Periodic Reporting for period 2 - GuMeCo (Gut-Brain Communication in Metabolic Control)
Berichtszeitraum: 2021-09-01 bis 2023-02-28
Sensory neurons that innervate the organs of the gastrointestinal (GI) tract are a major afferent pathway of the gut-brain axis. The primary function of these neurons is to transmit nutrient-related signals from the gut to the brain upon food consumption to mediate satiation and adaptive glucoregulatory responses so that meal termination and blood glucose levels are controlled. Impairment of this neural gut-to-brain communication has been associated with systemic metabolic dysfunction. Specifically, in obesity, impaired relay of gut-derived signals by sensory neurons has been attributed to overeating, body weight gain, and insulin resistance. Despite the established importance of sensory neurons in gut-to-brain communication, the identity of the population(s) that actually participate in the regulation of feeding and blood glucose levels remain unclear. Various populations, which are residing in nodose ganglia (NG; vagal afferents) and dorsal root ganglia (DRG; spinal afferents), are likely important as suggested by numerous compelling studies. However, a major obstacle in deciphering the metabolic functions of gut-innervating sensory neuron subtypes has been the technical difficulties associated with cell-type-specific targeting vagal and spinal afferents in NG and DRG, which are not only small in size but also difficult to access because of their locations close to the carotid artery and vertebral column, respectively. Therefore, the overarching aim of this project is to identify the sensory neuron subtypes that mediate gut-to-brain communication and to define their functional significance in metabolic control, which may ultimately lead to the development of innovative strategies to tackle prevalent metabolic disorders, such as obesity and type 2 diabetes.
We have successfully designed an intersectional (dual-recombinase) genetic approach that allows mapping and manipulating molecularly defined sensory neurons. Subsequent anatomical studies revealed the different gut innervation patterns of numerous vagal and spinal afferent populations and identified their central projections in the brainstem and spinal cord. Furthermore, through the use of transgenic mouse lines that allow for intersectional expression of the chemogenetic receptors hM3Dq and hM4Di, for acute activation and inhibition, respectively, we revealed the metabolic functions of discrete sensory neuron subtypes. These studies have provided novel insights about the feeding and glucoregulatory functions of discrete vagal and spinal afferents as well as the downstream pathways in the brain that these neurons engage.
Our findings demonstrate that molecularly distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuit. Future studies will address, how these neurons can be selectively manipulated using pharmacology strategies, which may ultimately provide specific targets for metabolic control. Further, we will employ our established intersectional approach, coupled with existing and newly generated transgenic mouse lines, for future functional interrogation of sensory neuron subtypes in gut-to-brain communication in normal and disease states.