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Review
. 2018 Jul 3:12:127.
doi: 10.3389/fnbeh.2018.00127. eCollection 2018.

A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications

Lívea Dornela Godoy  1 , Matheus Teixeira Rossignoli  2 , Polianna Delfino-Pereira  2 , Norberto Garcia-Cairasco  1   2 , Eduardo Henrique de Lima Umeoka  2
Affiliations
Review

A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications

Lívea Dornela Godoy et al. Front Behav Neurosci. .

Abstract

Stress is recognized as an important issue in basic and clinical neuroscience research, based upon the founding historical studies by Walter Canon and Hans Selye in the past century, when the concept of stress emerged in a biological and adaptive perspective. A lot of research after that period has expanded the knowledge in the stress field. Since then, it was discovered that the response to stressful stimuli is elaborated and triggered by the, now known, stress system, which integrates a wide diversity of brain structures that, collectively, are able to detect events and interpret them as real or potential threats. However, different types of stressors engage different brain networks, requiring a fine-tuned functional neuroanatomical processing. This integration of information from the stressor itself may result in a rapid activation of the Sympathetic-Adreno-Medullar (SAM) axis and the Hypothalamus-Pituitary-Adrenal (HPA) axis, the two major components involved in the stress response. The complexity of the stress response is not restricted to neuroanatomy or to SAM and HPA axes mediators, but also diverge according to timing and duration of stressor exposure, as well as its short- and/or long-term consequences. The identification of neuronal circuits of stress, as well as their interaction with mediator molecules over time is critical, not only for understanding the physiological stress responses, but also to understand their implications on mental health.

Keywords: HPA axis; HPA axis time-domain; SAM axis; clinical implications of stress; neuroanatomy; physical and psychological stressors; stress history; stress response.

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Figures

Figure 1
Figure 1
The stress system. Processing and coping with stressful situations requires the engagement of complex mechanisms that integrate brain and body. The response to stressful stimuli is articulated by a wide diversity of brain structures that collectively are able to detect or interpret events as either real or potential threats (stressors). The perception of these events as stressors involves different networks depending whether it is a physical or psychological stressor. The identification of a stressor leads to activation of two major constituents of the stress system and the release of its final mediating molecules. The sympathetic-adreno-medullar (SAM) axis, secretes noradrenaline and norepinephrine and the hypothalamus-pituitary-adrenal (HPA) axis, secretes glucocorticoids. Once these axes are activated in response to a given stressor, they will generate a coordinated response that starts within seconds and might last for days, providing quick responses enabling both, an appropriated strategy, almost immediately, and homeostasis restoration. To accomplish this, the stress response systemically promotes energy mobilization, metabolic changes, activation of the immune system and suppression of the digestive and reproductive systems. More specifically in the brain, the stress response induces short- and long-term effects through non-genomic, genomic and epigenetic mechanisms. These central effects, combined with proinflammatory signaling, lead to alterations in cellular excitability as well as synaptic and neuronal plasticity. Collectively, these body-brain effects mediate alterations in physiology and behavior that enable adaptation and survival.
Figure 2
Figure 2
Neuroanatomy of stress. Schematic representation of primarily neuroanatomical substrates responsible for physical (pink) and psychological (blue) stressors processing. Upper panels show that neural processing for different types of stressors detection and appraisal of the situation engage several structures, which may overlap at some instances on human and rodent brain (A,B, respectively). Bottom panels represent how physical and psychogenic stressors require engagement of different networks (C,D, respectively). Physical stressors mainly activate structures related to vital functions control located on brainstem and hypothalamus. Structures such as the nucleus of the solitary tract (NTS) and locus coeruleus (LC) have an important role in the physical stress pathways. However, prosencephalic regions also participate in physical stress processing, such as prelimbic area (PL) in pre-frontal cortex (PFC). Also, it is important to mention that the central nucleus of the amygdala (CeA) participates in autonomic response integration. For instance, psychological stressors are perceived in an anticipatory condition, which may heavily rely on limbic structures and can be modulated by the reward system. The PFC is critical to develop appropriate responses to environment changes, and it is densely innervated by dopaminergic projections from the Ventral Tegmental Area (VTA) and Nucleus Accumbens (NAc). PFC disruption is associated with anhedonia and aberrant reward-seeking behavior. Although PFC involvement is complex and integrates different stress responses in general, PL and Infralimbic (IL) regions coordinate a top-down control. The amygdaloid complex also participates on psychological stress circuitry and with PFC disruption its involvement becomes more prevalent, and the circuitry switches to a bottom-up control. Another important structure that stands out due to its importance on cognitive and memory function, and that is activated in response to both physical and psychological stressors is the Hippocampus (HIPPO). The CA1 region has important connections with the above-mentioned limbic structures and HIPPO is an important structure of the HPA axis negative feedback. The paraventricular nucleus of hypothalamus (PVN) and LC (shown in gray) represent the main relay of the stress response triggering respectively the HPA and the SAM axis. The cross-talk activity between those nuclei allows a cognitive processing of the stress response and enables complex behavioral responses.
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