Mechanisms of Memory Impairment Induced by Orexin-A via Orexin 1 and Orexin 2 Receptors in Post-traumatic Stress Disorder Rats

Han, Dan; Han, Fang; Shi, Yonghui; Zheng, Shilei; Wen, Lei

doi:10.1016/j.neuroscience.2020.02.026

Cited by 20 publications

(14 citation statements)

References 52 publications

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“…In this study, we administered 10 Hz EA for 14 days, a treatment strategy that was previously confirmed to be efficacious [19], and found that 10 Hz EA effectively reduced the OxA level in the CSF of 7-month-old SAMP8 mice within 24 h. The spontaneous alternation rate in the Y maze test and 11 Oxidative Medicine and Cellular Longevity the percentage of time spent in the target quadrant in the MWM probe test were increased, and the latency to find the hidden platform in the MWM test was decreased, indicating that the impairment of working memory and longterm spatial memory was effectively alleviated in SAMP8 mice. These results are similar to those of previous reports showing that direct injection of OX1R antagonists into the hippocampus can relieve social learning and memory impairment caused by acute stress in rats [34]. Orexin-1 receptor blockade differentially affects spatial and visual discrimination memory facilitation by intracranial selfstimulation [35].…”

Section: Discussionsupporting

confidence: 91%

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

Hou

Yang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Learning and memory disorders and decreased neuroplasticity are the main clinical manifestations of age-induced cognitive dysfunction. Orexin A (OxA) has been reported to show abnormally elevated expression in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) and to be associated with cognitive impairment. Here, we further assessed whether the excitatory neurotransmitter OxA is involved in neuroplasticity and cognitive function in senescence-accelerated mouse prone 8 (SAMP8) mice. In this study, we investigated the mechanism of OxA by using behavioral tests, CSF microdialysis, immunofluorescence, toluidine blue staining, gene silencing, transmission electron microscopy, and Western blotting. The results showed that 10 Hz electroacupuncture (EA) effectively alleviated learning and memory impairment in 7-month-old SAMP8 mice, reduced OxA levels in the CSF, increased the level of the neurotransmitter glutamate, alleviated pathological damage to hippocampal tissue, improved the synaptic structure, enhanced synaptic transmission, and regulated the expression of cAMP/PKA/CREB signaling pathway-related proteins. These results suggest that EA enhances neuroplasticity in SAMP8 mice by regulating the OxA-mediated cAMP/PKA/CREB signaling pathway, thus improving cognitive function. These findings suggest that EA may be beneficial for the prevention and treatment of age-induced cognitive impairment.

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Section: Discussionsupporting

confidence: 91%

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

Hou

Yang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…In addition, PTSD-like behavior of Firoc or wild-type mice submitted to 2.5 mA electric shocks is normalized by early chemogenetic inhibition of orexin neurons, which supports the use of orexin receptor antagonists for treatment of this condition [ 20 , 21 ]. Conversely, recent observations pose orexin activation in experimental PTSD as a mechanism of resilience [ 22 ], supporting the use of orexin agonists for treatment of PTSD [ 55 ]. These two apparently opposing observations may be reconciled by our findings.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons

et al. 2022

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Maladaptive coping behaviors are probably involved in post-traumatic stress disorders (PTSD), but underlying mechanisms are incompletely understood. We now report that mice lacking functional insulin-like growth factor I (IGF-I) receptors in orexin neurons of the lateral hypothalamus (Firoc mice) are unresponsive to the anxiolytic actions of IGF-I and develop PTSD-like behavior that is ameliorated by inhibition of orexin neurons. Conversely, systemic IGF-I treatment ameliorated PTSD-like behavior in a wild-type mouse model of PTSD (PTSD mice). Further, systemic IGF-I modified the GABA/Glutamate synaptic structure in orexin neurons of naïve wild-type mice by increasing the dephosphorylation of GABA(B) receptor subunit through inhibition of AMP-kinase (AMPK). Significantly, pharmacological inhibition of AMPK mimicked IGF-I, normalizing fear behavior in PTSD mice. Thus, we suggest that IGF-I enables coping behaviors by balancing E/I input onto orexin neurons in a context-dependent manner. These observations provide a novel therapeutic approach to PTSD through modulation of AMPK.

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“…While sensorimotor gating is dependent on dopamine release in the NAc, the ability to regulate PPI is not exclusive to this brain region. Brain regions such as the hippocampus, mPFC, and amygdala have also been shown to contribute to deficits in PPI 32 and previous studies have demonstrated orexin receptor expression and orexin receptor signaling in these regions is altered following stress [65][66][67] . Furthermore, the expression of OX 1 R and OX 2 R differs within these regions.…”

Section: Discussionmentioning

confidence: 99%

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

et al. 2021

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Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

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Mechanisms of Memory Impairment Induced by Orexin-A via Orexin 1 and Orexin 2 Receptors in Post-traumatic Stress Disorder Rats

Cited by 20 publications

References 52 publications

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

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