The Locus Coeruleus: Anatomy, Physiology, and Stress-Related Neuropsychiatric Disorders

Abstract

The locus coeruleus-norepinephrine (LC-NE) system is involved in mediating a wide array of functions, including attention, arousal, cognition, and stress response. Dysregulation of the LC-NE system is strongly linked with several stress-induced neuropsychiatric disorders, highlighting the LC's pivotal role in the development of these disorders. Located in the dorsal pontine tegmental area, the LC contains noradrenergic neurons that serve as the main source of NE in the central nervous system. Activation of the LC and subsequent release of NE at different levels of the neuroaxis is adaptive, allowing the body to adjust appropriately amid a challenging stimulus. However, prolonged and repeated LC activation leads to maladaptive responses that implicate LC-NE dysfunction in stress-induced neuropsychiatric disorders. As the primary initiator of the stress response, corticotropin-releasing factor (CRF) activates the hypothalamic-pituitary-adrenal axis. Following the discovery of CRF more than four decades ago, numerous studies established that CRF also acts as a neurotransmitter that governs the activity of other neurotransmitters in the brain neurotransmitter system. The LC-NE system receives abundant CRF afferents arising from several brain nuclei. CRF afferents to LC-NE are activated and recruited in the pathogenesis of stress-induced neuropsychiatric disorders. Presented in this review are the CRF neuroanatomical connectivity and physiological characteristics that modulate LC-NE function, which may contribute to the pathogenesis of stress-induced neuropsychiatric disorders. Additionally, this review illustrates the contribution of LC-NE to the apparent sex-dependent differences in stress-induced neuropsychiatric disorders. Hence, the LC-NE system is a promising target for the development of therapeutic strategies for stress-induced neuropsychiatric disorders.

Keywords: corticotropin releasing factor; locus coeruleus; norepinephrine; sex differences; stress; stress response.

FIGURE 1

Exposure to stressors (red small arrows) activates the hypothalamic–pituitary adrenal (HPA) axis and the locus coeruleus‐norepinephrine (LC‐NE) system. (A) Corticotropin‐releasing factor (CRF) is abundant in the hypothalamus, the paraventricular nucleus of the hypothalamus (PVN) in particular. CRF is releaseld from the PVN via the hypophysial portal system that signals the anterior pituitary (AP) gland to release the adrenocorticotropic hormone (ACTH) in the systemic circulation. In turn the ACTH stimulates the adrenal cortex (AG) to release glucocorticoids (cortisol in humans and corticosterone in rodents) that then modulates physiological and behavioral response. (B) CRF is abundant in the extrahypothalamic areas such as the central nucleus of the amygdala (CNA). Stress exposure increases CRF release (red arrow from the CNA) in the LC‐NE system that in turn increases LC tonic discharges and NE release (green arrows).

FIGURE 2

Schematics showing the corticotropin‐releasing factor (CRF) afferents to the locus coeruleus (LC). The nuclei that send CRF afferents projections to the LC originate from the Barrington's nucleus (BN), bed nucleus of stria terminalis (BNST), central nucleus of the amygdala (CNA), nucleus paragigantocellularis (PGi), and paraventricular nucleus of the hypothalamus (PVN).

FIGURE 3

Repeated and chronic exposure to stressors (red arrows on top of the panels) activates the hypothalamic–pituitary adrenal (HPA) axis and the locus coeruleus‐norepinephrine (LC‐NE) system. Depression and post‐traumatic stress disorders precipitated by a stressful event is associated with the hypersecretion of the corticotropin‐releasing factor (CRF) leading to elevated CRF levels (green arrows). Left panel: CRF hypersecretion in the PVN (green arrows) leads to CRF release via the hypophysial portal system (red arrow) that sends signals to the anterior pituitary (AP) and to the adrenal gland (AG). Consequently, this cascade of events leads to the dysregulation of the HPA axis (red dotted arrows). Right panel: CRF hypersecretion in the CNA (green arrows) releases CRF to the LC‐NE (red arrow) that leads to the dysregulation of the LC‐NE system (red dotted arrows).