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.