Prof. Dr. Marc Tittgemeyer

Research Area: Metabolism, Neurocircuitry, Human Behaviour

Branches: Computational BiologyMetabolismPhysiology

1. Research Background:

The regulation of neural control of bodily physiology has profound implications not only for metabolic homeostasis and potential disease but also for regulating ageing and developing a wide range of ageing-associated diseases, given the pivotal role of proper proteostasis in these processes.

Our organism constantly integrates information about the body’s metabolic state with external environmental cues to adapt behavioural and autonomic responses to ensure metabolic homeostasis. To that end, our group investigates how the human brain represents, integrates and prioritises these metabolic and external signals to initiate appropriate behavioural and physiological responses, focusing on circuit-level models, metabolic pathways and motivated human behaviour. Our primary research focus concerns the physiological mechanisms by which internal bodily signals are communicated to and sensed by the brain to adapt the organism´s behaviour to its metabolic state. We thereby complement and extend the basic research currently being pursued at the Max Planck Institute of Metabolism Research and CECAD on metabolic processes with studies on human physiology as well as clinical diseases and pertaining states.

2. Research questions addressed by the group:

The motivational force prompting behavioural adaptation must ultimately rely on learned sensory associations. Thus, we study the role of metabolic sensing in associative learning and determine how metabolic signals then prompt and external cues incentivise motivation and effort spending. In addition, we examine the identity of neural systems and behaviour in regulating food intake and the pathophysiological consequences of dysregulation in obesity, its related disorders and biological ageing.

3. Possible project(s):

  • Role of sensory perception in homeostatic regulation:
    While many homeostatic mechanisms operate based on internal feedback regulation, organisms have evolved systems to anticipate the impact of food consumption on homeostasis. These anticipatory physiological responses to food cues ensure limited disturbance in internal homeostasis due to ingested nutrients and that nutrients are metabolised rapidly and are more efficiently removed from circulation. To that end, visual, olfactory, and cognitive inputs related to the nutritional value and the internal energy state of the organism trigger numerous autonomic physiological changes, including increased heart rate, saliva production, the release of enteroendocrine peptides, and changes in lipid metabolism. Moreover, food perception enables organisms to adapt their behaviour in anticipation of a change in physiological need. Although numerous studies have contributed to understanding anticipatory sensory food perception (the so-called cephalic response phase), few murine studies have examined the neural control mechanisms and how this impacts signalling in peripheral organs. Drawing on recent breakthroughs in mice from the Brüning lab (Brandt et al., Cell, 2018; Henschke et al., Science, 2024), we will scrutinise the regulatory mechanism interfacing sensory perception (food anticipation), gut mediators (food ingestion), and adaptation of motivated behaviour in humans.
  • Role of inflammation and immune-senescence on motivated behaviour:
    Increasing evidence indicates that the brain regulates peripheral immunity, yet whether and how the brain represents the state of the immune system remains unclear. Notably, neuronal signals can affect immune functions, and immune cells can modulate the activity of neurons in the brain and spinal cord or the body in health and disease. Disturbances in immunological function may be associated with processes that can manifest in the CNS, resulting in psychiatric dimensions. Thereby, immunological disturbances are thought to play a predominant role among all recently discovered mediators that set into motion clinically relevant abnormalities in depressed patients — the typical dysregulation of the immune system linked with orthologic ageing (termed ‘immune senescence’) may already be sufficient to drive depressive symptoms in the elderly, affecting particularly motor control and reward processing. However, it is yet unclear how exactly immune activation and the release of inflammatory cytokines affect brain function.

We suggest studying elderly people with and without depressive symptoms using fMRI designed to assess neuronal circuit activity for both motor control and reward processing. Markers of inflammation will be measured and analysed as moderator variables in motor-symptom-related alterations of midbrain neuronal response and connectivity. To analyse the acquired data, we apply computational phenotyping of behaviour and generative causal modelling techniques to neuroimaging data to obtain quantitative in vivo markers of dopaminergic transmission and its modulation by inflammation markers, which predict individual expressions of motor function. The results will provide novel insights into the mechanisms underlying motor control and their associations to indicators of inflammation in the elderly.

4. Applied Methods and model organisms:

The group’s strategy requires a highly interdisciplinary approach combining theoretical and experimental work and an infrastructure supporting prospective studies in humans. Our aim of investigating the interplay of body and brain and its link with human behaviour is realised through recent technological advances to probe neurocircuitry in vivo. These include structural and functional MRI of the brain and spinal cord, quantitative MRI delivering markers for neuroinflammation, PET, and neuromodulatory techniques such as transcutaneous vagus nerve stimulation or pharmacological interventions.

5. Desirable skills and qualifications:

We seek a motivated and enthusiastic person with a keen interest in translational neuroscience, neurophysiology, and ethology. While expertise in human neuroscience and in-vivo imaging methods is advantageous, the desire to work in a multidisciplinary research environment and to engage with statistical data analysis is requested.

6. References and key publications:

  1. 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 Metab, 28: 33–44.e3
  2. 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 Metab 29: 695-706
  3. Hanssen R, Kretschmer AC, Rigoux L, Albus K, Edwin Thanarajah S, Sitnikow T, Melzer C, Cornely OA, Brüning JC, Tittgemeyer M (2021). GLP-1 and hunger modulate incentive motivation depending on insulin sensitivity in humans. Mol Metab 101163.
  4. Hanssen, R., Rigoux, L., Kuzmanovic, B., Iglesias, S., Kretschmer, A.C., Schlamann, M., Albus, K., Thanarajah, S.E., Sitnikow, T., Melzer, C., et al. (2023). Liraglutide restores impaired associative learning in individuals with obesity. Nat. Metab., 1–12. https://doi.org/10.1038/s42255-023-00859-y.
  5. 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. Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Rep. Med. 4, 100897. 10.1016/j.xcrm.2022.100897.
  6. Edwin Thanarajah SE, 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 Metab. 35, 571-584.e6.

*shared contribution