It has been shown that activation of the HPA axis is initiated in limbic structures, including direct projections from the central nucleus of the amygdala, or indirectly through the bed nucleus of the stria terminals (BNST), which project to the hypothalamic PVN [6]. Neurons of the PVN synthesize Corticotrophin Releasing Hormone (CRH), which is released to the hypophyseal portal blood to reach the anterior pituitary, where it up-regulates the transcription of the pro-opio-melanocortin (POMC) gene, a common precursor for adrenocorticotropin (ACTH) and related peptides, therefore stimulating the release of ACTH into the bloodstream. In addition, arginine–vasopressine is also released to reinforce the effect of CRH. Hence, ACTH reaches the adrenal cortex, where it stimulates the biosynthesis and release of glucocorticoids, particularly cortisol, which participate in widespread metabolic effects, mostly involved in the mobilization of resources aimed at improving physiological conditions to successfully cope with stressful situations. These steroid hormones bind to both mineralocorticoid receptors (MRs or type I) and glucocorticoid receptors (GRs or type II), constituting a hormone-receptor complex. Upon cortisol binding, these receptors undergo conformational changes to facilitate their recognition by and subsequent binding to a glucocorticoid response element (GRE) located in the promoter region of target genes [15], therefore activating or deactivating the expression of various target genes. Up-regulation may be achieved through the constitution of homo- or hetero-dimers of the cortisol–GRs complex, which recognize and bind to GREs [16], bringing together other co-factors, constituting a pre-initiation complex at the promoter region. Down-regulation may be achieved through binding to a negative GRE, as has been described for the negative regulation of the POMC gene [17] and the CRH gene [18], thereby down-regulating the HPA axis. In addition, cortisol may also down-regulate the HPA axis through binding to GRs in the hippocampus, which stimulate inhibitory projections to the PVN.

During chronic stress, sustained and persistent activation of the HPA system may disrupt physiological mechanisms, including negative-feedback loops [15]. Physiological rhythms characterized by wide variations, with morning zeniths and evening nadirs, result in increased levels of cortisol and blunted circadian rhythm, reflected in increased levels during the evening and mild changes in the morning [1]. Therefore, alterations in the regulation of the HPA axis, such as those observed during chronic stress, may develop into different clinical conditions, such as anxiety disorders and depression. Moreover, a significant association between stress and depression is now well documented [1, 4, 19, 20], where hyperactivity of the HPA axis, with the consequent hypercortisolism, represents one of the most consistent findings in both conditions [21, 22].

It has been shown that CRH plays a critical role in the regulation of the HPA axis, which has been clearly associated with activation of the hypothalamic PVN in response to stress. More recently, CRH-containing neurons have been also described in different cortical and subcortical areas, such as the central nucleus of the amygdala, participating in neural pathways involved in cognitive and emotional responses [23, 24]. In this regard, CRH projections from the amygdala have been shown to exert stimulatory effect on cells of the PVN, therefore activating the HPA axis. Reciprocal connections have been described between these CRH neurons and aminergic nuclei, such as the LC and the raphe nuclei (RN) [3]. They represent pathways of reciprocal interaction between the noradrenergic and the serotonergic systems and the HPA axis. All of them are involved in the stress response [3, 25]. In this regard, it has been shown that CRH projections stimulate NA release in the LC [26], with the consequent noradrenergic activation of the ANS and the HPA axis. It also exerts an inhibitory effect on serotonergic neurons in the raphe nucleus (RN) [27]. In this manner other structures are affected, through serotonergic projections to the PVN, the amygdala, and the hippocampus [3]. Hence, CRH has been associated with the regulation of the serotonergic and the noradrenergic systems, which are critically involved in mood and anxiety disorders, producing anxiogenic and depressogenic effects [28]. In addition, CRH has been also associated with anxiety and encoding of emotional memories [21, 28], therefore demonstrating its critical role in the stress response, not only during adulthood, but also as an important factor in long-lasting effects of early stressful experiences.

It has been shown that serotonin (5-hydroxi-triptamine, 5HT) plays a critical role in the pathophysiology of depression, developing and further supporting the serotonergic hypothesis of depression [29, 30], which associates a deficient or altered serotonergic neurotransmission in the CNS with the origin and development of depressive symptoms. The serotonergic system has its cell groups mainly located in the RN, which project to diverse cortical and limbic structures. The serotonergic projections to the forebrain originate mainly in the dorsal (DRN) and medial RN (MRN) [31]. The DRN–forebrain tract innervates diverse structures, including the amygdala and the nucleus accumbens (NAc) [32, 33]. They have also been associated with the state of anticipatory anxiety that plays an adaptive role in situations of alarm. It contributes to informing the amygdala about unpleasant experiences, and participates in the regulation of the resulting emotional reactions [10]. Dysfunction of this system has been associated with the development of phobic and generalized anxiety disorders [33]. The MRN–forebrain tract innervates complementary structures, most prominently the dorsal hippocampus and the hypothalamus [33, 34], It has been associated with tolerance to unpleasant, unavoidable, persistent aversive stimuli [35] such as those perceived during chronic stress. It is also associated with adaptive control on negative emotional experiences, generating relaxation, satisfaction, and inertia [10]. In consequence, dysfunction of this system, particularly involving MRN–hippocampal projections, may be associated with decreased tolerance to aversive stimuli, learned helplessness, and subsequent depression [33]. In addition, serotonergic neurons in the RN have been shown to be also interconnected and physiologically integrated with other monoaminergic systems, including the noradrenergic and dopaminergic [36].

At the molecular level, 5HT is released to the synaptic cleft to bind pre- and post-synaptic 5HT receptors. The control on serotonergic neurotransmission is exerted by the serotonin transporter (5HTT), which is responsible for the reuptake of 5HT, therefore regulating the concentrations of the neurotransmitter and its availability to bind and activate its receptors. The 5HTT represents the molecular target of various antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Therefore, 5HTT blockade by SSRIs is expressed into increased concentrations of 5HT in the synaptic cleft, leading in turn to increased activation of 5HT receptors. The efficacy of these antidepressants has also been associated with adaptive changes produced by its continuous administration, including desensitization or down-regulation of somato-dendritic 5HT_1A auto-receptors in the RN, and up-regulation of post-synaptic 5HT_1A and desensitization of 5HT_2A receptors [37]. In addition, it has been shown that post-synaptic 5HT_1A receptors in different limbic structures may be down-regulated or desensitized by glucocorticoids or exposure to chronic stress [38–40]. Cortisol may inhibit 5HT neurotransmission tonically through binding to MRs, while increased levels of cortisol, such as those observed during chronic stressful conditions, bind predominantly to GRs, therefore interacting with GREs and inhibiting the expression of the 5HT1A gene [38]. In addition, it has been shown that cortisol may exert a stimulatory effect on 5HT uptake in vitro, and this has been attributed to an increased expression of the 5HTT gene by cortisol [41], further supporting the notion of a reciprocal regulation between the HPA and 5HT systems, and their potential interactions in the interface between stress and depression.

Dopamine (DA) has been also involved in the stress responses, including stress-related regulation of the HPA axis, as well as in the pathophysiology of depression [42, 43]. The main groups of dopaminergic neurons in the CNS comprise the retro–rubro field (A8), the substantia nigra pars compacta (A9), and the ventral–tegmental area (VTA, A10), which originates the mesolimbic (M-L) and mesocortical (M-C) pathways, which have been shown to participate in cognitive and emotional functions [44]. The M-L pathway reaches the nucleus accumbens (NAc) and other limbic structures, such as the amygdala and the hippocampus, and participates in the processing and reinforcement of rewarding stimuli, the subjective experience of pleasure, and in motivation of behavioral responses [10]. The M-C pathway reaches the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC), among other structures. It has been associated with cognitive functions such as concentration, working memory, judgment, planning and execution of behavioral responses [10, 44]. Increased activity of the amygdala has been associated with the impact of environmental stressors, which has also been associated with increased concentration of DA in the PFC, hence contributing to giving exaggerated salience to relatively mild negative stimuli, with the resulting anhedonia [45].

The M-L pathway has been shown to be sensitive to stressful experiences [46]; therefore, exposure to unavoidable or uncontrollable stressors may lead to decreased DA release in the NAc and impaired response to environmental stimuli, which may further lead to the expression and exacerbation of depressive symptoms induced by stress [42]. It has also been demonstrated that altered dopaminergic function is critically involved in altered reward processing underlying anhedonia [47]. In addition, reciprocal regulation has been also observed between the VTA and the RN [43], and dopaminergic pathways have been also involved in certain regulatory effect on the HPA axis.

The role of norepinephrine (NE) has been also recognized in the pathophysiology of affective disorders, providing the first aminergic hypothesis of depression [48]. The main group of NE-containing neurons in the CNS is located in the LC, which sends various projections to different cortical and subcortical structures [49], including the amygdala, the hippocampus, and the PVN [23, 50]. Among these, noradrenergic projections to the VTA have been described. Here, NE exerts stimulatory effect on DA release. Noradrenergic projections to the RN have been also described. In this site, NE exerts a regulatory effect on 5HT release [49]. Reciprocal regulations between NE and 5HT have been described, not only through connections between both aminergic systems, but also through limbic structures, such as the hippocampus [51]. In addition, reciprocal connections between NE and CRH containing neurons suggest a critical role of the LC in the regulation of neural and neuroendocrine responses to stress [23].

The LC is activated in response to acute stressors. It induces the resulting release of NE throughout different neural structures, thereby leading to enhanced arousal and vigilance, in the context of adaptive responses to stress [6]. Activation of the LC also stimulates the lateral hypothalamus, which in turn participates in the activation of the sympathetic branch of the ANS. This complements the adaptive response to stress [23]. During chronic stress a potential dysfunction of the LC has been observed, with the consequent decrease in NE release. This fact has been associated with some features of learned helplessness, as well as problems in cognitive functions frequently observed in depression [52]. Alteration of the NE system has been also associated with altered states of arousal [49], commonly observed in anxiety disorders and in depression.

Various studies have focused on the role of neurotrophic factors in critical neural processes, such as neuroplasticity and neurogenesis, with particular attention on the neurotrophins (NT). This molecular group includes the nerve growth factor (NGF), the brain-derived neurotrophic factor (BDNF), NT3, and NT4. Among these, various studies have focused on the role of BDNF in the regulation of neuroplasticity and neurogenesis, strongly suggesting that decreased levels of BDNF may lead to depressive symptoms, whereas up-regulation of BDNF has been associated with clinical recovery [53]. In this regard, it has been shown that chronic stressful situations, with the resulting hyperactivity of the HPA axis and hypercortisolism, may induce atrophy of neurons in the hippocampus, where high concentrations of GRs have been described [54], and these have been also associated with decreased levels of BDNF. Moreover, it has been also suggested that increased levels of glucocorticoids may be involved in down-regulation of BDNF and, on the other hand, it has been shown that various antidepressants up-regulated the expression of BDNF in the hippocampus [53], therefore supporting a potential role for BDNF in their mechanism of action [55, 56]. The association between the observed up-regulation of BDNF in the hippocampus and the successful effects of certain antidepressants suggested that the enduring effects of antidepressants could be associated with neuroplastic changes in the hippocampus, amygdala and PFC, and this could be associated with up-regulation of BDNF [53].

It has been shown that the sustained and prolonged impact of stressful conditions may lead to alteration of limbic structures, such as the amygdala and the hippocampus, therefore affecting their projections to the PFC and the ANS, which are critically involved in cognitive and emotional regulation [57]. Increased activation of the HPA axis, with the resulting hypercortisolism, neuroplastic, and neurogenetic processes, may result in a critical effect on the hippocampus. This may lead to altered formation of new cognitions, thereby contributing to impair depressogenic conditions. Hence, successful antidepressive strategies should lead to substantial recovery of hippocampal function, with the resulting up-regulation of neuroplasticity and increasing neurogenesis. This may be directly achieved through increasing levels of 5HT [58], or indirectly, through modulation of the HPA axis, and increasing levels of BDNF [53].

The link between stress and depression has been clearly observed at the clinical level, where cognitive processing plays a critical role. The potentially noxious impact of environmental stressors may depend on different characteristics related to the events, such as length, intensity, and strength of the impact, the availability of subjective resources to cope with them, and the resulting cognitive appraisal, particularly the potential balance between stressors and resources, and the resulting coping strategies [59]. In this regard, cognitive appraisal may lead to a realization that not every stressor is necessarily noxious or negative. Certain stimuli, perceived as desirable, predictable, and controllable challenges, could be perceived as pleasant or exciting, and therefore are known as eustress. In the opposite direction, the more intense, persistent, undesirable, unpredictable, and uncontrollable challenges could be perceived as threatening, may lead to maladaptive responses, and therefore are known as distress [60]. Accordingly, distressful situations may lead to a defense reaction, representing an active mode of response, characterized by effortful coping strategies produced in situations of perceived threat to control, or a defeat reaction, representing a passive mode of response, characterized by severe difficulty or inability to cope, associated with situations of subjective loss of controllability. Therefore, chronic exposure to undesirable, unpredictable, unavoidable, or uncontrollable situations may lead to decreasing resources, or the subjective assessment that resources are not enough, which in turn is associated with subjective feelings of helplessness [19]. This has been associated with chronic stressful situations and the development of depressive symptoms. Many cognitive resources are shaped during childhood, and according to the cognitive model [61] early-life experiences provide the raw material to develop cognitive schemas, which in turn represent the basis to transform environmental information into cognitions, and these are the result of every learned experience stored in long-term memory. Therefore, early adverse events contribute to the shaping of particular cognitive schemas, with the consequent negative biases. Dysfunctional schemas shaped during childhood may be retained in silence over long periods, to be later activated by additional experiences during adulthood, thereby leading to negative biases in the information processing, with the consequent dysfunctional effects, including negatively biased appraisals and limitations in further processing of the resulting cognitions, thereby leading to feelings of helplessness and subsequent depression [62].