The hypothalamo-pituitary-adrenocortical (HPA axis) is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem), promote trans-synaptic inhibition by limbic structures (e.g, hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic and brainstem circuits. Importantly, an individual’s response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex and age. The context in which stressors occur will determine whether an individual’s acute or chronic stress responses are adaptive or maladaptive (pathological).

Environmental stimuli that signal real or potential threats to homeostasis lead to glucocorticoid secretion by the hypothalamic-pituitary-adrenocortical (HPA) axis. Glucocorticoids promote energy redistribution and are critical for survival and adaptation. This adaptation requires the integration of multiple systems and engages key limbic-neuroendocrine circuits. Consequently, glucocorticoids have profound effects on synaptic physiology, circuit regulation of stress responsiveness, and, ultimately, behavior. While glucocorticoids initiate adaptive processes that generate energy for coping, prolonged or inappropriate glucocorticoid secretion becomes deleterious. Inappropriate processing of stressful information may lead to energetic drive that does not match environmental demand, resulting in risk factors for pathology. Thus, dysregulation of the HPA axis may promote stress-related illnesses (e.g. depression, PTSD). This review summarizes the latest developments in central glucocorticoid actions on synaptic, neuroendocrine, and behavioral regulation. Additionally, these findings will be discussed in terms of the energetic integration of stress and the importance of context-specific regulation of glucocorticoids.

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

Background Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyper-locomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation.

Responding to real or potential threats in the environment requires the coordination of autonomic, neuroendocrine, and behavioral processes to promote adaptation and survival. These diverging systems necessitate input from the limbic forebrain to integrate and modulate functional output in accordance with contextual demand. In the current review, we discuss the potential role of the medial prefrontal cortex (mPFC) as a coordinator of behavioral and physiological stress responses across multiple temporal and contextual domains. Further, we highlight converging evidence from rodent and human research indicating the necessity of the mPFC for modulating physiological energetic systems to mobilize or limit energetic resources as needed to ultimately promote behavioral adaptation in the face of stress. We review literature that indicates that glucocorticoids act as one of the primary messengers in the reallocation of energetic resources having profound effects locally within the mPFC, as well as shaping how the mPFC acts within a network of brain structures to modulate responses to stress. Finally, we discuss how rodent, as well as human studies point toward a critical role of the mPFC in the coordination of anticipatory responses to stress and why this distinction is an important one to make in stress neurobiology.