Investigating brain-body allostasis via longitudinal in vivo imaging

/ Abstract Animal behavior manifests from a coalition of physiological states to enable effective navigation of a world which perpetually challenges homeostatic regulation. Whereas homeostatic feedback regimes maintain physiological thresholds, allostasis describes the flexible adjustment of thresholds during the experience of novel stressors. To achieve whole-body allostasis, multi-organ physiology must be coordinated through bidirectional communication between the brain and body, but the mechanisms driving this synchronization are still poorly understood. Astrocytes are a type of glia (non-neuronal) cell in the brain that have been classically described as the brain’s chief homeostatic regulators, but little is known regarding their role in facilitating brain state shifts. Interestingly, astrocyte networks display large, synchronized intracellular calcium events that occur across the entire brain and correlate with pupil dynamics. This suggests that astrocytes may be key players in coordinating the brain with whole-body allostasis, but little research has explored this possibility. Furthermore, the enteric glia surrounding the gut show similarities to astrocytes and could be a conserved mechanism by which whole-body allostasis is achieved. My laboratory aims to bridge astrocyte-linked brain states with allostatic shifts across other organ systems. To do this, we leverage simultaneous in vivo recording of a range of physiological readouts including sympathetic outflow, hormone circulation, cardiovascular dynamics, gut signaling, widefield brain imaging, and behavior in a head-fixed mouse model. We will also model ‘autonomy’ using a quantifiable sensory- motor feedback system to titrate brain states related to environmental control. Over the next five years, I will lead research projects under three main themes: 1) Characterizing brain-body physiology in a stress acclimation model of allostasis; 2) Investigating the role of augmenting environmental control in whole-body allostasis; and 3) Developing new soft-tissue fiber photometry to link enteric glial physiology with whole-body allostasis. Unfortunately, there is no shortage of psychological stress in the world today, especially in medical settings. It is time to bridge our understanding of the brain states underlying psychological stress with whole-body physiology. The allostasis model championed here promises to unify theories and evidence currently isolated to specific organ systems, and will improve individualized medicine, post-operative care, and therapeutic discovery. Project Number: 1R35GM162859-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Grayson Sipe | Institution: PENNSYLVANIA STATE UNIVERSITY, THE, UNIVERSITY PARK, PA | Award Amount: $407,603 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MCST-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11271214