Locus ceruleus

The Locus ceruleus, also spelled locus caeruleus or locus coeruleus (Latin for 'the blue spot'), is a nucleus in the brain stem responsible for physiological responses to stress and panic.

The locus ceruleus was first discovered by Félix Vicq-d'Azyr.

Caeruleus is the classical Latin spelling, but coeruleus, a more archaic form, is the more common spelling. The spelling ceruleus, formed by contraction of the diphthongs ae or oe into e, is an American English form.

Anatomy
The locus ceruleus (or "LC") is located within the dorsal wall of the rostral pons in the lateral floor of the fourth ventricle. This nucleus is the major location of norepinephrine in the brain, and is composed of mostly medium-sized neurons. Melanin granules inside the LC contribute to its blue color; it is thereby also known as the nucleus pigmentosus pontis, meaning "heavily pigmented nucleus of the pons". The neuromelanin is formed by the polymerization of norepinephrine and is analogous to the black dopamine-based neuromelanin in the substantia nigra.

Connections
The projections of this nucleus reach far and wide, innervating the spinal cord, the brain stem, cerebellum, hypothalamus, the thalamic relay nuclei, the amygdala, the basal telencephalon, and the cortex. The norepinephrine from the LC has an excitatory effect on most of the brain, mediating arousal and priming the brain’s neurons to be activated by stimuli. It has been said that a single noradrenergic neuron can innervate the entire cerebral cortex via its branches.

As the main homeostatic control center of the body, the locus ceruleus receives afferents from the hypothalamus. The cingulate gyrus and the amygdala also innervate the LC, allowing emotional pain and stressors to trigger noradrenergic responses. The cerebellum and afferents from the raphe nuclei also project to the LC, particularly the raphe pontis and raphe dorsalis.

The locus ceruleus receives inputs from a number of other brain regions, primarily:
 * Medial prefrontal cortex. The connection is constant, excitatory, and increases in strength with raised activity levels in the subject.
 * Nucleus paragigantocellularis. This region integrates autonomic and environmental stimuli.
 * Nucleus prepositus hypoglossi. This region is involved in gaze.
 * Lateral hypothalamus. This releases orexin which, as well as its other functions, is excitatory in the locus ceruleus.

Function
The locus ceruleus is studied in relation to clinical depression, panic disorder, and anxiety. Some antidepressant medications including Reboxetine, Venlafaxine, and Bupropion as well as ADHD medication Atomoxetine are believed to act on neurons in this area. This area of the brain is also intimately involved in REM sleep.

Psychiatric research has documented that enhanced noradrenergic postsynaptic responsiveness in the neuronal pathway (brain circuit) that originates in the locus ceruleus and end in the basolateral nucleus of the amygdala is a major factor in the pathophysiology of most stress-induced fear-circuitry disorders and especially in posttraumatic stress disorder (PTSD). The LC neurons are probably the origin of the first or second “leg” of what has been recently termed the "PTSD candidate circuit." Combat-related PTSD (in a 2005 study of deceased American army veterans from World War II) was shown to be associated with a postmortem diminished number of neurons in the locus coeruleus (LC) on the right side of the brain. The role of the LC in PTSD may explain the dramatic effectiveness of two generic medications; propranolol and prazosin for the secondary prevention and treatment of PTSD, respectively.

In Stress
The locus ceruleus is responsible for mediating many of the sympathetic effects during stress. The locus ceruleus is activated by stress and will respond by increasing norepinephrine secretion, which in turn will increase cognitive function (through the prefrontal cortex), increase motivation (through nucleus accumbens), activate the hypothalamic-pituitary-adrenal axis, and increase the sympathetic discharge/inhibit parasympathetic tone (through the brainstem). Specifically, in regards to the activation of the hypothalamo-pituitary adrenal axis, norepinephrine will stimulate the secretion of corticotropin-releasing factor from the hypothalamus, which induces adrenocorticotropic hormone release from the anterior pituitary and subsequent epinephrine/norepinephrine release from the adrenal glands. Norepinephrine released from locus ceruleus will feedback to inhibit its production, and corticotropin-releasing hormone will feedback to inhibit its production, while positively feeding to the locus ceruleus to increase norepinephrine production.