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Abstract: A recent article by Kwan and colleagues could elegantly demonstrate the necessary interaction
between neuronal serotonin (5-HT) systems and the hypothalamic-pituitary-adrenal (HPA) axis through
glucocorticoid receptors (GR), producing an adequate stress response, in this case, responding to hypoxia
with an increase in hematopoietic stem and progenitor cells (HSPC). There is an intricate system connecting
brain, body and mind and this exchange is only possible when all these systemsnervous, endocrine, and
immunehave receptors on critical cells to receive information (via messenger molecules) from each of the
other systems. There is evidence that the expression and function of GR in the hippocampus, mainly MR,
is regulated by the stimulation of 5-HT receptors. Stressful stimuli increase 5-HT release and turnover in
the hippocampus, and it seems reasonable to suggest that some of the changes in mineralocorticoid and
GR expression may be mediated, in part at least, by the increase in 5-HT. Also serotonin and HPA axis
dysfunctions have already been implicated in a variety of psychiatric disorders, especially depression. Early
life stress (ELS) can have profound impact on these systems and can predispose subjects to a variety of adult
metabolic and psychiatric conditions. It is important to analyze the mechanisms of this complex interaction
and its subsequent programming effects on the stress systems, so that we can find new ways and targets for
treatment of psychiatric disorders. Different areas of research on basic biological sciences are now being
integrated and this approach will hopefully provide several new insights, new pharmacological targets and
improve our global understanding of these highly debilitating chronic conditions, that we now call mental
disorders.
Keywords: Serotonin; early life stress (ELS); glucocorticoids (GC); hypothalamicpituitaryadrenal (HPA) axis
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that the causes, development, and outcomes of disorders linked to adaptive processes such as memory consolidation,
are determined by the relations of psychological, social, whereas MR-mediated effects have been associated with the
and cultural factors with biochemistry and physiology. appraisal and responsiveness to stressful experiences and
Biochemistry and physiology are not disconnected and with the negative feedback control of the HPA axis (9,10).
different from the rest of our experiences and life events (2). One thing that is important to realize is that different
It is now broadly accepted that psychological stress may kinds of stress will elicit that response (although by different
change the internal homeostatic state of an individual. inputs) whether they are hypoxic, metabolic, inflammatory,
During acute stress, adaptive physiological responses hematologic or even psychogenic or imagined stressful
occur, which include increased adrenocortical secretion of situations (7).
hormones, primarily cortisol. This action of the brain is the Thus, it is clear that the HPA axis constitutes one of
bodys first line of defense against illness, against aging, and the major endocrine systems that maintain homeostasis
for health and welfare (3). when the organism is challenged or stressed and activation
As we know, stress is vital for the adaptation of life of the HPA axis is perhaps the most important endocrine
on Earth. Although usually associated with disease, the component of the stress response (11).
physiological and behavioral responses to stressors are
critical mechanisms of resilience for healthy organisms (4).
Epigenetics and ELS
A stressor (or stressful event) can be defined as a physical
(or psychological) stimulus that disturbs or threatens to ELS is an important, although non-specific, risk factor for
disturb homeostasis. As stressors are omnipresent, stress major psychiatric and medical disorders, and that includes
is vital for survival. Sometimes, however, depending on intrauterine stress as well (12,13). Stress in pregnancy
the duration, intensity, and subject vulnerability, stress can has been shown to have a programming effect in the
induce physical or psychological dysfunction. Approximately offspring, and one of the most consistent findings is HPA
60% of cases of depressive episodes are preceded by axis alterations (14). Although GC plays a vital role in the
stressors, especially psychosocial ones (5). development of the embryo, prolonged exposures may
Genes, early life stress (ELS), adult experiences, life style, have deleterious neural effects, especially in brain areas
and stressful life experiences all add to the way the body that are rich in cortisol receptors (14). Consistent with
adapts to a changing environment; and all these factors help the findings of Kwan et al. (15) prenatal SSRI exposure
to determine the cost to the body or the allostatic load. of mothers seems to alter HPA axis function and cortisol
Emergent data in the field of psychoneuroimmunology levels (16) as well as neonatal corticosteroid binding
contributes to the understanding of the mechanisms by globulin (CBG) in the infants (17). CBG is an important
which traumatic events affect health. The interaction mediator of cortisol function, since only the free cortisol
between behavior, neurobiology, and endocrine system appears to exert its physiological effects. In normal
that may cause immunosuppression is the most interesting conditions more than 90% of circulating cortisol is bound
discovery in current medicine, and its implications are to CBG (18). Mice exposed to SSRIs also show altered
important for the prevention and treatment of somatic hormonal and behavioral response to stress, supposedly
diseases (6). mediated by GC resistance (19).
Faced with a stressful situation the organism will elicit Animal studies suggest that maternal immune activation
an immediate response via activation of the autonomous increase the risk of behavioural deficits (20) and depression-
nervous system (ANS) and a delayed response via like behaviour in the offspring (21). Since GCs are
hypothalamicpituitaryadrenal (HPA) axis-mediated thought to modulate immune function and that these
release of glucocorticoids (GC) (7). These hormones will in hormones can have important epigenetic effects (22), it is
turn have easy access to the brain and, once there, will bind now believed that this alterations can be passed on even
to mineralocorticoid receptors (MR) and glucocorticoid intergenerationally (12).
receptors (GR) to exert both rapid, non-genomic and slow, In an already classic animal study, Dias and Ressler
genomic actions on physiology and behavior (8). GRs are demonstrated that rats submitted to an olfactory cue and
highly expressed in most brain regions, whereas MRs are subsequently shocked passed on their behavioural reaction
predominantly expressed in limbic regions such as the to the same odour to their offspring that had not had
hippocampus and central amygdala. GR activation has been contact with the smell nor the shocks, but nevertheless
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showed an increased startle response to the olfactory cue. adapt and others will present with an increased risk for
Epigenetic mechanisms are thought to be involved and GC psychiatric disorders, especially depression. It seems that
is one plausible effector candidate (23). Another animal a complex interaction between genes and environment are
study suggests that paternal exposure to stress can alter responsible for these effects.
sperm microRNA content and have programming effects Polymorphisms in genes that code for 5-HT transporters
on the HPA axis of their offspring as well (24). have already been implicated in increased susceptibility for
Humans are probably subject to the same mechanisms, depression, when interacting with an environmental stressor,
as suggested by studies of the great Dutch famine of 1944 following the work of Caspi (31). More recent papers show
to 1945. These studies showed that prenatal maternal that these effects may also be mediated by the HPA axis (32),
malnutrition was associated with a variety of physical specially through the adrenal gland (33).
conditions in offspring when adults (25), as well as an
increased risk of schizophrenia spectrum disorder and
ELS, HPA axis and corticoid receptors
depression (26). The offspring of fathers that were
intrautero at that time (grandchildren of the malnourished) Dysregulation of the HPA axis is one of the most consistent
were found to have increased risk of obesity, suggesting a findings in patients with depression and ELS (34). Patients
transgenerational effect (27). with ELS are more likely to show hyperactivity of the HPA
These studies are mentioned only to illustrate the axis and present symptoms that are usually resistant to
magnitude and complexity of the effects of ELS, and when standard antidepressants but instead benefit from adjuvant
that can happen, being in childhood, intrautero or, it seems, treatment with psychotherapy (35-37).
even before conception takes place. Clearly, more studies Evidence indicates that stress in the early phases of
are needed to elucidate the precise mechanisms of these development can induce persistent changes in the ability of
effects and their relevance in human development, physical the HPA axis to respond to stress in adulthood, and that this
and mental health. mechanism can lead to a raised susceptibility to depression.
Studies of childhood maltreatment and their persistent These abnormalities appear to be related to changes in the
effects throughout the lifespan have been more studied and ability of circulating GCs to exert negative feedback on the
from now on we will refer to ELS as stress that occurs in secretion of HPA hormones through binding to GR and
early childhood. MR (18).
In agreement with Bernstein et al. (28), childhood In humans, while MRs are thought to be involved in
maltreatment may be subdivided into the following the tonic inhibitory activity within the HPA axis, GRs
domains: appear to switch off cortisol production at times of
(I) Physical abuse: physical aggression by someone stress. It seems that MRs are necessary for GC regulation
older, with the risk of or result of injury; of HPA axis activity during mild stressors but not during
(II) Emotional abuse: verbal aggression that affects the stressors that result in a stronger corticosteroid response.
welfare or morale of the child or any conduct that It is proposed that the maintenance in corticosteroid
humiliates, embarrasses, or threatens the child; homeostasis and the balance in MR-/GR-mediated effects
(III) Sexual abuse: any type of sexual contact or conduct limit vulnerability to stress-related diseases in genetically
between a child and someone older; predisposed individuals (18).
(IV) Emotional neglect: failure of caretakers to provide Three different mechanisms of GR resistance have been
for basic emotional and psychological needs such as considered: (I) downregulation secondary to persistent
love, motivation, and support; hypercortisolism, (II) a primary alteration in the genetic
(V) Physical neglect: failure of caretakers to provide structure, and (III) a decrease in GR function secondary to
for basic physical needs such as feeding, a home, alterations in ligand independent pathways (18). It has also
security, supervision, and health. been proposed that the balance between MR and GR is an
Childhood maltreatment significantly contributes to important factor in resilience to stress, and studies suggest
disease morbidity and mortality in adults (29,30) and it is that there may be an imbalance in the MR/GR ratio
essential to elucidate the mechanisms by which these early in depression (38). Another possibility (that can happen
life events can elicit illnesses that become apparent decades concomitantly or independent) is the excessive production of
after the presumed initial insult, and why some people can corticotropin release factor (CRF) from the hypothalamus.
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+
The serotonin hub
GABA Amygdala
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doi: 10.21037/sci.2017.02.01
Cite this article as: Juruena MF, Agustini B, Cleare AJ, Young
AH. A translational approach to clinical practice via stress-
responsive glucocorticoid receptor signaling. Stem Cell Investig
2017;4:13.
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