Altered Expression of Phox2 Transcription Factors in the Locus Coeruleus in Major Depressive Disorder Mimicked by Chronic Stress and Corticosterone Treatment In Vivo and In Vitro

Abstract

Phox2a and Phox2b are two homeodomain transcription factors playing a pivotal role in the development of noradrenergic neurons during the embryonic period. However, their expression and function in adulthood remain to be elucidated. Using human postmortem brain tissues, rat stress models and cultured cells, this study aimed to examine the alteration of Phox2a and Phox2b expression. The results show that Phox2a and Phox2b are normally expressed in the human locus coeruleus (LC) in adulthood. Furthermore, the levels of Phox2a protein and mRNA and protein levels of Phox2b were significantly elevated in the LC of brain donors that suffered from the major depressive disorder, as compared to age-matched and psychiatrically normal control donors. Fischer 344 rats subjected to chronic social defeat showed higher mRNA and protein levels of Phox2a and Phox2b in the LC, as compared to non-stressed control rats. In rats chronically administered oral corticosterone, mRNA and protein levels of Phox2b, but not Phox2a, in the LC were significantly increased. In addition, the corticosterone-induced increase of Phox2b protein was reversed by simultaneous treatment with either mifepristone or spironolactone. Exposing SH-SY5Y cells to corticosterone significantly increased expression of Phox2a and Phox2b, which was blocked by corticosteroid receptor antagonists. Taken together, these experiments reveal that Phox2 genes are expressed throughout the lifetime in the LC of humans and Fischer 344 rats. Alterations in their expression may play a role in major depressive disorder and possibly other stress-related disorders through their modulatory effects on the noradrenergic phenotype.

Phox2a Defines a Developmental Origin of the Anterolateral System in Mice and Humans

“…In light of this, the AS can be viewed as a pathway signaling deviations from homeostasis, such as changes in skin temperature, or the presence of noxious or pruritogenic stimuli, to brain regions that trigger compensatory autonomic responses (e.g., CVLM) or drive compensatory behavioral responses such as licking or scratching (e.g., pB). Given this, Phox2a AS neurons may specialize in transmitting somatic sensations with a motivational character such as cutaneous and deep pain, thermosensation, itch, visceral pain, nausea, and sexual arousal, all of which are abolished by anterolateral cordotomy in humans (Hyndman and Jarvis, 1940; Hyndman and Wolkin, 1943 Our results suggest that the molecular identity of mouse Phox2a AS neurons is conserved in the developing human spinal cord, pointing to a conserved molecular logic of somatosensory circuit development, supported, in part, by the expression of PHOX2A in the human LC (Fan et al, 2018). A genetic proof of this idea remains out of reach because of the lack of obvious nociceptive or autonomic deficits in humans with PHOX2A mutations, which may be due to hypomorphic alleles (Nakano et al, 2001).…”

An Exploratory Pilot Study with Plasma Protein Signatures Associated with Response of Patients with Depression to Antidepressant Treatment for 10 Weeks

“…Among them, PHOX2B and YWHAE were validated by LC-MRM/MS analysis in this study. SSRI stress in human brain cells was reported to be associated with a PHOX2B transcription factor [56]. The YWHAE genes have been reported to play a significant role in MDD in the Han Chinese population, with alterations in their protein-protein interactions [57].…”

Calcium-induced calcium release in noradrenergic neurons of the locus coeruleus

“…It has been implicated in the regulation of diverse functions of both the central nervous system and the peripheral autonomic nervous systems, including the activity of the sympathetic nervous system, arousal, attention, memory, sensory information processing, anxiety, sleep and pain sensation (Sara and Bouret, 2012;Sara, 2015;Aston-Jones and Waterhouse, 2016;Chandler, 2016;Takeuchi et al, 2016;Manella et al, 2017;Totah et al, 2018;Rodenkirch et al, 2019;Zerbi et al, 2019). Consistent with these roles, abnormal regulation of LC neuron activity has been implicated in a wide variety of neurological and psychiatric disorders, including autonomic dysfunction (Vermeiren and De Deyn, 2017), Parkinson's disease (Espay et al, 2014;Schapira et al, 2017;Vermeiren and De Deyn, 2017;Peterson and Li, 2018), Alzheimer's disease (Giorgi et al, 2017;Peterson and Li, 2018), dystonia (Hornykiewicz et al, 1986;McKeon et al, 1986), major depression (Fan et al, 2018), anxiety disorders (McCall et al, 2017), bipolar disorder (Cao et al, 2018), and migraine (Vila-Pueyo et al, 2019). Thus LC activity is crucial to the functions of the nervous system, and a deeper understanding of its regulation is expected to have an impact on the research of a variety of disorders.…”