1. Research Background:

Aging-related neurodegenerative diseases are generally associated with memory deficits and cognitive decline. These alterations have been attributed to impaired neurotransmission in higher cognitive brain regions, including the hippocampus and cortex. Neural abnormalities are, however, also present in the aging hypothalamus and brainstem, two brain regions that are essential for the control of food intake and metabolism regulation. It remains currently elusive whether aging-related neural abnormalities in hypothalamic and brainstem regions cause feeding behavior alterations, metabolic dysfunction, or body weight gain, which are all prominent features of aging.

Our group seeks to reveal the neurobiological mechanisms underlying the regulation of food intake and systemic metabolism. Because synapses are the functional units of information transfer in the brain, our research lines are designed to study the synaptic properties that organize the neural networks controlling feeding behavior and metabolic parameters. Accordingly, we study synapse physiology, plasticity, and metabolism regulation, working under the premise that network information flow is transmitted in a circuit-specific and plastic manner. One major goal of our research is to mechanistically link aging- associated synaptic dysfunction in the hypothalamus and brainstem with metabolic and behavioral alterations.

2. Research questions addressed by the group:

1. Food intake and metabolism are critically controlled by two distinct subsets of neurons that are located in the arcuate nucleus of the hypothalamus: Satiety- promoting pro-opiomelanocortin (POMC) and hunger-promoting agouti-related protein (AgRP) neurons. Importantly, neuropeptides released from these two key neurons control neuronal excitability and synaptic plasticity in various downstreambrain regions. In our ongoing studies we are aiming to unravel themetabolic and behavioral importance of these plastic changes in synaptic transmission and how this relates to aging-associated abnormalities.
2. Long-term consumption of calorically dense food - such as those high in fat and sugar – impairs satiety signaling and causes deterioration of blood glucose levels. These metabolic defects are, at least in part, attributed to disrupted communication between the gut and the brain. Currently, we are using novel transgenic mouse models to delineate the functional role of genetically distinct vagalsensory neurons in gut-brain communication. Further, we are aiming to elucidate the impact of high-fat diet consumption on vagal sensory neuron dysfunction, and how this relates to the development of obesity and diabetes.

3. Possible projects:

1. Studying the role of neuropeptides released from hypothalamic AgRP and POMC neurons in downstream neurocircuits with the ultimate goal to link synaptic dysfunction to aging-associated metabolic disorders.
2. Determining the impact of high-fat diet consumption on gut-brain communication relayed by genetically defined vagal sensory neurons that have a clear role in satiety and blood glucose regulation.

4. Applied Methods and model organisms:

All studies are performed in transgenic mice that allow targeting defined neural populations and studyingtheir functional roles using state-of-the art neuroscience approaches, including:

• In vivo monitoring of neuronal activity and neuropeptide release
• Behavioral and metabolic assessments using opto- and chemogenetics
• Single-cell sequencing technology
• Viral approaches for circuit mapping and synapse visualization
• Optogenetics combined with brain slice electrophysiology

5. Desirable skills and qualifications:

Background in neuroscience approaches in mice and/or electrophysiology is desirable, but not required.

6. References and key publications:

• NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation. Dodt S, Widdershooven NV, Dreisow ML, Weiher L, Steuernagel L, Wunderlich FT, Brüning JC, Fenselau H. Nat Commun. 2024 Jun 27;15(1):5439.
• Integrative neurocircuits that control metabolism and food intake. Brüning JC, Fenselau H. Science. 2023 Sep 29;381(6665):eabl7398. Review.
• A synaptic amplifier of hunger for regaining body weight in the hypothalamus. Grzelka K, Wilhelms H, DodtS, Dreisow ML, Madara JC, Walker SJ, Wu C, Wang D, Lowell BB, Fenselau H. Cell Metab. 2023 May 2;35(5):770-785.e5.
• Advanced neurobiological tools to interrogate metabolism. Mirabella PN, Fenselau H. Nat Rev Endocrinol. 2023 Nov;19(11):639-654. Review.
• Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism.Borgmann D, Ciglieri E, Biglari N, Brandt C, Cremer AL, Backes H, Tittgemeyer M, Wunderlich FT, Brüning JC, Fenselau H. Cell Metab. 2021 Jul 6;33(7):1466-1482.e7.