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Jan Fahrenkrug - One of the best experts on this subject based on the ideXlab platform.
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Cells of the Retinohypothalamic Tract
2016Co-Authors: Night In Pacap-containing Ganglion, Jens Hannibal, Niels Vrang, Patrick J. Card, Jan FahrenkrugAbstract:AbsTract Environmental light stimulation via the Retinohypothalamic Tract (RHT) is necessary for stable entrainment of circadian rhythms generated in the suprachiasmatic nucleus (SCN). In the current report, the authors characterized the functional activity and phenotype of retinal ganglion cells that give rise to the RHT of the rat. Retinal ganglion cells that give rise to the RHT were identified by transsynaptic passage of an attenuated alpha herpesvirus known to have selec-tive affinity for this pathway. Dual labeling immunocytochemistry demon-strated co-localization of viral antigen and pituitary adenylate cyclase activating polypeptide (PACAP) in retinal ganglion cells. This was confirmed using the anterograde tracer cholera toxin subunit B (ChB). In normal and retinally degen-erated monosodium glutamate (MSG)–treated rats, ChB co-localized with PACAP in axons of the retinorecipient zone of the SCN. Light-induced Fos-immunoreactivity (Fos-IR) was apparent in all PACAP-containing retinal ganglion cells and a population of non-PACAP-containing retinal ganglion cells at dawn of normal and MSG-treated animals. Within the next 3 h, Fos disap
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Melanopsin Is Expressed in PACAP-Containing Retinal Ganglion Cells of the Human Retinohypothalamic Tract
2013Co-Authors: Jens Hannibal, Birgitte Georg, Peter Hindersson, Jens Ostergaard, Philip J. Larsen, Steffen Heegaard, Jan FahrenkrugAbstract:PURPOSE. The putative circadian photoreceptor melanopsin is found in rodents in a subpopulation of intrinsic light-sensitive retinal ganglion cells (RGCs) constituting the Retinohypothalamic Tract (RHT). The study was conducted to determine whether melanopsin is expressed in the human retina and costored with the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), a marker for the RHT, projecting to the suprachiasmatic nucleus (SCN). Furthermore, whether melanopsin expression is conserved in retinas of blind patients with severe retinal degeneration was investigated. METHODS. In situ hybridization and immunohistochemistry was used to demonstrate melanopsin synthesis in human eyes of 17 donors and two postmortem hypothalami containing the SCN. The coexistence of melanopsin and PACAP in elements of the Retinohypothalamic Tract was studied by dual-labeling immunocytochemistry
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Lack of the PAC1 receptor alters the circadian expression of VIP mRNA in the suprachiasmatic nucleus of mice.
Brain Research, 2007Co-Authors: Birgitte Georg, Jens Hannibal, Jan FahrenkrugAbstract:AbsTract PACAP in the Retinohypothalamic Tract mediates photic information to the suprachiasmatic nucleus via the PAC 1 receptor. The diurnal and circadian VIP mRNA expressions in the suprachiasmatic nucleus of PAC 1 −/− and wild type mice were quantified. During light/dark cycles identical VIP mRNA rhythms were found while the oscillation pattern differed between the two types of animals during constant darkness. The results show that the circadian VIP mRNA expression is influenced by the absence of PAC 1 signalling.
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melanopsin is expressed in pacap containing retinal ganglion cells of the human Retinohypothalamic Tract
Investigative Ophthalmology & Visual Science, 2004Co-Authors: Jens Hannibal, Birgitte Georg, Peter Hindersson, Jens Ostergaard, Philip J. Larsen, Steffen Heegaard, Jan FahrenkrugAbstract:PURPOSE. The putative circadian photoreceptor melanopsin is found in rodents in a subpopulation of intrinsic light-sensitive retinal ganglion cells (RGCs) constituting the Retinohypothalamic Tract (RHT). The study was conducted to determine whether melanopsin is expressed in the human retina and costored with the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), a marker for the RHT, projecting to the suprachiasmatic nucleus (SCN). Furthermore, whether melanopsin expression is conserved in retinas of blind patients with severe retinal degeneration was investigated. METHODS. In situ hybridization and immunohistochemistry was used to demonstrate melanopsin synthesis in human eyes of 17 donors and two postmortem hypothalami containing the SCN. The coexistence of melanopsin and PACAP in elements of the Retinohypothalamic Tract was studied by dual-labeling immunocytochemistry. RESULTS. Melanopsin expression was found in a subpopulation of RGCs located in the ganglion cell layer and displaced in the inner nuclear cell layer. Melanopsin-containing cells comprised approximately 0. 8% of all RGCs, with a distinct morphology characterized by two to four dendritic processes constituting a panretinal network. Melanopsin immunoreactivity was primary present at perikaryal boundaries and neuronal processes and to some extent also in the cytoplasm. PACAP and melanopsin were colocalized in the RGCs and PACAP-containing nerve fibers, seemingly innervating the retinorecipient part of the SCN. Melanopsin-expressing RGCs were conserved in retinas of blind patients with severe degeneration of the outer and/or inner layers. CONCLUSIONS. Given the expression of melanopsin in PACAPcontaining RGCs of the human RHT, this photoreceptor is a likely first base in the chain of events leading to photoentrainment of both normal and blind people. (Invest Ophthalmol Vis Sci. 2004;45:4202‐4209) DOI:10.1167/iovs.04-0313
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Expression of melanopsin during development of the rat retina
Neuroreport, 2004Co-Authors: Jan Fahrenkrug, Henriette Svarre Nielsen, Jens HannibalAbstract:There is accumulating evidence that the new opsin-like protein, melanopsin, in adult rodents functions as non-visual photoreceptor. Here we report using immunohistochemistry and in situ hybridisation that melanopsin during rat retinal development is expressed already at prenatal day 18 in cells of the inner neuroblast layer. Perinatally the melanopsin positive cells increase in number and migrate towards the ganglion cell layer. During early postnatal development a melanopsin immunoreactive dendritic network is formed in the inner plexiform layer. Melanopsin is exclusively expressed in PACAP-containing cells which in adults become the retinal ganglion cells constituting the Retinohypothalamic Tract. The early expression of melanopsin argues for a photoreceptor role in the developing Retinohypothalamic Tract which is functional as early as the first day after birth.
Jens Hannibal - One of the best experts on this subject based on the ideXlab platform.
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Cells of the Retinohypothalamic Tract
2016Co-Authors: Night In Pacap-containing Ganglion, Jens Hannibal, Niels Vrang, Patrick J. Card, Jan FahrenkrugAbstract:AbsTract Environmental light stimulation via the Retinohypothalamic Tract (RHT) is necessary for stable entrainment of circadian rhythms generated in the suprachiasmatic nucleus (SCN). In the current report, the authors characterized the functional activity and phenotype of retinal ganglion cells that give rise to the RHT of the rat. Retinal ganglion cells that give rise to the RHT were identified by transsynaptic passage of an attenuated alpha herpesvirus known to have selec-tive affinity for this pathway. Dual labeling immunocytochemistry demon-strated co-localization of viral antigen and pituitary adenylate cyclase activating polypeptide (PACAP) in retinal ganglion cells. This was confirmed using the anterograde tracer cholera toxin subunit B (ChB). In normal and retinally degen-erated monosodium glutamate (MSG)–treated rats, ChB co-localized with PACAP in axons of the retinorecipient zone of the SCN. Light-induced Fos-immunoreactivity (Fos-IR) was apparent in all PACAP-containing retinal ganglion cells and a population of non-PACAP-containing retinal ganglion cells at dawn of normal and MSG-treated animals. Within the next 3 h, Fos disap
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Dissociation between Light-Induced Phase Shift of the Circadian Rhythm and Clock Gene Expression in Mice Lacking the Pituitary Adenylate Cyclase Activating Polypeptide Type 1 Receptor
2013Co-Authors: Jens Hannibal, Francoise Jamen, Harriette S. Nielsen, Laurant JournotAbstract:The circadian clock located in the suprachiasmatic nucleus (SCN) organizes autonomic and behavioral rhythms into a near 24 hr time that is adjusted daily to the solar cycle via a direct projection from the retina, the Retinohypothalamic Tract (RHT). This neuronal pathway costores the neurotransmitters PACAP and glutamate, which seem to be important for light-induced resetting of the clock. At the molecular level the clock genes mPer1 and mPer2 are believed to be target for the light signaling to the clock. In this study, we investigated the possible role of PACAP-type 1 receptor signaling in light-induced resetting of the behavioral rhythm and light-induced clock gene expression in the SCN. Light stimulation at early night resulted in larger phase delays in PACAP-type 1 receptor-deficient mice (PAC1 � / � ) compared with wild-type mice accompanied by a marked reduction in light-induced mPer1, mPer2, and c-fo
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Melanopsin Is Expressed in PACAP-Containing Retinal Ganglion Cells of the Human Retinohypothalamic Tract
2013Co-Authors: Jens Hannibal, Birgitte Georg, Peter Hindersson, Jens Ostergaard, Philip J. Larsen, Steffen Heegaard, Jan FahrenkrugAbstract:PURPOSE. The putative circadian photoreceptor melanopsin is found in rodents in a subpopulation of intrinsic light-sensitive retinal ganglion cells (RGCs) constituting the Retinohypothalamic Tract (RHT). The study was conducted to determine whether melanopsin is expressed in the human retina and costored with the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), a marker for the RHT, projecting to the suprachiasmatic nucleus (SCN). Furthermore, whether melanopsin expression is conserved in retinas of blind patients with severe retinal degeneration was investigated. METHODS. In situ hybridization and immunohistochemistry was used to demonstrate melanopsin synthesis in human eyes of 17 donors and two postmortem hypothalami containing the SCN. The coexistence of melanopsin and PACAP in elements of the Retinohypothalamic Tract was studied by dual-labeling immunocytochemistry
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melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies
Brain, 2010Co-Authors: Chiara La Morgia, Jens Hannibal, Fred N Rosscisneros, Alfredo A Sadun, Alessandra Munarini, Vilma Mantovani, Piero Barboni, Gaetano Cantalupo, Kevin R Tozer, Elisa SancisiAbstract:Mitochondrial optic neuropathies, that is, Leber hereditary optic neuropathy and dominant optic atrophy, selectively affect retinal ganglion cells, causing visual loss with relatively preserved pupillary light reflex. The mammalian eye contains a light detection system based on a subset of retinal ganglion cells containing the photopigment melanopsin. These cells give origin to the Retinohypothalamic Tract and support the non-image-forming visual functions of the eye, which include the photoentrainment of circadian rhythms, light-induced suppression of melatonin secretion and pupillary light reflex. We studied the integrity of the Retinohypothalamic Tract in five patients with Leber hereditary optic neuropathy, in four with dominant optic atrophy and in nine controls by testing the light-induced suppression of nocturnal melatonin secretion. This response was maintained in optic neuropathy subjects as in controls, indicating that the Retinohypothalamic Tract is sufficiently preserved to drive light information detected by melanopsin retinal ganglion cells. We then investigated the histology of post-mortem eyes from two patients with Leber hereditary optic neuropathy and one case with dominant optic atrophy, compared with three age-matched controls. On these retinas, melanopsin retinal ganglion cells were characterized by immunohistochemistry and their number and distribution evaluated by a new protocol. In control retinas, we show that melanopsin retinal ganglion cells are lost with age and are more represented in the parafoveal region. In patients, we demonstrate a relative sparing of these cells compared with the massive loss of total retinal ganglion cells, even in the most affected areas of the retina. Our results demonstrate that melanopsin retinal ganglion cells resist neurodegeneration due to mitochondrial dysfunction and maintain non-image-forming functions of the eye in these visually impaired patients. We also show that in normal human retinas, these cells are more concentrated around the fovea and are lost with ageing. The current results provide a plausible explanation for the preservation of pupillary light reaction despite profound visual loss in patients with mitochondrial optic neuropathy, revealing the robustness of melanopsin retinal ganglion cells to a metabolic insult and opening the question of mechanisms that might protect these cells.
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Lack of the PAC1 receptor alters the circadian expression of VIP mRNA in the suprachiasmatic nucleus of mice.
Brain Research, 2007Co-Authors: Birgitte Georg, Jens Hannibal, Jan FahrenkrugAbstract:AbsTract PACAP in the Retinohypothalamic Tract mediates photic information to the suprachiasmatic nucleus via the PAC 1 receptor. The diurnal and circadian VIP mRNA expressions in the suprachiasmatic nucleus of PAC 1 −/− and wild type mice were quantified. During light/dark cycles identical VIP mRNA rhythms were found while the oscillation pattern differed between the two types of animals during constant darkness. The results show that the circadian VIP mRNA expression is influenced by the absence of PAC 1 signalling.
Martha U Gillette - One of the best experts on this subject based on the ideXlab platform.
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Ca 2 � /cAMP Response Element-binding Protein (CREB)-dependent Activation of Per1 Is Required for Light-induced Signaling in the
2013Co-Authors: Martha U GilletteAbstract:Light is a prominent stimulus that synchronizes endogenous circadian rhythmicity to environmental light/ dark cycles. Nocturnal light elevates mRNA of the Period1 (Per1) gene and induces long term state changes, expressed as phase shifts of circadian rhythms. The cellular mechanism for Per1 elevation and light-induced phase advance in the suprachiasmatic nucleus (SCN), a process initiated primarily by glutamatergic neurotransmission from the Retinohypothalamic Tract, was examined. Glutamate (GLU)-induced phase advances in the rat SCN were blocked by antisense oligodeoxynucleotide (ODN) against Per1 and Ca 2 � /cAMP response element (CRE)-decoy ODN. CRE-decoy ODN also blocked light-induced phase advances in vivo. Furthermore, the CRE-decoy blocked GLU-induced accumulation of Per
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Mass spectrometry-based discovery of circadian peptides
Proceedings of the National Academy of Sciences, 2008Co-Authors: Nathan G. Hatcher, Martha U Gillette, Norman Atkins, Suresh P. Annangudi, Andrew J. Forbes, Neil L. Kelleher, Jonathan V. SweedlerAbstract:A significant challenge to understanding dynamic and heterogeneous brain systems lies in the chemical complexity of secreted intercellular messengers that change rapidly with space and time. Two solid-phase exTraction collection strategies are presented that relate time and location of peptide release with mass spectrometric characterization. Here, complex suites of peptide-based cell-to-cell signaling molecules are characterized from the mammalian suprachiasmatic nucleus (SCN), site of the master circadian clock. Observed SCN releasates are peptide rich and demonstrate the co-release of established circadian neuropeptides and peptides with unknown roles in circadian rhythms. Additionally, the content of SCN releasate is stimulation specific. Stimulation paradigms reported to alter clock timing, including electrical stimulation of the Retinohypothalamic Tract, produce releasate mass spectra that are notably different from the spectra of compounds secreted endogenously over the course of the 24-h cycle. In addition to established SCN peptides, we report the presence of proSAAS peptides in releasates. One of these peptides, little SAAS, exhibits robust Retinohypothalamic Tract-stimulated release from the SCN, and exogenous application of little SAAS induces a phase delay consistent with light-mediated cues regulating circadian timing. These mass spectrometry-based analyses provide a new perspective on peptidergic signaling within the SCN and demonstrate that the integration of secreted compounds with information relating time and location of release generates new insights into intercellular signaling in the brain.
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New light on an old paradox: site-dependent effects of carbachol on circadian rhythms.
Experimental Neurology, 2005Co-Authors: Gordon F Buchanan, Martha U GilletteAbstract:Acetylcholine (ACh) was the first neurotransmitter identified as a regulator of mammalian circadian rhythms. When injected in vivo, cholinergics induced biphasic clock resetting at night, similar to nocturnal light exposure. However, the Retinohypothalamic Tract connecting the eye to the suprachiasmatic nucleus (SCN) uses glutamate (GLU) to transmit light signals. We here resolve this long-standing paradox. Whereas injection of the cholinergic agonist, carbachol, into the mouse ventricular system in vivo induced light-like effects, direct application to the SCN in vitro or in vivo induced a distinct response pattern: phase advance of circadian rhythms throughout the nighttime. These results indicate that a new regulatory pathway, involving an extra-SCN cholinergic synapse accessible via ventricular injection, mediates the light-like cholinergic clock resetting reported previously.
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ca2 camp response element binding protein creb dependent activation of per1 is required for light induced signaling in the suprachiasmatic nucleus circadian clock
Journal of Biological Chemistry, 2003Co-Authors: Shelley A Tischkau, Sheue Houy Tyan, Gordon F Buchanan, Jennifer W Mitchell, Martha U GilletteAbstract:AbsTract Light is a prominent stimulus that synchronizes endogenous circadian rhythmicity to environmental light/dark cycles. Nocturnal light elevates mRNA of the Period1(Per1) gene and induces long term state changes, expressed as phase shifts of circadian rhythms. The cellular mechanism forPer1 elevation and light-induced phase advance in the suprachiasmatic nucleus (SCN), a process initiated primarily by glutamatergic neurotransmission from the Retinohypothalamic Tract, was examined. Glutamate (GLU)-induced phase advances in the rat SCN were blocked by antisense oligodeoxynucleotide (ODN) againstPer1 and Ca2+/cAMP response element (CRE)-decoy ODN. CRE-decoy ODN also blocked light-induced phase advances in vivo. Furthermore, the CRE-decoy blocked GLU-induced accumulation of Per1 mRNA. Thus, Ca2+/cAMP response element-binding protein (CREB) and Per1 are integral components of the pathway transducing light-stimulated GLU neurotransmission into phase advance of the circadian clock.
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Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock.
Journal of Biological Chemistry, 2002Co-Authors: Shelley A Tischkau, Sheue Houy Tyan, Gordon F Buchanan, Jennifer W Mitchell, Martha U GilletteAbstract:AbsTract Light is a prominent stimulus that synchronizes endogenous circadian rhythmicity to environmental light/dark cycles. Nocturnal light elevates mRNA of the Period1(Per1) gene and induces long term state changes, expressed as phase shifts of circadian rhythms. The cellular mechanism forPer1 elevation and light-induced phase advance in the suprachiasmatic nucleus (SCN), a process initiated primarily by glutamatergic neurotransmission from the Retinohypothalamic Tract, was examined. Glutamate (GLU)-induced phase advances in the rat SCN were blocked by antisense oligodeoxynucleotide (ODN) againstPer1 and Ca2+/cAMP response element (CRE)-decoy ODN. CRE-decoy ODN also blocked light-induced phase advances in vivo. Furthermore, the CRE-decoy blocked GLU-induced accumulation of Per1 mRNA. Thus, Ca2+/cAMP response element-binding protein (CREB) and Per1 are integral components of the pathway transducing light-stimulated GLU neurotransmission into phase advance of the circadian clock.
Robert Y. Moore - One of the best experts on this subject based on the ideXlab platform.
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Ciba Foundation Symposium 183 - Circadian Clocks and their Adjustment - Organization of the mammalian circadian system.
Novartis Foundation Symposia, 2007Co-Authors: Robert Y. MooreAbstract:The mammalian circadian timing system is a set of related neural structures whose function is to provide a temporal organization for physiological processes and behaviour. The system has three major components, entrainment pathways, pacemakers and output pathways that couple the pacemakers to effector systems that express circadian functioning. The Retinohypothalamic Tract is a direct retinal projection to the circadian pacemakers, the suprachiasmatic nuclei. The Retinohypothalamic Tract arises from a discrete set of retinal ganglion cells that receive photic information from a unique population of retinal photoreceptors and it mediates photic entrainment of the suprachiasmatic nuclei. The geniculohypothalamic Tract arises from neurons of a specialized subdivision of the lateral geniculate complex, the intergeniculate leaflet. The intergeniculate leaflet and geniculohypothalamic Tract appear to provide integrated photic and non-photic input to the suprachiasmatic nuclei to modulate pacemaker function. The suprachiasmatic nuclei comprise individual neuronal oscillators coupled into a neural network. The output of the suprachiasmatic nuclei is quite restricted but becomes amplified by a set of downstream components of the system that appear to provide a widespread circadian signal.
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Serotonin innervation of the primate suprachiasmatic nucleus.
Brain Research, 2004Co-Authors: Robert Y. Moore, Joan C. SpehAbstract:The suprachiasmatic nucleus (SCN) in rodents receives a dense innervation from serotonin neurons of the midbrain raphe. This projection overlaps the terminal field of the Retinohypothalamic Tract in the SCN core, the central part of the nucleus characterized by a population of vasoactive intestinal polypeptide (VIP)-containing neurons. To determine whether a similar pathway is present in primates, we carried out an immnunocytochemical investigation of the primate SCN using antisera against either serotonin (monkey) or the serotonin transporter (human). This demonstrated a dense serotonergic plexus over the SCN core in both species. As in rodents, the distribution of the serotonin innervation of the primate SCN overlaps that of the Retinohypothalamic input and the VIP neuronal population. We also find a supraependymal plexus of serotonin axons in the third and lateral ventricles of the human and monkey brains that is similar in distribution, but less dense, than the one reported in rodents.
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CIRCADIAN RHYTHMS: Basic Neurobiology and Clinical Applications
Annual Review of Medicine, 1997Co-Authors: Robert Y. MooreAbstract:Circadian rhythms are major features of adaptation to our environment. In mammals, circadian rhythms are generated and regulated by a circadian timing system. This system consists of entertainment pathways, pacemakers, and pace-maker output to effector systems that are under circadian control. The primary entertainment pathway is the Retinohypothalamic Tract, which terminates in the circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The output of the suprachiasmatic nuclei is principally to the hypothalamus, the midline thalamus, and the basal forebrain. This provides a temporal organization to the sleep-wake cycle, to many physiological and endocrine functions, and to psychomotor performance functions. Disorders of circadian timing primarily affect entertainment and pacemaker functions. The pineal hormone, melatonin, appears to be promising agent for therapy of some circadian timing disorders.
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The Retinohypothalamic Tract originates from a distinct subset of retinal ganglion cells.
The Journal of Comparative Neurology, 1995Co-Authors: Robert Y. Moore, Joan C. Speh, J. Patrick CardAbstract:The retinal ganglion cells giving rise to Retinohypothalamic projections in the rat were identified using retrograde transport of horseradish peroxidase (HRP) or Fluoro Gold injected into the suprachiasmatic nucleus (SCN), and using transneuronal transport of the Bartha strain of the swine herpesvirus (PRV-Bartha). When PRV-Bartha is injected into one eye, it is taken up by retinal ganglion cells, replicated, transported to axon terminals in the SCN, and released. There the virus may take one, or both, of two paths to retinal ganglion cells in the contralateral eye: (1) uptake by SCN neurons, replication, and release from the neurons with uptake and retrograde transport in retinal afferents originating in the contralateral retina; (2) transneuronal passage through axo-axonic appositions between retinal afferents in the SCN with subsequent retrograde transport of virus to the contralateral retina. The ganglion cells thus labeled are a homogeneous population of small neurons (mean diameter, 12.8 ± 2.2 μm an mean area, 81.8 ± 21.8 μm2) with sparsely branching dendrites that are widely distributed over the retina. This population is best identified when virus labeling of retinal projections in areas beyond the hypothalamus is eliminated by lateral geniculate lesions that transect the optic Tract at its entry into the geniculate complex. The same population is labeled with retrograde tracers but, with both HRP and Fluoro Gold, other ganglion cells are labeled, presumably from uptake by fibers of passage, indicating that the virus is a more reliable marker for ganglion cells giving rise to Retinohypothalamic projections. The ganglion cells identified correspond to a subset of type III, or W, cells. © 1995 Wiley-Liss, Inc.
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Glutamate shifts the phase of the circadian neuronal firing rhythm in the rat suprachiasmatic nucleus in vitro.
Neuroscience Letters, 1994Co-Authors: Tetsuo Shirakawa, Robert Y. MooreAbstract:The effect of glutamate (GLU) on the phase of the circadian neuronal firing rhythm of the rat suprachiasmatic nucleus (SCN) was examined in vitro. GLU application in late subjective night produces phase-advances whereas GLU applied in early subjective night produces either phase-delays or a bimodal peak in the firing rhythm that appears to be a combination of phase-advances and phase-delays. Optic chiasm (OC) stimulation, or exposure of animals to light just prior to sacrifice, produces phase-delays in early subjective night, and phase-advances in late subjective night. None of GLU, light and OC stimulation produces significant phase-changes during subjective day. The results indicate that GLU is the neurotransmitter of the Retinohypothalamic Tract.
Charles N. Allen - One of the best experts on this subject based on the ideXlab platform.
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Retinohypothalamic Tract synapses in the rat suprachiasmatic nucleus demonstrate short-term synaptic plasticity.
Journal of Neurophysiology, 2010Co-Authors: Charles N. AllenAbstract:The master circadian pacemaker located in the suprachiasmatic nucleus (SCN) is entrained by light intensity–dependent signals transmitted via the Retinohypothalamic Tract (RHT). Short-term plasticity at glutamatergic RHT–SCN synapses was studied using stimulus frequencies that simulated the firing of light sensitive retinal ganglion cells. The evoked excitatory postsynaptic current (eEPSC) was recorded from SCN neurons located in hypothalamic brain slices. The eEPSC amplitude was stable during 0.08 Hz stimulation and exhibited frequency-dependent short-term synaptic depression (SD) during 0.5 to 100 Hz stimulus trains in 95 of 99 (96%) recorded neurons. During SD the steady-state eEPSC amplitude decreased, whereas the cumulative charge transfer increased in a frequency-dependent manner and saturated at 20 Hz. SD was similar during subjective day and night and decreased with increasing temperature. Paired-pulse stimulation (PPS) and voltage-dependent Ca2+ channel (VDCC) blockers were used to characterize a presynaptic release mechanism. Facilitation was present in 30% and depression in 70% of studied neurons during PPS. Synaptic transmission was reduced by blocking both N- and P/Q-type presynaptic VDCCs, but only the N-type channel blocker significantly relieved SD. Aniracetam inhibited AMPA receptor desensitization but did not alter SD. Thus we concluded that SD is the principal form of short-term plasticity at RHT synapses, which presynaptically and frequency-dependently attenuates light-induced glutamatergic RHT synaptic transmission protecting SCN neurons against excessive excitation.
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Calcium Response to Retinohypothalamic Tract Synaptic Transmission in Suprachiasmatic Nucleus Neurons
Journal of Neuroscience, 2007Co-Authors: Robert P. Irwin, Charles N. AllenAbstract:Glutamate released from Retinohypothalamic Tract (RHT) synapses with suprachiasmatic nucleus (SCN) neurons induces phase changes in the circadian clock presumably by using Ca2+ as a second messenger. We used electrophysiological and Ca2+ imaging techniques to simultaneously record changes in the membrane potential and intracellular calcium concentration ([Ca2+]i) in SCN neurons after stimulation of the RHT at physiologically relevant frequencies. Stimulation of the RHT sufficient to generate an EPSP did not produce detectable changes in [Ca2+]i, whereas EPSP-induced action potentials evoked an increase in [Ca2+]i, suggesting that the change in postsynaptic somatic [Ca2+]i produced by synaptically activated glutamate receptors was the result of membrane depolarization activating voltage-dependent Ca2+ channels. The magnitude of the Ca2+ response was dependent on the RHT stimulation frequency and duration, and on the SCN neuron action potential frequency. Membrane depolarization-induced changes in [Ca2+]i were larger and decayed more quickly in the dendrites than in the soma and were attenuated by nimodipine, suggesting a compartmentalization of Ca2+ signaling and a contribution of L-type Ca2+ channels. RHT stimulation at frequencies that mimicked the output of light-sensitive retinal ganglion cells (RGCs) evoked [Ca2+]i transients in SCN neurons via membrane depolarization and activation of voltage-dependent Ca2+ channels. These data suggest that for Ca2+ to induce phase advances or delays, light-induced signaling from RGCs must augment the underlying oscillatory somatic [Ca2+]i by evoking postsynaptic action potentials in SCN neurons during a period of slow spontaneous firing such as occurs during nighttime.
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Presynaptic GABAB Receptors Regulate Retinohypothalamic Tract Synaptic Transmission by Inhibiting Voltage-Gated Ca2+ Channels
Journal of Neurophysiology, 2006Co-Authors: Robert P. Irwin, Charles N. AllenAbstract:Presynaptic GABAB receptor activation inhibits glutamate release from Retinohypothalamic Tract (RHT) terminals in the suprachiasmatic nucleus (SCN). Voltage-clamp whole cell recordings from rat SCN...
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Developmental changes in calbindin-D28k and calretinin expression in the mouse suprachiasmatic nucleus.
European Journal of Neuroscience, 2003Co-Authors: Masayuki Ikeda, Charles N. AllenAbstract:The hypothalamic suprachiasmatic nucleus, the primary circadian pacemaker in mammals, and the Retinohypothalamic Tract, the retinal afferent fibres to the suprachiasmatic nucleus, both mature during early postnatal life. The establishment of circadian rhythms is thought to depend on input from the retina, but the mechanism remains unknown. Here we examined developmental changes in the expression of the Ca 2 + -binding proteins calbindin-D28k and calretinin in the mouse hypothalamus. Robust calbindin-D28k immunoreactivity was observed in the dorsomedial suprachiasmatic nucleus and the supraoptic nucleus in neonatal mice (postnatal day 3). The calbindin-D28k immunoreactivity decreased significantly in the suprachiasmatic nucleus but not in the supraoptic nucleus during postnatal days 9-15, when Retinohypothalamic Tract projections to the suprachiasmatic nucleus are completed. Calretinin immunoreactivity was low in the neonatal suprachiasmatic nucleus and increased with development in the ventrolateral suprachiasmatic nucleus, in parallel with the developmental reduction of calbindin-D28k immunoreactivity observed in the dorsomedial suprachiasmatic nucleus. Developmentally stable calretinin immunoreactivity was also observed in Retinohypothalamic Tract fibres. Organotypic slice cultures of the suprachiasmatic nucleus were prepared from postnatal day 3 mice to examine the effect of the absence of Retinohypothalamic Tract inputs on developmental changes in calbindin-D28k and calretinin expression. After 12 days in vitro, the cultured suprachiasmatic nucleus slices exhibited dense calbindin-D28k immunoreactivity similar to neonatal mice, and calretinin immunoreactivity in the ventrolateral suprachiasmatic nucleus similar to young adult mice. These results demonstrate a developmental reduction in calbindin-D28k expression that paralleled Retinohypothalamic Tract formation and a developmental increase in calretinin expression that is independent of Retinohypothalamic Tract connections to suprachiasmatic nucleus neurons.