Neural Regulation of Endocrine and Autonomic Stress Responses

Brainstem systems

The brainstem receives inputs that signal major homeostatic perturbations such as blood loss, respiratory distress, visceral or somatic pain and inflammation³. Sympathetic responses to these inputs involve reflex arcs that communicate with areas in the medulla (e.g., rostral ventrolateral medulla) and preganglionic sympathetic neurons in the intermediolateral cell column of the spinal cord¹ (Figure 2). Coordinate alteration of the parasympathetic branch of the ANS also occurs following stress, altering ‘vagal tone’ to the heart and lungs¹ and helping to control the duration of autonomic responses. This parasympathetic response to stress is mediated by the nucleus ambiguus and dorsal motor nucleus of the vagus nerve, possibly via input from the nucleus of the solitary tract (NTS)¹ (Figure 2). In addition, medullary and spinal cord systems inform higher-order autonomic integrative sites in the hindbrain (e.g., raphe pallidus, lateral parabrachial nucleus and Kölliker-Fuse nucleus), midbrain and forebrain (e.g., dorsomedial hypothalamus)¹, which modulate the autonomic response to stressors in accordance with descending information from hypothalamus and limbic forebrain. Although all of these circuits participate in autonomic integration, their precise role(s) in stress-induced responses is not yet defined.

Signals of homeostatic imbalance in the brainstem also lead to activation of the HPA axis: ascending brainstem (and perhaps spinal) pathways project heavily to the parvocellular divisions of the paraventricular nucleus of the hypothalamus (PVN) (Figure 3). For example, catecholaminergic (e.g., noradrenaline and adrenaline) projections to the hypophysiotrophic zone of the PVN originate in the NTS and C1–C3 regions^{4, 5} and participate in HPA activation (see⁶). NTS projections to the same area release additional neuroactive factors (including neuropeptide Y, glucagon-like peptide 1, inhibin β, somatostatin and enkephalin^7–9) that can regulate HPA activation. In some but not all NTS neurons these factors are co-localized with noradrenaline and adrenaline⁸.

Destruction of ascending noradrenaline/adrenaline neurons reduces HPA-axis responses to stimuli that signal homeostatic perturbations (e.g., hypoglycemia or interleukin 1β injection)^{10, 11}, but does not affect psychogenic responses, leading to the hypothesis that ascending catecholaminergic pathways mediate systemic-stress responses³. However, some non-catecholaminergic NTS cell groups (e.g., glucagon-like peptide 1 neurons)¹² are involved in the generation of HPA responses to both psychogenic and systemic stressors, suggesting some degree of functional specialization among NTS-PVN pathways.

The parvocellular PVN also receives serotonergic innervation from the median raphe nuclei in the midbrain. Serotonin activates the HPA axis¹³ through activation of serotonin 2A receptors on PVN neurons¹⁴. Serotonergic fibers project equally to the PVN and surrounding regions¹⁵, raising the possibility that serotonin also influences local circuit neurons projecting into the PVN.

Circumventricular organs: integration of peripheral signals

Components of the lamina terminalis system in the forebrain (i.e. the median preoptic nucleus, the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis) respond to perturbations in fluid and electrolyte balance and blood pressure. This system is essential for the central regulation of blood pressure by angiotensin II. The SFO¹⁶ has direct angiotensin II-containing projections to the medial parvocellular PVN, where it stimulates HPA-axis activity via activation of the angiotensin II type-I receptor¹⁷. The lamina terminalis also projects to other hypothalamic structures, including the anteroventral preoptic nucleus, DMH and preautonomic PVN¹⁸, through which it can initiate stress-induced changes in cardiovascular activity¹⁹.

Paraventricular and Dorsomedial Nuclei

Among several hypothalamic nuclei directly involved in the regulation of HPA axis and autonomic responses to stressors, the PVN stands out as a principal integrator of stress signals. The PVN houses distinct populations of neurons that project to the median eminence and to autonomic targets in the brainstem and spinal cord, such as the intermediolateral cell column, parabrachial nucleus, dorsal motor nucleus of the vagus and NTS²⁰. Transneuronal tracing studies indicate that parasympathetic and sympathetic projection neurons are intermingled in the PVN, suggesting input into both arms of ANS function²¹.

The PVN is heavily innervated by GABAergic inputs²², which provide a substantial inhibitory tone^{23, 24} (Figures 3 and 4). Some of the GABAergic innervation to the PVN comes from neurons in the peri-PVN region²⁵, which in turn is targeted by several limbic brain regions, enabling it to translate limbic information into modulation of HPA axis or autonomic activation²⁶.

The DMH regulates autonomic and perhaps also HPA-axis responses to psychogenic stimuli. Local stimulation of the DMH increases heart rate, blood pressure and HPA-axis responses to a psychological stressor²⁷, whereas inhibition attenuates stress-induced increases in heart rate and blood pressure²⁸. However, inactivation of the DMH does not affect cardiovascular responses to hemorrhage²⁸, indicating that hypovolaemic stimuli are processed elsewhere (most likely through brainstem reflex pathways). The DMH may also be involved in gating PVN activation: local inhibition of the dorsal DMH reduces ACTH release and neural excitation (as reflected by immediate early gene (Fos) activation²⁹) in the parvocellular PVN to psychogenic, but not systemic stimuli³⁰. Moreover, the ventral DMH inhibits neuronal activity in the PVN³¹, indicating that the DMH contains anatomically segregated neuronal populations that activate or inhibit HPA-axis activity (Figure 3).

Amygdala

The amygdala is structurally complex with numerous downstream targets that modulate autonomic and neuroendocrine stress responses (Figure 4). The central nucleus of the amygdala (CeA) has received considerable attention as a key node for stress integration, given its involvement in autonomic regulation and its association with stress-related behaviors (specifically, fear responses)³². The CeA is differentially activated by homeostatic disruption^{33, 34} and systemic³⁵, but not psychogenic^{36, 37} stressors. Nonetheless, CeA lesions impair bradycardic responses during exposure to psychological stressors^{38, 39}, suggesting a role in integrating the autonomic components of psychogenic stress. Overall, the role of the CeA appears specific to stimulus modality, and may be preferentially weighted toward autonomic rather than HPA-axis responses to stress.

The medial (MeA) and basolateral (BLA) amygdala nuclei are preferentially activated by psychological stressors^{33, 40, 41}: lesions of the MeA produce selective deficits in HPA axis responses to psychogenic but not homeostatic stressors³⁶. and BLA lesions dampen HPA-axis responses to restraint⁴². The impact of the MeA and BLA on HPA responses is likely mediated by extensive interactions with intervening PVN-projecting neurons, as there are few direct connections between the PVN and these amygdala nuclei⁴³. The roles of the MeA and BLA in regulation of autonomic stress responses have yet to be definitively tested; however, based on the paucity of MeA and BLA projections to principal autonomic output nuclei, it appears unlikely that these regions directly modulate autonomic stress responses to a significant extent.

Hippocampus

Numerous studies link the hippocampus with inhibition of the HPA axis^{3, 44}. Hippocampal stimulation decreases glucocorticoid secretion in rats and humans^{45, 46}, whereas hippocampal damage increases stress-induced and in some cases, basal glucocorticoid secretion^{3, 44}. Notably, lesion effects are most pronounced during the recovery phase of stress-induced glucocorticoid secretion, implicating the hippocampus in regulating the termination of stress-initiated HPA responses.

Hippocampal regulation of the HPA axis is region- and stressor-specific. The inhibitory effects of the hippocampus on the PVN are subserved by a relatively circumscribed population of neurons in the ventral subiculum⁴⁷ (Figure 4). Lesions of this area result in increased corticosterone release following psychogenic, but not systemic stressors⁴⁷, consistent with context-specific modulation of stress responses by the hippocampus.

The hippocampus also influences autonomic tone. Hippocampal stimulation decreases heart rate, blood pressure and respiratory rate in awake rats, effects that are blocked by lesions of the medial prefrontal cortex (mPFC)⁴⁸. The hippocampus has no major direct projections to the brainstem, but connects with NTS-projecting regions of the mPFC, such as the infralimbic cortex⁴⁹, suggesting that hippocampal actions on autonomic function may be routed through the mPFC.

Medial prefrontal cortex (mPFC)

The mPFC is also complex, with different subregions contributing to different aspects of stress output (Figure 4). The prelimbic mPFC preferentially inhibits HPA-axis responses to psychogenic stressors^50–53 and, like the hippocampus, regulates the duration but not the peak levels of glucocorticoid secretion, suggesting involvement in response termination. Inhibition of the prelimbic mPFC or local injection of noradrenaline enhances heart-rate responses to psychological stimuli⁵⁴, consistent with a role for the prelimbic PFC in inhibiting autonomic stress responses.

In contrast, the infralimbic PFC is involved in the initiation of autonomic and HPA responses to psychogenic stimuli^{52, 55}. Electrical stimulation of the ventromedial mPFC (which encompasses the infralimbic cortex) increases blood pressure in unanesthetized rats, whereas lesion or inactivation of this region inhibits conditioned cardiovascular responses^{56, 57}. Inactivation of this area does not affect baseline heart rate or blood pressure, suggesting that the infralimbic cortex is selectively involved in stress-induced cardiovascular regulation, perhaps via modification of the parasympathetic component of the baroreflex⁵⁸. Collectively, the data indicate that the prelimbic and infralimbic cortices have different roles in the coordination of stress responses, with outflow from the dorsal mPFC and the prelimbic cortex conferring inhibition, and that from the infralimbic cortex conferring stimulation. By virtue of its interconnections with the hippocampus and amygdala, the prefrontal cortex is positioned at the top of the response initiation hierarchy, and may be a principal, but not sole, limbic coordinator of physiological reactivity.

Other Limbic Sites

There is also evidence for stress-regulatory roles of other limbic sites, including the lateral septum, supramammillary nucleus and anterior thalamus^{40, 59, 60}. For example, the lateral septum inhibits HPA axis and autonomic responses to acute stressors⁵⁹, a role it shares with its principal afferent source, the hippocampus.

Top-down integration of glucocorticoid negative feedback

The HPA axis is subject to feedback inhibition by its principal product, glucocorticoids (Text Box 2), which is mediated at least in part by limbic forebrain structures. Both glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) are abundantly expressed in the hippocampus and are likely co-localized in some neurons⁶¹. As MRs and GRs have different affinities for corticosterone (see Box 2), this renders the hippocampus responsive to both basal and stress-induced elevations of corticosterone⁶². GRs are also highly expressed in the mPFC, but the expression of MRs is more limited here, suggesting that the mPFC may be less responsive to low glucocorticoid levels. Implants of corticosteroids in the mPFC inhibit HPA-axis responses to restraint but not ether⁵¹, supporting a possible role in feedback inhibition of psychogenic responses. Given that both the hippocampus and mPFC attenuate stress-induced increases in heart rate and blood pressure, it is possible that one or both glucocorticoid receptors influence autonomic outflow in addition to HPA axis activity, but this possibility has yet to be investigated.

Forebrain GRs are involved in regulating both basal HPA tone and termination of the stress response. Mice with selective deletion of the GR in the cortex, hippocampus and BLA have elevated basal glucocorticoids and prolonged corticosterone responses to psychogenic but not systemic stress^{63, 64}, and are resistant to the inhibitory effect of exogenous glucocorticoids on HPA-axis activation⁶³. Overexpression of GR in forebrain leads to reduced peak ACTH and corticosterone levels following stress, suggesting that forebrain GR are sufficient to reduce stress reactivity^{65, 66}. Forebrain MRs have a more subtle role in acute HPA-axis feedback regulation. Deletion of MRs in the limbic forebrain has no effect on basal HPA tone or the peak response to restraint (recovery was not assessed)⁶⁷. Overexpression of MR produces a mild suppression of acute stress responding only in female mice⁶⁸.

Collectively, the data are consistent with a limbic interface between glucocorticoid signals and feedback regulation of the HPA axis. The relative importance of limbic glucocorticoid signaling depends on the stress modality: it regulates HPA axis responses to psychogenic but not systemic stress and so provides a context-specific feedback signal that modifies HPA axis inhibition.

Bed nucleus of the stria terminalis (BST)

The BST has numerous subregions that differ markedly in their contributions to stress integration (Figures 3–4). Anteroventral subregions are important in HPA-axis excitation, as lesions there reduce HPA-axis responses and inhibit acute activation of PVN neurons following restraint^{72, 73} (Figure 4). The anterolateral BST contains PVN-projecting CRH neurons^74,75, suggesting a mechanism for central excitatory actions of CRH on the HPA axis. In contrast, lesions of the posteromedial BST increase ACTH and corticosterone secretion, PVN Fos activation and PVN CRH mRNA expression^{72, 73}, consistent with a loss of inhibitory input to the HPA axis (Figure 4). Tracing studies indicate that PVN-projecting neurons in this region are predominantly GABAergic⁷⁶, suggesting that, in contrast to the anterolateral PVN, posterior regions inhibit HPA responses to stress.

The precise role of the BST in autonomic regulation remains to be defined. In anesthetized rats, chemical or electrical stimulation of the BST produces predominantly depressor actions, particularly when the stimulation is directed to the anteromedial subregion^77–79. However, in awake animals, pharmacological activation of this region elicits a rapid pressor response, followed by bradycardia^{80, 81}, whereas inactivation exacerbates restraint-induced increases in heart rate⁸². This indicates that BST signaling is necessary for inhibiting cardiovascular responses to stress. Modulation of heart rate by BST stimulation or inhibition seems to be mediated by the parasympathetic nervous system^{80, 81}.

Hypothalamic nuclei

Several hypothalamic regions provide potential interaction between descending limbic input and homeostatic integration. Hypothalamic relays between limbic sites and HPA and ANS output neurons provide a means to gate responses to stressors with respect to ongoing physiological status.

The medial preoptic hypothalamus (mPOA) supplies GABAergic innervation to the PVN (figure 3). mPOA lesions enhance HPA-axis responses to stressors⁸³ and local inactivation enhances ACTH release, both consistent with a loss of inhibitory input to the PVN⁸⁴. Moreover, mPOA lesions block the excitatory effect of amygdala stimulation on corticosterone release⁸⁵, suggesting that the amygdala is an upstream modulator of mPOA neurons controlling the HPA axis response. Indeed, the mPOA is a prominent target of projections from the hippocampus and medial amygdala and is important in the integration of gonadal steroid signals, body temperature and sleep⁸⁶; it thus provides a site for interaction between limbic inputs and physiological regulatory processes.

Limbic efferents also innervate the mediobasal hypothalamus, including the arcuate nucleus⁸⁷ (Figure 3), which is a key regulator of energy balance and uses the PVN as a down-stream effector to regulate feeding and energy expenditure (via neuropeptidergic and GABAergic projections)⁸⁸. The net output from the arcuate to the PVN is complex, communicating both orexigenic (neuropeptide Y, Agouti-related peptide) and anorexic (e.g., alpha-MSH)⁸⁸ signals. Notably, many of these peptides activate the HPA axis, implying that both positive and negative energy balance represent homeostatic stressors⁸⁹.

Lateral hypothalamic neurons are activated by stressors⁴⁰, positioning them to modulate autonomic and/or HPA tone. The lateral hypothalamus is targeted by hippocampal, prefrontal cortical and amygdalar efferents and is important in the coordination of ingestive behaviors⁸⁶. Glutamatergic, GABAergic and peptidergic neurons are highly intermingled in this region, making it difficult to predict its net impact on stress responses^{90, 91}.

The suprachiasmatic nucleus (SCN) has a substantial impact on basal HPA and autonomic tone and on responses to psychogenic stressors^92–94. The SCN has few direct projections to the PVN, but heavily innervates the area surrounding the PVN⁹⁵, where it can interface with input from limbic sites. The SCN is the primary coordinator of physiologic rhythms, and is thus positioned to modulate HPA axis output in conjunction with time-of-day cues.

Sensitization of stress responses

Neurochemical evidence suggests that chronic stress enhances the excitability of the HPA and the sympatho-adrenomedullary systems. Facilitated ACTH and corticosterone responses to novel stressors occur after chronic drive by either homotypical or unpredictable stress regimens^{104, 105}. This response facilitation occurs despite clear evidence for ongoing or cumulative elevation in glucocorticoid levels, implying that feedback efficacy is diminished and/or drive is increased.

Chronic stress can recruit pathways that are distinct from those involved in acute responses. For example, lesions of the paraventricular thalamus inhibit the development of chronic-stress induced facilitation of HPA-axis activation, but do not affect responses to acute stress¹⁰⁶, indicating that this region is engaged during repeated, chronic stress exposure. In contrast, lesions of the hippocampus do not affect HPA-axis responses associated with chronic stress⁴⁷, suggesting that its role in HPA-axis regulation is diminished upon repeated stress exposure. The BST seems to be differentially involved in acute and chronic-stress responses, as lesions of the anterolateral BST reduce HPA-axis responses to acute stress, but enhance chronic-stress-induced facilitation of HPA axis activation¹⁰⁷.

Repeated exposure to cold enhances stress-induced noradrenaline release in the frontal cortex and sensitizes the firing rate of locus coeruleus neurons following a novel stressor^108–110. Chronic cold stress also increases the sensitivity of the locus coeruleus to CRH, suggesting that it increases the responsiveness to a factor that is released during stress¹⁰⁹. Finally, chronic stress increases the expression of tyrosine hydroxylase, the rate-limiting enzyme in noradrenaline synthesis, in the locus coeruleus, as well as that of co-localized neuropeptides (e.g., galanin), which is consistent with an enhanced capacity for noradrenaline release (^{111, 112} but see also¹¹³). The locus coeruleus does not have substantial projections to the PVN⁵, suggesting that contributions to HPA-axis regulation are mediated by upstream (e.g., hippocampus, mPFC and amygdala) or downstream (ventrolateral medulla, spinal cord) targets.

The CeA is implicated in chronic stress regulation by virtue of its sensitivity to corticosteroids. High levels of glucocorticoids increase CRH mRNA expression in the CeA¹¹⁴, an effect that is mimicked by some chronic stress regimens (e.g., chronic immobilization, chronic pain)¹¹⁵ but not others (e.g., chronic restraint, chronic unpredictable stress, repeated predator exposure)¹¹⁶. In sheep, repeated stress (dog exposure) causes CRH release in the CeA, which appears crucial for sensitization of both the CRH response in the PVN and cortisol release upon repeated exposure¹¹⁷. The amygdalar CRH response to repeated stress is blocked by pretreatment with a GR antagonist, implying that corticosteroids are required for the enhanced CRH release in the CeA during repeated stress^{117, 118}.

Although glucocorticoid secretion could be important for stress sensitization of the amygdala, chronic stress produces marked reductions in glucocorticoid signaling in other brain regions. Numerous chronic-stress regimens cause down-regulation of GR (and to a lesser extent, MR) mRNA, binding and protein levels in the mPFC and the hippocampus^{99, 119–121}. This down-regulation could be associated with a loss of glucocorticoid negative-feedback sensitivity, at least in terms of inhibiting the circadian rise in corticosterone levels^{120, 121}. Thus, chronic stress seems to be sufficient to both dampen negative-feedback signaling by stress-inhibitory pathways and to enhance positive drive through regions such as the CeA, which, together or alone, could contribute to an enhanced drive of the PVN.

Sensitization of autonomic responses is observed in some chronic stress models. In rats, chronic mild stress produces exaggerated heart rate and pressor responses to a novel stressor¹²². However, the neural substrates of ANS sensitization are not known.

Habituation of stress responses

Response habituation has been observed upon repeated exposure to mild stressors. In this case, the magnitude of the response diminishes with each exposure, even as responses to novel stressors are facilitated^{104, 123}. The decreased physiological responses are paralleled by a decrement in central stress-induced Fos activation¹²⁴. The habituation process seems to involve MRs, as systemic treatment with MR antagonists reverses the reduced corticosterone responses to repeated restraint¹²⁵. Lesions of the paraventricular thalamus inhibit habituation of corticosterone responses to repeated restraint¹²⁶ (however, see¹²⁷) without affecting acute responding. In combination with the effects of lesions of this region on facilitation¹⁰⁶, the paraventricular thalamus seems to be important in transducing information regarding the chronicity of stress exposure. Notably, this region receives heavy projections from the ventral subiculum and the mPFC^{76, 128, 129} and projects heavily to the CeA^{130, 131}, providing a possible intermediary relay between stress-inhibitory and stress-excitatory brain regions.

Habituation of autonomic responses is highly dependent on the stress regimen. In mice, chronic social stress causes limited habituation of heart-rate responses to attack in submissive, but not dominant mice¹³². Chronic stress produces long-term changes in autonomic function, including increased heart rate, decreased heart rate variability (rats)¹²² and decreased blood pressure variability (mice)¹³³. As was the case for response facilitation, the neural mechanisms underlying habituation of autonomic changes by chronic stress have yet to be explored.

Emotional learning and memory

Interpretating the predictive significance of environmental stimuli is crucial for appropriate control of physiological responses to stressors: the response to stimuli associated with a highly salient negative (or positive) outcome should produce a physiological response that is appropriate for coping with those stimuli, whereas a response generated to innocuous stimuli would be inefficient and metabolically costly. Thus, certain memories encourage responses to situations that predict an adverse outcome and discourage responses to irrelevant or habituated stimuli.

Limbic sites that regulate HPA and ANS responses — including the amygdala, hippocampus and mPFC — are involved in the conditioning of behavioral responses to emotional stimuli (reviewed in^{134,135–137}) and are thus also poised to mediate conditioning of HPA and ANS activity. In support of this, conditioned HPA activation after conditioned taste aversion (Text Box 3) is blocked by hippocampectomy¹³⁸, and the expression of conditioned HPA responses after contextual or tone-footshock conditioning is blocked by CeA lesions¹³⁹. Conditioned pressor and tachycardia responses to contextual footshock conditioning are also reduced by pretreatment of the ventral mPFC with CoCl₂ (a nonselective synapse blocker), an NMDA receptor antagonist, or nNOS inhibitors^57,140.

There is also evidence for conditioning of stress responses at the level of the relay areas to HPA and autonomic effectors. Lesions of the BST block corticosterone responses to contextual, but not tone, conditioning, purportedly due to connections between the BST and hippocampus¹³⁹. Lesions of the perifornical hypothalamus and lateral hypothalamus disrupt some types of conditioned stress responses^141–144, raising the possibility that conditioned HPA and ANS activation might also be integrated at the level of limbic-hypothalamic relay areas, which in turn suggests that both limbic and homeostatic signals are involved in the generation of learned responses.

Stress and reward

There seems to be a reciprocal relationship between reward and stress processing in the brain. Exposure to natural rewards buffers the effect of stressors on HPA activity, and stress increases reward-seeking behavior (e.g., intake of palatable food, reinstatement of drug-taking behavior). Experiences with rewarding stimuli generally evoke stress-like HPA and ANS responses (see Text Box 4). The effects vary depending on whether the reward is ‘natural’ (e.g., sexual behavior, voluntary wheel running, palatable food intake) or ‘pharmacological’ (e.g., drugs of abuse), and on whether the experiences were self-administered (e.g, contingent on level pressing, self-choice) or investigator-delivered.

The primary brain reward circuit consists of dopaminergic projections from the ventral tegmental area to the nucleus accumbens (NAc) and has extensive connections with the BLA and mPFC (reviewed in^145–147). The NAc, BLA and mPFC are widely recognized as key mediators of responses to natural rewards and drugs of abuse^145–147. As the mPFC and BLA regulate stress responses and are involved in conditioning to salient emotional stimuli, these structures are likely to regulate HPA and ANS responses to both unconditioned and conditioned reward exposure. It is not clear whether the NAc also regulates HPA axis and ANS activity, but projections from the NAc core and shell to brain regions such as the lateral hypothalamus, BST, lateral preoptic area and parabrachial nucleus^{148, 149} provide an anatomical substrate for potential physiological effects on the HPA axis and ANS. Thus, there is considerable anatomical overlap among the brain regions subserving reward processing, emotional learning and stress responses.

Overlapping circuits mediating stress, memory and reward: functional significance

Stress responses allow the animal to cope with aversive stimuli that represent real or anticipated threats to homeostasis, but mounting a stress response is energetically demanding. Thus, there is an advantage to learning when a particular situation is not a threat and to preemptively reducing an ensuing stress response; moreover, it is advantageous to be able to associate specific environmental cues with a particular stressor so that stress responses can be mounted in anticipation of predicted stressors, thereby minimizing homeostatic disruption.

Rewarding stimuli (particularly those that are novel, unpredicted and/or not self-administered) can be considered stressful because they disrupt homeostasis. In particular, drugs of abuse elicit strong unconditioned and conditioned activation of the HPA axis and ANS that are linked to the addiction process^{150, 151}. However, rewarding stimuli provide fundamentally different experiences from other types of stressors because animals are motivated to obtain them. In fact, chronic voluntary engagement in naturally rewarding behaviors, such as palatable food intake, reduces stress responses; these fundamentally ‘pleasurable’ experiences seem to have anti-stress effects. In this manner, the brain can tailor stress responses based on the collective experiences of an individual.