Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure

Stanojlović, Miloš; Yllescas, Jean Pierre Pallais; Mavanji, Vijaya; Kotz, Catherine M.

doi:10.1152/ajpregu.00383.2018

Cited by 16 publications

(22 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The orexin system plays a major role in the regulation of physical activity (Zeitzer et al, 2004; Burgess, 2010). In our recent study (Stanojlovic et al, 2019), we observed that DREADD-induced activation of orexin neurons increased locomotion in both young, 5-month-old, and middle-aged, 12-month-old WT mice. In the current study, however, activation of orexin neurons did not have an effect on locomotion in A53T mice.…”

Section: Discussionmentioning

confidence: 76%

Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease

2019

Self Cite

View full text Add to dashboard Cite

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD symptomology is recognized as heterogeneous and in addition to motor function decline includes cognitive, mood, sleep, and metabolic disorders. Previous studies showed early reductions in anxiety and locomotion in the A53T mice model of PD. Since inflammation and astrogliosis are an integral part of PD pathology and impair proper neuronal function, we were keen to investigate if behavioral changes in A53T mice are accompanied by increased inflammation and astrogliosis in the hippocampus (Hipp) and motor cortex (mCtx) brain regions involved in the regulation of anxiety and locomotion, respectively. To test this, we used 3-, 5-, and 7-month-old A53T mice to examine anxiety-like behavior, locomotion, and expression of inflammation and astrogliosis markers in the Hipp and mCtx. Further, we examined the presence of alpha-synuclein accumulation in orexin neurons and orexin neuronal loss. The data show early reductions in anxiety-like behavior as well as increased locomotor activity, which was accompanied by inflammation and astrogliosis in the Hipp and mCtx. Due to the persistence of the orexin neuron population in A53T mice and the involvement of orexin in anxiety and locomotor regulation, we hypothesized that chemogenetic modulation of orexin neurons would reverse the observed reductions in anxiety-like behavior and the increases in locomotor activity in these animals. We showed that chemogenetic activation of orexin neurons in A53T mice restores anxiety-like behavior back to control levels without affecting locomotor activity, whereas the inhibition of orexin neurons reverses the elevated locomotor activity without any effects on anxiety-like behavior. This study exemplifies the complex role of orexin neurons in this model of PD and demonstrates the novel finding that changes in locomotor and anxiety-like behavior are accompanied by inflammation and astrogliosis. Together, these data suggest that the orexin system may play a significant role in early and late stages of PD.

show abstract

Section: Discussionmentioning

confidence: 76%

Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…For behavioral tests, 3 mg/kg of CNO in saline or saline was injected via a small gauge (32) syringe once 30 min prior to testing. For indirect calorimetry and SPA studies, animals were given CNO dissolved in drinking water (0.25 mg/mL) or drinking water [ 94 ]. This was necessary to leave unbroken the gas-exchange seal of the indirect calorimetry units.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease

Stanojlović

Pallais

Kotz

2021

IJMS

Self Cite

View full text Add to dashboard Cite

Aside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesized that Parkinson’s-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson’s, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson’s disease pathology. This study implicates the involvement of orexin in early Parkinson’s-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson’s disease symptomology.

show abstract

“…Firoc mice were obtained by crossing Orexin‐Cre mice (a kind gift of T Sakurai, Tsukuba Univ, Japan) a mouse model extensively used, 29‐31 with IGF‐IR f/f mice (B6, 129 background; Jackson Labs; stock number: 012251; exon 3 floxed). Cre recombination of the floxed IGF‐IR results in deletion of exon 3, functional inactivation of the receptor 32 and substantial reduction of IGF‐IR expression 33 .…”

Section: Methodsmentioning

confidence: 99%

Insulin‐like growth factor I modulates sleep through hypothalamic orexin neurons

et al. 2020

View full text Add to dashboard Cite

Although sleep disturbances are common co-morbidities of metabolic diseases, the underlying processes linking both are not yet fully defined. Changes in the duration of sleep are paralleled by changes in the levels of insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation and activitydependent entrance in the brain. However, the specific role, if any, of IGF-I in this universal homeostatic process remains poorly understood. We now report that the activity of orexin neurons, a discrete cell population in the lateral hypothalamus that is involved in the circadian sleep/wake cycle and arousal, is modulated by IGF-I. Furthermore, mice with blunted IGF-I receptor activity in orexin neurons have lower levels of orexin in the hypothalamus, show altered electro-corticographic patterns with predominant slow wave activity, and reduced onset-sleep latency. Collectively, these results extend the role in the brain of this pleiotropic growth factor to shaping sleep architecture through the regulation of orexin neurons. We speculate that poor sleep quality associated to diverse conditions may be related to disturbed brain IGF-I input to orexin neurons.

show abstract

Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure

Cited by 16 publications

References 92 publications

Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease

Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease

Insulin‐like growth factor I modulates sleep through hypothalamic orexin neurons

Contact Info

Product

Resources

About