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Stress can make your body want to shut down. Try these 5 tips to gain your energy back. Stress can affect all systems of the body, including the amount of vital oxygen getting to your muscles and organs. If you feel you're always stressed or get stressed out easily, you might be dealing with chronic stress or burnout.

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Psych Central. Conditions Discover Quizzes Resources. Quiz Symptoms Causes Treatment Find Support. All About Stress. Medically reviewed by Nathan Greene, PsyD — By Madelyn Brown — Updated on May 28, Definition Negative stress responses Causes Signs and symptoms How to manage stress When to seek help Takeaway Everyone experiences stress at some point in their lives.

What is stress? Impact of distress on your mental health. Causes of stress. Symptoms and effects of stress. How to manage stress. When to seek help. pdf Aschbacher K, et al. Good stress, bad stress and oxidative stress: Insights from anticipatory cortisol reactivity.

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Other important structures for triggering the stress response are the circumventricular organs i. For instance, the activation of the medial parvocellular PVN by the SFO is essential for the central blood pressure regulation by angiotensin II and regulation of drinking behavior Simpson and Routtenberg, ; Hindmarch and Ferguson, And finally, it has also been described that limbic forebrain regions may contribute to physical stressors processing as well, influencing the functions in the autonomic responses to stress and the activation of the HPA-axis Ulrich-Lai and Herman, These limbic stress circuits involve the amygdala, hippocampus and prefrontal cortex PFC that receive associational information from subcortical and cortical areas and their output converge to subcortical relay sites, making downstream processing of limbic information top-down regulation; Ulrich-Lai and Herman, Those circuitries will be explored in the circuits overlapping section and we have highlighted how stressors might interact with the reward approaching × aversion system.

While stressors that are predominantly physically demanding are more likely to evoke autonomic stress responses, psychological uncontrollable and social-evaluative threatening stressors elicit both physical and cognitive stress responses Skoluda et al.

Together with the prosencephalic nuclei, components of limbic circuits such as the PFC, amygdala, hippocampus HIPPO , PVN, ventral tegmental area VTA and nucleus accumbens NAc have a fundamental role in the regulation of stress response Ulrich-Lai and Herman, ; Russo and Nestler, The PFC is critical to develop appropriate responses to environment changes, enabling behavioral plasticity Ridderinkhof et al.

However, the involvement of PFC in stress response is complex, since different anatomic subdivisions play different roles. Bilateral lesions of prelimbic PL cortex portion increases plasma level of adenocorticotrophic hormone ACTH , corticosterone and PVN c-Fos expression Dioro et al.

However, lesions of infralimbic IL cortex reduce corticosterone secretion Sullivan and Gratton, Moreover, studies with animal behaviors showed that lesions in dorsal sites of PFC result in anxiogenic effects, while lesions in ventral sites of PFC have anxiolytic effects Sullivan and Gratton, These data indicate that PL and IL have opposite effects in psychological stressors response, inhibiting PVN activity with anxiolytic effects or stimulating PVN with anxiogenic behaviors, respectively Radley et al.

Despite the functional connection between PFC and PVN, anatomical studies indicate that PFC only has indirect projections to PVN Herman et al.

The PL innervates several GABAergic neurons in the BST, which induces inhibition of PVN, whereas it is suggested that IL pathway projects to non-GABAergic in the BST to stimulate the PVN Radley, However, it remains to be elucidated the exact pathways between PVN and PFC Bains et al.

The PFC also has major projections to the amygdala, an important structure associated with emotional processing Gabbott et al.

Initially, the entire amygdala complex appears to promote synthesis and secretion of corticosteroids Kawakami et al. However, subsequent studies showed that amygdala subnuclei have distinct roles in stress response Roozendaal et al.

The amygdala complex can be divided in the basolateral nucleus BLA , the central nucleus of the amygdala CeA and the medial nucleus MeA. Among these, the BLA has a major role in processing psychological stressors Janak and Tye, , being mainly activated by anticipatory stressors Cullinan et al.

However, BLA does not affect corticosterone release itself Seggie, The role of BLA in the processing of psychological stressors seems to be more critical to the consolidation of aversive memories Roozendaal et al. Intra-BLA infusions of GABAergic receptor agonists impair aversive memory consolidation Brioni et al.

Besides, after emotional arousal, BLA neurons show lasting increases in the spontaneous firing rates, which could facilitate the consolidation of emotional memories through synaptic plasticity changes Pelletier et al. Alterations in emotional and associative learning i.

In specific, some studies indicate that BLA-PFC pathway plays a major role in memory consolidation and stress response Laviolette and Grace, ; Felix-Ortiz et al. The BLA have extensive bi-directional monosynaptic glutamatergic projections with PFC PL and IL; Gabbott et al. Finally, the activity of stress response in the BLA is probably not only dependent on interactions with PFC, but also mediated by projections between PVN and amygdala Prewitt and Herman, The BLA has abundant output to the CeA and MeA, which have multisynaptic connections to the PVN Herman et al.

The CeA and MeA innervate brainstem structures that directly projects to PVN, such as the bed nucleus of the stria terminalis BNST; Prewitt and Herman, However, recent evidence with optogenetics approaches indicates that PVN projections to the CeA are activated during retrieval of long-term fear memories.

In contrast, retrieval of short-term memories is mostly dependent on PFC inputs to the BLA, indicating a time-dependent shift in fear memories circuits Do-Monte et al.

In turn, CeA has direct connections to periaqueductal gray PAG , a fundamental area that organizes the threat response LeDoux, Specifically, dorsal PAG is related to unconditioned threats exposure and ventral PAG is activated in conditioned threats, each one with distinct behavioral outputs.

While lesions in dorsal PAG increased freezing behavior, damage to the ventral PAG decreased freezing De Oca et al. Another important limbic structure for stress processing is the hippocampal formation McEwen et al. While the DG receives most of extra-hippocampal afferents from the entorhinal cortex via the perforant path Witter, , the CA1 and subiculum pyramidal neurons are the main HIPPO output to several areas, such as excitatory projections to PFC PL and IL and indirect inhibitory projections to PVN Barbas and Blatt, ; Herman and Mueller, The hippocampal inhibitory control over the HPA axis acts in a negative feedback manner inhibiting it Jacobson and Sapolsky, ; Herman et al.

The mainly indirect hypothalamic input of HIPPO originates in the CA1 and subiculum that densely innervate BNST and hypothalamic structures, except PVN Canteras and Swanson, ; Cullinan et al.

Projections from HIPPO to both the PFC and BLA present some of the most important role in memory but especially for the regulation of psychological stress response Godsil et al. HIPPO has bidirectional connections with BLA, but at the same time allows PFC to modulate the stress system with a top-down control Mcdonald, ; Janak and Tye, ; Radley et al.

However, the CA1 and subiculum monosynaptic glutamatergic efferents to PL and IL can become functionally disrupted after intense psychological stress Zheng and Zhang, In a strong emotional experience, HIPPO and BLA rapidly activate memory-related mechanisms of synaptic plasticity while PFC functioning is suppressed, promoting long-lasting flashbulb memories Diamond et al.

Therefore, in the presence of psychological stressors, if the activity of the amygdala and HIPPO becomes more prevalent, the stress system can switch to a bottom-up control Arnsten, On top of that, prolonged psychological stress decreases glutamatergic projection to interneurons in BLA, leading to loss of BLA inhibition by the PFC and finally, to the hyperexcitability of BLA, which is responsible for behavioral abnormalities related to stress Wei et al.

At this point, among several hypothalamic nuclei that are directly involved in regulating HPA axis and autonomic responses to stressors, the PVN stands out as the principal integrator of stress signals Herman et al.

In general, the medial parvocellular neurons of the PVN receive projections of first or second order of somatic afferent nociceptive, visceral, humoral or sensory pathways, beyond those of the limbic and reward system such as PFC, amygdala, HIPPO, VTA and NAc Russo and Nestler, ; Bains et al.

As already mentioned before, most limbic—PVN connections are indirect and are made through GABAergic cell groups in the BNST and peri-PVN regions of the hypothalamus Crestani et al. Studies involving activity mapping mostly c-Fos expression have demonstrated an important role for BNST in the regulation of the HPA axis Zhu et al.

In the reward system, pharmacological inhibition of NAc increased c-Fos expression in PVN Noh et al. Lastly, the parvocellular neurons of the PVN are strategically connected with several brainstem and forebrain nuclei such as NTS, DMH, LC, VLM, DMX and NA, important to the processing and integration of both modalities of stressors, physical and psychological, which results in a rapid activation of the HPA axis Ulrich-Lai and Herman, ; Senst and Bains, Many of the above circuitry and brain areas responsible for physical and psychological stressors may sound exclusively related to brainstem and forebrain, respectively.

However, some structures are also engaged with different modalities of stressor Figure 2. The best-characterized reward circuit in the brain is made up of dopaminergic neurons in the VTA that project to the NAc, a subdivision of the ventral striatum Bath et al.

The primary brain reward centers are inter-connected in complex ways in the brain reward circuitry, but mostly VTA and NAc regulates limbic areas mentioned above Heshmati and Russo, The dopaminergic tonus of VTA is fundamental to the recognition of rewards or punishment in the environment Russo and Nestler, On the other hand, the optogenetic stimulation of VTA dopaminergic neurons drives to a conditioned place preference Tsai et al.

However, VTA is composed by different neuronal subpopulations, which participate in distinct circuits that encode different motivational signature Lammel et al.

Dopaminergic neurons of VTA project to NAc, HIPPO, BLA and PFC, however, the NAc also receives glutamatergic innervations from ventral HIPPO, BLA and PFC Russo and Nestler, ; Lammel et al.

Indeed, dopaminergic neurons that innervate the mPFC show reduced firing after social defeat chronic stress Chaudhury et al. Dopaminergic neurons in VTA exhibit two patterns of spontaneous firing activity: a slow-frequency, single-spike firing and a burst firing, effectively regulating the activity of neurons in dopaminergic target areas and encoding reward-related signals Grace et al.

This mechanism of encoding and engaging specific networks makes sense since the behavioral response to a rewarding approach vs. an aversive experience aversion is different and therefore involves different, perhaps overlapping, neural circuits Lammel et al.

Accordingly, associating this fined-tuned VTA regulation to the stress processing, it has been proposed that a specific ventral VTA pathway is related to painful physical stress.

Several findings showed that dopaminergic cells that specifically project to the mPFC regulate the process of noxious stimuli Abercrombie et al.

But it is important to mention that although dopamine has a central role in processing physical stressors, in this scenario, the NAc detains the central role in regulating the reward system Grace et al. Essentially, HIPPO projections to NAc promote susceptibility to psychological stress, BLA-NAc pathway increases reward seeking behavior and PFC-NAc promotes resilience Stuber et al.

Increased firing of VTA dopaminergic neurons that innervate the NAc occurs only in susceptible mice after chronic social defeat stress, while VTA-PFC pathway reduced firing after the same protocol Chaudhury et al.

Therefore, we can see that while mesocortical pathways encode physical processing, the NAc may represent an important hub in processing psychological stress. Not only the PFC activity corresponds to an integrative hot point of limbic and reward circuitry, but also its contribution to the inhibition of the HPA axis by PFC top-down control is crucial.

If the inhibitory HPA axis feedback does not function properly, as in the case of chronic stress and neuropsychiatric disorders, the loss of negative feedback in the PVN regulated by the PFC and HIPPO, associated to the hyperexcitability of BLA and silencing of NAc creates a positive feedback in the PVN that can both overload the stress system Duvarci and Paré, ; Willner et al.

Also, regarding the PFC, interesting data have revealed that stimulation of PL enhances hypoxia-mediated corticosterone responses and PVN by using c-Fos activation mapping Jones et al. Some brainstem nuclei that regulate autonomic response, such as DMX and NAc, receive and send information from and to other regions of the CNS, respectively, including IL and PL portions of PFC, the CeA and BNST Ulrich-Lai and Herman, The CeA, previously mentioned as a central hub in fear response is also considered as a key node for stress integration Ulrich-Lai and Herman, Moreover, NTS is also densely innervated by afferent projections from the CeA Smith and Vale, The NTS can be activated during conditioning paradigms, suggesting that this pathway also plays a role in the integration of anticipatory stress Pezzone et al.

It is important to highlight that different modalities of stressors that activate the PVN also activate the LC-Norepinephrine LC-NE system, such as restraint, shock notably unpredictable , audiogenic stress, autonomic and immunological challenges and also social stress Wood and Valentino, The LC is a compact pontine nucleus adjacent to the fourth ventricle and houses the majority of the NE-expressing neurons in the brain and innervates the entire neuraxis Swanson and Hartman, Activation of the LC-NE occurs in parallel and coordinated with PVN activation.

This cross-talk between those nuclei allows a cognitive processing of the stress response engaging limbic and prosencephalic regions, such as the HIPPO and cortex, which govern neuronal excitability, cognition, memory and complex behaviors Joëls and de Kloet, ; Wood and Valentino, Recent techniques, such as chemogenetics, optogenetics, combined with traditional retrograde tracing, which enable selective manipulation of LC-NE system in rodents, determined the pivotal role of the LC-NE, for example, for stress-induced anxiety-like behavior McCall et al.

Interestingly, Corticotrophin Release Hormone CRH , which initially was discovered and defined as the hormone that initiates the cascade that ultimately leads to glucocorticoids release, seems to stand out as the molecule that coordinates the cross-talk between the two systems Valentino and Van Bockstaele, The LC-NE network is a major target of CRH Chappell et al.

During stress, CRH is released into the LC, increasing neuronal firing rate and consequently NE release in forebrain targets Valentino et al. Different structures that coordinate autonomic and limbic processing such as CeA Van Bockstaele et al. Interestingly, CRH release within the LC is regulated by basal levels of corticosteroids as well Valentino and Van Bockstaele, This communication between HPA and LC-NE axis determines the structural basis for emotional arousal, facilitates cognition and promote flexible behavioral responses to stress Cole and Koob, ; Valentino and Van Bockstaele, , since CRH release in the LC during stress facilitates shifting of attention between diverse stimuli Snyder et al.

Therefore, this crosstalk enables organisms to tailor different strategies to coping with constant changing environmental challenges. In fact, epinephrine E and NE are secreted from adrenal medulla Cannon, ; de Kloet et al.

The circuitry responsible for these autonomic modulations includes direct projections from PVN, LC and RVLM Iversen et al. Each pre-ganglionic fiber connects with many post-ganglionic neurons located in one or several pre-spinal ganglia or sympathetic paravertebral nuclei Boron and Boulpaep, Although, there are many efferent pathways of the ANS, only two neurons are necessary to transmit impulses between the CNS to the effector tissue Mccorry, Other pre-ganglionic neurons, which end at the spinal cord, do not make synapses with a post-ganglionic neuron.

For instance, they make synapses directly with chromaffin cells in the adrenal medulla Mccorry, ; Boron and Boulpaep, Thus, these two components increase the capacity of the sympathetic division in influencing body visceral responses Boron and Boulpaep, The sympathetic system activation leads to activation of signaling pathways that evoke changes in blood vessels, glands, visceral organs and smooth muscles Tank and Lee Wong, Pre-ganglionic parasympathetic neurons originate from craniosacral vertebral segments brainstem and sacral spinal cord synapse with post-ganglionic neurons in the terminal nodes located more peripherally, and usually on the wall of the target organs.

Post-parasympathetic ganglionic neurons stimulate the muscarinic and nicotinic receptors present on the membrane of the target cells by releasing acetylcholine Boron and Boulpaep, The effect caused by any of these substances, acetylcholine, norepinephrine and epinephrine, depends on the biochemical properties of the cells and on the receptor distribution in a determined tissue Mccorry, In general, SAM activation is considered to mediate short-term effects, with rapid responses, while the HPA axis activation leads to short and long-term effects Joëls and Baram, ; Tank and Lee Wong, Although, these sympathetic and parasympathetic systems act independently from each other Antunes-Rodrigues et al.

E and NE interact with adrenergic receptors present in cell membranes of smooth muscles and in numerous organs, as well as in neurons widespread in the CNS Mccorry, ; Tank and Lee Wong, These receptors are the G-protein coupled receptors GPCRs , which are homologous to muscarinic receptors, i.

There are two major types of adrenergic receptors; α- adrenergic and β-adrenergic receptors, with their subtypes Langer, ; Guimarães and Moura, ; Dünser and Hasibeder, Their effects include: maintaining alertness, metabolic actions increased glucose via glycogenolysis and gluconeogenesis, lipolysis, increased oxygen consumption and thermogenesis and cardiovascular actions Aires, The central noradrenergic system, specifically the LC is involved in multiple neurochemical circuits, having connections with neuroanatomical structures involved in the stress response, such as the HIPPO, amygdala and temporal neocortex.

Studies indicate an important role of the LC in response to acute stress Myers et al. However, chronic activation of the LC may have a potential role in the development of pathological behaviors related to stress Southwick et al. Thus, the release of NE has central actions, coordinates and modulates autonomic, endocrine and neuroendocrine responses, through extensive brain and spinal cord connections, while direct projections from LC to medial parvocellular division of the PVN Cunningham and Sawchenko, allows the modulation of the HPA axis Armario et al.

On the other hand, the activity of LC itself may be influenced by CRH through afferent projections from amygdala and brainstem nuclei McCall et al. When an organism faces a threatening stimulus, whether it is psychological or physical, as explained in the previous sections, many brain areas are activated in a coordinated fashion to recruit a complex structure known as hypothalamus, which is composed by many sub nuclei.

As already discussed, among those nuclei is the PVN, which is responsible for eliciting the activation of the HPA axis, one of the main components of the stress response.

The PVN synthesizes three different neurochemical compounds that behave either as neurotransmitters or hormones, depending on where they are acting. These compounds are oxytocin, vasopressin and CRH Vale et al. The pituitary is situated caudally and above the optical chiasm, and consists of an anterior portion adenohypophysis , that synthesizes and secretes hormones and of a posterior portion neuro-hypophysis , that stores oxytocin and vasopressin synthesized by the parvocellular neurons in the PVN McCann and Brobeck, ; Joëls and Baram, When CRH reaches the anterior pituitary, it stimulates the corticotrophs to synthesize and release the ACTH Vale et al.

ACTH is secreted through the hypophyseal portal system, and acts on the cortex of the adrenal gland, more specifically on the middle layer named fascicullata Vale et al.

The main glucocorticoid in humans is cortisol, and its equivalent in rodents is corticosterone de Kloet, Although the HPA axis has an ultradian rhythm Young et al. There are many evidences indicating that the suprachiasmatic nucleus SCN of the hypothalamus is the generator of the circadian rhythm Welsh et al.

Glucocorticoids act on the anterior pituitary, PVN and other brain structures, such as the HIPPO McEwen et al. This phenomenon is called short and long negative feedback loops, respectively de Kloet et al. Glucocorticoids are steroids and easily trespass cell membranes and since they are released in the bloodstream they can virtually reach any cell in the body.

Although peripherally the glucocorticoids act massively in several target-organs, here we focus on their effects on the brain. Cortisol, or corticosterone in rodents, exerts their effects in the brain by binding to two types of receptors, the glucocorticoid receptor GR and the mineralocorticoid receptor MR; Reul and de Kloet, ; de Kloet et al.

These receptors mediate the effects of glucocorticoids in the brain through genomic and non-genomic mechanisms Verkuyl et al. The MR shows 10 times higher affinity for corticosterone than GR Reul and de Kloet, Such difference is translated to receptor occupancy throughout the day, during the through phase of the circadian cycle, when glucocorticoid levels are low, MRs are occupied whereas the GRs are mostly free.

During the peak phase of the circadian cycle, or after high glucocorticoid release due to the stress response, MRs are completely occupied while GRs are partially occupied Kitchener et al. Although glucocorticoids are able to reach all neurons in the brain, they exert effects on those neurons expressing GRs and MRs.

GRs are abundant and widely spread throughout the brain. On the other hand, MRs are expressed in restricted areas of the brain Reul and de Kloet, It is also important to mention that there are some key structures that express both receptors, such as the PVN, HIPPO, amygdala, lateral septum, LC and NTS, among others.

Moreover, GR and MR also co-localize with adrenoreceptors allowing the interplay between the SAM and HPA axes Härfstrand et al.

These delayed and long-lasting effects of GR and MR receptor activation Joëls et al. Moreover, it has also been shown that not only genomic processes are triggered by GR and MR, actually there are studies clearly showing rapid effects of membrane-located MR and GR activation Borski, ; Johnson et al.

Important to mention, it has been demonstrated that GR levels, and consequently HPA axis function, can be modulated by the environment, as well as life experiences acute and chronic stressors , through stable changes in the DNA chromatin, which does not alter DNA sequence, a mechanism known as epigenetics Hunter et al.

Alterations such as methylation and acetylation of histones occur genomewide enhancing or hampering chromatin activity, however DNA methylation can also occur in a gene-specific fashion altering its expression Tsankova et al. In fact, Weaver et al.

These authors demonstrated that pups, which received low care licking and grooming the pups from their dams, had higher hippocampal NC3R1 methylation associated with lower GR expression, when compared to those that received high levels of licking and grooming. Epigenetic modulation of GR expression has also been described in humans as highlighted by Palma-Gudiel et al.

In the other hand, pre-clinical data have associated stress-induced epigenetic alterations with vulnerability or resilience to psychiatry-like conditions Covington et al.

Although, the discovery of the interplay between the inflammatory and endocrine systems is dated as a long-time story, it still remains as a hot topic in the field of stress research. At the same period Hans Selye discovered his canonical findings on stress, the prestigious Mayo Clinique developed the substance E Neeck, ; Hillier, ; Lupien, This substance crystalized by Dr.

Kendall Mason et al. Most recently, research on the relationship between stress hormones and immune system has unraveled many intricate pathways that also can be explored for their clinical implications. It has been postulated that besides preparing the body to deal with the environment demands, stress activates the immune system, which engages active defense against physical injury and pathogens.

Ultimately, cytokines are produced to promote multiple kinds of inflammatory responses Takahashi et al. But reports stated that stress-enhanced inflammatory activity is present in the absence of infectious pathogens, especially in depressed patients Audet et al.

To address whether stress or its hormones are pro or anti-inflammatory, evidence using rodent models demonstrated that stress itself can be both pro- and anti-inflammatory.

Some authors have proposed that the timing of immune challenges and measurements determines the direction of glucocorticoid actions. Those authors proposed that glucocorticoids initially present anti-inflammatory action, but later on sensitizes the immune response on the recovery phase after stressor; Frank et al.

Stress can directly influence immune signaling in two main ways, by reducing the inhibitory effects of glucocorticoid actions, or by directly stimulating the immune system via HPA axis and SAM Liu et al. But not only the neural components of stress engage the immune system, the immune system also affects the CNS, modulating the HPA axis Berkenbosch et al.

Therefore, acutely, stressful experiences enhanced levels of circulatory pro-inflammatory cytokines Steptoe et al. Some of these inflammatory cytokines are either locally produced by activated microglia Wohleb et al.

Interestingly, the sites that have increased pro-inflammatory immune reactivity appear to be related to acute stressor modalities. Social stressors increased expression of pro-inflammatory interleukins and activated microglia in sites such as PFC, amygdala and HIPPO Audet et al.

Stress mediators operate in a feedback loop after HPA axis activation, and regulate, in a positive or negative way, different brain structures to restore homeostasis de Kloet et al.

When the timing of stress response is inappropriate, aberrant HPA axis activity could lead to pathological states Heim et al.

We can divide basal regulation of glucocorticoids release in ultradian and circadian cycles, and also categorize the effects of stress response in rapid or delayed regarding their initiation, and in short or long-term, regarding their duration, in both scenarios they range from milliseconds to days Joëls et al.

Moreover, stress also differs when it occurs in early-life or adulthood of an individual, which can increase or decrease the possibility of developing brain disorders Lupien et al. In ultradian and circadian cycles, peaks of corticosterone release contribute to regulation of basal metabolic demand and the responsiveness of stress Lightman and Conway-Campbell, The origin of pulsatile corticosterone release in an ultradian and circadian fashion is not fully elucidated, but it has been a general assumption that the hypothalamus modulates this phenomenon, specifically, the hypothalamic SCN has efferent projections to neuroendocrine cells in the PVN that trigger the HPA axis activation Engeland and Arnhold, Acute stress mediators start acting within seconds after the stressor detection and provide quick responses to an appropriated strategy, involving modulation of limbic-cortical circuits Bains et al.

After corticosterone is released, frequency of miniature excitatory postsynaptic currents mEPSCs in PVN are suppressed, which decreases glutamatergic excitability and increases GABA inhibition Di et al.

These effects of corticosterone in the PVN occur mainly via non-genomic GR activity and endocannabinoid signaling Di et al. However, in other structures, excitatory activity is increased after acute stress Joëls et al. Similarly, mEPSC frequency in BLA is also increased via MR after acute corticosterone release Karst et al.

Interestingly, firing frequency of BLA neurons remains at high levels even after corticosterone washout, mainly modulated by GR and cannabinoid receptor 1 Karst et al. In cortical structures, such as the PFC, acute stress situation increases GR-dependent glutamate release Musazzi et al.

Hours after stressor exposure, delayed effects start to occur in a different way on limbic-cortical structures Joëls et al. Neurons of CA1 have enhanced amplitude but not frequency of mEPSCs via GR Karst et al.

The GR activity also modulates synaptic plasticity in CA1, promoting Long-term Depression LTD and impairs Long-term Potentiation LTP; Pavlides et al. In opposite, corticosterone presents delayed effects via MR by increasing the induction of LTP in CA1 Pavlides et al.

In BLA, delayed effects of corticosterone increase excitability of neurons, maintaining excitability after acute stress Duvarci and Paré, Similarly, corticosterone enhances glutamatergic transmission and reduces inhibitory post-synaptic currents mIPSCs in the PFC Hill et al.

These delayed effects of stress in limbic-cortical structures restore homeostasis, as well as retain important information to better cope with similar situations in the future Joëls et al.

When there is an over-exposure to stressors, lasting from hours to days, it is possible to observe structural changes in limbic-cortical areas and even in the reward system Joëls et al.

Dendritic complexity is progressively reduced in HIPPO and PFC, after chronic exposure to stressors McEwen and Magarinos, ; Holmes and Wellman, By contrast, neurons in the BLA and NAc increase dendritic density, increase excitatory tone and decrease inhibitory tone in this context Vyas et al.

At the cellular level, chronic stress impairs induction of LTP in CA1 of the HIPPO and reduces both AMPA and NMDA-mediated synaptic transmission Joëls et al. The behavioral consequences of these structural changes were associated with anxious behavior, probably by hypertrophy of the amygdala Mitra and Sapolsky, and deficits in learning, which could be explained by impaired hippocampal and PFC structures Joëls et al.

It is interesting to note that when chronic stress is experienced early in life, its effects on the brain last longer than when it occurs during adulthood Lupien et al.

When rodent pups are exposed to prolonged maternal separation, the density of CRH binding sites increases in HIPPO, amygdala and PFC Anisman et al. Activity of CRH mediates stress-related synaptic plasticity loss in the HIPPO, anxiogenic behavior dependent of amygdala and cognitive impairment associated with PFC Schulkin et al.

At this point, in our evolutionary history, stress could be implied in a maladaptive performance in a large proportion of the population, considering the large number of comorbidities that occur from dysfunction of the stress system de Kloet et al. The HPA axis dysregulation and prolonged exposure to glucocorticoids reduce the ability of neurons to resist insults, increasing the risk for injury by other toxic events Lupien et al.

Moreover, new researches have called attention to adversities in early life, which are greatly associated with higher vulnerability to disorders later in life, causing a long-term impact in the circuitry responsible for cognitive and emotional function Gold et al. In this sense, both basic and clinical researches have advanced in recent years but much remains to be understood about the subject.

In general, animal models have provided a comprehensive view of the stress effects on the brain, abundantly on the limbic structures Hariri and Holmes, The amygdala is a highly conserved brain structure that is fundamental to detect potential danger Janak and Tye, , while HIPPO provides support to encoding environmental information associated with the stressor Herman et al.

The identification of these highly evolutionary conserved networks that are affected by stress, allowed important discoveries in clinical research Hariri and Holmes, Increasing data highlight that highly debilitating stress comorbidities such as depression, anxiety disorders, PTSD and epilepsy share pathogenic mechanisms with stress dysfunction and between each other.

These mechanisms are probably deeply connected and the structural and functional change caused by one disease triggers the other, despite these it is still not clear on the relationship between them Gold et al. Considering this, we presented in this review a short glimpse of how stress is related to these CNS pathologies.

For further review, we suggest to look into the literature cited here. A significant percentage of patients with Major Depression MD have increased concentrations of cortisol in plasma, urine and cerebrospinal fluid, exaggerated cortisol response after ACTH hormone stimulation and hyperplasia of the pituitary and adrenal glands Gold et al.

Chronic stressors in early life result in permanent epigenetic, endocrine, neural, immune and inflammatory changes, constituting a relevant risk factor for several neuropsychiatric diseases in adult life Xiong and Zhang, ; Zhang et al.

In epilepsy, stress can influence in multiple ways, often as seizure-precipitating but also increased the risk of epilepsy development van Campen et al.

However, studies indicate that infancy coincides with a period referred as hyporesponsive period to stress Stress Hyporesponsive Period—SHRP , which is supposed to be a period that is necessary for the proper development of the brain after birth Sapolsky and Meaney, ; de Kloet et al.

It corresponds with a period of low peripheral concentration of glucocorticoids, in which a physiological response to mild stress increased glucocorticoids and adrenaline, increased cardiovascular circulation, immune system modifications does not occur.

There is no consensus when exactly this period starts or how long it lasts, but it is suggested that it could last from around the 2nd to 12th postnatal day in rodents Sapolsky and Meaney, and up to 5 years in humans Gunnar and Donzella, ; Curley et al.

Interestingly, psychological Sapolsky and Meaney, and multimodal stressors Godoy et al. The effects of stress during early life ELS on the brain have been deeply studied for review see Lupien et al. ELS disrupts the proper development and function of limbic structures, leading to lifelong susceptibility to stress on behavior and cognition as well as on the reward system Peña et al.

More recently it has been demonstrated that ELS led to an early emergence of timed developmental suppression of fear behavior that correlates to an early maturation Bath et al.

Depression-anxiety comorbidity is strongly associated with impairment in health, as well as in cognitive and emotional functions Kroenke et al.

Similarly, chronic treatment with corticosterone not only generates depressive-like symptoms but also induces amygdala hypertrophy and increases anxiogenic behavioral responses Mitra and Sapolsky, In humans, individual differences in amygdala reactivity to threat-related facial expressions predict vulnerability to stress, such as subjects with hyperactivation of the amygdala are more likely to experience depression and anxiety symptoms Yang et al.

Also, hyperactivation of LC-NE is related to neuropsychiatric disorders such as PTSD and MD, the activation of this system out of proper context may lead to hyperarousal, loss of concentration, restlessness and impaired focused attention, which are characteristic symptoms of stress-related psychiatric disorders Southwick et al.

For instance, PTSD is associated with increased rates of anxiety and depression Nemeroff et al. However, some clinical investigations reported low levels of cortisol in PTSD patients, while individuals with anxiety disorders or depression show an increase of cortisol response Daskalakis et al. Actually, the literature reports alterations in the HPA axis in PTSD patients and from the study by Mason et al.

However, there are studies also showing no differences Baker et al. Because this topic remains controversial in the literature, more insights such as those presented in Zoladz and Diamond are recommended.

Alterations in other compartments of the HPA axis were also identified in PTSD patients such as enhanced GR sensitivity and HPA axis enhanced negative feedback Grossman et al.

Animal models of PTSD can directly address these questions, but it is known that different types of aversive exposure in PTSD models e. Actually, exposure to severe stressors such as urban violence, sexual abuse, combat in war, disasters and many others, is believed to be associated to development of PTSD, leading individuals to present physiological and behavioral alterations including nightmares, hypervigilance, flashbacks of the trauma and sleep disturbances DSM-V, Zoladz and Diamond, ; Yehuda et al.

Although a positive correlation has been reported between the severity of the trauma and PTSD symptomatology in veteran soldiers Snow et al.

It has also been reported that the type of stressor seems to play a bigger role than its severity Kessler et al. Interestingly, not everybody develops PTSD after trauma exposure, which suggests that other factors despite the trauma severity and type , such as socioeconomic profile, psychiatry disorder history, substance abuse, immune system, genetics and epigenetics play a role on the susceptibility for PTSD.

Actually, there are evidences showing that the interplay between environment and genetics and epigenetics are risk factors for PTSD development Mehta and Binder, ; Wilker and Kolassa, ; DiGangi et al.

In patients with epilepsy, stress is usually reported as one of the major seizure precipitants Frucht et al. In adults, there is a positive correlation between stress and frequency of epileptic seizures Swinkels et al. Epileptogenesis is a multi-stage process that can begin early in life and may be negatively influenced by stress Joëls, , and it is now suggested that early life stress can create permanent vulnerability to the development of epilepsy Huang, Therefore, many evidences indicate that stress is relevant in the phases of epileptogenesis, both in adults and young people.

Corticosterone plays a contributory role in the epileptogenic process in animal models of epilepsy Karst et al. This could occur indirectly through the genomic effects of glucocorticoids, resulting in alterations of networks associated with seizures, or by direct non-genomic effects of these on the excitability of the limbic system Joëls, Other pathologies affect the peripheral nervous system and many different organs.

The CRH circuitry connecting LC-NE and PVN is strategically positioned so it may control autonomic responses to visceral stimuli and may underlie the co-morbidity of pelvic visceral and behavioral symptoms observed in many stress-related disorders Valentino et al.

Although most immediate responses coordinated by SAM axis are important for survival, when levels of circulating catecholamines are maintained elevated for prolonged periods of time, they can lead to different pathologies.

In the past decades identification of neuronal circuits associated to stress, as well as their interaction with mediators over time, was critical not only for understanding physiological stress responses, but also to understand their clinical implications.

Stress-related brain disorders are extremely prevalent, so identification of mechanisms related to stress and consequently the potential development of new pharmacological therapeutic approaches are necessary and urgent. As an example, pre-clinical studies on psychopathology-related topics are being done with classic GR antagonist RU Arp et al.

These compounds are the so-called selective glucocorticoid receptor modulators SGRMs which upon binding to the GR promote a differential conformation of the receptor leading to differential recruitment of corregulators and therefore enhancing or hampering gene expression in a cell-tissue specific manner.

Thus, the same compound can induce agonist- and antagonist-like effects, for instance the SGRMs C acts as an antagonist in neurogenesis related processes such as proliferation and survival of hippocampal neurons, and as an agonist in fear memory retention on the avoidance behavior task Zalachoras et al.

In the other hand the C compound acts as an antagonist in the same task whereas showing agonist effects on plasmatic corticosterone levels Atucha et al. From our own experience the Wistar Audiogenic Rat WAR strain is a genetically selected experimental epilepsy model, which displays after 56 generations of inbreeding, not only seizure-associated behaviors and electrophysiological alterations, but also comorbidities which includes high anxiety, hyperactive HPA axis, adrenal medulla hyperplasia, ectopic beats, high blood pressure, tachychardia and central respiratory alterations Fazan et al.

Further experiments are therefore needed in order to evaluate the pharmacological profile of new anti-epileptic, anxiolytic or even anti-depressive drugs, using as a model of comorbidities of the WAR strain.

In the clinical scenario a final comment can be done, when referring to the additional complexity associated, for example, to the presence of comorbid neurological and neuropsychiatric conditions, such as, for example, the epilepsies, autism and mood disorders, recognizing that we are talking about network disorders Kanner et al.

In the particular case of depression, anxiety and epilepsy, Kanner and Nogueira et al. Therefore stressors, which work as triggers, such as those cited in the current review, are common to all the situations.

On the other hand, Rayner highlights that complex cognitive networks associated to depression interact so strongly with epilepsy related networks, in a way that the difficulties with diagnosis and treatment increase, as soon as we recognize that those networks share common structures and mechanisms.

One way to overcome this, in order to make relevant and reliable contributions in this field, is the construction of algorhythms from computational neuroscience modeling, where actual data, either from basic science or from human clinical settings are used to generate predictions with translational value.

In that context, recently Spiga et al. inflammatory stress. In brief, these authors showed in a rat model, that although the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, coupling the regulatory network with the immune system would explain dissociated dynamics between ACTH and glucocorticoids observed when inflammatory stress is present.

We are able to adapt to the dynamic and challenging environment we live in, as well as to unexpected life events we face every now and then.

Examples are endless and, most of the time, we can overcome these events. We are able to do so because the existence of quite complex networks, which integrate body and brain, in order to enhance performance, promote adaptation and ultimately survival, the stress system.

A diversity of brain areas integrates sensorial, physiological and emotional signs. When different brain networks interpret these signs as a threat real or potential , a series of responses follow, increasing performance to deal with the situation and retain that information to better cope with similar situations in the future, characterizing the stress response.

The downside of the stress system is that sometimes it is not able to overcome the environmental, physiological or emotional demand. The aim of this review article was to bring comprehensive basic concepts about the stress system such as history of stress research, neuroanatomy, major effectors of the stress response, time domains of stress and the clinical implication of malfunction might have over the susceptibility to the development of increasingly-common brapdin disorders.

LDG, MTR and PD-P wrote the manuscript draft. NG-C and EHLU conceptualize, wrote and corrected the manuscript. LDG and MTR contributed equally to this work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank all students enrolled in the Course on Behavioural, Neuro-Psychopharmacological, Endocrine and Molecular Aspects of Stress RFI held at the Graduate Program in Physiology PROEX-CAPES of the FMRP-USP in July , who contributed with insightful discussions.

To the Course Staff Marian Joëls, Ron de Kloet, Mário Juruena, Marcus Brandão, Samia Joca and Cristiane Baes for their inspirational lectures. Abercrombie, E. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex.

doi: PubMed Abstract CrossRef Full Text Google Scholar. Aires, M. Rio de Janeiro: Guanabara-Koogan. Alt, S. Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed.

Psychoneuroendocrinology 35, — Amaral, D. The three-dimensional organization of the hippocampal formation: a review of anatomical data.

Neuroscience 31, — Amir, M. Type of trauma, severity of posttraumatic stress disorder core symptoms, and sssociated features. Andersen, P. The hippocampal lamella hypothesis revisited. Brain Res. Angeli, A. Modulation by cytokines of glucocorticoid action.

N Y Acad. Anisman, H. Do early-life events permantently alter behavior and hormonal responses to stressors? Antunes-Rodrigues, J. Neuroendocrinologia: Básica e Aplicada. Rio de Janeiro: Guanabra-Koogan. Armario, A. What can we know from pituitary-adrenal hormones about the nature and consequences of exposure to emotional stressors?

Arnsten, A. Stress signaling pathways that impair prefrontal cortex structure and function. Arp, J. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.

Atucha, E. Endocrinology , — Audet, M. Social defeat promotes specific cytokine variations within the prefrontal cortex upon subsequent aggressive or endotoxin challenges.

Brain Behav. Behavior and pro-inflammatory cytokine variations among submissive and dominant mice engaged in aggressive encounters: moderation by corticosterone reactivity.

Cytokine variations and mood disorders: influence of social stressors and social support. Bagot, R. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Bains, J. Stress-related synaptic plasticity in the hypothalamus. Baker, D. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder.

Psychiatry , — PubMed Abstract Google Scholar. Banks, W. The blood-brain barrier in psychoneuroimmunology. Barbas, H. Topographically specific hippocampal projections target functionally distinct prefrontal areas in the rhesus monkey. Hippocampus 5, — Başoglu, M.

Factors related to long-term traumatic stress responses in survivors of torture in Turkey. JAMA , — Bassareo, V. Differential expression of motivational stimulus properties by dopamine in nucleus accumbens shell versus core and prefrontal cortex. Bath, K. Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice.

Circuit and synaptic mechanisms of repeated stress: perspectives from differing contexts, duration, and development. Stress 7, — Bennur, S. Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator.

Neuroscience , 8— Berens, A. Biological embedding of childhood adversity: from physiological mechanisms to clinical implications. BMC Med. Berkenbosch, F. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin Science , — Boron, W.

The human costs of unmanaged work-related stress is extensive. Feeling unhappy about the amount of time you spend at work and neglecting other aspects of life because of work may increase your vulnerability to stress.

Increased levels of stress can, if not addressed early enough, lead to burnout or more severe mental health problems.

In , mental health accounted for , cases of work-related illness with a related estimated cost of £ Money and debt concerns place huge pressure on us, so it comes as no surprise that they have a marked effect on our stress levels. The effects of the cost-of-living crisis in has affected everyone in some capacity.

A survey of adults commissioned by the Mental Health Foundation in November found that one in ten UK adults was feeling hopeless about their financial circumstances. More than one-third were feeling anxious and almost three in ten were feeling stressed.

The combination of chronic stress and debt can result in depression and anxiety and has been highlighted as a factor linked to suicidal thoughts and attempts. You could also talk to your GP or a trusted health professional if you are worried about how debt is affecting your mental and physical health.

Some people smoke, drink alcohol and use recreational drugs to reduce stress. But, this often makes problems worse. Research shows that smoking may increase feelings of anxiety. Nicotine creates an immediate, temporary, sense of relaxation, which can then lead to withdrawal symptoms and cravings.

Similarly, people may use alcohol as a means to manage and cope with difficult feelings, and to temporarily reduce feelings of anxiety.

But, alcohol can make existing mental health problems worse. It can make you feel more anxious and depressed in the long run. Prescription drugs , such as tranquillisers and sleeping tablets, which may have been prescribed for very good reasons, can also cause mental and physical health problems if used for long periods of time.

Street drugs , such as cannabis or ecstasy, are usually taken for recreational purposes. For some people, problems start as their bodies get used to repeated use of the drug. This leads to the need for increased doses to maintain the same effect.

Stress is a natural reaction to difficult situations in life, such as work, family, relationships and money problems. We mentioned earlier on that a moderate amount of stress can help us perform better in challenging situations, but too much or prolonged stress can lead to physical problems.

This can include lower immunity levels, digestive and intestinal difficulties such as irritable bowel syndrome IBS , or mental health problems such as depression. The first person to approach is your GP. They should be able to give you advice about treatment, and may refer you to another local professional.

Cognitive Behavioural Therapy and Mindfulness -based approaches are known to help reduce stress. There are also a number of voluntary organisations which can help you to tackle the causes of stress and advise you about ways to get better.

Some teams provide hour services so that you can contact them in a crisis. You should be able to contact your local CMHT through your local social services or social work team.

Everybody is different and what works for one person might not work for another. Here are tips, find what works for you and give them a try. If you feel affected by the content you have read, please see our get help page for support. The Mental Health Foundation today welcomes publication of the Mental Health Strategy for Northern Ireland.

Breadcrumb Home Explore mental health Publications. How to manage and reduce stress. This guide provides you with tips on how to manage and reduce stress Stress is a feeling of being under abnormal pressure, whether from an increased workload, an argument with a family member, or financial worries.

What is stress? Stress affects us in lots of ways, both physically and emotionally, and in varying intensities.

Physical symptoms of stress People react differently to stress. Behavioural and emotional effects of stress When you are stressed you may have lots of different feelings, including anxiety, irritability or low self-esteem, which can lead you to become withdrawn, indecisive or tearful.

Identifying the signs of stress Everyone experiences stress. While stress affects everyone differently, there are common signs and symptoms for you to look out for: Feelings of constant worry or anxiety Feelings of being overwhelmed Difficulty concentrating Mood swings or changes in mood Irritability or having a short temper Difficulty relaxing Depression Low self-esteem Eating more or less than usual Changes in sleeping habits Using alcohol, tobacco or illegal drugs to relax Aches and pains, particularly muscle tension Diarrhoea and constipation Feelings of nausea or dizziness Loss of sex drive If you experience these symptoms for a prolonged period of time, and feel they are affecting your everyday life or making you feel unwell, speak to your GP.

What causes stress? When an organism faces a threatening stimulus, whether it is psychological or physical, as explained in the previous sections, many brain areas are activated in a coordinated fashion to recruit a complex structure known as hypothalamus, which is composed by many sub nuclei.

As already discussed, among those nuclei is the PVN, which is responsible for eliciting the activation of the HPA axis, one of the main components of the stress response.

The PVN synthesizes three different neurochemical compounds that behave either as neurotransmitters or hormones, depending on where they are acting.

These compounds are oxytocin, vasopressin and CRH Vale et al. The pituitary is situated caudally and above the optical chiasm, and consists of an anterior portion adenohypophysis , that synthesizes and secretes hormones and of a posterior portion neuro-hypophysis , that stores oxytocin and vasopressin synthesized by the parvocellular neurons in the PVN McCann and Brobeck, ; Joëls and Baram, When CRH reaches the anterior pituitary, it stimulates the corticotrophs to synthesize and release the ACTH Vale et al.

ACTH is secreted through the hypophyseal portal system, and acts on the cortex of the adrenal gland, more specifically on the middle layer named fascicullata Vale et al.

The main glucocorticoid in humans is cortisol, and its equivalent in rodents is corticosterone de Kloet, Although the HPA axis has an ultradian rhythm Young et al. There are many evidences indicating that the suprachiasmatic nucleus SCN of the hypothalamus is the generator of the circadian rhythm Welsh et al.

Glucocorticoids act on the anterior pituitary, PVN and other brain structures, such as the HIPPO McEwen et al. This phenomenon is called short and long negative feedback loops, respectively de Kloet et al. Glucocorticoids are steroids and easily trespass cell membranes and since they are released in the bloodstream they can virtually reach any cell in the body.

Although peripherally the glucocorticoids act massively in several target-organs, here we focus on their effects on the brain. Cortisol, or corticosterone in rodents, exerts their effects in the brain by binding to two types of receptors, the glucocorticoid receptor GR and the mineralocorticoid receptor MR; Reul and de Kloet, ; de Kloet et al.

These receptors mediate the effects of glucocorticoids in the brain through genomic and non-genomic mechanisms Verkuyl et al. The MR shows 10 times higher affinity for corticosterone than GR Reul and de Kloet, Such difference is translated to receptor occupancy throughout the day, during the through phase of the circadian cycle, when glucocorticoid levels are low, MRs are occupied whereas the GRs are mostly free.

During the peak phase of the circadian cycle, or after high glucocorticoid release due to the stress response, MRs are completely occupied while GRs are partially occupied Kitchener et al.

Although glucocorticoids are able to reach all neurons in the brain, they exert effects on those neurons expressing GRs and MRs. GRs are abundant and widely spread throughout the brain. On the other hand, MRs are expressed in restricted areas of the brain Reul and de Kloet, It is also important to mention that there are some key structures that express both receptors, such as the PVN, HIPPO, amygdala, lateral septum, LC and NTS, among others.

Moreover, GR and MR also co-localize with adrenoreceptors allowing the interplay between the SAM and HPA axes Härfstrand et al. These delayed and long-lasting effects of GR and MR receptor activation Joëls et al. Moreover, it has also been shown that not only genomic processes are triggered by GR and MR, actually there are studies clearly showing rapid effects of membrane-located MR and GR activation Borski, ; Johnson et al.

Important to mention, it has been demonstrated that GR levels, and consequently HPA axis function, can be modulated by the environment, as well as life experiences acute and chronic stressors , through stable changes in the DNA chromatin, which does not alter DNA sequence, a mechanism known as epigenetics Hunter et al.

Alterations such as methylation and acetylation of histones occur genomewide enhancing or hampering chromatin activity, however DNA methylation can also occur in a gene-specific fashion altering its expression Tsankova et al.

In fact, Weaver et al. These authors demonstrated that pups, which received low care licking and grooming the pups from their dams, had higher hippocampal NC3R1 methylation associated with lower GR expression, when compared to those that received high levels of licking and grooming.

Epigenetic modulation of GR expression has also been described in humans as highlighted by Palma-Gudiel et al. In the other hand, pre-clinical data have associated stress-induced epigenetic alterations with vulnerability or resilience to psychiatry-like conditions Covington et al.

Although, the discovery of the interplay between the inflammatory and endocrine systems is dated as a long-time story, it still remains as a hot topic in the field of stress research.

At the same period Hans Selye discovered his canonical findings on stress, the prestigious Mayo Clinique developed the substance E Neeck, ; Hillier, ; Lupien, This substance crystalized by Dr. Kendall Mason et al.

Most recently, research on the relationship between stress hormones and immune system has unraveled many intricate pathways that also can be explored for their clinical implications.

It has been postulated that besides preparing the body to deal with the environment demands, stress activates the immune system, which engages active defense against physical injury and pathogens. Ultimately, cytokines are produced to promote multiple kinds of inflammatory responses Takahashi et al.

But reports stated that stress-enhanced inflammatory activity is present in the absence of infectious pathogens, especially in depressed patients Audet et al.

To address whether stress or its hormones are pro or anti-inflammatory, evidence using rodent models demonstrated that stress itself can be both pro- and anti-inflammatory.

Some authors have proposed that the timing of immune challenges and measurements determines the direction of glucocorticoid actions.

Those authors proposed that glucocorticoids initially present anti-inflammatory action, but later on sensitizes the immune response on the recovery phase after stressor; Frank et al.

Stress can directly influence immune signaling in two main ways, by reducing the inhibitory effects of glucocorticoid actions, or by directly stimulating the immune system via HPA axis and SAM Liu et al. But not only the neural components of stress engage the immune system, the immune system also affects the CNS, modulating the HPA axis Berkenbosch et al.

Therefore, acutely, stressful experiences enhanced levels of circulatory pro-inflammatory cytokines Steptoe et al.

Some of these inflammatory cytokines are either locally produced by activated microglia Wohleb et al. Interestingly, the sites that have increased pro-inflammatory immune reactivity appear to be related to acute stressor modalities.

Social stressors increased expression of pro-inflammatory interleukins and activated microglia in sites such as PFC, amygdala and HIPPO Audet et al. Stress mediators operate in a feedback loop after HPA axis activation, and regulate, in a positive or negative way, different brain structures to restore homeostasis de Kloet et al.

When the timing of stress response is inappropriate, aberrant HPA axis activity could lead to pathological states Heim et al. We can divide basal regulation of glucocorticoids release in ultradian and circadian cycles, and also categorize the effects of stress response in rapid or delayed regarding their initiation, and in short or long-term, regarding their duration, in both scenarios they range from milliseconds to days Joëls et al.

Moreover, stress also differs when it occurs in early-life or adulthood of an individual, which can increase or decrease the possibility of developing brain disorders Lupien et al. In ultradian and circadian cycles, peaks of corticosterone release contribute to regulation of basal metabolic demand and the responsiveness of stress Lightman and Conway-Campbell, The origin of pulsatile corticosterone release in an ultradian and circadian fashion is not fully elucidated, but it has been a general assumption that the hypothalamus modulates this phenomenon, specifically, the hypothalamic SCN has efferent projections to neuroendocrine cells in the PVN that trigger the HPA axis activation Engeland and Arnhold, Acute stress mediators start acting within seconds after the stressor detection and provide quick responses to an appropriated strategy, involving modulation of limbic-cortical circuits Bains et al.

After corticosterone is released, frequency of miniature excitatory postsynaptic currents mEPSCs in PVN are suppressed, which decreases glutamatergic excitability and increases GABA inhibition Di et al. These effects of corticosterone in the PVN occur mainly via non-genomic GR activity and endocannabinoid signaling Di et al.

However, in other structures, excitatory activity is increased after acute stress Joëls et al. Similarly, mEPSC frequency in BLA is also increased via MR after acute corticosterone release Karst et al.

Interestingly, firing frequency of BLA neurons remains at high levels even after corticosterone washout, mainly modulated by GR and cannabinoid receptor 1 Karst et al. In cortical structures, such as the PFC, acute stress situation increases GR-dependent glutamate release Musazzi et al.

Hours after stressor exposure, delayed effects start to occur in a different way on limbic-cortical structures Joëls et al. Neurons of CA1 have enhanced amplitude but not frequency of mEPSCs via GR Karst et al. The GR activity also modulates synaptic plasticity in CA1, promoting Long-term Depression LTD and impairs Long-term Potentiation LTP; Pavlides et al.

In opposite, corticosterone presents delayed effects via MR by increasing the induction of LTP in CA1 Pavlides et al. In BLA, delayed effects of corticosterone increase excitability of neurons, maintaining excitability after acute stress Duvarci and Paré, Similarly, corticosterone enhances glutamatergic transmission and reduces inhibitory post-synaptic currents mIPSCs in the PFC Hill et al.

These delayed effects of stress in limbic-cortical structures restore homeostasis, as well as retain important information to better cope with similar situations in the future Joëls et al.

When there is an over-exposure to stressors, lasting from hours to days, it is possible to observe structural changes in limbic-cortical areas and even in the reward system Joëls et al. Dendritic complexity is progressively reduced in HIPPO and PFC, after chronic exposure to stressors McEwen and Magarinos, ; Holmes and Wellman, By contrast, neurons in the BLA and NAc increase dendritic density, increase excitatory tone and decrease inhibitory tone in this context Vyas et al.

At the cellular level, chronic stress impairs induction of LTP in CA1 of the HIPPO and reduces both AMPA and NMDA-mediated synaptic transmission Joëls et al. The behavioral consequences of these structural changes were associated with anxious behavior, probably by hypertrophy of the amygdala Mitra and Sapolsky, and deficits in learning, which could be explained by impaired hippocampal and PFC structures Joëls et al.

It is interesting to note that when chronic stress is experienced early in life, its effects on the brain last longer than when it occurs during adulthood Lupien et al. When rodent pups are exposed to prolonged maternal separation, the density of CRH binding sites increases in HIPPO, amygdala and PFC Anisman et al.

Activity of CRH mediates stress-related synaptic plasticity loss in the HIPPO, anxiogenic behavior dependent of amygdala and cognitive impairment associated with PFC Schulkin et al.

At this point, in our evolutionary history, stress could be implied in a maladaptive performance in a large proportion of the population, considering the large number of comorbidities that occur from dysfunction of the stress system de Kloet et al. The HPA axis dysregulation and prolonged exposure to glucocorticoids reduce the ability of neurons to resist insults, increasing the risk for injury by other toxic events Lupien et al.

Moreover, new researches have called attention to adversities in early life, which are greatly associated with higher vulnerability to disorders later in life, causing a long-term impact in the circuitry responsible for cognitive and emotional function Gold et al.

In this sense, both basic and clinical researches have advanced in recent years but much remains to be understood about the subject. In general, animal models have provided a comprehensive view of the stress effects on the brain, abundantly on the limbic structures Hariri and Holmes, The amygdala is a highly conserved brain structure that is fundamental to detect potential danger Janak and Tye, , while HIPPO provides support to encoding environmental information associated with the stressor Herman et al.

The identification of these highly evolutionary conserved networks that are affected by stress, allowed important discoveries in clinical research Hariri and Holmes, Increasing data highlight that highly debilitating stress comorbidities such as depression, anxiety disorders, PTSD and epilepsy share pathogenic mechanisms with stress dysfunction and between each other.

These mechanisms are probably deeply connected and the structural and functional change caused by one disease triggers the other, despite these it is still not clear on the relationship between them Gold et al. Considering this, we presented in this review a short glimpse of how stress is related to these CNS pathologies.

For further review, we suggest to look into the literature cited here. A significant percentage of patients with Major Depression MD have increased concentrations of cortisol in plasma, urine and cerebrospinal fluid, exaggerated cortisol response after ACTH hormone stimulation and hyperplasia of the pituitary and adrenal glands Gold et al.

Chronic stressors in early life result in permanent epigenetic, endocrine, neural, immune and inflammatory changes, constituting a relevant risk factor for several neuropsychiatric diseases in adult life Xiong and Zhang, ; Zhang et al.

In epilepsy, stress can influence in multiple ways, often as seizure-precipitating but also increased the risk of epilepsy development van Campen et al. However, studies indicate that infancy coincides with a period referred as hyporesponsive period to stress Stress Hyporesponsive Period—SHRP , which is supposed to be a period that is necessary for the proper development of the brain after birth Sapolsky and Meaney, ; de Kloet et al.

It corresponds with a period of low peripheral concentration of glucocorticoids, in which a physiological response to mild stress increased glucocorticoids and adrenaline, increased cardiovascular circulation, immune system modifications does not occur.

There is no consensus when exactly this period starts or how long it lasts, but it is suggested that it could last from around the 2nd to 12th postnatal day in rodents Sapolsky and Meaney, and up to 5 years in humans Gunnar and Donzella, ; Curley et al.

Interestingly, psychological Sapolsky and Meaney, and multimodal stressors Godoy et al. The effects of stress during early life ELS on the brain have been deeply studied for review see Lupien et al. ELS disrupts the proper development and function of limbic structures, leading to lifelong susceptibility to stress on behavior and cognition as well as on the reward system Peña et al.

More recently it has been demonstrated that ELS led to an early emergence of timed developmental suppression of fear behavior that correlates to an early maturation Bath et al. Depression-anxiety comorbidity is strongly associated with impairment in health, as well as in cognitive and emotional functions Kroenke et al.

Similarly, chronic treatment with corticosterone not only generates depressive-like symptoms but also induces amygdala hypertrophy and increases anxiogenic behavioral responses Mitra and Sapolsky, In humans, individual differences in amygdala reactivity to threat-related facial expressions predict vulnerability to stress, such as subjects with hyperactivation of the amygdala are more likely to experience depression and anxiety symptoms Yang et al.

Also, hyperactivation of LC-NE is related to neuropsychiatric disorders such as PTSD and MD, the activation of this system out of proper context may lead to hyperarousal, loss of concentration, restlessness and impaired focused attention, which are characteristic symptoms of stress-related psychiatric disorders Southwick et al.

For instance, PTSD is associated with increased rates of anxiety and depression Nemeroff et al. However, some clinical investigations reported low levels of cortisol in PTSD patients, while individuals with anxiety disorders or depression show an increase of cortisol response Daskalakis et al.

Actually, the literature reports alterations in the HPA axis in PTSD patients and from the study by Mason et al. However, there are studies also showing no differences Baker et al. Because this topic remains controversial in the literature, more insights such as those presented in Zoladz and Diamond are recommended.

Alterations in other compartments of the HPA axis were also identified in PTSD patients such as enhanced GR sensitivity and HPA axis enhanced negative feedback Grossman et al.

Animal models of PTSD can directly address these questions, but it is known that different types of aversive exposure in PTSD models e. Actually, exposure to severe stressors such as urban violence, sexual abuse, combat in war, disasters and many others, is believed to be associated to development of PTSD, leading individuals to present physiological and behavioral alterations including nightmares, hypervigilance, flashbacks of the trauma and sleep disturbances DSM-V, Zoladz and Diamond, ; Yehuda et al.

Although a positive correlation has been reported between the severity of the trauma and PTSD symptomatology in veteran soldiers Snow et al. It has also been reported that the type of stressor seems to play a bigger role than its severity Kessler et al.

Interestingly, not everybody develops PTSD after trauma exposure, which suggests that other factors despite the trauma severity and type , such as socioeconomic profile, psychiatry disorder history, substance abuse, immune system, genetics and epigenetics play a role on the susceptibility for PTSD.

Actually, there are evidences showing that the interplay between environment and genetics and epigenetics are risk factors for PTSD development Mehta and Binder, ; Wilker and Kolassa, ; DiGangi et al.

In patients with epilepsy, stress is usually reported as one of the major seizure precipitants Frucht et al. In adults, there is a positive correlation between stress and frequency of epileptic seizures Swinkels et al.

Epileptogenesis is a multi-stage process that can begin early in life and may be negatively influenced by stress Joëls, , and it is now suggested that early life stress can create permanent vulnerability to the development of epilepsy Huang, Therefore, many evidences indicate that stress is relevant in the phases of epileptogenesis, both in adults and young people.

Corticosterone plays a contributory role in the epileptogenic process in animal models of epilepsy Karst et al. This could occur indirectly through the genomic effects of glucocorticoids, resulting in alterations of networks associated with seizures, or by direct non-genomic effects of these on the excitability of the limbic system Joëls, Other pathologies affect the peripheral nervous system and many different organs.

The CRH circuitry connecting LC-NE and PVN is strategically positioned so it may control autonomic responses to visceral stimuli and may underlie the co-morbidity of pelvic visceral and behavioral symptoms observed in many stress-related disorders Valentino et al.

Although most immediate responses coordinated by SAM axis are important for survival, when levels of circulating catecholamines are maintained elevated for prolonged periods of time, they can lead to different pathologies.

In the past decades identification of neuronal circuits associated to stress, as well as their interaction with mediators over time, was critical not only for understanding physiological stress responses, but also to understand their clinical implications.

Stress-related brain disorders are extremely prevalent, so identification of mechanisms related to stress and consequently the potential development of new pharmacological therapeutic approaches are necessary and urgent.

As an example, pre-clinical studies on psychopathology-related topics are being done with classic GR antagonist RU Arp et al. These compounds are the so-called selective glucocorticoid receptor modulators SGRMs which upon binding to the GR promote a differential conformation of the receptor leading to differential recruitment of corregulators and therefore enhancing or hampering gene expression in a cell-tissue specific manner.

Thus, the same compound can induce agonist- and antagonist-like effects, for instance the SGRMs C acts as an antagonist in neurogenesis related processes such as proliferation and survival of hippocampal neurons, and as an agonist in fear memory retention on the avoidance behavior task Zalachoras et al.

In the other hand the C compound acts as an antagonist in the same task whereas showing agonist effects on plasmatic corticosterone levels Atucha et al. From our own experience the Wistar Audiogenic Rat WAR strain is a genetically selected experimental epilepsy model, which displays after 56 generations of inbreeding, not only seizure-associated behaviors and electrophysiological alterations, but also comorbidities which includes high anxiety, hyperactive HPA axis, adrenal medulla hyperplasia, ectopic beats, high blood pressure, tachychardia and central respiratory alterations Fazan et al.

Further experiments are therefore needed in order to evaluate the pharmacological profile of new anti-epileptic, anxiolytic or even anti-depressive drugs, using as a model of comorbidities of the WAR strain.

In the clinical scenario a final comment can be done, when referring to the additional complexity associated, for example, to the presence of comorbid neurological and neuropsychiatric conditions, such as, for example, the epilepsies, autism and mood disorders, recognizing that we are talking about network disorders Kanner et al.

In the particular case of depression, anxiety and epilepsy, Kanner and Nogueira et al. Therefore stressors, which work as triggers, such as those cited in the current review, are common to all the situations.

On the other hand, Rayner highlights that complex cognitive networks associated to depression interact so strongly with epilepsy related networks, in a way that the difficulties with diagnosis and treatment increase, as soon as we recognize that those networks share common structures and mechanisms.

One way to overcome this, in order to make relevant and reliable contributions in this field, is the construction of algorhythms from computational neuroscience modeling, where actual data, either from basic science or from human clinical settings are used to generate predictions with translational value.

In that context, recently Spiga et al. inflammatory stress. In brief, these authors showed in a rat model, that although the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, coupling the regulatory network with the immune system would explain dissociated dynamics between ACTH and glucocorticoids observed when inflammatory stress is present.

We are able to adapt to the dynamic and challenging environment we live in, as well as to unexpected life events we face every now and then. Examples are endless and, most of the time, we can overcome these events.

We are able to do so because the existence of quite complex networks, which integrate body and brain, in order to enhance performance, promote adaptation and ultimately survival, the stress system.

A diversity of brain areas integrates sensorial, physiological and emotional signs. When different brain networks interpret these signs as a threat real or potential , a series of responses follow, increasing performance to deal with the situation and retain that information to better cope with similar situations in the future, characterizing the stress response.

The downside of the stress system is that sometimes it is not able to overcome the environmental, physiological or emotional demand. The aim of this review article was to bring comprehensive basic concepts about the stress system such as history of stress research, neuroanatomy, major effectors of the stress response, time domains of stress and the clinical implication of malfunction might have over the susceptibility to the development of increasingly-common brapdin disorders.

LDG, MTR and PD-P wrote the manuscript draft. NG-C and EHLU conceptualize, wrote and corrected the manuscript. LDG and MTR contributed equally to this work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We would like to thank all students enrolled in the Course on Behavioural, Neuro-Psychopharmacological, Endocrine and Molecular Aspects of Stress RFI held at the Graduate Program in Physiology PROEX-CAPES of the FMRP-USP in July , who contributed with insightful discussions.

To the Course Staff Marian Joëls, Ron de Kloet, Mário Juruena, Marcus Brandão, Samia Joca and Cristiane Baes for their inspirational lectures. Abercrombie, E. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex.

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This can help people to fall asleep faster and stay asleep longer, leading to improved quality of rest. Given how important sleep is for both our physical and mental wellbeing, those with air conditioning units in their homes will hopefully stay on top of any Preventative Maintenance to ensure that they will continue to sleep sound in the perfect temperature throughout the whole year.

Cooler temperatures have been found to increase alertness and productivity in humans. As such, it is not surprising that offices tend to keep their air conditioning set lower than residential homes as this helps employees focus on their work better.

It stands to reason that if hot temperatures make us angry and irritable, then over long periods of time this can lead to mental health issues. Studies have found that hotter climates can contribute to feelings of depression and anxiety in people who are prone to these conditions.

Research has shown conclusively that air conditioning is essential for preserving our mental health. It not only helps control the temperature and humidity levels, but it also lowers stress, enhances sleep quality, and keeps us awake and productive.

Also, installing an air conditioning system in our homes or places of business can prevent us from experiencing mental health problems. Hence, keeping excellent emotional and mental health requires having an air conditioning system.

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