Convergent regulation of locus coeruleus activity as an adaptive response to stress

Although hypothalamic–pituitary–adrenal axis activation is generally considered to be the hallmark of the stress response, many of the same stimuli that initiate this response also activate the locus coeruleus–norepinephrine system. Given its functional attributes, the parallel engagement of the locus coeruleus–norepinephrine system with the hypothalamic–pituitary–adrenal axis serves to coordinate endocrine and cognitive limbs of the stress response. The elucidation of stress-related afferents to the locus coeruleus and the electrophysiological characterization of these inputs are revealing how the activity of this system is fine-tuned by stressors to facilitate adaptive cognitive responses. Emerging from these studies, is a picture of complex interactions between the stress-related neuropeptide, corticotropin-releasing factor (CRF), endogenous opioids and the excitatory amino acid neurotransmitter, glutamate. The net effect of these interactions is to adjust the activity and reactivity of the locus coeruleus–norepinephrine system such that state of arousal and processing of sensory stimuli are modified to facilitate adaptive behavioral responses to stressors.This review begins with an introduction to the basic anatomical and physiological characteristics of locus coeruleus neurons. The concept that locus coeruleus neurons operate through two activity modes, i.e., tonic vs. phasic, that determine distinct behavioral strategies is emphasized in light of its relevance to stress. Anatomical and physiological evidence are then presented suggesting that interactions between stress-related neurotransmitters that converge on locus coeruleus neurons regulate shifts between these modes of discharge in response to the challenge of a stressor. This review focuses specifically on the locus coeruleus because it is the major source of norepinephrine to the forebrain and has been implicated in behavioral and cognitive aspects of stress responses.