Periodic Reporting for period 4 - GuMeCo (Gut-Brain Communication in Metabolic Control)
Reporting period: 2024-09-01 to 2025-02-28
The gastrointestinal (GI) tract communicates with the brain and this interaction – commonly described as the gut-brain axis – regulates appetite, feeding behavior, and body weight. Given the continued rise of obesity world wide, it is critical to gain greater insights into the regulatory function exerted by the gut-brain axis. Peripheral sensory neurons are a major afferent highway of the gut-brain axis. Upon food consumption, these neurons detect nutrient-related signals with their peripheral endings innervating the organs of the GI tract, which they transmit to the brain. In turn, they induce meal termination and initiate mechanisms so that blood glucose levels are controlled. Importantly, impairment of this negative-feedback mechanism has been associated with metabolic dysfunction. Besides the GI tract, sensory neurons also transmit multimodal sensory information from other peripheral and inner organs, such as the lung and the heart, and control further key homeostatic functions. However, the relevant populations of sensory involved in food intake and metabolism regulation and the underlying neurocircuitry were largely unknown. Therefore, the overarching aim of this project was to decipher the neurocircuitry of sensory neurons that mediate gut-brain communication underlying metabolic control, with the overall perspective to develop new therapies to treat obesity and obesity-related disease, such as type 2 diabetes.
We have successfully developed and employed an intersectional genetic approach, that facilitates genetic entry into sensory neurons, for highly specific and efficient targeting of distinct subtypes that innervate the organs of the GI tract. This allowed us to comprehensively reconstruct their peripheral and central anatomical organization, as well as to manipulate their activity for gain- and loss-of-function studies interrogating the gut-brain axis. In summary, we revealed that glucagon-like peptide 1 receptor (GLP1R)- and GPR65 vagal afferents selectively innervate the stomach and intestine and have topographically disparate projections in the brainstem, and that the activity of these cells differentially regulates feeding behavior and glucose metabolism. These findings provide for the first time information about the discrete metabolic functions of molecularly distinct gut-innervating sensory neurons. Further, the developed intersectional targeting approach is broadly applicable for mapping and manipulating highly selective molecularly defined sensory neurons, and therefore provides an experimental blueprint for defining the function of discrete sensory neurocircuits.
In addition, we developed an extensive set of Dre-recombinase specific viral approaches to express chemo- and optogenetic tools - cornerstones of modern neuroscience research – in molecular distinct neuron types. This additional toolbox will enable scientist to define the interaction, connectivity, and mode of communication of different sets of neuron types in the nervous system with unprecedent precision.
In addition, we developed an extensive set of Dre-recombinase specific viral approaches to express chemo- and optogenetic tools - cornerstones of modern neuroscience research – in molecular distinct neuron types. This additional toolbox will enable scientist to define the interaction, connectivity, and mode of communication of different sets of neuron types in the nervous system with unprecedent precision.
Our findings led to the discovery that distinct populations of gut-innervating vagal afferent neurons differentially regulate feeding behavior and glucose metabolism—a remarkable insight, given that most previous studies have attributed a uniform function to these cell types. Furthermore, our intersectional genetic approach, combined with our newly developed Dre-recombinase-dependent viruses and both existing and newly generated transgenic mouse lines, provides a powerful framework for future functional investigations of the nervous system. In particular, these tools enable precise interrogation of gut-brain communication in both physiological and disease states, paving the way for deeper insights into metabolic regulation and potential therapeutic targets.