The Role of Orexin in Decision Making

It is imperative that the brain has an accurate understanding of the metabolic needs to guide adaptive behaviors. Physiologically relevant changes in metabolism often occur on slow timescales governed by energy-balancing processes. Decisions, in contrast, can be extremely rapid and can require behavioral responding to stimuli which are extremely transient in nature. It is not clear if/how the brain coordinates using slow metabolic information to guide rapid decision-making. A candidate system for bridging decision making and metabolism is the hypothalamus. This region is best known for responding to metabolic events on timescales ranging from minutes (e.g. blood glucose) to decades (e.g. growth, puberty and aging). Therefore, in terms of rapid decision-making, it would classically be presumed that metabolically sensitive elements in the hypothalamus could only act in the sensory domain, serving as a relay of slow tonic levels of nutrients and hormones in the periphery. However, it has been known for at least 100 years that the hypothalamus also experiences dynamic changes in activity on timescales far faster than could be metabolically relevant. In the past decades, novel behavioral paradigms and genetically targeted tools have illuminated correlative and causal roles of the hypothalamus in decision-making processes. This thesis is built upon the shoulders of this previous knowledge and specifically focuses on a subset of the hypothalamus: hypocretin/orexin producing neurons (HONs) for their role in driving decisions related to physical activity, feeding, and cognitive constraints on decision-making. The first part of this thesis will focus on how HONs multiplex metabolic and movement-related information across multiple timescales. Then, we will implement a decision-making task showing how HONs govern the decision to exercise or eat, specifically when one must make a choice between the two options. Finally, we will examine these metabolite-sensing neurons for their role in governing the overall complexity of decision policies. Overall, the findings in this thesis advance our understanding of how the brain employs systems which sense metabolic information to guide adaptive decision-making and cognitive processes.

Grantor dc:publisher

ETH Zurich

Year dc:date

2025

Author dc:creator

• Tesmer, Alexander Lee

Contributors dc:contributor

• Burdakov, Denis; id_orcid0000-0002-9134-9165
• Polania, Rafael Hernan; id_orcid0000-0002-9134-9165
• Apergis-Schoute, John

• Natural sciences

Statement dc:rights

• info:eu-repo/semantics/openAccess
• Creative Commons Attribution 4.0 International

Licence

• http://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.3929/ethz-c-000789420

OAI identifier oai:identifier

oai:www.research-collection.ethz.ch:20.500.11850/789420