Cara M. Altimus

Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision

Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain by means of retinal ganglion cells (RGCs). These retinal outputs support not only pattern vision but also non-image-forming (NIF) functions, which include circadian photoentrainment and pupillary light reflex (PLR). In mammals, NIF functions are mediated by rods, cones and the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). Rod–cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions. The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod–cone networks. To determine how the ipRGCs relay rod–cone light information for both image-forming and non-image-forming functions, we genetically ablated ipRGCs in mice. Here we show that animals lacking ipRGCs retain pattern vision but have deficits in both PLR and circadian photoentrainment that are more extensive than those observed in melanopsin knockouts. The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three photoreceptor classes. These results indicate that light signals for irradiance detection are dissociated from pattern vision at the retinal ganglion cell level, and animals that cannot detect light for NIF functions are still capable of image formation.

Aberrant light directly impairs mood and learning through melanopsin-expressing neurons

The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep–wake cycles to the correct temporal niche. Changes in day-length, shift-work, and transmeridian travel lead to mood alterations and cognitive function deficits. Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules. Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.

Distinct contributions of rod, cone, and melanopsin photoreceptors to encoding irradiance.

Summary Photoreceptive, melanopsin-expressing retinal ganglion cells (mRGCs) encode ambient light (irradiance) for the circadian clock, the pupillomotor system, and other influential behavioral/physiological responses. mRGCs are activated both by their intrinsic phototransduction cascade and by the rods and cones. However, the individual contribution of each photoreceptor class to irradiance responses remains unclear. We address this deficit using mice expressing human red cone opsin, in which rod-, cone-, and melanopsin-dependent responses can be identified by their distinct spectral sensitivity. Our data reveal an unexpectedly important role for rods. These photoreceptors define circadian responses at very dim “scotopic” light levels but also at irradiances at which pattern vision relies heavily on cones. By contrast, cone input to irradiance responses dissipates following light adaptation to the extent that these receptors make a very limited contribution to circadian and pupillary light responses under these conditions. Our data provide new insight into retinal circuitry upstream of mRGCs and optimal stimuli for eliciting irradiance responses.

Rods-cones and melanopsin detect light and dark to modulate sleep independent of image formation

Light detected in the retina modulates several physiological processes including circadian photo-entrainment and pupillary light reflex. Intrinsically photosensitive retinal ganglion cells (ipRGCs) convey rod-cone and melanopsin-driven light input to the brain. Using EEGs and electromyograms, we show that acute light induces sleep in mice during their nocturnal active phase whereas acute dark awakens mice during their diurnal sleep phase. We used retinal mutant mouse lines that lack (i) the ipRGCs, (ii) the photo-transduction pathways of rods and cones, or (iii) the melanopsin protein and showed that the influence of light and dark on sleep requires both rod-cone and melanopsin signaling through ipRGCs and is independent of image formation. We further show that, although acute light pulses overcome circadian and homeostatic drives for sleep, upon repeated light exposures using a 3.5 h/3.5 h light/dark cycle, the circadian and homeostatic drives override the light input. Thus, in addition to their known role in aligning circadian physiology with day and night, ipRGCs also relay light and dark information from both rod-cone and melanopsin-based pathways to modulate sleep and wakefulness.

Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities.

In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

A genetic network for the clock of Neurospora crassa

A diverse array of organisms from bacteria to humans may have evolved the ability to tell time in the presence or absence of external environmental cues. In the lowly bread mould, Neurospora crassa, biomolecular reactions involving the white-collar-1 (wc-1), white-collar-2 (wc-2), and frequency (frq) genes and their products constitute building blocks of a biological clock. Here we use genetic network models to explain quantitatively, from a systems perspective, how these building blocks interact, and how a complex trait like clock oscillation emerges from these interactions. We use a recently developed method of genetic network identification to find an ensemble of oscillating network models quantitatively consistent with available RNA and protein profiling data on the N. crassa clock. Predicted key features of the N. crassa clock system are a dynamically frustrated closed feedback loop, cooperativity in frq gene activation, and/or WC-1/WC-2 protein complex deactivation and substantial posttranscriptional enhancement of wc-1 RNA lifetime. Measuring the wc-1 mRNA lifetime provides a critical test of the genetic networks.

Multiple Photoreceptors Contribute to Nonimage-forming Visual Functions Predominantly through Melanopsin-containing Retinal Ganglion Cells

In the absence of functional rod and cone photoreceptors, mammals retain the ability to detect light for a variety of physiological functions such as circadian photoentrainment and pupillary light reflex. This is attributed to a third class of photoreceptors, the intrinsically photosensitive retinal ganglion cells that express the photopigment melanopsin. Even though in the absence of rods and cones, mammals retain the ability to detect light for various nonimage-forming visual functions, rods and cones can compensate for the absence of the melanopsin protein in nonvisual light-dependent physiological behaviors. Several studies have addressed the relative contribution of each photoreceptor type to nonimage-forming visual functions; however, a comprehensive model for these interactions is far from complete. Under conditions where melanopsin-containing retinal ganglion cells were genetically ablated, image formation is maintained, whereas circadian photoentrainment and pupillary light reflex are severely impaired. The findings indicate that multiple photoreceptors contribute to nonimage-forming visual functions through signaling via melanopsin-containing retinal ganglion cells. Future studies will aim to determine more quantitatively the relative contributions of each retinal photoreceptor in signaling light for nonimage-forming visual functions.

Photoreceptor regulation of spatial visual behavior.

PURPOSE To better understand how photoreceptors and their circuits support luminance-dependent spatial visual behavior. METHODS Grating thresholds for optokinetic tracking were measured under defined luminance conditions in mice with genetic alterations of photoreceptor activity. RESULTS The luminance conditions that enable cone- and rod-mediated behavior, and the luminance range over which rod and cone functions overlap, were characterized. The AII amacrine pathway was found to support low-resolution and high-contrast function, with the rod-cone pathway supporting high-resolution and low-contrast function. Rods alone were also shown to be capable of driving cone-like spatial visual function, but only when cones were genetically maintained in a physiological dark state. CONCLUSIONS The study defined how luminance signals drive rod- and cone-mediated spatial visual behavior and revealed new and unexpected contributions for rods that depend on an interaction between cone and rod systems.

Abnormal wake/sleep pattern in a novel gain-of-function model of DISC1

Sleep disturbances are common in psychiatric disorders, but the causal relationship between the two and the underlying genetic factors is unclear. The DISC1 gene is strongly linked to mood disorders and schizophrenia in a Scottish pedigree. In an earlier study we found a sleep homeostasis disturbance in a Drosophila model overexpressing wild-type human DISC1. Here we aimed to explore the relationship between sleep and the DISC1 gene in a mammalian model, a novel transgenic mouse model expressing full-length human DISC1. We assessed circadian rhythms by monitoring wheel running activity under normal 24-h light:dark conditions and in constant darkness and found the DISC1 mice to have normal circadian photoentrainment and normal intrinsic circadian period. We also assessed sleep duration and quality in the DISC1 mice and found that they were awake longer than wild-type controls at baseline with a tendency for lower rebound of delta activity during recovery from a short sleep deprivation. Thus we suggest that DISC1 may be involved in sleep regulation.

Disordered Ripples Are a Common Feature of Genetically Distinct Mouse Models Relevant to Schizophrenia

We present results from a novel comparative approach to the study of the mechanisms of psychiatric disease. Previous work has examined neural activity patterns in the hippocampus of a freely behaving mouse model associated with schizophrenia, the calcineurin knockout mouse. Here, we examined a genetically distinct mouse model that exhibits a similar set of behavioral phenotypes associated with schizophrenia, a transgenic model expressing a putative dominant-negative DISC1 (DN-DISC1). Strikingly, the principal finding of the earlier work is replicated in the DN-DISC1 mice, that is, a selective increase in the numbers of sharp-wave ripple (SWR) events in the hippocampal local field potential (LFP), while at the same time other LFP patterns such as theta and gamma are unaffected. SWRs are thought to arise from hippocampal circuits and reflect the coordinated activity of the principal excitatory cells of the hippocampus in specific patterns that represent reactivated memories of previous experiences and imagined future experiences that predict behavior. These findings suggest that multiple genetic alterations could converge on distinct patterns of aberrant neurophysiological function to give rise to common behavioral phenotypes in psychiatric disease.