Quinolinate induces selective loss of melanin-concentrating hormone neurons, rather than orexin neurons, in the hypothalamus of mice and young rats

Obukuro, Kanae; Takigawa, Moeko; Hisatsune, Akinori; Isohama, Yoichiro; Katsuki, Hiroshi

doi:10.1016/j.neuroscience.2010.06.081

Cited by 11 publications

(20 citation statements)

References 39 publications

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“…An important pathway leading to neuron death by NO is ER stress (Gotoh and Mori, 2006), and our previous study in hypothalamic slice cultures demonstrated vulnerability of orexin neurons to ER stress (Michinaga et al, 2011). Here we found that expression of BiP, a component of unfolded protein response (UPR), was significantly increased in the hypothalamus at 3 h after injection of 50 nmol NOC18 ( Fig.…”

Section: No Induces Er Stress and Formation Of Orexin-a-immunoreactivmentioning

confidence: 90%

“…Sleep deprivation (SD) was initiated at 8:00, and deprivation for 6 and 12 h during light phase (6 h SD and 12 h SD, respectively) was performed by gentle handling of mice as described previously (Naidoo et al, 2005). For several groups of mice, SD for 12 h during light phase was repeated for 7 consecutive days (12 h SD for 7 d).…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical examinations were performed essentially according to the methods described previously (Obukuro et al, 2010). Mice were anesthetized with pentobarbital and perfused transcardially with PBS followed by 4% paraformaldehyde (Nacalai) in phosphate buffer.…”

Section: Methodsmentioning

confidence: 99%

“…In patients with narcolepsy characterized by excessive daytime sleepiness, a selective decrease of orexin neurons (Thannickal et al, 2000) and a decreased CSF level of orexin-A (Nishino et al, 2000) have been demonstrated. Also, plasma level of orexin-A in patients with anorexia is lower than that in healthy control (Janas-Kozik et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Protein misfolding, often accompanied by increased endoplasmic reticulum (ER) stress, is recognized as a key mechanism of pathogenic events in various neurodegenerative disorders (Matus et al, 2011). Moreover, we have previously reported that orexin neurons in rat hypothalamic slice cultures are more vulnerable to ER stress than other neuropeptide-containing neurons (Michinaga et al, 2011). Importantly, protein disulfide isomerase (PDI), a critical enzyme for rearrangement of disulfide bond formation, undergoes NOmediated S-nitrosation (Uehara et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase

Obukuro

Nobunaga²,

Takigawa³

et al. 2013

Journal of Neuroscience

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We addressed the role of nitric oxide (NO) in orexin neuron degeneration that has been observed under various pathological conditions. Administration of an NO donor NOC18 (50 nmol) into the third ventricle of mice resulted in a significant decrease of orexinimmunoreactive (-IR) neurons, in contrast to a modest change in melanin-concentrating hormone-IR neurons. In addition, NOC18 promoted formation of orexin-A-IR aggregates within orexin neurons. An endoplasmic reticulum stress inducer tunicamycin replicated the effect of NOC18 with regard to decrease of orexin-IR neurons and formation of aggregates. We also found that NOC18 caused an increase in S-nitrosation of protein disulfide isomerase (PDI) and a decrease in PDI activity in hypothalamic tissues. Moreover, PDI inhibitors, such as cystamine and securinine, caused a selective decrease of orexin neurons and promoted formation of orexin-A-IR aggregates. Aggregate formation in orexin-IR neurons was also induced by local injection of small interfering RNA targeting PDI. Interestingly, sleep deprivation for 7 consecutive days induced a selective decrease of orexin-IR neurons, which was preceded by aggregate formation in orexin-IR neurons and an increase in S-nitrosated PDI in the hypothalamus. Activity of neuronal NO synthase (nNOS)-positive neurons in the lateral hypothalamus as assessed by c-Fos expression was elevated in response to sleep deprivation. Finally, sleep deprivation-induced decrease of orexin-IR neurons, formation of aggregates, and S-nitrosation of PDI were not observed in nNOS knock-out mice. These results indicate that nNOS-derived NO may mediate specific pathological events in orexin neurons, including neuropeptide misfolding via S-nitrosation and inactivation of PDI.

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Section: No Induces Er Stress and Formation Of Orexin-a-immunoreactivmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase

Obukuro

Nobunaga²,

Takigawa³

et al. 2013

Journal of Neuroscience

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An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb

Fadool

Storace

2023

J of Comparative Neurology

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Olfactory cues play a key role in natural behaviors such as finding food, finding mates, and avoiding predators. In principle, the ability of the olfactory system to carry out these perceptual functions would be facilitated by signaling related to an organism's physiological state. One candidate pathway includes a direct projection from the hypothalamus to the main olfactory bulb, the first stage of olfactory sensory processing. The pathway from the hypothalamus to the main olfactory bulb is thought to include neurons that express the neuropeptide orexin, although the proportion that is orexinergic remains unknown. A current model proposes that the orexin population is heterogeneous, yet it remains unknown whether the proportion that innervates the main olfactory bulb reflects a distinct subpopulation of the orexin population. Herein, we carried out combined retrograde tract tracing with immunohistochemistry for orexin‐A in the mouse to define the proportion of hypothalamic input to the main olfactory bulb that is orexinergic and to determine what fraction of the orexin‐A population innervates the bulb. The numbers and spatial positions of all retrogradely labeled neurons and all the orexin‐A‐expressing neurons were quantified in sequential sections through the hypothalamus. Retrogradely labeled neurons were found in the ipsilateral hypothalamus, of which 22% expressed orexin‐A. The retrogradely labeled neurons that did and did not express orexin‐A could be anatomically distinguished based on their spatial position and cell body area. Remarkably, only 7% of all the orexin‐A neurons were retrogradely labeled, suggesting that only a small fraction of the orexin‐A population directly innervate the main olfactory bulb. These neurons spatially overlapped with the orexin‐A neurons that did not innervate the bulb, although the two cell populations were differentiated based on cell body area. Overall, these results support a model in which olfactory sensory processing is influenced by orexinergic feedback at the first synapse in the olfactory processing pathway.

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Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

et al. 2015

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Infants at risk of sudden infant death syndrome (SIDS) have been shown to have dysfunctional sleep and poor arousal thresholds. In animal studies, both these attributes have been linked to impaired signalling of the neuropeptide orexin. This study examined the immunoreactivity of orexin (OxA and OxB) in the tuberal hypothalamus (n = 27) and the pons (n = 15) of infants (1-10 months) who died from SIDS compared to age-matched non-SIDS infants. The percentage of orexin immunoreactive neurons and the total number of neurons were quantified in the dorsomedial, perifornical and lateral hypothalamus at three levels of the tuberal hypothalamus. In the pons, the area of orexin immunoreactive fibres were quantified in the locus coeruleus (LC), dorsal raphe (DR), laterodorsal tegmental (LDT), medial parabrachial, dorsal tegmental (DTg) and pontine nuclei (Pn) using automated methods. OxA and OxB were co-expressed in all hypothalamic and pontine nuclei examined. In SIDS infants, orexin immunoreactivity was decreased by up to 21 % within each of the three levels of the hypothalamus compared to non-SIDS (p ≤ 0.050). In the pons, a 40-50 % decrease in OxA occurred in the all pontine nuclei, while a similar decrease in OxB immunoreactivity was observed in the LC, LDT, DTg and Pn (p ≤ 0.025). No correlations were found between the decreased orexin immunoreactivity and previously identified risk factors for SIDS, including prone sleeping position and cigarette smoke exposure. This finding of reduced orexin immunoreactivity in SIDS infants may be associated with sleep dysfunction and impaired arousal.

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Quinolinate induces selective loss of melanin-concentrating hormone neurons, rather than orexin neurons, in the hypothalamus of mice and young rats

Cited by 11 publications

References 39 publications

Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase

Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase

An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

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