New directions for the treatment of depression: Targeting the photic regulation of arousal and mood (PRAM) pathway

Abstract

Both preclinical and clinical studies demonstrate that depression is strongly associated with reduced light availability, which in turn contributes to decreased function of brain regions that control mood. Here, we review findings that support a critical pathway for the control of mood that depends upon ambient light. We put forward a novel hypothesis, functionally linking retina to locus coeruleus (LC) in depression, and discuss the role of norepinephrine in affective disease. Finally, we discuss how utilizing the chemogenetic tool Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to precisely control this retina-LC circuit may be used as a novel therapeutic to treat depression.

Keywords: antidepressants; anxiety/anxiety disorders; depression; mood disorders; pharmacotherapy; seasonal affective disorder; sleep disorders; stress; treatment.

FIGURE 1

The photic regulation of arousal and mood (PRAM) pathway. A midsaggital section of a rat brain illustrating loci involved in PRAM-associated depressive-like behavior. Structures of PRAM pathway are indicated by blue boxes. SCN, suprachiasmatic nucleus; DMH, dorsomedial hypothalamus; LC, locus coeruleus. Melanopsin-containing retinal ganglion cells (RGCs) are putative the origin of the PRAM pathway, as they project directly onto SCN, their major target, which then projects indirectly onto LC via DMH. Dysregulation of the PRAM pathway may lead to the decreased noradrenergic-LC signaling (red arrows) that is associated with depression