title: Geniculohypothalamic GABAergic projections gate suprachiasmatic nucleus responses to retinal input.
abstract: Visual input to the suprachiasmatic nucleus circadian clock is critical for animals to adapt their physiology and behaviour in line with the solar day. In addition to direct retinal projections, the clock receives input from the visual thalamus, although the role of this geniculohypothalamic pathway in circadian photoreception is poorly understood. In the present study, we develop a novel brain slice preparation that preserves the geniculohypothalamic pathway to show that GABAergic thalamic neurons inhibit retinally-driven activity in the central clock in a circadian time-dependent manner. We also show that in vivo manipulation of thalamic signalling adjusts specific features of the hypothalamic light response, indicating that the geniculohypothalamic pathway is primarily activated by crossed retinal inputs. Our data provide a mechanism by which geniculohypothalamic signals can adjust the magnitude of circadian and more acute hypothalamic light responses according to time-of-day and establish an important new model for future investigations of the circadian visual system.
  
  
  
  Sensory input to the master mammalian circadian clock, the suprachiasmatic nucleus (SCN), is vital in allowing animals to optimize physiology and behaviour alongside daily changes in the environment. Retinal inputs encoding changes in external illumination provide the principle source of such information. The SCN also receives input from other retinorecipient brain regions, primarily via the geniculohypothalamic tract (GHT), although the contribution of these indirect projections to circadian photoreception is currently poorly understood. To address this deficit, in the present study, we established an in vitro mouse brain slice preparation that retains connectivity across the extended circadian system. Using multi-electrode recordings, we first confirm that this preparation retains intact optic projections to the SCN, thalamus and pretectum and a functional GHT. We next show that optogenetic activation of GHT neurons selectively suppresses SCN responses to retinal input, and also that this effect exhibits a pronounced day/night variation and involves a GABAergic mechanism. This inhibitory action was not associated with overt circadian rhythmicity in GHT output, indicating modulation at the SCN level. Finally, we use in vivo electrophysiological recordings alongside pharmacological inactivation or optogenetic excitation to show that GHT signalling actively modulates specific features of the SCN light response, indicating that GHT cells are primarily activated by crossed retinal projections. Taken together, our data establish a new model for studying network communication in the extended circadian system and provide novel insight into the roles of GHT-signalling, revealing a mechanism by which thalamic activity can help gate retinal input to the SCN according to time of day.
authors.affiliation: Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Lydia
authors.identifier: 0000-0002-5000-6676
authors.initials: L
authors.lastname: Hanna
authors.affiliation: Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Walmsley
authors.affiliation: Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Pienaar
authors.affiliation: Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Howarth
authors.affiliation: Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Timothy M
authors.identifier: 0000-0002-5625-4750
authors.initials: TM
authors.lastname: Brown
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055351:Retinal Neurons / Q000502:physiology*; D000074523:Suprachiasmatic Nucleus Neurons / Q000502:physiology*; D014785:Vision, Ocular
keywords: channelrhodopsin; circadian; electrophysiology; intergeniculate leaflet; mouse