Development of melanopsin-based irradiance detecting circuitry

McNeill, David S.; Sheely, Catherine; Ecker, Jennifer L.; Badea, Tudor C.; Morhardt, Duncan R.; Guido, William; Hattar, Samer

doi:10.1186/1749-8104-6-8

Cited by 81 publications

(91 citation statements)

References 37 publications

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“…We propose that the targeting of the ipsilateral SCN by the contralateral ipRGCs occurs later in development when the robo1-slit or analogous repulsive signals have been down-regulated. Consistent with this idea, the SCN is fully innervated by retinal fibers only ∼10 d after birth (40).…”

Section: Discussionsupporting

confidence: 66%

Architecture of retinal projections to the central circadian pacemaker

Fernandez

Chang

Hattar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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131

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The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/ gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCNprojecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.melanopsin | circadian | suprachiasmatic nucleus | non-image-forming functions | ipRGCs T he suprachiasmatic nucleus (SCN) houses a central pacemaker that orchestrates circadian (circa: "about" and diem: "day") behaviors that cycle with a period close to 24 h. This endogenous clock is self-sustained even in the complete absence of external stimuli, but can be entrained to the light/dark cycle of the solar day in a process defined as circadian photoentrainment (1). In mammals, phototransduction solely occurs in the retina (2). Retinal ganglion cells (RGCs) are projection neurons of the retina that send light information to brain targets (3). Although the majority of RGCs project to brain areas involved in object tracking and image formation, some RGCs also innervate non-image-forming brain regions to influence circadian activity, sleep, the pupillary light response, mood, and learning functions (4).Recent studies showed that a small subpopulation of RGCs expresses a photopigment called melanopsin (Opn4), making these cells intrinsically photosensitive (ip)RGCs (5-7). It is now known that there are at least five different ipRGC subtypes (M1-M5) (8, 9). Using genetic tracing techniques, it was shown that ipRGCs send projections to non-image-forming centers in the brain, including the SCN, which receives retinal input predominantly from M1 ipRGCs (10-12) and to a lesser extent from M2 ipRGCs (12). The SCN is a smal...

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Section: Discussionsupporting

confidence: 66%

Architecture of retinal projections to the central circadian pacemaker

Fernandez

Chang

Hattar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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131

134

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“…Whereas all SCN neurons are GABAergic, the shell and the core subdivisions show, respectively, localized expression of arginine vasopressin (AVP) or vasoactive intestinal peptide (VIP), and gastrin-releasing peptide (GRP). Anatomical studies have shown that the SCN is densely innervated by retinal axonal projections (Hattar et al 2006;McNeill et al 2011), the core subdivision being the principal site of direct and indirect retinal innervation. The discovery that light-mediated resetting of the SCN clock was accompanied by the induced expression of immediate-early genes such as cfos in the retinorecipient core directed the analysis of circadian timekeeping in mammals toward signal transduction and transcriptional regulation.…”

Section: A Brief Timeline Of the Scn Clockmentioning

confidence: 99%

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

Herzog

Hermanstyne

Smyllie

et al. 2017

Cold Spring Harb Perspect Biol

197

171

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The suprachiasmatic nucleus (SCN) is the principal circadian clock of the brain, directing daily cycles of behavior and physiology. SCN neurons contain a cell-autonomous transcription-based clockwork but, in turn, circuit-level interactions synchronize the 20,000 or so SCN neurons into a robust and coherent daily timer. Synchronization requires neuropeptide signaling, regulated by a reciprocal interdependence between the molecular clockwork and rhythmic electrical activity, which in turn depends on a daytime Na þ drive and nighttime K þ drag. Recent studies exploiting intersectional genetics have started to identify the pacemaking roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing information through the interactions between key groups of neurons within the SCN circuit. The field is now poised to elucidate these computations, their underlying cellular mechanisms, and how the SCN clock interacts with subordinate circadian clocks across the brain to determine the timing and efficiency of the sleep -wake cycle, and how perturbations of this coherence contribute to neurological and psychiatric illness.W e wake and sleep each day. Hormones reach peak plasma levels at specified times, for example cortisol peaks in the early morning. These, and many other physiological and behavioral, daily rhythms depend on an internal circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. Prior reviews have provided excellent summaries of research progress in the location and function of this body clock (Weaver 1998). This work focuses on recent advances in our understanding of the genetic basis for cell-autonomous generation of circadian time, and how cells within the SCN synchronize their daily rhythms across the circuit to produce a coherent oscillation in neuronal activity. It is these circuit-level emergent properties of the SCN that ultimately direct daily behaviors such as wake and sleep.

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“…38 The ablation of all Brn3b-positive M1-M5 pRGCs was also shown to disrupt the PLR, yet, given the widespread loss of pRGC subtypes using this approach, it is not possible to conclude from this study which class of pRGC mediates the PLR or other behaviours. However, the timeline with which M1 cells innervate the shell of the OPN coincides with the development of the PLR, 37 and the selective ablation of M1-type pRGCs has been shown to severely impair the PLR. 47 Therefore it would seem that the PLR is driven by M1-type pRGCs, and thus distinct subsets of M1-type pRGCs are responsible for driving circadian entrainment and the PLR.…”

Section: Physiological Roles Performed By Prgc Subtypesmentioning

confidence: 99%

“…To date at least five distinct subtypes of pRGC have been identified, termed M1-M5-type pRGCs. 1,2,[32][33][34][35] These cells show differences in morphology and retinal connections, and exhibit light responses with markedly different kinetics and sensitivities ( Figure 1b) [32][33][34][37][38][39] (Figure 1c), and would therefore seem to be tasked with performing different physiological roles (for review see Schmidt et al 36,40 ). However, the innervations of each class of pRGC are only partially resolved, and the specific roles performed by each class of pRGC are yet to be fully determined.…”

Section: Subtypes Of Prgcmentioning

confidence: 99%

“…32 Subsequent studies using Opn4.Cre mice have allowed the combined innervations of M1-M5-type pRGCs to be studied, 33,37 and identified a number of additional brain regions that receive input exclusively from non-M1 pRGCs, including the dorsal lateral geniculate nucleus (dLGN), the core region of the OPN, and additional innervations of the SC. 33 However, these Opn4.Cre-based models do not allow the separation of projections from the different pRGC subtypes, as such the regions of the brain innervated specifically by M2, M3, M4, and M5 types pRGCs remain largely undetermined.…”

Section: Innervations Of Prgc Subtypesmentioning

confidence: 99%

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Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells

Hughes

Jagannath

Rodgers

et al. 2016

Eye

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Over the past two decades there have been significant advances in our understanding of both the anatomy and function of the melanopsin system. It has become clear that rather than acting as a simple irradiance detector the melanopsin system is in fact far more complicated. The range of behavioural systems known to be influenced by melanopsin activity is increasing with time, and it is now clear that melanopsin contributes not only to multiple non-image forming systems but also has a role in visual pathways. How melanopsin is capable of driving so many different behaviours is unclear, but recent evidence suggests that the answer may lie in the diversity of melanopsin light responses and the functional specialisation of photosensitive retinal ganglion cell (pRGC) subtypes. In this review, we shall overview the current understanding of the melanopsin system, and evaluate the evidence for the hypothesis that individual pRGC subtypes not only perform specific roles, but are functionally specialised to do so. We conclude that while, currently, the available data somewhat support this hypothesis, we currently lack the necessary detail to fully understand how the functional diversity of pRGC subtypes correlates with different behavioural responses, and ultimately why such complexity is required within the melanopsin system. What we are lacking is a cohesive understanding of how light responses differ between the pRGC subtypes (based not only on anatomical classification but also based on their site of innervation); how these diverse light responses are generated, and most importantly how these responses relate to the physiological functions they underpin.

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Development of melanopsin-based irradiance detecting circuitry

Cited by 81 publications

References 37 publications

Architecture of retinal projections to the central circadian pacemaker

Architecture of retinal projections to the central circadian pacemaker

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells

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