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Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.

Kyna Conn¹, Laura Milton¹, Alyssa Teoh¹

¹Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.

Brain, Behavior, and Immunity

|September 29, 2025

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Cancer-related cachexia impairs cognitive flexibility more than calorie restriction alone. Pancreatic cancer mice showed reduced task performance, unlike calorie-restricted mice, suggesting sickness impacts brain function differently.

Area of Science:

Neuroscience
Oncology
Metabolic Syndrome

Background:

Cachexia affects 50-80% of cancer patients, involving inflammation, appetite loss, and muscle wasting.
Cancer cachexia is linked to more severe cognitive impairment, but studying this in humans is difficult.

Purpose of the Study:

To investigate cognitive performance in a mouse model of pancreatic cancer (PDAC) cachexia.
To differentiate cognitive effects of cancer cachexia from those of calorie restriction.

Main Methods:

Used an in-cage operant device (FED3) and a reversal learning task in PDAC mice, ad libitum fed (PBS), and calorie-restricted (CR) mice.
Administered lithium chloride (LiCl) to CR mice to mimic sickness and assessed anxiety-like behaviors using maze tests.

Keywords:

Behaviour Cancer cachexia Cognitive flexibility Instrumental learning LiCl Malaise Mouse model Reversal learning

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Main Results:

PDAC mice showed impaired cognitive flexibility compared to CR mice, with no difference between PDAC and PBS groups.
Sickness induced by LiCl reduced reward-seeking behavior, suggesting sickness-induced devaluation of reward.
No significant differences in anxiety-like behaviors were observed between PDAC and PBS groups.

Conclusions:

Cancer cachexia specifically impacts cognitive flexibility, distinct from weight loss due to calorie restriction.
Sickness, not just weight loss, may be a key factor in cognitive deficits associated with cancer.
Elevated pro-cachexia factors (GDF15, Activin A/B) were not sufficient to induce behavioral changes in anxiety tests.