Top-down modulation of the retinal code via histaminergic neurons of the hypothalamus

Warwick, Rebekah A.; Riccitelli, Serena; Heukamp, Alina; Yaakov, Hadar; Ankri, Lea; Mayzel, Jonathan; Gilead, N.; Parness-Yossifon, Reut; Rivlin‐Etzion, Michal

doi:10.1101/2022.04.26.489509

Cited by 4 publications

(8 citation statements)

References 101 publications

(163 reference statements)

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“…For MEA experiments, the retina was mounted on a MEA as previously described (Warwick et al, 2022). In short, the MEA was coated with poly-d-lysine solution (PDL, 1.0 mg/ml in H 2 O, Merck Millipore, CAT: A-003-E) for 1 h. After washing off the PDL, the dorsal half of the retina was mounted with the RGC layer facing the electrodes as previously described in Karamanlis et al (2021).…”

Section: Tissue Preparationmentioning

confidence: 99%

Dopamine differentially affects retinal circuits to shape the retinal code

Warwick

Heukamp

Riccitelli

et al. 2023

The Journal of Physiology

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Dopamine has long been reported to enhance antagonistic surrounds of retinal ganglion cells (RGCs). Yet, the retina contains many different RGC subtypes and the effects of dopamine can be subtype‐specific. Using multielectrode array (MEA) recordings we investigated how dopamine shapes the receptive fields of RGCs in the mouse retina. We found that the non‐selective dopamine receptor agonist apomorphine can either increase or decrease RGCs’ surround strength, depending on their subtype. We then used two‐photon targeted patch‐clamp to target a specific RGC subtype, the transient‐Off‐αRGC. In line with our MEA recordings, apomorphine did not increase the antagonistic surround of transient‐Off‐αRGCs but enhanced their responses to Off stimuli in the centre receptive field. Both D1‐ and D2‐like family receptor (D1‐R and D2‐R) blockers had the opposite effect and reduced centre‐mediated responses, but differently affected transient‐Off‐αRGC's surround. While D2‐R blocker reduced surround antagonism, D1‐R blocker led to surround activation, revealing On responses to large stimuli. Using voltage‐clamp recordings we separated excitatory inputs from Off cone bipolar cells and inhibitory inputs from the primary rod pathway. In control conditions, cone inputs displayed strong surround antagonism, while inputs from the primary rod pathway showed no surround. Yet, the surround activation in the D1‐R blockade originated from the primary rod pathway. Our findings demonstrate that dopamine differentially affects RGC subtypes via distinct pathways, suggesting that dopamine has a more complex role in shaping the retinal code than previously reported. Key points Receptive fields of retinal ganglion cells (RGCs) have a centre–surround organisation, and previous work has shown that this organisation can be modulated by dopamine in a light‐intensity‐dependent manner. Dopamine is thought to enhance RGCs’ antagonistic surround, but a detailed understanding of how different RGC subtypes are affected is missing. Using a multielectrode array recordings, clustering analysis and pharmacological manipulations, we found that dopamine can either enhance or weaken antagonistic surrounds, and also change response kinetics, of RGCs in a subtype‐specific manner. We performed targeted patch‐clamp recordings of one RGC subtype, the transient‐Off‐αRGC, and identified the underlying circuits by which dopamine shapes its receptive field. Our findings demonstrate that dopamine acts in a subtype‐specific manner and can have complex effects, which has implications for other retinal computations that rely on receptive field structure.

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Section: Tissue Preparationmentioning

confidence: 99%

Dopamine differentially affects retinal circuits to shape the retinal code

Warwick

Heukamp

Riccitelli

et al. 2023

The Journal of Physiology

Self Cite

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“…In rodents, these projections originate primarily in the hypothalamus and the raphe nucleus, are histaminergic and serotonergic, respectively (Gastinger et al, 2006), and could have slow and long-lasting effects (Celada et al, 2013, Frazao et al, 2011). Recent in vitro evidence also suggests that top-down projection from the hypothalamus modulates retina activity through H1R (Warwick et al, 2022), possibly through effects on.horizontal cells and multiple types of amacrine cells (Frazao et al, 2011, Yu et al, 2011). In accordance with these studies, we demonstrated that H1R antagonist mepyramine could significantly reduce the cross-correlation between movement and retinal calcium dynamics (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study reported top-down histaminergic modulation of retina activity (Warwick et al, 2022)) mediated by the H1 receptor (H1R). To test whether movement modulates retina activity through H1R, we injected H1R blocker mepyramine (200nL, 500uM) to the eye and performed repeat in situ retinal calcium imaging.…”

Section: Movement Modulates In Situ Retinal Activity Through the Hist...mentioning

confidence: 99%

“…In addition to possible presynaptic mechanisms in terminal brain regions, previous reports showed that histaminergic retinopetal axons branch extensively in the ganglion cell and inner plexiform layers (Greferath et al, 2009; Gastinger et al, 2006). In vitro results indicate that efferent projections from the hypothalamus can modulate retinal ganglion neurons (Warwick et al, 2022). Utilizing our unique setup to image the retina in situ in awake animals, we demonstrated that some amacrine cells were substantially modulated by movement mediated through the H1 receptor during early development, suggesting that the retina receives ongoing efferent feedback from the brain starting at an early age.…”

Section: Introductionmentioning

confidence: 99%

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In Situ Imaging of Retinal Calcium Dynamics in Awake Animals

Wang¹,

Su²,

Jin³

et al. 2023

Preprint

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Mammalian vision starts in the retina. The study of retinal circuits in vivo is essential for comprehending retinal neural dynamics under physiological conditions. While several transpupillary retina imaging techniques have been utilized in anesthetized animals, the in situ imaging of retinal activity in awake animals has been more difficult to accomplish. These limits have frustrated crucial scientific inquiries, such as how visual processing in the retina is modulated by behavior. In this study, we present novel experimental approaches that stabilize the eye to access in situ retinal dynamics with optical techniques in awake mice. Our findings demonstrate that this method can be utilized to: 1) image neural activity in distinct cell types across multiple ages, 2) record meso-scale (e.g. spontaneous retinal waves) or cellular retinal dynamics, 3) study retina functional connectivity in vivo, and 4) pharmacologically manipulate retinal activity. We applied these novel approaches to demonstrate that retinal activity is strongly modulated by movement through H1R-dependent histaminergic transmission in vivo, even at the amacrine cell level. These methods are suitable to simultaneously record retinal and brain activity dynamics or to investigate retinal responses to patterned visual stimuli, making accessible fundamental questions about visual processing that have previously been very challenging to achieve.

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“…What is not well-captured by connectomic approaches are ‘wireless’ interactions mediated by neuromodulators, which comprise a broad variety of very different small molecules, including monoamines (e.g., dopamine (15, 16), histamine (17, 18), serotonin (19)), endocannabinoids (20–22), gasotransmitters such as nitric oxide (NO) (23, 24)), as well as a variety of neuropeptides (e.g., neuropeptide Y (25, 26)). Only few of the >20 neuromodulators (27) found in the retina are released from centrifugal fibers (e.g., histamine and serotonin (17–19, 28)), whereas most of them are released in addition to GABA or glycine by ACs (27, 29– 32). Neuromodulators have long been implicated in adapting the retina to different contextual states necessary to robustly perform in a highly dynamic visual environment (e.g., (33–36)).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide modulates contrast suppression in a subset of mouse retinal ganglion cells

Gonschorek,

Goldin,

Oesterle

et al. 2023

Preprint

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Neuromodulators have major influences on the regulation of neural circuit activity across the nervous system. Nitric oxide (NO) is a prominent neuromodulator in many circuits, and has been extensively studied in the retina across species. NO has been associated with the regulation of light adaptation, gain control, and gap junction coupling, but its effect on the retinal out-put, specifically on the different types of retinal ganglion cells (RGCs), is still poorly understood. Here, we used two-photon Ca2+imaging to record RGC responses to visual stimuli to investigate the neuromodulatory effects of NO on the cell type-level in theex vivomouse retina. We found that about one third of the RGC types displayed highly reproducible and cell type-specific response changes during the course of an experiment, even in the absence of NO. Accounting for these adaptational changes allowed us to isolate NO effects on RGC responses. This revealed that NO affected only a few RGC types, which typically became more active due to a reduction of their response suppression. Notably, NO had no discernible effect on their spatial receptive field size and surround strength. Together, our data suggest that NO specifically modulates suppression of the temporal response in a distinct group of contrast-suppressed RGC types. Finally, our study demonstrates the need for recording paradigms that takes adaptational, non-drug-related response changes into account when analysing potentially subtle pharmacological effects.

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Top-down modulation of the retinal code via histaminergic neurons of the hypothalamus

Cited by 4 publications

References 101 publications

Dopamine differentially affects retinal circuits to shape the retinal code

Dopamine differentially affects retinal circuits to shape the retinal code

In Situ Imaging of Retinal Calcium Dynamics in Awake Animals

Nitric oxide modulates contrast suppression in a subset of mouse retinal ganglion cells

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