1. Research Background:

The ability to adapt physiology and behaviour to changing internal and external demands is a fundamental property of living organisms. Maintaining this adaptive capacity requires continuous communication between peripheral organs and the central nervous system, enabling metabolic, endocrine, immune and visceral signals to be integrated with environmental information to coordinate appropriate physiological and behavioural responses. Preserving physiological resilience within such adaptive regulation is a hallmark of healthy ageing.

Our lab studies the systems physiology of body-brain communication in humans, asking how peripheral physiological signals shape neural circuit function to coordinate adaptive physiology and behaviour.

Although remarkable progress has been made in identifying molecular and cellular signalling pathways involved in metabolism and homeostatic regulation, considerably less is known about how these signals are integrated within the intact human organism to dynamically regulate neural circuit function. Addressing this challenge requires bridging mechanistic discoveries from experimental models with systems-level investigations in humans.

To this end, we combine multimodal neuroimaging, computational modelling, behavioural phenotyping, metabolic interventions, pharmacology and precision neuromodulation to investigate body-brain communication in humans. Close collaborations with researchers using complementary animal models enable a bidirectional translational strategy in which mechanistic discoveries are translated into experimentally testable hypotheses in humans, while observations in humans inform mechanistic studies in experimental systems.

Together, this integrative approach identifies conserved biological principles governing body-brain communication while revealing how these mechanisms operate within the intact human organism. By establishing a systems-level understanding of adaptive physiology, our research provides a biological foundation for understanding how physiological resilience is maintained throughout life and how it may change during ageing.

2. Research questions addressed by the group:

By integrating human systems physiology with mechanistic insights from complementary animal models, our research aims to identify conserved biological principles that govern communication between the body and the brain. Our work is centred around three overarching research questions:

1. How do peripheral physiological signals shape neural circuit function to coordinate adaptive physiology and behaviour
   We investigate how metabolic, endocrine, immune and visceral signals are integrated within distributed brain circuits to regulate learning, motivation, motor control and behavioural flexibility in humans.

2. How does body-brain communication enable physiological resilience?
   We study how dynamic physiological states influence adaptive responses to changing internal and environmental demands, providing the biological basis for flexible behaviour and organismal homeostasis.

3. Which mechanisms of body-brain communication are conserved across species, and how can they be translated to human physiology?
   Through multimodal MRI, computational modelling, behavioural analyses, metabolic interventions, pharmacological manipulations and precision neuromodulation in humans, together with complementary mechanistic studies in animal models, we identify fundamental biological principles governing body-brain communication across levels of biological organisation.

This unique translational strategy bridges molecular and circuit-level biology with human systems physiology, enabling us to determine how conserved signalling pathways give rise to integrated physiological function in humans. The resulting mechanistic framework provides a foundation for understanding how physiological resilience is maintained throughout life and why its progressive decline represents a defining feature of healthy ageing.

3. Possible project(s):

Predictive regulation—how the organism anticipates future physiological demands: Physiological resilience depends not only on responding to changes in internal state but also on anticipating future physiological demands. Sensory cues associated with food, including visual, olfactory and cognitive information, trigger coordinated autonomic, endocrine and metabolic responses before nutrients enter the circulation. These feed-forward mechanisms, collectively referred to as cephalic responses, prepare the organism for nutrient absorption, minimise disturbances in metabolic homeostasis and enable adaptive behavioural responses. Despite their fundamental importance, remarkably little is known about the neural mechanisms through which sensory information is integrated with peripheral physiology to coordinate these anticipatory responses in humans.Recent breakthroughs in mouse models have identified hypothalamic circuits that translate sensory food perception into anticipatory physiological regulation, providing an opportunity for mechanistic translation. Building on these discoveries provides an opportunity to investigate how sensory food cues, internal metabolic state and gut-derived signals interact to regulate body-brain communication in humans, using multimodal MRI, behavioural phenotyping, metabolic measurements and computational modelling.

Loss of resilience—how ageing and immunosenescence impair body-brain communication: Ageing is accompanied by progressive changes in immune function, characterised by chronic low-grade inflammation and immunosenescence. While acute inflammatory responses trigger highly adaptive physiological and behavioural changes that support recovery from infection (collectively termed sickness behaviour), persistent low-grade inflammation during ageing may chronically engage these regulatory mechanisms, thereby reducing physiological resilience. However, the neural mechanisms through which immune signalling influences adaptive physiology in humans remain poorly understood. To that end, we aim to investigate how inflammatory signals alter body-brain communication and reshape adaptive physiological and behavioural responses during healthy ageing. We hypothesise that age-associated changes in immune signalling modify the neural integration of peripheral physiological information, leading to altered motivation, movement, energy regulation and behavioural flexibility. Rather than representing isolated behavioural changes, these alterations may reflect a fundamental reorganisation of physiological priorities in response to chronic inflammatory signalling.

4. Applied Methods and model organisms:

Our research is based on an integrative and translational approach to human systems physiology. We combine multimodal neuroimaging, computational modelling, behavioural analyses, metabolic and pharmacological interventions, and precision neuromodulation to investigate body-brain communication in vivo in humans. Mechanistic insights are generated through close collaboration with complementary animal studies, allowing conserved signalling pathways to be translated across species. This strategy bridges molecular and circuit-level biology with integrated physiological function in humans.

5. Desirable skills and qualifications:

We seek a highly motivated and enthusiastic candidate with a strong interest in human systems physiology, body-brain communication and translational research. Applicants should enjoy working in an interdisciplinary environment at the interface of neuroscience, physiology and metabolism. Experience in human neuroimaging, computational methods or quantitative data analysis is advantageous but not required.

6. References and key publications:

DiFeliceantonio AG, Coppin G, Rigoux L, Edwin Thanarajah S, Dagher A, Tittgemeyer M*, Small DM.* (2018). Supra-Additive Effects of Combining Fat and Carbohydrate on Food Reward. Cell Metabolism, 28: 33–44.e3

Edwin Thanarajah S, DiFeliceantonio AG, Albus K, Kuzmanovic B, Rigoux L, Iglesias, S, Hanssen R, Schlamann M, Cornely OA, Brüning JC, Tittgemeyer M*, Small DM* (2023) Habitual daily intake of a sweet and fatty snack modulates reward processing in humans. Cell Metabolism 35, 571-584.e6.

Edwin Thanarajah S, Backes H, Difeliceantonio AG, Albus K, Cremer AL, Hanssen R, Lippert RN, Cornely OA, Small DM, Brüning JC, Tittgemeyer M (2019). Food Intake Recruits Orosensory and Post-ingestive Dopaminergic Circuits to Affect Eating Desire in Humans. Cell Metabolism 29: 695-706

Grove JCR, Hakimi AM, Li Q, Zhang J, Backes H, Kuzmanovic B, Choi J, Ubadiah V, Qiu L, Liu Z, Small DM, Tittgemeyer M, Knight ZA (2025) A lateralized pathway for associating nutrients with flavors. bioRxiv [Preprint] 2025.02.09.637334.

Hanssen R, Rigoux L, Kuzmanovic B, Sandra Iglesias, Alina Kretschmer, Schlahmann M, Albus K, Edwin Thanarajah S, Sitnikow T, Melzer C, Cornely OA, Brüning JC, Tittgemeyer M (2023) Liraglutide restores impaired associative learning in people with obesity. Nature Metabolism 5, 1352–1363. 

Hanssen R*, Rigoux L*, Albus K, Kretschmer AC, Edwin Thanarajah S, Chen W, Hinze Y, Giavalisco P, Steculorum SM, Cornely OA, Brüning JC, Tittgemeyer M (2023) Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Reports Medicine 4, 100897.

Minère M, Wilhelms H, Kuzmanovic B, Lundh S, Fusca D, Claßen A, Shtiglitz S, Prilutski Y, Talpir I, Tian L, Kieffer B, Davis J, Kloppenburg P, Tittgemeyer M, Livneh Y, Fenselau H (2025) Thalamic opioids from POMC satiety neurons switch on sugar appetite. Science 387(6735):750-758.

Tittgemeyer M, Kuzmanovic B, Melzer C, Jessen F, Stephan KE, Rigoux L (2026). Metabolic state and energy reserves jointly regulate adaptive behavioural control. bioRxiv [Preprint] 2026.03.22.713499.