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The central histaminergic system slows visual processing in the retina and lateral geniculate nucleus of awake mice [1]

['Matteo Tripodi', 'Epigenetics', 'Neurobiology Unit', 'Embl Rome', 'European Molecular Biology Laboratory', 'Monterotondo', 'Hiroki Asari']

Date: 2025-11 

Sensory processing is dynamically modulated by an animal’s behavior and internal states. Growing evidence suggests that such modulation starts from early stages, already at the retina, but the underlying mechanisms remain elusive. Combining pharmacological and chemogenetic tools with single-unit extracellular recordings in awake head-fixed mice, here we identified that the visual responses of retinal ganglion cells and the lateral geniculate nucleus were both made weaker and slower by histaminergic projections from the tuberomammillary nucleus of the posterior hypothalamus. The observed changes in the visual responses were, however, not directly linked with histaminergic modulation of pupil dynamics or locomotion behavior. Instead, our computational modeling analysis suggests that the temporal response modulations arise from changes in the intrinsic properties of the circuit, such as gain modulation via the histamine H1 receptors in the retina. Facilitation of visual processing at low histamine levels may offer an ethological advantage, enabling animals to respond rapidly to visual threats during periods of reduced activity.

Combining in vivo single-unit extracellular recordings from either the lateral geniculate nucleus (LGN) or the optic tract (OT) with pharmacological and chemogenetic tools, here we explored how histamine affects the early visual processing in awake head-fixed mice. During the recording sessions, we simultaneously monitored the subject animal’s behavior, such as pupil dynamics and locomotion, to better correlate the effects of histamine on the visual response properties with those on the behavioral measures. We also took a computational approach to clarify the net effect of histamine on the visual responses from functional viewpoints. Because visual processing in the brain fully relies on the signals from the retina, characterization of the retinal operation in vivo is indispensable to better understand how the visual system works.

The retina performs the first stage of visual processing, and conveys visual information to the brain via spike trains of retinal ganglion cells (RGCs). Growing evidence supports that the activity of RGCs is correlated with various behavioral measures, such as locomotion and pupil size [ 26 – 29 ], pointing to a more dynamic role of the retina than is assumed for a deterministic processor. The vertebrate retina is part of the central nervous system equipped with both intrinsic and extrinsic neuromodulation mechanisms, much as other brain regions are [ 24 , 25 ]. For instance, dopamine is synthesized and released by a group of retinal amacrine cells under the control of circadian rhythm, and contributes to adjusting the retinal circuitry for rod or cone vision by modulating gap-junction couplings [ 30 ]. Such retinal intrinsic mechanisms of neuromodulation are, however, much slower than needed to modulate retinal function to follow rapid behavioral changes [ 31 , 32 ]. To this end, the retina seems to exploit the centrifugal system to receive inputs from a variety of brain regions in a species-specific manner [ 4 ]. For example, histaminergic and serotonergic projections from TMN and DRN, respectively, have been anatomically described in the mammalian retina [ 3 , 5 , 6 , 33 ]. However, compared to the isthmo-optic pathway in birds [ 34 ] or the olfacto-retinal circuit in fish [ 35 ], little is known about the function of the mammalian centrifugal system [ 36 , 37 ].

In the mammalian brain, histaminergic neurons are exclusively located in the tuberomammillary nucleus (TMN) and surrounding areas of the posterior hypothalamus [ 1 ]. They express histidine decarboxylase (HDC) and innervate widely across the brain [ 2 ], including the retina [ 3 – 6 ]. These neurons remain silent during sleep, but increase their firing during wakefulness and reach their maximal activity at the state of high vigilance, much as other monoaminergic systems do, such as the serotonergic neurons in the dorsal raphe nucleus (DRN) of the brain stem [ 2 , 7 , 8 ]. Brain histamine exerts its effects on neurons via three types of receptors: the H1 and H2 receptors mediate excitation of postsynaptic cells, while the H3 receptors serve as an auto-receptor to presynaptically inhibit histamine release [ 1 ]. The role of the H4 receptors in the central nervous system remains unknown [ 9 ]. The central histaminergic system has been implicated in regulating an animal’s internal state and a broad range of behavior, including the sleep–wake cycle [ 10 , 11 ], arousal [ 12 , 13 ], suppression of food intake [ 14 – 16 ], and learning [ 17 – 20 ]. Histaminergic neurons, however, corelease γ-aminobutyric acid (GABA) [ 21 ] and interact with other neuromodulatory systems, such as the cholinergic and serotonergic systems [ 2 , 22 , 23 ]. This makes it difficult to dissect the effects of histamine by itself on neural circuit functions. In particular, histaminergic modulation of sensory processing remains largely elusive [ 24 , 25 ].

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003406

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