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

Abstract

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.

Figure 1

Schematic depicting different modes of locus coeruleus activity and the relationship between tonic and phasic activity. Representative poststimulus time histograms (PSTHs) are shown that indicate neuronal activation (ordinates) in response to repeated presentations of a brief sensory stimulus (arrowhead). The abscissae of the histograms indicate time before and after the stimulus. When locus coeruleus tonic activity is low (left), the response to sensory stimuli is relatively low and this is associated with drowsiness and disengagement from the environment. There is an optimal level of tonic locus coeruleus discharge rate at which the response to sensory stimuli is high (Phasic). This is associated with electrotonic coupling of locus coeruleus neurons, focused attention and the maintenance of ongoing behavior. Increases in tonic discharge rate above this optimal level result in a loss of selective sensory responses. This is associated with uncoupling, increased arousal, scanning attention and sampling of behaviors. By increasing tonic discharge, CRF shifts the mode of locus coeruleus activity towards the right of this spectrum. This is predicted to occur during stress. During stress termination, endogenous opioids acting at μ–opiate receptors in the locus coeruleus shift the mode of activity towards the left. Excitatory amino acid neurotransmission in the locus coeruleus may favor the phasic mode.

Figure 2

Schematic depicting the localization of CRF afferents to the locus coeruleus and sites of termination in the locus coeruleus region. CRF neurons from Barrington’s nucleus (Bar) and the nucleus paragigantocellularis (PGi) terminate in the nuclear core of the locus coeruleus. These nuclei also project to preganglionic parasympathetic and sympathetic neurons, respectively and thereby may coordinate autonomic activity with cognitive functions. The central nucleus of the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus (PVN) terminate outside of the nuclear core in the peri-coerulear region where locus coeruleus dendrites extend.

Figure 3

Schematic depicting potential consequences of CRF morphological effects on locus coeruleus dendrites. In contrast to autonomically-related CRF afferents to the locus coeruleus that terminate in the nuclear core, limbic sources of CRF terminate outside of the core in the peri-coerulear region where locus coeruleus dendrites extend. By promoting the extension of locus coeruleus dendrites into this region, CRF potentially increases the probability that these dendrites will synapse with limbic afferents that convey affective information and enhance the influence of these afferents on locus coeruleus activity. Through this mechanism, CRF can determine the structural basis for emotional arousal.