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Neural regulation of endocrine and autonomic stress responses

Key Points

  • The response of mammals to external or internal challenge involves engagement of multiple physiological systems, prominently including the hypothalamic-pituitary-adrenocortical (HPA) axis and the autonomic nervous system (ANS).

  • Autonomic and HPA axis responses to systemic stressors are initiated by brainstem and hypothalamic structures that receive direct and indirect homeostatic feedback.

  • Psychological stress responses are activated and inhibited by limbic system structures, such as the medial prefrontal cortex, the hippocampus and the amygdala, which send multisynaptic input to brainstem and hypothalamic activators of the HPA axis and the ANS.

  • 'Psychological' information and homeostatic information are integrated by telencephalic and diencephalic relays prior to the elaboration of HPA axis or ANS responses.

  • HPA axis and ANS components of the stress response are probably encoded in distinct yet highly interconnected limbic subregions.

  • Chronic stress induces neuroplasticity in central stress-processing networks, causing sensitization as well as habituation of HPA axis and ANS responses.

  • Limbic stress response networks overlap extensively with memory and reward circuitry, allowing stress responses to be coloured by prior experience and expected outcomes.


The survival and well-being of all species requires appropriate physiological responses to environmental and homeostatic challenges. The re-establishment and maintenance of homeostasis entails the coordinated activation and control of neuroendocrine and autonomic stress systems. These collective stress responses are mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and the brainstem, so that the respective contributions of the neuroendocrine and autonomic systems are tuned in accordance with stressor modality and intensity. Limbic regions that are responsible for regulating stress responses intersect with circuits that are responsible for memory and reward, providing a means to tailor the stress response with respect to prior experience and anticipated outcomes.

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Figure 1: General scheme of brain acute-stress regulatory pathways.
Figure 2: The brain circuitry that regulates autonomic stress responses.
Figure 3: The brain circuitry that regulates HPA axis stress responses.
Figure 4: Organization of limbic outputs.


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The authors thank present and past members of the Herman laboratory for their contributions to this work, and S. Woods for his comments on the Review. The authors' work cited in this Review was supported by US National Institutes of Health grants MH049698, MH069860, MH069725, AG12962 and DK078906.

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Correspondence to James P. Herman.

Supplementary information

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Conditioning of stress responses (PDF 196 kb)

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Reward and stress effectors (PDF 286 kb)

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Limbic system

The collection of highly interconnected forebrain structures that are involved in processing emotion and memory.

Chronic stress

Ongoing or repeated exposure to one or more types of stress stimuli over a period ranging from days to months.


Relating to the first neuron in the two-neuron chains that mediate autonomic responses.


Relating to the second neuron in the two-neuron chains that mediate autonomic responses.

Subfornical organ

A forebrain circumventricular organ that lacks a blood–brain barrier.


Relating to the CNS neurons that are involved in regulating preganglionic sympathetic or parasympathetic neurons in the spinal cord and/or brainstem.


An immediate early gene, expression of which is tightly linked to recent cellular excitation.

Bradycardic response

A slowing of the heart rate.

Depressor response

A decrease in blood pressure.

Pressor response

An increase in blood pressure.

Glutamic acid decarboxylase

(GAD). The enzyme that synthesizes GABA. It exists in two isoforms, GAD65 and GAD67.

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Ulrich-Lai, Y., Herman, J. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10, 397–409 (2009).

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