Dr. Henning Fenselau

Research Area: Synaptic function in aging

Website: http://www.sf.mpg.de/research/fenselau

1. Research Background:

Aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), are primarily characterized by progressive memory deficits and cognitive decline. These alterations have been attributed to dysfunctional synapses in memory-related brain regions including the hippocampus. In addition, neural abnormalities associated with neurodegenerative disorders are also present in brain regions that control metabolism and motivated behavior, such as the hypothalamus and the striatum. However, whether abnormal synapse function in defined hypothalamic or striatal neurocircuits causes body weight alterations or behavioral abnormalities – two prominent features of AD patients often preceding cognitive defects – remains currently elusive.

Our group studies synaptic physiology and synaptic plasticity – such as long-term potentiation and long-term depression – at defined synapses within neurocircuits that regulate energy balance and glucose homeostasis as well as motivated behavior. The goal of our research is to link synaptic (dys-)function in defined neurocircuits with specific changes in metabolism and behavior. With this in mind, we are keen to understand how aging and aging-associated diseases affect the function of hypothalamic and striatal synapses.

2. Research questions addresses by the group:

Energy balance and glucose homeostasis are critically controlled by two distinct neuronal subsets in the arcuate nucleus of the hypothalamus: Anorexigenic Pro-opiomelanocortin (POMC) and orexigenic Agouti-related protein (AgRP) neurons. Interestingly, neuropeptides released from these two key opposing regulators control synaptic function in distinct brain sites as we have recently demonstrated. In our ongoing studies we are aiming to unravel the metabolic and behavioral importance of synaptic plasticity in defined hypothalamic neurocircuits as well as how this relates to POMC and AgRP neurons and the neuropeptides they release.

Long-term consumption of calorically dense food - such as those high in fat – is associated with impaired satiety regulation and deterioration of blood glucose levels. These metabolic defects are, at least in part, attributed to impaired communication between the site where food is digested, the gut, and the brain sites where this information is processed, e.g. the hypothalamus and the striatum. Currently, we are aiming to elucidate how high-fat diet consumption affects synaptic transmission in defined neurocircuits, including in the hypothalamus and the striatum, and how this relates to the regulation of satiety and blood glucose levels.

3. Possible projects:

Possible projects for PhD students:

  1. Studying synaptic transmission in defined metabolic neurocircuits in the hypothalamus in relation to AgRP and POMC neuron activity with the ultimate goal to link aging-associated disorders with hypothalamic dysfunction.  
  2. Determining the impact of high-fat diet consumption on synaptic function in defined hypothalamic or striatal neurocircuits that have a known role in satiety and blood glucose level regulation.

4. Applied Methods and model organisms:

All studies will be performed in transgenic mice that allow targeting defined neuronal subsets in metabolism-regulating brain sites and studying their synaptic function using state-of-the art neuroscience tools, including the following:

  • Optogenetics combined with brain slice electrophysiology
  • Behavioral and metabolic assessments using opto- and chemogenetics
  • Single-cell sequencing technology
  • AAV-based viral approaches
  • In vivo imaging of neuronal activity

5. Desirable skills and qualifications:

Background in electrophysiology and/or animal handling is desirable, but not required.  

6. References:

  • Zeltser LM, Seeley RJ, Tschöp MH. Synaptic plasticity in neuronal circuits regulating energy balance. Nat Neurosci. 2012 Oct;15(10):1336-42. 
  • Fenselau H, Campbell JN, Verstegen AM, Madara JC, Xu J, Shah BP, Resch JM, Yang Z, Mandelblat-Cerf Y, Livneh Y, Lowell BB. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat Neurosci. 2017 Jan;20(1):42-51.