# Retinal Regulation of Locus Coeruleus and Mood: A Chemogenetic Approach to Treat Depression

> **NIH NIH R21** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2020 · $238,500

## Abstract

Project Summary
 Depression creates a significant burden of morbidity and mortality worldwide, but current
pharmacologic treatments are suboptimal even when combined with psychological intervention. Designer
Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a powerful, new chemogenetic
tool that is transforming neuropsychiatric research. However, current DREADD technology requires injection
of a viral-vector into the brain, limiting clinical application. The eye presents a promising alternate route of
DREADD vector administration to treat depression, as i) the retina can be accessed without the risk of invasive
brain surgery, and ii) the retina is a major input to a signaling pathway that we previously identified as
potentially involved in least some forms of depression. Indeed, we found that we can express Gq (excitatory)
DREADDS in retinal ganglion cells (RGCs) with a simple intravitreal AAV injection. Then, using the retina as
a chemogenetic target, we prevented the emergence of depression normally induced by prolonged light
deprivation by stimulating these retinal DREADDs. We hypothesize that this anti-depressive effect occurs
via a retina > suprachiasmatic nucleus (SCN) > dorsomedial hypothalamus (DMH) > locus coeruleus
(LC) circuit. We refer to this pathway as the photic regulation of arousal and mood (PRAM) pathway.
Additionally, we found that activating the retinal source of the PRAM pathway increases the tonic firing rate of
LC neurons, and prevents damage in LC neurons (as seen with p85-PARP) and loss of DβH+ fibers in
prefrontal cortex (PFC) that otherwise occurs after light deprivation. A goal of this proposal is to test the
hypothesis that DREADD activation of RGCs will also reverse depressive-like behavior; our initial results
indicate that this may indeed be the case. This would be important for broad translational application of
our PRAM approach. We also will test the roles of LC noradrenergic, and SCN, neurons in the ability of
PRAM stimulation to decrease depressive-like behaviors.
 Our proposed studies will lead to a better understanding of retina-associated pathways in the brain that
influence mood. Because these studies employ DREADD technology to manipulate the retina for the purpose
of controlling brain activity, it represents a novel but simple approach to the precise control of neural
networks, while eliminating the need for brain surgery. Therefore, the development of this technique could
have great impact on clinical approaches to treating depression. As LC is involved in a wide array of
neuropsychiatric disorders, results will also have implications for new ways to treat a variety of mental health
issues.

## Key facts

- **NIH application ID:** 9876360
- **Project number:** 1R21MH121723-01
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Gary S. Aston-Jones
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $238,500
- **Award type:** 1
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876360

## Citation

> US National Institutes of Health, RePORTER application 9876360, Retinal Regulation of Locus Coeruleus and Mood: A Chemogenetic Approach to Treat Depression (1R21MH121723-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9876360. Licensed CC0.

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