Effects of Intranasal Orexin-A (Hypocretin-1) Administration on Neuronal Activation, Neurochemistry, and Attention in Aged Rats

Calva, Coleman B.; Fayyaz, Habiba; Fadel, Jim R.

doi:10.3389/fnagi.2019.00362

Cited by 15 publications

(10 citation statements)

References 107 publications

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“…Orexin innervated cholinergic neurons in basal forebrain that project to PFC and are involved in attention and cognition 28,30 . Intranasal orexin A administration attenuated cognitive performance in young rats, 44 while intraventricular infusion of orexin A attenuated distracter induced attention deficit 42 . Interestingly, orexin expression in female rats were found to be much higher than males 43,48 .This suggests a more important role of orexin in females, which could be the reason for the sex‐specific IDS deficit in the present study.…”

Section: Discussionmentioning

confidence: 51%

“…The aim of our study was to investigate how brain‐wide orexin deficiency affects cognitive flexibility. Although, there are existing research on orexin's role in attention and cognition, 28,30,42‐44 this is the first study investigating how complete or partial loss of orexin neuropeptide affects cognitive flexibility in mice. Complete loss of orexin neuropeptide in the homozygous orexin‐deficient mice attenuated or improved cognitive flexibility in a sex‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Orexin deficiency modulates cognitive flexibility in a sex‐dependent manner

Durairaja

Fendt

2020

Genes Brain and Behavior

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Cognitive flexibility is an important executive function and refers to the ability to adapt behaviors in response to changes in the environment. Of note, many brain disorders are associated with impairments in cognitive flexibility. Several classical neurotransmitter systems including dopamine, acetylcholine and noradrenaline are shown to be important for cognitive flexibility, however, there is not much known about the role of neuropeptides. The neuropeptide orexin, which is brain‐widely released by neurons in the lateral hypothalamus, is a major player in maintaining sleep/wake cycle, feeding behavior, arousal, and motivational behavior. Recent studies showed a role of orexin in attention, cognition and stress‐induced attenuation of cognitive flexibility by disrupting orexin signaling locally or systemically. However, it is not known so far whether brain‐wide reduction or loss of orexin affects cognitive flexibility. We investigated this question by testing male and female orexin‐deficient mice in the attentional set shifting task (ASST), an established paradigm of cognitive flexibility. We found that orexin deficiency impaired the intra‐dimensional shift phase of the ASST selectively in female homozygous orexin‐deficient mice and improved the first reversal learning phase selectively in male homozygous orexin‐deficient mice. We also found that these orexin‐mediated sex‐based modulations of cognitive flexibility were not correlated with trait anxiety, narcoleptic episodes, and reward consumption. Our findings highlight a sexually dimorphic role of orexin in regulating cognitive flexibility and the need for further investigations of sex‐specific functions of the orexin circuitry.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Orexin deficiency modulates cognitive flexibility in a sex‐dependent manner

Durairaja

Fendt

2020

Genes Brain and Behavior

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“…Hrct increases ACh release in the prefrontal cortex [200][201][202] and the Hcrt-R1 antagonist SB-334867 impaired performance in an acetylcholinemediated sustained attention task [203]. Cognitive flexibility is impaired in Hcrt-KO mice [204] and improved in aged rats by intranasal Hcrt [107]. Lower plasma Hcrt-1 is associated with reduced cognitive flexibility in subjects with AN [143], whilst NT1 patients perform sub-optimally in the decision-making Iowa Gambling Task [205].…”

Section: Cognitive Disordersmentioning

confidence: 99%

Hypocretins (orexins): The ultimate translational neuropeptides

2022

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The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin‐induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance‐use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit‐related neuropsychiatric and neurodegenerative conditions.

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“…It is also possible that the behavioral effects of intranasal OXA involve brain regions other than the hippocampus. Intranasal OXA enhances neural activity within the prefrontal and insular cortex and increases cholinergic transmission in the prefrontal cortex and basal forebrain in nocturnal laboratory rats (Calva et al, 2018; Calva et al, 2019; Calva & Fadel, 2020). Therefore, intranasal OXA could improve cognitive function acting in extra‐hippocampal neural sites that support wakefulness and/or attentional processes, a possibility that will be explored in future studies.…”

Section: Discussionmentioning

confidence: 99%

Orexin (hypocretin) mediates light‐dependent fluctuation of hippocampal function in a diurnal rodent

et al. 2021

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Environmental lighting conditions play a central role in cognitive function, but the underlying mechanisms remain unclear. Utilizing a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus), we previously found that daytime light intensity affects hippocampal function in this species in a manner similar to its effects in humans. Compared to animals housed in a 12:12 h bright light–dark (brLD) cycle, grass rats kept in a 12:12 h dim light–dark (dimLD) cycle showed impaired spatial memory in the Morris water maze (MWM) and reduced CA1 apical dendritic spine density. The present study explored the neural substrates mediating the effects of daylight intensity on hippocampal function focusing on the hypothalamic orexin (hypocretin) system. First, animals housed in dimLD were treated with daily intranasal administration of orexin A peptide over five training days of the MWM task. Compared to vehicle controls, this treatment led to superior spatial memory accompanied by increased phosphorylation of Ca2+/calmodulin‐dependent protein kinase II α and glutamate receptor 1 within the CA1. To assess the role of hippocampal orexinergic signaling, an adeno‐associated viral vector (AAV) expressing an orexin receptor 1 (OX1R) shRNA was injected into the dorsal hippocampus targeting the CA1 of animals housed in brLD. AAV‐mediated knockdown of OX1R within the hippocampus resulted in deficits in MWM performance and reduced CA1 apical dendritic spine density. These results are consistent with the view that the hypothalamic orexinergic system underlies the modulatory role of daytime illumination on hippocampal function in diurnal mammals.

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Effects of Intranasal Orexin-A (Hypocretin-1) Administration on Neuronal Activation, Neurochemistry, and Attention in Aged Rats

Cited by 15 publications

References 107 publications

Orexin deficiency modulates cognitive flexibility in a sex‐dependent manner

Orexin deficiency modulates cognitive flexibility in a sex‐dependent manner

Hypocretins (orexins): The ultimate translational neuropeptides

Orexin (hypocretin) mediates light‐dependent fluctuation of hippocampal function in a diurnal rodent

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