Effects of Hypocretin/Orexin and Major Transmitters of Arousal on Fast Spiking Neurons in Mouse Cortical Layer 6B (original) (raw)
Related papers
Behavioral Correlates of Activity in Identified Hypocretin/Orexin Neurons
Neuron, 2005
cus coeruleus (LC), and dorsal raphe (Yoshida et al., 2004). Lyudmila I. Kiyashchenko, 1,3,4 Hcrt null mutant mice exhibit symptoms of narcoand Jerome M. Siegel 1,2,3, * lepsy including periodic losses of muscle tone during 1 Department of Psychiatry and Biobehavioral certain behaviors, and disrupted sleep and waking Sciences states (Chemelli et al., 1999). Genetically narcoleptic 2 Brain Research Institute dogs have mutations of Hcrt receptor-2 (Lin et al., University of California, Los Angeles 1999). Human narcolepsy is linked to a relatively selec-Los Angeles, California 90095 tive loss of Hcrt cells (Peyron et al., 2000; Thannickal et 3 Veterans Administration Greater Los Angeles al., 2000; Thannickal et al., 2003), whereas Hcrt levels Healthcare System-Sepulveda are normal in most other neurodegenerative disorders North Hills, California 91343 (Ripley et al., 2001). The link between Hcrt cell loss and narcolepsy led to investigations of how the activity of these cells might Summary be modulated across the sleep-wakefulness (S-W) cycle. An indirect way to address this question is by moni-Micropipette recording with juxtacellular Neurobiotin toring c-Fos expression. Estabrooke et al. (2001) reejection, linked micropipette-microwire recording, and ported that c-Fos immunoreactivity in Hcrt cells in rats antidromic and orthodromic activation from the venwas elevated in waking and was reduced during tral tegmental area and locus coeruleus were used to periods containing both slow wave (SW) and rapid eye identify hypocretin (Hcrt) cells in anesthetized rats movement (REM) sleep, suggesting that Hcrt cellular and develop criteria for identification of these cells in activity was minimal at these times. In contrast, a study unanesthetized, unrestrained animals. We found that in freely moving cats showed that Hcrt release in the Hcrt cells have broad action potentials with elongated hypothalamus and basal forebrain was increased in later positive deflections that distinguish them from REM sleep (Kiyashchenko et al., 2002). Thus, direct readjacent antidromically identified cells. They are relacording of the neuronal activity of Hcrt cells is required tively inactive in quiet waking but are transiently actito determine the nature of their sleep cycle discharge. vated during sensory stimulation. Hcrt cells are silent Many studies, some conducted long before the disin slow wave sleep and tonic periods of REM sleep, covery of Hcrt/orexin, have investigated S-W cycle diswith occasional burst discharge in phasic REM. Hcrt charge in cells in the Hcrt-containing regions of the hycells discharge in active waking and have moderate pothalamus (Beyer et al., 1971; Findlay and Hayward, and approximately equal levels of activity during 1969; Glotzbach et al., 1987; Izumi, 1968; Parmeggiani grooming and eating and maximal activity during exet al., 1987; Steininger et al., 1999; Vanni-Mercier et al., ploratory behavior. Our findings suggest that these 1984). Most studies reported that cells in this region cells are activated during emotional and sensorimowere active in wakefulness and had diminished activity tor conditions similar to those that trigger cataplexy in SW sleep. Both increased unit activity and decreased in narcoleptic animals. unit activity were seen in REM sleep. Recent studies, in general, confirmed these results. About 30%-50% of Introduction perifornical (PFH) and lateral hypothalamic (LH) neurons have maximal activity in both active waking (AW) Hypocretin (Hcrt or orexin) was discovered in 1998 (de and REM sleep. About 20%-40% of neurons are most Lecea et al., 1998; Sakurai et al., 1998). Anatomical active in wakefulness, and only about 8% of neurons studies showed that neurons synthesizing this peptide are most active in SW sleep (Alam et al., 2002; Koyama project to brain monoaminergic cell groups, including et al., 2003). Prior studies did not identify Hcrt cells. cells containing norepinephrine, serotonin, histamine, Furthermore, none characterized the waking behavioral and dopamine (Peyron et al., 1998). Hcrt cells also procorrelates of discharge in hypothalamic cell types. ject strongly to cholinergic cells in the basal forebrain The VTA receives dense Hcrt projections and is a maand brainstem and to other brain regions (Nambu et al., jor region of passage of Hcrt axons to the caudal brain-1999; Peyron et al., 1998). Hcrt has been found to be stem and spinal regions (
2017
Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities. Salient stimuli activate spiking of locus coeruleus noradrenergic (NALC) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response. Hypothalamic HCRT neurons provide one of the densest input to NALC cells. To functionally address the HCRT-to-NA connection, we selectively disrupted the Hcrtr1 gene in NA neurons, and analyzed resulting (Hcrtr1Dbh-CKO) mice’, and their control littermates’ electrocortical response in several contexts of enhanced arousal. Under enforced wakefulness (EW), or after cage change (CC), Hcrtr1Dbh-CKO mice exhibited a weakened ability to lower infra-θ frequencies (1-7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz). A fast-γ (55-80 Hz) response, whose dynamics closely para...
GABAB receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus
The Journal of Physiology, 2006
Hypocretin/orexin (Hcrt) is a critical neurotransmitter for the maintenance of wakefulness and has been implicated in several other functions, including energy metabolism and reward. Using whole-cell patch-clamp recordings from transgenic mice in which enhanced green fluorescent protein was linked to the Hcrt promoter, we investigated GABAergic control of the Hcrt neurones in hypothalamic slices. Bath application of GABA or muscimol caused an early hyperpolarization mediated by Cl − and a late depolarization mediated by the efflux of bicarbonate. These GABA A receptor-mediated responses were blocked by picrotoxin and bicuculline. Under the GABA A blockade condition, GABA produced consistent hyperpolarization, decreased firing rate and input resistance. The selective GABA B agonist (R)-baclofen caused a similar response with an EC 50 of 7.1 μM. The effects of (R)-baclofen were blocked by the GABA B antagonist CGP 52432 but persisted in the presence of tetrodotoxin, suggesting direct postsynaptic effects. The existence of GABA B modulation was supported by GABA B(1) subunit immunoreactivity on Hcrt cells colabelled with antisera to the Hcrt-2 peptide. Furthermore, GABA B receptor activation inhibited the presynaptic release of both glutamate and GABA. (R)-Baclofen depressed the amplitude of evoked excitatory postsynaptic currents (EPSCs) and inhibitory synaptic currents (IPSCs), and also decreased the frequency of both spontaneous and miniature EPSCs and IPSCs with a modest effect on their amplitudes. These data suggest that GABA B receptors modulate Hcrt neuronal activity via both pre-and postsynaptic mechanisms, which may underlie the promotion of non-rapid eye movement sleep and have implications for the use of GABA B agonists in the treatment of substance addiction through direct interaction with the Hcrt system.
The orexinergic neurons receive synaptic input from C1 cells in rats
Journal of Comparative Neurology, 2014
23 Abbott SB, Kanbar R, Bochorishvili G, Coates MB, Stornetta RL, Guyenet PG. 2012. C1 neurons excite locus coeruleus and A5 noradrenergic neurons along with sympathetic outflow in rats. J Physiol 590:2897-2915. Abbott SB, Stornetta RL, Fortuna MG, Depuy SD, West GH, Harris TE, Guyenet PG. 2009a. Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces longlasting activation of breathing in rats. J Neurosci 29:5806-5819. Abbott SB, Stornetta RL, Socolovsky CS, West GH, Guyenet PG. 2009b. Photostimulation of channelrhodopsin-2 expressing ventrolateral medullary neurons increases sympathetic nerve activity and blood pressure in rats. J Physiol 587:5613-5631. Adamantidis A, de Lecea L. 2009. The hypocretins as sensors for metabolism and arousal. J Physiol 587:33-40. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, De Lecea L. 2007. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450:420-424. Berridge CW, Schmeichel BE, Espana RA. 2012. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev 16:187-197. Bochorishvili G, Stornetta RL, Coates MB, Guyenet PG. 2012. Pre-Botzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J Comp Neurol 520:1047-1061. Card JP, Sved JC, Craig B, Raizada M, Vazquez J, Sved AF. 2006. Efferent projections of rat rostroventrolateral medulla C1 catecholamine neurons: Implications for the central control of cardiovascular regulation. J Comp Neurol 499:840-859. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai LH, Moore CI. 2010. Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of Channelrhodopsin-2. Nat Protoc 5:247-254.
Exclusive postsynaptic action of hypocretin-orexin on sublayer 6b cortical neurons
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004
The hypocretin-orexin (hcrt-orx) neurons are thought to maintain wakefulness because their loss results in narcolepsy. This role may be fulfilled by the excitatory action that the hcrt-orx peptide exerts on multiple brainstem and forebrain systems that, in turn, promote cortical activation. Here, we examined whether hcrt-orx may also exert a postsynaptic excitatory action at the level of the cortex, where hcrt-orx fibers project. However, we found that neurons in layers 2-5 in the primary somatosensory cortex (SSp) were unresponsive to hcrt-orx. We then found that although all neurons tested in sublayer 6a were also unresponsive to hcrt-oxr, all those tested in sublayer 6b were highly sensitive to the peptide. The sublayer selectivity of hcrt-oxr was not restricted to the somatosensory cortex, because it was also found to be present in the primary visual cortex, the motor cortex, and the cingulate cortex. In the SSp, in which the hcrt-oxr effect was investigated further, it was demo...
Regulatory Peptides, 2002
Dysfunction of the orexin/hypocretin neurotransmitter system leads to the sleep disorder narcolepsy. Narcolepsy is characterized by excessive daytime sleepiness and the occurrence of cataplexy -a sudden loss of muscle tone triggered by emotionally arousing events. Both symptoms can be treated with drugs that act on dopaminergic systems. Here we have investigated the effect of orexins on the firing of dopaminergic and GABAergic neurons of the substantia nigra (SN) in brain slices. Surprisingly, dopaminergic neurons in pars compacta were unaffected by orexins. In contrast, bath application of orexin A (100 nM) or orexin B (5 -300 nM) greatly increased the firing rate of GABAergic neurons in pars reticulata. The orexin B-mediated excitation was unaffected by blocking synaptic transmission (using low-Ca 2 + / high-Mg 2 + solution). However, the effect of orexin B was reduced significantly by thapsigargin (1 mM) and inhibitors of protein kinase A. The presence of orexinergic fibres in the SN pars reticulata was demonstrated by immunohistochemical methods with the fibre density increasing in the rostrocaudal direction. The orexin excitation of SN reticulata cells may help to maintain their high firing rate during waking. Furthermore, the absence of orexin effects in narcolepsy may predispose affected individuals to attacks of cataplexy. D
Behavioral/Systems/Cognitive Hypocretin/Orexin Innervation and Excitation of Identified
2013
Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum – diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cho...
Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons
Journal of Neuroscience, 2004
Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cholinergic neurons with similar EC 50 values. The Hcrt effect was dependent on external Na ϩ , reduced by external Ba 2ϩ , and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K ϩ current, presumably an inward rectifier, and a Na ϩ-dependent component. The Na ϩ component was dependent on internal Ca 2ϩ , blocked by replacing external Na ϩ with Li ϩ , and also blocked by bath-applied Ni 2ϩ and KB-R7943, suggesting involvement of the Na ϩ-Ca 2ϩ exchanger. Using double-immunolabeling studies at light and ultrastructural levels, we also provide definitive evidence for a hypocretin innervation of cholinergic neurons. Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal.