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Project

Connections and connectivity in the gut-brain axis

In this project we will investigate how the enteric neurons embedded in the intestinal wall connect to other nerve networks within but also outside the intestine. The enteric nervous system (ENS) consists of two ganglionated plexus layers that surround the gastrointestinal tract and extend along its full length. The best characterized layer is the myenteric plexus situated between the circular and longitudinal muscle layers, which controls motility patterns in the gut. The submucous plexus, situated closer to the mucosa, is responsible for absorption and secretion. Both layers arise from (vagal and some sacral) progenitors that during development have the challenging task to migrate and proliferate and timely differentiate into all necessary subclasses of neurons while the gut grows and elongates rapidly. If these progenitors fail to colonize the entire gut, the distal part of the large intestine is left without innervation, leading to the life-threatening Hirschsprung’s disease. Although the architecture of plexus layers in several distinct regions of the gut and in different species has been described in quite some detail, it still remains elusive what factors are important for the submucous plexus to form and to align itself so distinctly in the intestinal wall. Moreover it is not known how these two layers communicate with each other. Both send sensory projections into the mucosa to sense luminal contents, but how these two layers integrate their information and return a functional output is not well understood. In preliminary experiments we found that the activated circuitry in the submucous and myenteric plexus influence each other but the mechanisms and rules underlying this communication are elusive. These two nerve networks do not only communicate with each other but are also connected via extrinsic fibers to the central nervous system (CNS). This gut-brain connection has recently received a lot of attention as it conveys signals related to nutritional content, microbiota composition, reward and pain to the brain. These extrinsic neurons can also act as a physical route via which caustic agents, viruses or misfolded proteins make their way to the CNS. The popular Braak hypothesis (Braak et al. 2006) stipulates that Parkinson’s disease may have its origin in the gut. Despite evidence from culture and animal experiments that transport of misfolded α-synuclein can occur (Pan-Montojo et al. 2015; Anselmi et al. 2019), evidence that the submucous plexus (Desmet et al. 2017; Vanden Berghe and Shannon, 2017) acts as a gateway is lacking. Similar as for the submucous plexus, here again it is not known what the molecular factors are that guide the vagal and spinal afferents towards their correct location in the developing gut. During normal physiological functioning, the extrinsic connections modulate the activity of the enteric nervous system, but again the mechanisms and rules that underlie this communication remain elusive. The overall goal is to investigate how the typical 3D architecture of the intestinal innervation is formed and how different layers act in concert to produce the correct physiological output. We will specifically focus on how the myenteric plexus interacts with the submucous plexus and the extrinsic nerves, when either one of them is activated. This will advance the knowledge on how these nerve networks connect and communicate. The results will not only be important to understand the neurophysiology of gut function but will also provide the knowledge and the models to investigate possible pathophysiological mechanisms in GI and neurodegenerative diseases. We will mostly use the specialized imaging equipment that is available in the Lab for Enteric NeuroScience, including widefield, confocal, multiphoton and superresolution techniques. This PhD project is part of a large (FETPROACT funded) project, in which material science, developmental biology, systems biology and physiology labs have engaged to model a gut-brain connection on a (microfluidic) chip. To this end we will use iPSC and (commercial) hESC derived enteric and central neurons which we will grow in multi compartment culture systems as a model for the gut-brain connection. The ultimate goal of this consortium is to build a 2 or 3 compartment chip onto which a sufficiently reliable model of the gut-brain connection can be grown. Our experiments directed to identification and characterization of attraction factors for extrinsics as well as for submucous neurons will be instrumental to guide the successful generation of such a microfluidic chip.

Date:1 Sep 2019 →  1 Sep 2023
Keywords:Enteric nervous system
Disciplines:Neurosciences not elsewhere classified
Project type:PhD project