. The altered
function of the blood-brain barrier would explain the diverse
independent effects of REM sleep loss previously reported,
such as reduced hippocampal neurogenesis [11, 12],
increased concentration of the excitatory amino acids
glutamate, aspartate and glutamine in the hippocampus and
cerebral cortex [13], and increased apoptosis in the REMsleep controlling nuclei of the brain stem [14]. Therefore it
seems plausible that REM sleep may be preserving bloodbrain barrier integrity. Hence, this study aimed to elucidate
the effect of REM sleep loss and subsequent recovery upon
blood-brain barrier permeability to a blood-circulating dye,
Evans blue.
MATERIALS AND METHODS
*Address correspondence to this author at the Area of Neurosciences,
Department of Biology of Reproduction, CBS, Universidad Autónoma
Metropolitana, Unidad Iztapalapa, Av. San Rafael Atlixco No. 186, Col.
Vicentina, Iztapalapa, Mexico City, Mexico, Zip Code. 09340;
Tel/Fax: 52 55 58046559; E-mails: [email protected],
[email protected]
#
Both authors contributed equally to the work
Received: April 22, 2013
Revised: May 10, 2013
Accepted: May 15, 2013
1875-5739/13 $58.00+.00
Subjects
Three month-old male Wistar rats (n=39) were used. Rats
were caged in groups of 6-8 in our laboratory vivarium under
a 12h light/dark cycle (lights on at 23 hour) at room
temperature of 20-25°C. Commercial rat chow and tap water
were available ad libitum to all rats throughout the
© 2013 Bentham Science Publishers
GOMEZ-GONZALEZ_BEATRIZ
1. Front Integr Neurosci. 2014 Jan 10;7:80. doi: 10.3389/fnint.2013.00080. eCollection 2014.
Pericytes: brain-immune interface modulators.
Hurtado-Alvarado G1, Cabañas-Morales AM1, Gómez-Gónzalez B1.
Author information
Abstract
The premise that the central nervous system is immune-privileged arose from the fact that direct
contact between immune and nervous cells is hindered by the blood-brain barrier. However, the
blood-brain barrier also comprises the interface between the immune and nervous systems by
secreting chemo-attractant molecules and by modulating immune cell entry into the brain. The
majority of published studies on the blood-brain barrier focus on endothelial cells (ECs), which
are a critical component, but not the only one; other cellular components include astroglia,
microglia, and pericytes. Pericytes are poorly studied in comparison with astrocytes or ECs;
they are mesenchymal cells that can modify their ultrastructure and gene expression in
response to changes in the central nervous system microenvironment. Pericytes have a unique
synergistic relationship with brain ECs in the regulation of capillary permeability through
secretion of cytokines, chemokines, nitric oxide, matrix metalloproteinases, and by means of
capillary contraction. Those pericyte manifestations are related to changes in blood-brain barrier
permeability by an increase in endocytosis-mediated transport and by tight junction disruption.
In addition, recent reports demonstrate that pericytes control the migration of leukocytes in
response to inflammatory mediators by up-regulating the expression of adhesion molecules and
releasing chemo-attractants; however, under physiological conditions they appear to be
immune-suppressors. Better understanding of the immune properties of pericytes and their
participation in the effects of brain infections, neurodegenerative diseases, and sleep loss will
be achieved by analyzing pericyte ultrastructure, capillary coverage, and protein expression.
That knowledge may provide a mechanism by which pericytes participate in the maintenance of
the proper function of the brain-immune interface.
KEYWORDS:
REM sleep loss; blood–brain barrier; brain endothelial cell; cytokines; immune response; inflammation;
pericytes; tight junction disruption
PMID: 24454281
2. Front Integr Neurosci. 2014 Mar 13;8:26. doi: 10.3389/fnint.2014.00026. eCollection 2014.
Beyond the borders: the gates and fences of neuroimmune interaction.
Velázquez-Moctezuma J1, Domínguez-Salazar E1, Gómez-González B1.
Author information
KEYWORDS:
brain barriers; neuroendocrinology; neuroimmunoendocrinology; neuroimmunology;
neuroimmunomodulation
PMID: 24659958
3. Curr Neurovasc Res. 2013 Aug;10(3):197-207.
REM sleep loss and recovery regulates blood-brain barrier function.
Gómez-González B1, Hurtado-Alvarado G, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano
JÁ, Velázquez-Moctezuma J.
Author information
Abstract
The functions of rapid eye movement (REM) sleep have remained elusive since more than 50
years. Previous reports have identified several independent processes affected by the loss and
subsequent recovery of REM sleep (hippocampal neurogenesis, brain stem neuronal cell death,
and neurotransmitter content in several brain regions); however, a common underlying
mechanism has not been found. We propose that altered brain homeostasis secondary to
blood-brain barrier breakdown may explain all those changes induced by REM sleep loss.
Therefore, the present report aimed to study the consequences of REM sleep restriction upon
blood-brain barrier permeability to Evans blue. REM sleep restriction was induced by the
multiple platform technique; male rats were REM sleep restricted 20h daily (with 4h sleep
opportunity) during 10 days; control groups included large platform and intact rats. To study
blood-brain barrier permeability Evans blue was intracardially administered; stained brains were
sliced and photographed for optical density quantification. An independent experiment was
carried out to elucidate the mechanism of blood-brain breakdown by transmission electron
microscopy. REM sleep restriction increased blood-brain barrier permeability to Evans blue in
the whole brain as compared to both control groups. Brief periods of sleep recovery rapidly and
effectively restored the severe alteration of blood-brain barrier function by reducing blood-tobrain transfer of Evans blue. The mechanism of blood-brain barrier breakdown involved
increased caveolae formation at brain endothelial cells. In conclusion, our data suggest that
REM sleep regulates the physical barrier properties of the blood-brain barrier.
PMID: 23713739
4. Clin Dev Immunol. 2013;2013:801341. doi: 10.1155/2013/801341. Epub 2013 Dec 3.
Sleep loss as a factor to induce cellular and molecular inflammatory
variations.
Hurtado-Alvarado G1, Pavón L2, Castillo-García SA1, Hernández ME2, Domínguez-Salazar E1, VelázquezMoctezuma J1, Gómez-González B1.
Author information
Abstract
A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical
and experimental studies in humans and animal models have shown that immune function is
impaired when sleep loss is experienced. Sleep loss exerts a strong regulatory influence on
peripheral levels of inflammatory mediators of the immune response. An increasing number of
research projects support the existence of reciprocal regulation between sleep and low-intensity
inflammatory response. Recent studies show that sleep deficient humans and rodents exhibit a
proinflammatory component; therefore, sleep loss is considered as a risk factor for developing
cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer's
disease, and multiple sclerosis). Circulating levels of proinflammatory mediators depend on the
intensity and duration of the method employed to induce sleep loss. Recognizing the fact that
the concentration of proinflammatory mediators is different between acute and chronic sleeploss may expand the understanding of the relationship between sleep and the immune
response. The aim of this review is to integrate data from recent published reports (2002-2013)
on the effects of sleep loss on the immune response. This review may allow readers to have an
integrated view of the mechanisms involved in central and peripheral deficits induced by sleep
loss.
PMID: 24367384
5. Ann N Y Acad Sci. 2012 Jul;1261:97-106. doi: 10.1111/j.1749-6632.2012.06616.x.
Role of sleep in the regulation of the immune system and the pituitary
hormones.
Gómez-González B1, Domínguez-Salazar E, Hurtado-Alvarado G, Esqueda-Leon E, Santana-Miranda
R, Rojas-Zamorano JA, Velázquez-Moctezuma J.
Author information
Abstract
Sleep is characterized by a reduced response to external stimuli and a particular form of
electroencephalographic (EEG) activity. Sleep is divided into two stages: REM sleep,
characterized by muscle atonia, rapid eye movements, and EEG activity similar to wakefulness,
and non-REM sleep, characterized by slow EEG activity. Around 80% of total sleep time is nonREM. Although it has been intensely studied for decades, the function (or functions) of sleep
remains elusive. Sleep is a highly regulated state; some brain regions and several hormones
and cytokines participate in sleep regulation. This mini-review focuses on how pituitary
hormones and cytokines regulate or affect sleep and how sleep modifies the plasma
concentration of hormones as well as cytokines. Also, we review the effects of hypophysectomy
and some autoimmune diseases on sleep pattern. Finally, we propose that one of the functions
of sleep is to maintain the integrity of the neuro-immune-endocrine system.
© 2012 New York Academy of Sciences.
PMID: 22823399
6. Int J Dev Neurosci. 2011 Dec;29(8):839-46. doi: 10.1016/j.ijdevneu.2011.08.003. Epub 2011 Aug 16.
Increased transvascular transport of WGA-peroxidase after chronic
perinatal stress in the hippocampal microvasculature of the rat.
Gómez-González B1, Larios HM, Escobar A.
Author information
Abstract
Brain endothelial ultrastructural properties contribute to maintain proper blood-brain barrier
(BBB) function. Several physiological and pathological conditions have been shown to alter BBB
permeability to blood-borne molecules, acute and chronic stress among them. In the rat, early
life stress increased transvascular transport of Evans blue, however, the route of tracer
extravasation is not fully known; therefore the aim of the present experiment was to describe the
ultrastructural changes in endothelial cells subsequent to chronic perinatal stress in order to
ascertain the route for transvascular transport of an electrodense tracer. Pregnant Wistar rats
and their litters were used. Four pregnant rats were subjected to forced swimming between
gestational days 10 to 20. After delivery, half of the control litters underwent 180 min maternal
separation from postnatal day 2 to 20. Controls were kept free of any stress manipulation. At
sacrifice between postnatal days 1 to 30 subjects were given intracardially the lectin wheat
germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). WGA-HRP stained
hippocampi were processed for ultrastructural analysis, transmission electron micrographs were
obtained and endothelial ultrastructural parameters quantified using the ImageJ software. Both
stress procedures accelerated gross microvessel development by decreasing capillary wall
thickness and endothelial microvilli. However, early-life stress also neutralized endothelial
glycocalyx, increased vesicle-mediated transport and tended to promote the formation of
secondary lysosomes containing endocytosed WGA-HRP vesicles, all parameters of altered
endothelial cell function. Tight junction development in both stress groups was similar to the
control pups.
Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.
PMID: 21864670
7. Acta Neuropathol. 2010 Mar;119(3):303-15. doi: 10.1007/s00401-009-0590-4. Epub 2009 Sep 16.
Prenatal stress alters microglial development and distribution in
postnatal rat brain.
Gómez-González B1, Escobar A.
Author information
Abstract
Stress affects microglial function and viability during adulthood and early postnatal life; however,
it is unknown whether stress to the pregnant dam might alter offspring microglia. The effects of
prenatal stress on microglial development and distribution in the postnatal brain were studied
using Wistar rats. Prenatal stress consisting of 20 min of forced swimming occurred on
embryonic days 10-20. On postnatal days 1 and 10, stressed and control pups were killed.
Microglia were identified using Griffonia simplicifolia lectin and quantified in the whole
encephalon. In addition, plasma corticosterone was measured in dams at embryonic day 20,
and in pups on postnatal days 1 and 10. At postnatal day 1, there was an increase in number of
ramified microglia in the parietal, entorhinal and frontal cortices, septum, basal ganglia,
thalamus, medulla oblongata and internal capsule in the stressed pups as compared to controls,
but also there was a reduction of amoeboid microglia and the total number of microglia in the
corpus callosum. By postnatal day 10, there were no differences in the morphologic type or the
distribution of microglia between the prenatal stress and control groups, except in the corpus
callosum; where prenatal stress decreased the number of ramified microglia. The stress
procedure was effective in producing plasma rise in corticosterone levels of pregnant rats at
embryonic day 20 when compared to same age controls. Prenatal stress reduced the number of
immature microglia and promoted an accelerated microglial differentiation into a ramified form.
These findings may be related to an increase in plasma corticosterone in the pregnant dam.
PMID: 19756668