Illuminating and Sniffing Out the Neuromodulatory Roles of Dopamine in the Retina and Olfactory Bulb

Abstract

In the central nervous system, dopamine is well-known as the neuromodulator that is involved with regulating reward, addiction, motivation, and fine motor control. Yet, decades of findings are revealing another crucial function of dopamine: modulating sensory systems. Dopamine is endogenous to subsets of neurons in the retina and olfactory bulb (OB), where it sharpens sensory processing of visual and olfactory information. For example, dopamine modulation allows the neural circuity in the retina to transition from processing dim light to daylight and the neural circuity in the OB to regulate odor discrimination and detection. Dopamine accomplishes these tasks through numerous, complex mechanisms in both neural structures. In this review, we provide an overview of the established and emerging research on these mechanisms and describe similarities and differences in dopamine expression and modulation of synaptic transmission in the retinas and OBs of various vertebrate organisms. This includes discussion of dopamine neurons' morphologies, potential identities, and biophysical properties along with their contributions to circadian rhythms and stimulus-driven synthesis, activation, and release of dopamine. As dysregulation of some of these mechanisms may occur in patients with Parkinson's disease, these symptoms are also discussed. The exploration and comparison of these two separate dopamine populations shows just how remarkably similar the retina and OB are, even though they are functionally distinct. It also shows that the modulatory properties of dopamine neurons are just as important to vision and olfaction as they are to motor coordination and neuropsychiatric/neurodegenerative conditions, thus, we hope this review encourages further research to elucidate these mechanisms.

Keywords: Parkinson’s disease; biophysical properties; circadian rhythms; dopamine; olfaction; olfactory bulb; retina; vision.

FIGURE 1

A schematic of the layers and neuronal circuitry of the retina, including the pathways of rods, cones that respond to light (middle photoreceptor), and cones that respond to dark (right photoreceptor). For clarity and simplicity, many neurons and synapses have been excluded. The various modulatory mechanisms of retinal dopamine neurons (blue) affect nearly every retinal neuron to allow the retina to adapt to photopic conditions. Green arrows indicate excitatory (glutamatergic) synapses, red arrows indicate inhibitory (GABAergic/glycinergic) synapses, and blue arrows indicate mixed synaptic effects. A potential excitatory en passant synapse (between ON-bipolar cell axon and dopamine neuron) is shown in strata 1 of the inner plexiform layer. Retinal gap junctions, which are also targets of various dopaminergic and other modulatory mechanisms, are represented by squiggles. The green squiggle indicates depolarization via heterotypic coupling, red squiggles indicate dopaminergic uncoupling of gap junctions, and blue squiggle indicates mixed effects of dopamine on the coupling or uncoupling of gap junctions. AC, amacrine cell; BC, bipolar cell (including those depolrized – ON – and inhibited – OFF – by light); GCL, ganglion cell layer; HC, horizontal cell; INL, inner nuclear layer; IPL, inner plexiform layer (including the OFF – 1 and 2 – and ON – 3, 4, and 5 – strata); ipRGC, intrinsically photosensitive retinal ganglion cell; ONL, outer nuclear layer; OPL, outer plexiform layer; RGC, retinal ganglion cell (including the ON and OFF-RGCs).

FIGURE 2

A schematic of the layers and neuronal circuitry of the olfactory bulb (many neurons and synapses have been excluded for clarity and simplicity). Because the neuronal identity of dopamine neurons is not agreed upon, they are classified in this figure simply as “dopamine neurons” and not as a specific type of juxtaglomerular cell (e.g., PGC or SAC). Green arrows indicate excitatory (glutamatergic) synapses, red arrows indicate inhibitory (GABAergic and/or dopaminergic) synapses, and blue arrows indicate mixed synaptic effects (inhibition through GABA, followed by an increased likelihood for excitation by dopamine). Three pathways are shown, each either receiving a weak or a strong odor stimulus. A weak odor or artificial stimulus is hypothesized to activate dopamine neurons (blue neurons), while a strong odor stimulus is hypothesized to inactivate dopamine neurons (Ennis et al., 2001; Korshunov et al., 2020). In our previous work (Korshunov et al., 2020), we showed that rat olfactory bulb dopamine neurons are more responsive (produced more action potentials) to weak rather than strong current stimuli, potentially increasing the release of dopamine and/or GABA, resulting in presynaptic inhibition (McGann, 2013). Dopamine activity within fish olfactory bulbs was shown to reduce the transmission of weak stimuli while strong stimuli were processed more than weak stimuli (Bundschuh et al., 2012). Thus, the dopamine neuron in the center glomerulus does not provide presynaptic inhibition or other modulation in response to a strong odor stimulus, while the dopamine neurons in the left and right glomeruli respond to weak stimuli with inhibitory or mixed synaptic effects. In showing potential dopaminergic synaptic effects, this schematic illustrates one of the potential mechanisms of lateral inhibition and odor discrimination. EPL, external plexiform layer; ETC, external tufted cell; GC, granule cell; GCL, granule cell layer; GL, glomerular layer; IPL, internal plexiform layer; MCL, mitral cell layer; OE, olfactory epithelium; ONL, olfactory nerve layer; OSN, olfactory sensory neuron; PGC, periglomerular cell; SAC, short-axon cell.

FIGURE 3

The daily rhythms of dopamine and melatonin activity, as established within the retina (A) and proposed within the olfactory bulb (B). Increasing yellow gradient indicates an increase in the level of light to which the retina is exposed (A) or is an indicator of the time of day for the olfactory bulb (B). (A) Retinal dopamine synthesis and activity is highest during daytime, while retinal melatonin activity is highest during nighttime. This figure does not make the distinction between light-driven and circadian dopamine synthesis and release. While both would produce similar rhythms (dopamine is highest during the daytime or subjective day), dopamine release in constant darkness (circadian) would be much lower than light-stimulated dopamine release. (B) The proposed daily rhythm of dopamine in the olfactory bulb based on our prior study on dopamine content and release over 24 h in a12-h light/dark cycle. We found that olfactory bulb dopamine demonstrates diurnal activity, with highest activity occurring when lights are on and lowest levels when lights are off (Corthell et al., 2013). The proposed daily melatonin rhythm in the olfactory bulb is based on our prior determination of levels of mRNA for melatonin synthesizing enzymes in rats exposed to 12-h light/dark cycles. We found that HIOMT mRNA, for example, fluctuates in a diurnal fashion, with the lowest expression during lights-on and highest expression during lights-off (Corthell et al., 2014). Thus, this figure illustrates potential diurnal rhythms of olfactory bulb dopamine and melatonin, which peak in the daytime and nighttime, respectively. However, it has not been determined whether olfactory bulb dopamine and melatonin display circadian rhythms.