Characterization of Neocortical Orexin/Hypocretin Receptor Expression in Dementias with Sleep Disturbances

Liu, Yu chen (Rellie)

doi:10.25740/xx803sw5514

Characterization of Neocortical Orexin/Hypocretin Receptor Expression in Dementias with Sleep Disturbances

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Abstract/Contents

Abstract: Neuropsychiatric symptoms are extremely prevalent in Alzheimer’s disease (AD) and other dementias such as diffuse Lewy body disease (DLBD), yet the relationship between the manifestation of these symptoms and cognitive decline remains understudied. This thesis addresses the critical need for comprehensive research into the molecular basis of disturbances of the sleep-wake cycle, a common neuropsychiatric symptom that not only results in substantial clinical burden but has also been suggested to have an important bidirectional relationship with the progression of disease pathology. Previous research has revealed the importance of the orexin/hypocretin pathway in sleep regulation, primarily focusing on murine models and brainstem pathways. The neocortical substrate in human tissue remains, however, largely unexplored. In this project, I investigated the expression of orexin/hypocretin 2 receptors (HCRTR2) in relation to KIT-expressing interneurons, a subtype of neocortical interneurons that our lab has found to be dysregulated at early-stages of AD pathology. Using immunohistochemistry and in-situ hybridization methods, I assessed the expression profiles of both KIT and HCRTR2 in postmortem human brain tissue from cohorts of AD, DLBD, and healthy age-matched controls. I also confirmed that this particular interneuron subtype is also present in mice. Interestingly, the results demonstrate a significant decrease in KIT and HCRTR2 mRNA expression levels as AD level pathology increases, but not in protein expression levels. This discrepancy between expression profiles can potentially be explained by the differential stabilities of proteins and RNAs or the decline in proteasome activity. More importantly, however, given that both disruptions in interneuron function and irregular sleep patterns may occur before cognitive symptoms manifest, the decline of cortical interneurons expressing mRNA signals encoding for the HCRTR2 protein could potentially contribute to the onset of sleep disturbances in AD and other forms of dementia. This project highlights the critical need for further investigations into the molecular mechanisms underlying sleep disturbances across different forms of dementia and draws a potential link between early interneuron dysregulation in AD and the development of dysregulated sleep circuits in the brain.

Description

Type of resource	text
Publication date	May 2, 2024

Creators/Contributors

Author	Liu, Yu chen (Rellie)	https://orcid.org/0000-0002-9666-0075 (unverified)
Thesis advisor	Cobos, Inma	https://orcid.org/0000-0002-2043-1890 (unverified)
Thesis advisor	Tan, Longzhi	https://orcid.org/0000-0002-5618-1299 (unverified)
Thesis advisor	Heller, H Craig	https://orcid.org/0000-0003-4479-5880 (unverified)
Contributor	Sanz Ros, Jorge	https://orcid.org/0000-0002-6598-056X (unverified)
Contributor	Vallejo, Kristen	https://orcid.org/0009-0005-1418-7931 (unverified)
Degree granting institution	Stanford University, Department of Biology

Subjects

Subject	Alzheimer's disease
Subject	Sleep
Subject	Neuropsychiatric symptoms
Subject	Orexins
Subject	Hypocretins
Subject	Lewy body dementia
Subject	Neuropathology
Subject	Diffuse lewy body disease
Genre	Text
Genre	Thesis

Bibliographic information

DOI	https://doi.org/10.25740/xx803sw5514
Location	https://purl.stanford.edu/xx803sw5514

Access conditions

Use and reproduction: User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
License: This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).

Preferred citation

Preferred citation: Liu, Y. and Cobos, I. (2025). Characterization of Neocortical Orexin/Hypocretin Receptor Expression in Dementias with Sleep Disturbances. Stanford Digital Repository. Available at https://purl.stanford.edu/xx803sw5514. https://doi.org/10.25740/xx803sw5514.

Collection

Undergraduate Theses, Department of Biology, 2023-2024

Contact information

Contact: liliu31@stanford.edu

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