1. Research Background:

Our organism constantly integrates information about the body’s metabolic state with external environmental cues to adapt behavioural and autonomic responses to ensure physiological homeostasis. To that end, we investigate how the human brain represents, integrates and prioritizes these metabolic and external signals to initiate appropriate behavioural and physiological responses with a special focus on circuit-level models, metabolic pathways and motivated behaviour in humans. Our group’s main 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 complements and extends the basic research currently being pursued at the Max Planck Institute of Metabolism Research Institute 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:

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

3. Possible project(s):

In a series of pilot studies, we have already started to examine (1) the influence that sensory food priming has on behavioural adaptation, (2) the role of inflammation and immune-senescence on motivated behaviour, and (3) the neuronal processing and regulation of metabolic needs by vagal afferents. Here we propose to follow-up on one of these research line.

First, from a neurobiological point of view, evolutionary valuable responses in the hypothalamus, such as the negative-valence signalling of melanocortin neurons, leave us with an unpleasant feeling when our body detects a homeostatic shortfall. Indeed, humans are hardwired to search for nutritive food and discern food-related cues even before we consciously notice. However, it is currently still poorly understood how these perceptual and interoceptive sensations prime our behaviour and can bias our decision making. New findings have recently demonstrated that the sight and smell of food is sufficient to induce sympathetic nerve activation through a hypothalamic circuit, suggesting a mechanism by which metabolic changes required for nutrient intake are anticipated. To replicate these findings from murine studies in humans as well as to examine the implication of an assumed sympathetic priming effect on cognitive dimensions in humans, we propose a study to perceptually manipulate human participants accordingly while they are engaging in a learning task. This study will form the basis for future research investigating the link between internal sensory signals to motivational drive and, finally, behavioural processes that bring about hunger-mediated increases in reward value and perception of food.

Second, 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 in the rest of the body (known as the periphery), 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 — in fact, the typical dysregulation of the immune system linked with orthologic aging (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.

In collaboration with Frank Jessen from the Department of Psychiatry at the UHC  and the Oliver Cornely from the translational platform of the CECAD, we suggest to study 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. For analysis of the acquired data, we apply computational phenotyping of behavior and generative causal modelling techniques to neuroimaging data with the goal of obtaining 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.

Third, the interaction between the central nervous system (CNS) and peripheral organs involved in processing of ingested food recruits endocrine and neuronal pathways for the regulation of glucose and energy homeostasis. The nodose ganglion (cell bodies of the vagus nerve) connects peripheral innervation of the stomach, intestine and portal vein to the brainstem. These afferent nerve endings have receptors that can bind to many hormones and nutrients. Furthermore, blood flow from the intestine dumps first into the portal vein and then into the general circulation. Thus, signals that are increased postprandially can have endocrine or direct neural pathways to signal the CNS about changes in physiological need state. To that end, we here aim to unravel the specific functional context of molecularly defined vagus nerve-mediated energy and glucose homeostasis to contribute to the understanding of disease mechanisms as well as to identify new targets for pharmacological intervention in the treatment of diabetes and obesity. These studies will involve animal experimentation as well as human imaging. Moreover, using spinal cord MRI, we also aim to define the role of somatosensory spinal afferents in bypassing the vagal signalling route.

4. Applied Methods and model organisms:

The group’s strategy requires a highly interdisciplinary approach combining theoretical and experimental work along with an infrastructure that supports prospective validation studies in humans. Our aim of investigating the interplay of body and brain and its link with human behaviour and cognition is realized through the use of 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 as well as neuromodulatory techniques such as transcutaneous vagus nerve stimulation or pharmacological interventions.

5. Desirable skills and qualifications:

A keen interest in translational neuroscience, human neurophysiology and ethology. While pre-existing expertise in high-resolution in-vivo imaging methods is helpful —but not necessary, the desire to work in a multi-disciplinary 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. 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.
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.