Reconstructing a physiological state space via chronic jugular microdialysis in freely moving mice

Maintaining physiological homeostasis requires a complex interplay among endocrine organs, peripheral tissues, and distributed neuroendocrine control circuits, all of which are coupled through feedback loops that operate over minutes to hours. Although many physiological needs are broadcast through hormones, metabolites, and other chemical compounds circulating in the bloodstream, we rarely observe more than a few of these messengers together and at high cadence during behavior. To address this, we developed a minimally disruptive workflow to measure the free fraction of hundreds of amines and small peptides at a 7.5-minute cadence for [~]8 hrs in freely moving mice using chronic jugular microdialysis implants and chemical isotope labeling Liquid Chromatography-Mass Spectrometry. Single-compound profiles behave according to known physiology, such as purine turnover correlating with movement, delayed histamine/5-HIAA changes, and coordinated amino-acid dynamics. Our multiplexed measures enable high-dimensional analyses that uncover properties of the underlying dynamics. For example, systems-level analyses show that 10 dimensions explain over 70% of the variance in hormone/metabolite covariation, consistent with a low rank description of the physiological state space, with projections aligned to locomotion state transitions. Our work opens avenues for the discovery of hormonal dynamics, compound interactions, and their effects on behavior.