# Rod/cone gap junctions initiate an irradiance pathway

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $535,644

## Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in transmitting non-image-forming
visual information to the brain. Recent evidence has implicated ipRGCs in conscious vision as well as in
serious conditions such as migraine pain and seasonal affective disorder. Despite the fundamental importance
of ipRGCs in the visual process, the underlying synaptic mechanisms and circuits that control ipRGC function
are unknown. IpRGCs express their own photopigment - melanopsin and, at high light intensities, intrinsic
responses drive ipRGC function. However, surprisingly, at lower intensities, even in the photopic range,
ipRGCs are predominantly driven by rods and not cones. These data suggest that a sustained signal
originating from rods must travel through the retina to carry information about irradiance to ipRGCs. In this
proposal, we will test the primary hypothesis that the irradiance pathway through the mammalian retina is
driven via rod-to-cone gap junctions.
Our preliminary studies provide evidence that a novel irradiance pathway contains the following elements:
rod→rod/cone gap junction→cone→ON cone bipolar cell→ectopic synapse→M1-type ipRGCs and
dopaminergic amacrine cells (DACs). In turn, M1 ipRGCs drive non-image-forming visual behavior such as the
pupillary light reflex and circadian photoentrainment, while dopamine release may control network adaptation
in the retina. To test these hypotheses, we have developed and validated several mouse lines in which Cx36
has been conditionally deleted in either rods or cones, and therefore lack rod/cone gap junctions.
In Aim 1, we will test the hypothesis that rod/cone gap junctions are required to drive the PLR, circadian
photoentrainment and negative masking, non-imaging-forming visual functions also driven by M1 ipRGCs.
In Aim 2, we will test the hypothesis that rod/cone gap junctions are also essential for the release of dopamine,
in the mammalian retina. Furthermore, we will test the hypothesis that dopamine-dependent network
adaptation relies on the irradiance pathway via rod/cone gap junctions.
In Aim 3, we will test the function of the irradiance pathway at two key points: rod/cone gap junctions and
ectopic bipolar synapses in the inner plexiform layer.
In summary, we propose that rod/cone coupling generates an irradiance signal transmitted via ipRGCs that not
only controls the pupillary light reflex, it also entrains the circadian clock every day. The biological influence of
the circadian clock is pervasive yet it may be driven via gap junctions between the first two cell types in the
visual system. Furthermore, there is a link between dopamine and myopia. If, in turn, the irradiance pathway
controls dopamine release, this may inform a new approach to myopia.

## Key facts

- **NIH application ID:** 9971533
- **Project number:** 5R01EY029408-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** STEPHEN C MASSEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $535,644
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971533

## Citation

> US National Institutes of Health, RePORTER application 9971533, Rod/cone gap junctions initiate an irradiance pathway (5R01EY029408-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971533. Licensed CC0.

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