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| Paper IPM / Cognitive / 15008 |
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Chronic light-deprivation induces a depressive-like phenotype via a locus coeruleus norepinephrine (LC-NE)-dependent mechanism (Gonzalez and Aston-Jones, 2008). Suprachiasmatic nucleus (SCN) provides indirect circadian input onto LC via dorsomedial hypothalamus (DMH) (Aston-Jones et al 2001). SCN is therefore in a key position to integrate light information with LC via the pathway: retinaâSCNâDMHâLC. We refer to this pathway as the Photic Regulation of Arousal and Mood (PRAM) pathway. We tested the hypothesis that increasing PRAM pathway activity prevents darkness-induced depression-like behavior. Methods: Expt 1. Sprague Dawley rats received intraocular injections of excitatory hM3Dq DREADD (AAV2-hSyn-hM3D(Gq)-mCherry) control virus (AAV2-hSyn-EGFP) or no virus. Rats were placed in continuous darkness for 8 weeks, and those that received virus were concurrently subjected to daily intraperitoneal injections of clozapine-N-oxide (CNO; 2 mg/kg), the DREADD-activating ligand. Rats were then subjected to assays of mood (saccharin preference test, elevated plus maze and forced swim test) or vision (electroretinagram: ERG). LC tissue was stained for Poly ADP ribose polymerase (PARP, a marker of apoptosis) and tyrosine hydroxilase (TH). Expt 2. To determine the retinal cell-type responsible for depression-like behavior, intrinsically photosensitive retinal ganglion cells (ipRGCs) of animals raised in 12:12 light:dark conditions were ablated using a saporin (SAP) toxin that selectively eliminates melanopsin-expressing cells (Mel-SAP). Two control groups received intraocular injections of vehicle and were kept in either continuous darkness or in 12:12 light:dark conditions. Ten weeks later, rats were subjected to identical analyses as those in Expt 1. Results: Expt 1. ERG analysis showed that CNO-activation of retinal DREADDs increased RGC activity. Constant darkness induced a depression-like phenotype in control animals, which was prevented by daily activation of retinal DREADDs by CNO. Expt 2. Mel-SAP induced a depression-like phenotype in animals maintained in normal light-dark conditions. This was also associated with increased apoptosis in LC-NE cells as seen with PARP staining. Conclusion: Dysregulation of the PRAM pathway may induce neural damage in LC-NE neurons that is associated with a depressive behavioral phenotype. DREADD-induced activation of RGCs can prevent depression-like behaviors that normally occur in rats kept in chronic darkness. The PRAM pathway presents a novel circuit for the regulation of mood, and thus a possible new direction for the treatment of some forms of depression in humans.
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