Comparative Neurology of Circadian Photoreception: The Retinohypothalamic Tract (RHT) in Sighted and Naturally Blind Mammals

The mammalian eye contains two systems for light perception: an image detecting system constituted primarily of the classical photoreceptors, rods and cones, and a non-image forming system (NIF) constituted of a small group of intrinsically photosensitive retinal ganglion cells driven by melanopsin (mRGCs). The mRGCs receive input from the outer retina and NIF mediates light entrainment of circadian rhythms, masking behavior, light induced inhibition of nocturnal melatonin secretion, pupillary reflex (PLR), and affect the sleep/wake cycle. This review focuses on the mammalian NIF and its anatomy in the eye as well as its neuronal projection to the brain. This pathway is known as the retinohypothalamic tract (RHT). The development and functions of the NIF as well as the knowledge gained from studying gene modified mice is highlighted. Furthermore, the similarities of the NIF between sighted (nocturnal and diurnal rodent species, monkeys, humans) and naturally blind mammals (blind mole rats Spalax ehrenbergi and the Iberian mole, Talpa occidentalis) are discussed in relation to a changing world where increasing exposure to artificial light at night (ALAN) is becoming a challenge for humans and animals in the modern society.

Effect of Retinohypothalamic Tract Dysfunction on Melatonin Level in Patients with Chronic Disorders of Consciousness

Objective: The aim of this study is to compare the secretion level of nocturnal melatonin and the characteristics of the peripheral part of the visual analyzer in patients with chronic disorders of consciousness (DOC). Materials and Methods: We studied the level of melatonin in 22 patients with chronic DOC and in 11 healthy volunteers. The fundus condition was assessed using the ophthalmoscopic method. Results: The average level of nocturnal melatonin in patients with DOC differed by 80% from the level of indole in healthy volunteers. This reveals a direct relationship between etiology, the level of consciousness, gaze fixation, coma recovery scale-revised score and the level of melatonin secretion. Examination by an ophthalmologist revealed a decrease in the macular reflex in a significant number of DOC patients, which in turn correlates negatively with the time from brain injury and positively with low values of nocturnal melatonin.

Rest-activity cycles and melatonin phase angle of circadian entrainment in people without cone-mediated vision

Light is strong zeitgeber to the human circadian system, entraining internal rhythms in physiology and behaviour to the external world. This is mediated by the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which sense light in addition to the classical photoreceptors, the cones and rods. Circadian responses depend on light intensity, with exposure to brighter light leading to bigger circadian phase shifts and melatonin suppression. In congenital achromatopsia (prevalence 1 in 30,000 to 50,000 people), the cone system is non-functional, resulting in light avoidance and photophobia at light levels which are tolerable and habitual to individuals with a normal, trichromatic retina. Here, we examined chronotype and self-reported sleep, actigraphy-derived rest-activity cycles and increases melatonin in the evening in a group of genetically confirmed congenital achromats. We found normal rest-activity patterns in all participants, and normal melatonin phase angles of entrainment in 2/3 of our participants. Our results suggest that a functional cone system and exposure to daytime light intensities are not necessary for regular behavioural and hormonal entrainment. This may point to a compensation mechanism in circadian photoreception, which in conjunction with non-photic zeitgebers, ensures synchronisation of activity to the external world.Significance statementRhythms in physiology and behaviour are synchronised to the external cycle of light exposure. This is mediated by the retinohypothalamic tract, which connects the photoreceptors in the eye with the “circadian pacemaker” in our brain, the suprachiasmatic nucleus. What happens to our circadian rhythm when we lack the cone photoreceptors in the eye that enable us to see in daylight? We examined this question in a group of rare congenital achromats. Our work reveals that normal rhythms in rest and activity, and production of hormones, does not require a functional cone system.

Functional Pre- and Postsynaptic Changes between the Retinohypothalamic Tract and Suprachiasmatic Nucleus during Rat Postnatal Development

The suprachiasmatic nucleus (SCN) is the main brain clock in mammals. The SCN synchronizes to the light-dark cycle through the retinohypothalamic tract (RHT). RHT axons release glutamate to activate AMPA-kainate and N-methyl-D-aspartate (NMDA) postsynaptic receptors in ventral SCN neurons. Stimulation of SCN NMDA receptors is necessary for the activation of the signaling cascades that govern the advances and delays of phase. To our knowledge, no research has been performed to analyze the functional synaptic modifications occurring during postnatal development that prepare the circadian system for a proper synchronization to light at adult ages. Here, we studied the pre- and postsynaptic developmental changes between the unmyelinated RHT-SCN connections. Spontaneous NMDA excitatory postsynaptic currents (EPSCs) were greater in amplitude and frequency at postnatal day 34 (P34) than at P8. Similarly, both quantal EPSCs (miniature NMDA and evoked quantal AMPA-kainate) showed a development-dependent increase at analyzed stages, P3-5, P7-9, and P13-18. Moreover, the electrically evoked NMDA and AMPA-kainate components were augmented with age, although the increment was larger for the latter, and the membrane resting potential was more depolarized at early postnatal ages. Finally, the short-term synaptic plasticity was significantly modified during postnatal development as was the estimated number of quanta released and the initial release probability. All of these synaptic modifications in the unmyelinated RHT-SCN synapses suggest that synchronization to light at adult ages requires developmental changes similar to those that occur in myelinated fast communication systems.

Light exposure induces short- and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is the locus of a hypothalamic circadian clock that synchronizes physiological and behavioral responses to the daily light-dark cycle. The nucleus is composed of functionally and peptidergically diverse populations of cells for which distinct electrochemical properties are largely unstudied. SCN neurons containing gastrin-releasing peptide (GRP) receive direct retinal input via the retinohypothalamic tract. We targeted GRP neurons with a green fluorescent protein (GFP) marker for whole cell patch-clamping. In these neurons, we studied short (0.5–1.5 h)- and long-term (2–6 h) effects of a 1-h light pulse (LP) given 2 h after lights off [Zeitgeber time (ZT) 14:00–15:00] on membrane potential and spike firing. In brain slices taken from light-exposed animals, cells were depolarized, and spike firing rate increased between ZT 15:30 and 16:30. During a subsequent 4-h period beginning around ZT 17:00, GRP neurons from light-exposed animals were hyperpolarized by ∼15 mV. None of these effects was observed in GRP neurons from animals not exposed to light or in immediately adjacent non-GRP neurons whether or not exposed to light. Depolarization of GRP neurons was associated with a reduction in GABAA-dependent synaptic noise, whereas hyperpolarization was accompanied both by a loss of GABAA drive and suppression of a TTX-resistant leakage current carried primarily by Na. This suggests that, in the SCN, exposure to light may induce a short-term increase in GRP neuron excitability mediated by retinal neurotransmitters and neuropeptides, followed by long-term membrane hyperpolarization resulting from suppression of a leakage current, possibly resulting from genomic signals.