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The ability of the retina and brain to report the absolute light intensity (irradiance) in the environment was first observed half a century ago. However, its physiological basis is still poorly understood. The only retinal output neurons that are capable of transmitting intensity-encoding signals are called ipRGCs - intrinsically photosensitive retinal ganglion cells. These intensity signals have a remarkably diverse array of functional effects at many levels of the central nervous system, from modulation of sleep, activity and hormonal rhythms, through regulation of pupil size, to light avoidance and retinal development. New evidence suggests that they affect both the retina itself (a possible substrate for light adaptation) and the limbic thalamus and cortex (through which they appear to mediate effects of light on mood). Our current research is devoted to better understanding both of these novel output modalities of the ipRGC network.

We use mouse genetic models and combine:
· Reconstruction of neural circuits using light and electron microscopy
· in vitro and in vivo electrophysiology and functional imaging
· Optogenetic and chemogenetic manipulations of neural activity
· Behavioral analysis
These powerful and complementary approaches allow us to reveal the operation of specific neural circuits and their role in shaping the behavior of animals in unprecedented detail.

Effect of abnormal lighting on mood

Effect of abnormal lighting on mood.JPG 

One branch of our research program focuses on the role of abnormal lighting and retinto-thalamo-cortical networks in the pathophysiology of diverse mood disorders. Lighting and light cycles affect mood. We all appreciate the appeal of a sunny day or a sunny apartment, and inversely, the negative effects on our sleep and mood of jet lag or viewing computer displays at night. Additionally, recent evidence suggests that the timing and intensity of light exposure can induce or exacerbate mood disorders, as in seasonal affective disorder (SAD), bipolar disorder, and major depression. On the other hand, phototherapy for less than an hour a day, at the right time, has been shown to significantly reduce the severity of major depression and bipolar depression. These mood alterations are generally assumed to be secondary to circadian disturbance. However, new evidence indicates that abnormal lighting can have direct effects on mood, independent of circadian effects. For example, animals exposed to abnormal lighting regimes exhibit a normal circadian rhythm, but show increased depression-like behaviors that can be alleviated by administration of antidepressants.

A possible substrate for this direct effect of light on mood has been identified recently. In mammals, circadian photoentrainment is mediated by ipRGCs that project light intensity information to the master circadian clock, the suprachiasmatic nucleus (SCN). These light signals affect the SCN clock and are thought to ultimately reach the ventromedial prefrontal cortex (vmPFC) and mediate mood changes. However, in the recently discovered pathway (Fernandez et al., 2018), a subset of ipRGCs communicate with the vmPFC through a newly identified nucleus of the dorsal thalamus – the perihabenula (PHb). Therefore, this pathway may mediate a direct effect of light on mood, independent of any effect on the SCN or circadian rhythms. Truly remarkably, chronic activation of neurons in the PHb is sufficient to induce depression-like behaviors, while silencing the PHb protects the animals against depression. At present, not much else is known about this fascinating pathway. Therefore, we are currently dissecting the mechanistic basis, organization and behavioral outputs of this pathway. This branch of research holds immediate and far-reaching implications to our understanding of the role of aberrant lighting in the pathophysiology of mood disorders, and may lead to the development of treatments for diverse mood disorders.



Fernandez DC, Fogerson PM, Ospri LL, Layne RM, Akasako M, Singer JH, Berson DM, Hattar S (2018) Light affects mood and learning through distinct retina-brain pathways. Cell 175:71-84.

Role of ipRGCs and wide-field amacrine cells in light adaptation

Role of ipRGCs and wide-field amacrine cells in light adaptation.JPGAnother branch of our research program focuses on dissecting retinal circuits encoding intensity vs. contrast and their roles in light adaptation. While ipRGCs transmit intensity-encoding signals, all other RGCs are optimized for the transmission of contrast-encoding signals and support detection and recognition of objects, color and motion. Though contrast and intensity signals are carried through these distinct sets of retinal outputs, they also appear to interact in the context of light adaptation. Light adaptation allows the retina to encode contrast over a huge range of light intensities, from starlight to midday sunlight. To date, the role of ipRGC networks in light adaptation as well as the route by which they modulate the responses of retinal neurons has only been implied, but never confirmed. We will explore how intensity signals propagate in the retina, affect the physiology of inner retinal neurons, and possibly mediate light adaptation. This work will contribute not only to our understanding of light adaptation, which is an important and intensive field of research, but also to our understanding of neural adaptation in general, in other sensory systems.