Contextual generalization of social stress learning is modulated by orexin receptors in basolateral amygdala

Yaeger, Jazmine D.W.; Krupp, Kevin T.; Summers, Tangi R.; Summers, Cliff H.

doi:10.1016/j.neuropharm.2022.109168

Cited by 17 publications

(12 citation statements)

References 64 publications

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“…Ox2r is abundantly expressed in the NDB, histaminergic TMV neurons, DRN, and PPT, mildly expressed in the VTA, and parabrachial nucleus, and not expressed in the LC or LDT. These observations are generally consistent with those of previous studies (14, 25–28, 35, 36). Furthermore, the cellular resolution analysis showed that the DRN expresses both Ox1r and Ox2r but serotonergic cells expressing both receptors are a minor population of DRN neurons.…”

Section: Discussionsupporting

confidence: 93%

“…We also showed that Ox1r -expressing cells and Ox2r -expressing cells in the same region tend to be classified into different subpopulations, such as glutamatergic and GABAergic neurons. For example, Ox1r and Ox2r were expressed predominantly in Vgat -negative cells and Vgat -positive cells, respectively, in isocortex layer II/III, olfactory areas, and the cortical subplate in the cerebrum, as shown in the BLA (28). In the cerebrum, although Vglut2 was not expressed in almost all of the excitatory neurons, almost all of the Vgat -negative neurons expressed Vglut1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The rough distribution of orexin receptors was reported in rat brains by radiolabeled probes approximately 20 years ago and is still the most comprehensive information available (23,24). Cell resolution information of OX1R and OX2R has been available only for brain regions that abundantly express orexin receptors, such as the amygdala, tuberomammillary nucleus, raphe nuclei, locus coeruleus, and laterodorsal tegmental nucleus (14,(25)(26)(27)(28). At this time, the Allen Brain Atlas fails to show positive signals for orexin receptors and reliable antibodies for OX1R and OX2R that work for immunohistochemistry are not available.…”

Section: Introductionmentioning

confidence: 99%

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Whole brain mapping of orexin receptor mRNA expression visualized by branchedin situhybridization chain reaction

Tsuneoka,

Funato

2023

Preprint

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Orexins, which are produced within neurons of the lateral hypothalamic area, play a pivotal role in the regulation of various behaviors, including sleep/wakefulness, reward behavior, and energy metabolism, via orexin receptor type 1 (OX1R) and type 2 (OX2R). Despite the advanced understanding of orexinergic regulation of behavior at the circuit level, the precise distribution of orexin receptors in the brain remains unknown. Here, we develop a new branched in situ hybridization chain reaction (bHCR) technique to visualize multiple target mRNAs in a semiquantitative manner, combined with immunohistochemistry, which provided comprehensive distribution of orexin receptor mRNA and neuron subtypes expressing orexin receptors in mouse brains. Only a limited number of cells expressing both Ox1r and Ox2r were observed in specific brain regions, such as the dorsal raphe nucleus and ventromedial hypothalamic nucleus. In many brain regions, Ox1r-expressing cells and Ox2r-expressing cells belong to different cell types, such as glutamatergic and GABAergic neurons. Moreover, our findings demonstrated considerable heterogeneity in Ox1r- or Ox2r-expressing populations of serotonergic, dopaminergic, noradrenergic, cholinergic, and histaminergic neurons. The majority of orexin neurons did not express orexin receptors. This study provides valuable insights into the mechanism underlying the physiological and behavioral regulation mediated by the orexin system, as well as the development of therapeutic agents targeting orexin receptors.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Whole brain mapping of orexin receptor mRNA expression visualized by branchedin situhybridization chain reaction

Tsuneoka,

Funato

2023

Preprint

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“…Though we did not explore the neural circuitry underlying these therapeutic effects here, the fact that DORA-12 and oxytocin affected the same behavioral outcomes, but in opposite directions, raises the possibility that their actions are mediated via similar brain regions and mechanisms. A potential common site of action is the basolateral amygdala; orexin inputs to the basolateral amygdala, particularly involving the Ox1R, have been implicated in cued reinstatement of drug seeking [ 93 ], and evidence suggests they also process stress-related information within this circuit [ 94 , 95 ], consistent with a role for orexin in stress-induced forms of relapse [ 96 , 97 ]. Intranasal oxytocin therapy for the treatment of posttraumatic stress disorder has also been shown to normalize functional connectivity in basolateral amygdala circuits [ 98 ].…”

Section: Discussionmentioning

confidence: 99%

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

et al. 2022

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As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats—heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.

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“…CRH and FKBP5, key regulators of the HPA axis, were also enriched in the orexin-receptor pathway (WP5094) [73]. Recently, the orexin-signaling pathway has also been involved in the pathophysiology and clinical features of PTSD [74][75][76][77][78][79]. Orexin signaling was recently implicated in contextual generalization of social-stress learning in the BLA [79] and in conditioned fear [80] and emotional behaviors [81] in the central amygdala.…”

Section: Discussionmentioning

confidence: 99%

Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

Núñez-Rios¹,

Martínez‐Magaña²,

Nagamatsu³

et al. 2023

Complex Psychiatry

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Introduction: Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly-understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrate brain-specific molecular findings of PTSD from humans and animals. Methods: A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal-stress paradigms. Results: Gene- and pathway-level convergence analyses revealed PTSD-dysregulated genes and biological pathways across brain regions and species. A total of 243 genes converged across species, 17 of them significantly enriched for PTSD. Chemical-synaptic transmission and signaling by G-protein-coupled receptors (GPCRs) were consistently enriched in across -omics and species. Discussion: Our findings point out dysregulated genes highly replicated across PTSD studies in humans and animal models and suggest a potential role for the corticotropin-releasing hormone/orexin pathway in PTSD’s pathophysiology. Further, we highlight current knowledge gaps and limitations and recommend future directions to address them.

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Contextual generalization of social stress learning is modulated by orexin receptors in basolateral amygdala

Cited by 17 publications

References 64 publications

Whole brain mapping of orexin receptor mRNA expression visualized by branchedin situhybridization chain reaction

Whole brain mapping of orexin receptor mRNA expression visualized by branchedin situhybridization chain reaction

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

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