Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropepti... more Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting th...
Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, rewar... more Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, reward and stress-associated behavior and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor type-1 (Hcrtr1), Hypocretin receptor type-2 (Hcrtr2), or both receptors (Hcrtr1&2) in dopamine neurons and analyzed the consequences on vigilance states, brain oscillations, and cognitive performance in freely behaving mice. Unexpectedly, loss of Hcrtr2, but not Hcrtr1 or Hcrtr1&2, led to dramatic increases in theta (7-11 Hz) electroencephalographic (EEG) activity during both wakefulness and rapid-eye-movement (REM) sleep. Compared to controls, DAHcrtr2-deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, as well as exhibited prolonged REM sleep. Additionally, both wake and REM sleep displayed enhanced theta-gamma phase-amplitude coupling...
Proceedings of the National Academy of Sciences, 2019
Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively pr... more Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT ( Peg3 , Ahr1 , Six6 , Nr2f2 , and Prrx1 ) and MCH ( Lmx1 , Gbx2 , and Peg3 ) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigen...
Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalit... more Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first-degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking. Here we performed whole genome single-nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage interval. The variant was found to segregate in all affected and one presumably unaffected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other lo...
Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the ... more 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...
Proceedings of the National Academy of Sciences of the United States of America, Jul 19, 2017
Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to par... more Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrt(ko/ko) mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6.0 to 9.5 Hz) and fast-γ (55 to 80 Hz) activity in prior waking. We algorithmically identify a theta-dominated wakefulness (TDW) substate underlying motivated behaviors and typically preceding cataplexy in Hcrt(ko/ko) mice. Hcrt(ko/ko) mice fully implement TDW when waking is enforced, but spontaneous TDW episode duration is greatly reduced. A reformulation of the classic sleep homeostasis model, where homeostatic pressure rises exclusively in TDW rather than all waking, predict...
Proceedings of the National Academy of Sciences, 2006
A glomerulus in the mammalian olfactory bulb receives axonal inputs from olfactory sensory neuron... more A glomerulus in the mammalian olfactory bulb receives axonal inputs from olfactory sensory neurons (OSNs) that express the same odorant receptor (OR). Glomeruli are generally thought to represent functional units of olfactory coding, but there are no data on the electrophysiological properties of OSNs that express the same endogenous OR. Here, using patch clamp recordings in an intact epithelial preparation, we directly measured the transduction currents and receptor potentials from the dendritic knobs of mouse OSNs that express the odorant receptor MOR23 along with the green fluorescent protein. All of the 53 cells examined responded to lyral, a known ligand for MOR23. There were profound differences in response kinetics, particularly in the deactivation phase. The cells were very sensitive to lyral, with some cells responding to as little as 10 nM. The dynamic range was unexpectedly broad, with threshold and saturation in individual cells often covering three log units of lyral co...
Both dopaminergic (DA) and orexinergic (OX) systems establish brain-wide neuromodulatory circuits... more Both dopaminergic (DA) and orexinergic (OX) systems establish brain-wide neuromodulatory circuits that profoundly influence brain states and behavioral outputs. To unravel their interactions, we inactivated OX-to-DA neurotransmission by selective disruption of HcrtR1/OxR1, or HcrtR2/OxR2, or both receptors, in DA neurons. Chronic loss of OXR2 in DA neurons (OxR2Dat-CKO mice) dramatically increased electrocorticographic (EcoG) theta rhythms in wakefulness and REM sleep. Episode duration and total times spent in active wakefulness and REMS were prolonged, and theta/fast-gamma wave coupling was enhanced in both states. Increased theta in OxR2DatCKO mice baseline wake was accompanied by diminished infra-theta and increased fast-gamma activities, i.e. the mice exhibited signs of constitutive electrocortical hyperarousal, albeit uncoupled with locomotor activity. These effects were not seen in OxR1-ablated dopaminergic mutants, which tended to show opposite phenotypes, resembling those ca...
Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The... more Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic neuropeptide, QRFP, is lost in mouse models with HCRT cell-ablation, but tends to be even increased in Hcrt gene knockout mice, suggesting that QRFP expression can be used as a proxy for the presence or absence of HCRT neurons. Similar to Hcrt knockout mice, narcolepsy patients show intact hypothalamic QRFP expression, and cerebrospinal fluid levels of QRFP peptide are increased, suggesting their HCRT neurons are intact. We show that the human HCRT gene promoter is methylation-sensitive in vitro, and is hypermethylated in the hypothalamus of patients selectively at a putative PAX5:ETS1 binding site within the proximal HCRT promoter. Ets1-...
Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of... more Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency. Cataplexy is classically considered to be an abnormal manifestation of REM sleep and is treated by selective serotonin (5HT) reuptake inhibitors. Here we show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep. Additionally, double knockout mice showed a significant deficit in the buildup of sleep need. Deleting one allele of the 5HT transporter in hypocretin knockout mice strongly increased EEG theta power during REM sleep and theta and gamma powers during wakefulness. Deleting hypocretin receptors in the dorsal raphe neurons of adult mice did not induce cataplexy but consolidated REM sleep. Our results indicate that cataplexy and REM sleep are regulated by different mechanisms and both states and sleep need are regulated by the hypocretinergic input into 5HT ne...
The neuromodulators noradrenaline (NA) and hypocretins (Hcrt) both have major, but distinct, role... more The neuromodulators noradrenaline (NA) and hypocretins (Hcrt) both have major, but distinct, roles in implementing the brain circuit processing modes that define wakefulness and waking behaviors. The A6 NA cell group in the locus coeruleus (LC-NA) receives dense projections from the Hcrt cells of the hypothalamus, and acts as critical mediator of Hcrt-induced arousal. The range of behaviors relying on the Hcrt-to-LC-NA neuronal connection however remains undefined. We generated a conditionally inactivated allele of Hcrtr1, the Hcrt receptor gene expressed by LC-NA cells, and used a Dbh-Cre transgene to create mice with NA-specific Hcrtr1 inactivation (Hcrtr1Dbh-CKO mice). Electrocortical activity (ECoG) of these mice was analyzed in distinct behavioral contexts, and contrasted to the one of Cre-less control littermates. While baseline waking was grossly normal albeit for enhanced activity in the slow-delta (δ) range, upon exposure to a novel environment, Hcrtr1Dbh-CKO mice displayed (i) a slowing of the waking ECoG, with enhanced δ and inter-δ/θ band activity, (ii) blunting of the θ rhythm and fast-γ activity, while (iii) β and slow-γ activities were enhanced. Moreover, locomotor and ECoG responses to sleep deprivation (SD) were markedly reduced. Surprisingly, while deficits in manually-enforced wakefulness resembled those following cage change (CC), spontaneous dark phase waking, and after providing nest material, were enhanced in θ and fast-γ oscillatory activities. Our data suggest that Hcrtr1Dbh-CKO mice are deficient in adaptive regulation of wakefulness in stress-associated conditions with electrocortical signs of decreased alertness and hippocampal θ activation. Furthermore, their waking θ and fast-γ ECoG power show concerted, but opposite, trends in stressful versus rewarding contexts. Finally, slow-wave-sleep (SWS) following SD and CC both showed a profound deficit in slow-δ activity, suggesting that Hcrt-to-NA signalling is critical in active waking to induce the homeostatic slow-δ rebound that characterizes ensuing SWS.
Did hypocretin receptor 2 auto-antibodies cause narcolepsy with hypocretin deficiency in Pandemri... more Did hypocretin receptor 2 auto-antibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.’s findings.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1995. Includes bibliogr... more Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1995. Includes bibliographical references (p. 118-120). by Anne Vassalli. Ph.D.
Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropepti... more Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting th...
Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, rewar... more Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, reward and stress-associated behavior and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor type-1 (Hcrtr1), Hypocretin receptor type-2 (Hcrtr2), or both receptors (Hcrtr1&2) in dopamine neurons and analyzed the consequences on vigilance states, brain oscillations, and cognitive performance in freely behaving mice. Unexpectedly, loss of Hcrtr2, but not Hcrtr1 or Hcrtr1&2, led to dramatic increases in theta (7-11 Hz) electroencephalographic (EEG) activity during both wakefulness and rapid-eye-movement (REM) sleep. Compared to controls, DAHcrtr2-deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, as well as exhibited prolonged REM sleep. Additionally, both wake and REM sleep displayed enhanced theta-gamma phase-amplitude coupling...
Proceedings of the National Academy of Sciences, 2019
Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively pr... more Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT ( Peg3 , Ahr1 , Six6 , Nr2f2 , and Prrx1 ) and MCH ( Lmx1 , Gbx2 , and Peg3 ) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigen...
Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalit... more Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first-degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking. Here we performed whole genome single-nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage interval. The variant was found to segregate in all affected and one presumably unaffected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other lo...
Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the ... more 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...
Proceedings of the National Academy of Sciences of the United States of America, Jul 19, 2017
Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to par... more Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrt(ko/ko) mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6.0 to 9.5 Hz) and fast-γ (55 to 80 Hz) activity in prior waking. We algorithmically identify a theta-dominated wakefulness (TDW) substate underlying motivated behaviors and typically preceding cataplexy in Hcrt(ko/ko) mice. Hcrt(ko/ko) mice fully implement TDW when waking is enforced, but spontaneous TDW episode duration is greatly reduced. A reformulation of the classic sleep homeostasis model, where homeostatic pressure rises exclusively in TDW rather than all waking, predict...
Proceedings of the National Academy of Sciences, 2006
A glomerulus in the mammalian olfactory bulb receives axonal inputs from olfactory sensory neuron... more A glomerulus in the mammalian olfactory bulb receives axonal inputs from olfactory sensory neurons (OSNs) that express the same odorant receptor (OR). Glomeruli are generally thought to represent functional units of olfactory coding, but there are no data on the electrophysiological properties of OSNs that express the same endogenous OR. Here, using patch clamp recordings in an intact epithelial preparation, we directly measured the transduction currents and receptor potentials from the dendritic knobs of mouse OSNs that express the odorant receptor MOR23 along with the green fluorescent protein. All of the 53 cells examined responded to lyral, a known ligand for MOR23. There were profound differences in response kinetics, particularly in the deactivation phase. The cells were very sensitive to lyral, with some cells responding to as little as 10 nM. The dynamic range was unexpectedly broad, with threshold and saturation in individual cells often covering three log units of lyral co...
Both dopaminergic (DA) and orexinergic (OX) systems establish brain-wide neuromodulatory circuits... more Both dopaminergic (DA) and orexinergic (OX) systems establish brain-wide neuromodulatory circuits that profoundly influence brain states and behavioral outputs. To unravel their interactions, we inactivated OX-to-DA neurotransmission by selective disruption of HcrtR1/OxR1, or HcrtR2/OxR2, or both receptors, in DA neurons. Chronic loss of OXR2 in DA neurons (OxR2Dat-CKO mice) dramatically increased electrocorticographic (EcoG) theta rhythms in wakefulness and REM sleep. Episode duration and total times spent in active wakefulness and REMS were prolonged, and theta/fast-gamma wave coupling was enhanced in both states. Increased theta in OxR2DatCKO mice baseline wake was accompanied by diminished infra-theta and increased fast-gamma activities, i.e. the mice exhibited signs of constitutive electrocortical hyperarousal, albeit uncoupled with locomotor activity. These effects were not seen in OxR1-ablated dopaminergic mutants, which tended to show opposite phenotypes, resembling those ca...
Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The... more Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic neuropeptide, QRFP, is lost in mouse models with HCRT cell-ablation, but tends to be even increased in Hcrt gene knockout mice, suggesting that QRFP expression can be used as a proxy for the presence or absence of HCRT neurons. Similar to Hcrt knockout mice, narcolepsy patients show intact hypothalamic QRFP expression, and cerebrospinal fluid levels of QRFP peptide are increased, suggesting their HCRT neurons are intact. We show that the human HCRT gene promoter is methylation-sensitive in vitro, and is hypermethylated in the hypothalamus of patients selectively at a putative PAX5:ETS1 binding site within the proximal HCRT promoter. Ets1-...
Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of... more Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency. Cataplexy is classically considered to be an abnormal manifestation of REM sleep and is treated by selective serotonin (5HT) reuptake inhibitors. Here we show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep. Additionally, double knockout mice showed a significant deficit in the buildup of sleep need. Deleting one allele of the 5HT transporter in hypocretin knockout mice strongly increased EEG theta power during REM sleep and theta and gamma powers during wakefulness. Deleting hypocretin receptors in the dorsal raphe neurons of adult mice did not induce cataplexy but consolidated REM sleep. Our results indicate that cataplexy and REM sleep are regulated by different mechanisms and both states and sleep need are regulated by the hypocretinergic input into 5HT ne...
The neuromodulators noradrenaline (NA) and hypocretins (Hcrt) both have major, but distinct, role... more The neuromodulators noradrenaline (NA) and hypocretins (Hcrt) both have major, but distinct, roles in implementing the brain circuit processing modes that define wakefulness and waking behaviors. The A6 NA cell group in the locus coeruleus (LC-NA) receives dense projections from the Hcrt cells of the hypothalamus, and acts as critical mediator of Hcrt-induced arousal. The range of behaviors relying on the Hcrt-to-LC-NA neuronal connection however remains undefined. We generated a conditionally inactivated allele of Hcrtr1, the Hcrt receptor gene expressed by LC-NA cells, and used a Dbh-Cre transgene to create mice with NA-specific Hcrtr1 inactivation (Hcrtr1Dbh-CKO mice). Electrocortical activity (ECoG) of these mice was analyzed in distinct behavioral contexts, and contrasted to the one of Cre-less control littermates. While baseline waking was grossly normal albeit for enhanced activity in the slow-delta (δ) range, upon exposure to a novel environment, Hcrtr1Dbh-CKO mice displayed (i) a slowing of the waking ECoG, with enhanced δ and inter-δ/θ band activity, (ii) blunting of the θ rhythm and fast-γ activity, while (iii) β and slow-γ activities were enhanced. Moreover, locomotor and ECoG responses to sleep deprivation (SD) were markedly reduced. Surprisingly, while deficits in manually-enforced wakefulness resembled those following cage change (CC), spontaneous dark phase waking, and after providing nest material, were enhanced in θ and fast-γ oscillatory activities. Our data suggest that Hcrtr1Dbh-CKO mice are deficient in adaptive regulation of wakefulness in stress-associated conditions with electrocortical signs of decreased alertness and hippocampal θ activation. Furthermore, their waking θ and fast-γ ECoG power show concerted, but opposite, trends in stressful versus rewarding contexts. Finally, slow-wave-sleep (SWS) following SD and CC both showed a profound deficit in slow-δ activity, suggesting that Hcrt-to-NA signalling is critical in active waking to induce the homeostatic slow-δ rebound that characterizes ensuing SWS.
Did hypocretin receptor 2 auto-antibodies cause narcolepsy with hypocretin deficiency in Pandemri... more Did hypocretin receptor 2 auto-antibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.’s findings.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1995. Includes bibliogr... more Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1995. Includes bibliographical references (p. 118-120). by Anne Vassalli. Ph.D.
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bioRxiv preprint first posted online Mar. 31, 2017;
doi:http://dx.doi.org/10.1101/123075.
bioRxiv preprint first posted online Mar. 31, 2017;
doi:http://dx.doi.org/10.1101/123075.