Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility

Grafe, Laura A.; Cornfeld, Amanda D.; Luz, Sandra; Valentino, Rita J.; Bhatnagar, Seema

doi:10.1016/j.biopsych.2016.10.013

Cited by 111 publications

(122 citation statements)

References 41 publications

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“…Our previous work has revealed that the neuropeptides orexins mediate sex differences in habituation to repeated stress (Grafe et al, 2017). Specifically, elevated levels of orexins in female rats impair habituation to repeated restraint stress.…”

Section: Discussionmentioning

confidence: 99%

“…We aimed to determine if there were observable structural differences in these putative orexinergic dendrites in males compared with females in basal conditions, and if repeated restraint stress affects any sex differences observed. As we observed greater prepro-orexin mRNA and activation in basal, non-stressed females (Grafe et al, 2017), we hypothesized that there would be more complex dendritic morphology and a greater number of spines in control females compared with males. This would be reflective of more excitable orexin cells in females.…”

Section: Introductionmentioning

confidence: 91%

“…We recently found that non stressed female rats have higher basal prepro-orexin expression and activation of orexinergic neurons compared with males, leading to impaired habituation of the HPA axis to repeated restraint stress and subsequent cognitive deficits (Grafe et al, 2017). Importantly, inhibition of orexin neurons allowed female rats to habituate more fully to repeated restraint stress at multiple levels, including reduced struggle behavior, lower activation in the paraventricular nucleus (PVN) of the hypothalamus, and decreased HPA hormones.…”

Section: Introductionmentioning

confidence: 99%

“…This would be reflective of more excitable orexin cells in females. As females do not habituate as fully as males to repeated restraint stress (Grafe et al, 2017), we expected that this may remain high in females after repeated restraint. However, since males habituate more fully to repeated restraint, we expected dendritic complexity and number of spines would decrease with 5 days of repeated restraint stress in males rats.…”

Section: Introductionmentioning

confidence: 99%

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Sex- and Stress-Dependent Effects on Dendritic Morphology and Spine Densities in Putative Orexin Neurons

et al. 2019

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We recently found that non-stressed female rats have higher basal prepro-orexin expression and activation of orexinergic neurons compared to non-stressed males, which leads to impaired habituation to repeated restraint stress at the behavioral, neural, and endocrine level. Here, we extended our study of sex differences in the orexin system by examining spine densities and dendritic morphology in putative orexin neurons in adult male and female rats that were exposed to 5 consecutive days of 30 min restraint. Analysis of spine distribution and density indicated that putative orexinergic neurons in control non-stressed females had significantly more dendritic spines than those in control males, and the majority of these were mushroom spines. This morphological finding may suggest more excitatory input onto orexin neurons in female rats. As orexin neurons are known to promote the HPA response, this morphological change in orexin neurons could underlie the impaired habituation to repeated stress in female rats. Dendritic complexity did not differ between non-stressed males and females, however repeated restraint stress decreased total dendritic length, nodes, and branching primarily in males. Thus, reduced dendritic complexity of putative orexinergic neurons is observed in males but not in females after 5 days of repeated restraint stress. This morphological change might be reflective of decreased orexin system function, which may allow males to habituate more fully to repeated restraint than females.These results extend our understanding of the role of orexin neurons in regulating habituation and demonstrate changes in putative orexin cell morphology and spines that may underlie sex differences in habituation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex- and Stress-Dependent Effects on Dendritic Morphology and Spine Densities in Putative Orexin Neurons

et al. 2019

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“…Studies of humans (Shields, Trainor, Lam, & Yonelinas, 2016) and mice (Laredo et al, 2015) have found that cognitive flexibility in males was more significantly impaired following a stressor, although one recent study found that female rats were more affected (Grafe, Cornfeld, Luz, Valentino, & Bhatnagar, 2017). Sex-differences in cognitive performance between men and women are also reported in pathological conditions.…”

Section: Exercise Sex and Age Effects On Cognitive Flexibility And mentioning

confidence: 99%

Sex-dependent effects of chronic exercise on cognitive flexibility in aging mice

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Bui

Zbukvic

et al. 2020

Preprint

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Cognitive impairments associated with advanced age are a growing concern in our aging society. Such impairments are associated with alterations in brain structure and function, especially in the hippocampus, which changes to experience throughout life. It is well-known that regular exercise can maintain hippocampus volume. The hippocampus is critical for cognitive flexibility involved with extinction and reinstatement of conditioned fear. Therefore, we asked whether voluntary chronic exercise in middle-aged mice can improve extinction and/or reinstatement of conditioned fear compared to standard housing. Eight-month-old male and female C57Bl/6J mice had access to a running wheel or remained in standard housing until 11 months of age. Alongside control standard-housed young adult (3-monthold) mice, they received tone-footshock pairings, which were subsequently extinguished with tone-alone presentations the next day. Half of the mice then received a reminder treatment in the form of a single footshock. Both male and female 11-month-old mice housed in standard conditions exhibited impaired reinstatement compared to young adult mice.However, for males that had access to a running wheel from 8 months of age, the reminder treatment rescued reinstatement ability. This was not observed in females. Additionally, exercise during middle age in both sexes increased expression of Bdnf mRNA in the hippocampus, specifically exon 4 mRNA. These results show that, at least for males, physical exercise is beneficial for reducing age-related decline in cognitive abilities. Despite not rescuing their impaired reinstatement, exercise also increased Bdnf gene expression in the female hippocampus, which could potentially benefit other forms of hippocampaldependent cognition.

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The arousal effect of hyperbaric oxygen through orexin/hypocretin an upregulation on ketamine/ethanol‐induced unconsciousness in male rats

Bian

Huang

et al. 2019

J of Neuroscience Research

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Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.

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Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility

Cited by 111 publications

References 41 publications

Sex- and Stress-Dependent Effects on Dendritic Morphology and Spine Densities in Putative Orexin Neurons

Sex- and Stress-Dependent Effects on Dendritic Morphology and Spine Densities in Putative Orexin Neurons

Sex-dependent effects of chronic exercise on cognitive flexibility in aging mice

The arousal effect of hyperbaric oxygen through orexin/hypocretin an upregulation on ketamine/ethanol‐induced unconsciousness in male rats

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