A neuroimmune circuit mediates cancer cachexia-associated apathy 2025 Kepecs et al

Structured Abstract

INTRODUCTION
Cachexia is a debilitating wasting syndrome that affects most advanced cancer patients, characterized by profound involuntary weight loss, muscle and fat depletion, and disrupted energy balance. Beyond physical decline, patients commonly experience severe fatigue, apathy, and depression that further diminish their quality of life. Despite these pervasive neuropsychiatric symptoms, the biological mechanisms linking peripheral wasting to brain dysfunction and behavioral changes remain poorly understood, hindering the development of effective treatments.

RATIONALE
Systemic inflammation, marked by elevated circulating cytokines, is a key driver of cancer cachexia. Although inflammation could broadly compromise neuronal function, we hypothesized that it acts through specialized circuits that conserve energy during acute illness. In cancer, persistent activation of these circuits may drive chronic fatigue and depression, providing a mechanistic framework for how inflammation dynamically regulates motivation.

RESULTS
To investigate cachexia’s impact on motivation, we used an established preclinical model: mice subcutaneously implanted with colon adenocarcinoma cells (C26). Within weeks, the mice exhibited classical cachexia symptoms—weight loss, muscle wasting, and decreased feeding—accompanied by pronounced motivational deficits. A battery of behavioral assays uncovered specific deficits in effort-sensitive tasks such as patch foraging and progressive ratio tests. By contrast, tests of physical activity (open-field exploration), reward sensitivity (sucrose preference, a measure of anhedonia), and despair (tail suspension, forced swim tests) remained unchanged, although home-cage activity was reduced. This identifies a specific reduction in effort-based motivation, indicative of apathy and distinct from general weakness or anhedonia.

A comprehensive cytokine screen showed rising interleukin-6 (IL-6) levels in the blood and brain that paralleled cachexia progression. Whole-brain, cellular-resolution activity mapping and viral tracing uncovered a circuit originating in the area postrema, a circumventricular organ specialized for detecting blood-borne signals. IL-6–sensing neurons in this region project to the parabrachial nucleus, which in turn activates the substantia nigra pars reticulata inhibitory neurons, ultimately suppressing dopamine release in the nucleus accumbens. Optogenetic stimulation of area postrema neurons rapidly suppressed accumbens dopamine release. Longitudinal dopamine monitoring during cachexia progression revealed a progressive decline in accumbens dopamine that tracked with worsening motivational deficits.

Targeting this IL-6–sensing pathway reversed cachexia-induced apathy. Blocking IL-6 with systemic antibodies, knocking down (genetic reduction of gene expression) IL-6 receptors in the area postrema, or ablating area postrema–to–parabrachial neurons each alleviated the motivational deficits. Conversely, boosting dopamine signaling in the nucleus accumbens—through optogenetic stimulation of dopamine neurons or local dopamine agonist infusion—restored motivation despite ongoing inflammation, even at late stages of cancer progression.

CONCLUSION
We identified an immune-to-neural circuit through which inflammation drives motivational deficits in cancer cachexia. Area postrema neurons detect circulating IL-6 and relay this signal to the basal ganglia to suppress mesolimbic dopamine, thereby increasing effort sensitivity. This specialized interoceptive pathway demonstrates that inflammation engages discrete neural circuits rather than causing broad disruption and cumulative neural damage. Although this circuit is likely adaptive during acute illness—conserving energy by dampening motivation—its persistent engagement in chronic conditions such as cancer cachexia is detrimental. This reveals that psychiatric symptoms such as apathy in cachexia are not secondary effects of physical decline but can arise directly from the same pathological mechanisms driving the illness itself.

Targeting this circuit through ablation of IL-6 sensing or boosting dopamine release relieved motivational deficits, opening therapeutic avenues for neuropsychiatric symptoms in cachexia and possibly other inflammatory conditions where IL-6 is elevated. Moreover, by quantifying effort sensitivity as a dimension of motivation that is measurable across species establishes that inflammation specifically drives apathy-like behavior, enabling clinical translation and treatments for inflammation-driven motivational deficits common to conditions ranging from cancer to depression.

Paywall

 

Why is this labeled ‘inflammation’ instead of just saying that they have elevated circulating cytokines?

This seems like a description of sickness behaviour as initiated by the innate immune system? Are there other interpretations?

 

If cachexia involves loss of muscle mass, wouldn’t that in itself lead to poorer performance in any physical tasks? Does anyone know how they accounted for that in the tests where they seemingly reversed the motivational deficits?

 

I cannot follow the detail of the mechanistic unpicking in brain areas. It looks as if they have shown that IL-6 in mice can do what we have understood 'cachexins' (i.e cytokines) can do in humans for a long time. And as you say, there will be other routes involved in the end result behaviour.

We can be reasonably sure that IL-6 is not the mediator in ME/CFS because CRP levels are nowhere near as high as they are in some other conditions.

 

The problem with this approach is that individuals might have different circuitry. It could be that PWME have a circuit that has high sensitivity to a certain molecule, but that's only one in 100 individuals, so checking a few people (or mice) via time-consuming testing seems a poor method. The responsiveness of downstream circuitry would also vary, as would other associated functions. So, for 100 PWME, you might have only a fraction with that one circuit being studied acting abnormally, while in others it's the related circuits malfunctioning.

 

Using motivation here is really unhelpful. Not because it itself is problematic, but because of how easy it is to be confused about how if you increase motivation, then you can manage the problem. It just doesn't work this way, and this naive approach where pretending that how things are used in the world is not the problem of people who misuse it, or of people who use the same labels that others misuse in similar contexts.

It's probably fine in this context, but because of the biopsychosocial ideology's creep into all aspects of health care, it just isn't. It reeks of the attitudes about "fighting" disease and the idea of dying because people "gave up". So of course the real problem is the existence of biopsychosocial ideology and their need to coopt the meaning of words to retroactively support the ideology, taking what happens after and attributing it as the cause (or perpetuation, whatever floats their boat in how they want to pretend to describe it), but this is the world we live in, not the world we could live in if we were a mature species.