Anatomical and Functional Characteristics of Vagal, Brainstem, and Cerebellar Circuits: Novel Synaptic Modulation by Gut-Derived Peptides

Caitlin Ritchey

Goal-oriented feeding behaviors are driven by ancient and extensive neurocircuitry that integrate both the metabolic and motivational drives for food. The current theoretical framework considers this a “top-down” process, orchestrated largely via the prefrontal cortex (PFC) in conjunction with the mesolimbic reward circuitry in the midbrain. However, it is now understood that initiation of feeding behavior requires complex interactions between this “top-down” circuitry and “bottom-up” homeostatic pathways originating in the hindbrain. Yet, the origins and mechanisms of “bottom-up” interoceptive pathways that convey peripheral physiological information to the higher-level brain regions implicated in appetitive feeding behaviors are incompletely understood. My dissertation explores the “bottom-up” circuitry, identifying the vagus nerves, brainstem nucleus of the solitary tract (NTS), and cerebellum as key regions that sense, encode, and relay interoceptive information with the potential to influence appetitive feeding behavior. In Chapter 2, I used a combination of molecular profiling and fluorescent calcium imaging to explore differences in gene expression and functional signaling between the left and right nodose ganglia (NG) neurons. My results showed that the left NG exhibited greater expression of the transient receptor potential vanilloid 1 (TRPV1), though calcium responses to TRPV1 were similar across sides. Conversely, the right NG expressed higher levels of the cholecystokinin (CCK) 1 receptor (CCK1R) and exhibited stronger responses to high doses of CCK, particularly among TRPV1+ neurons, supporting previous work suggesting functional asymmetry in vagal afferent signaling. In Chapter 3 I focused on the central integration of vagal information within the NTS and transmission of this information to the ventral tegmental area (VTA). Anatomical tracing and molecular profiling revealed that VTA-projecting NTS neurons originate from nearly all NTS subnuclei and include tyrosine hydroxylase–expressing catecholaminergic neurons and glucagon-like peptide-1 (GLP-1)–producing neurons. My electrophysiological experiments further revealed that these neurons primarily receive polysynaptic vagal input, suggesting that these neurons are positioned to integrate processed information rather than direct afferent input. Notably, I found that these neurons were predominantly inhibited by CCK, in contrast to nearby NTS neurons that are typically excited by this peptide, revealing a novel functional specialization within this distinct subpopulation. Finally, Chapter 4 explores the cerebellum as a noncanonical region in feeding control. Using immunohistochemistry and molecular analysis, I examined GLP-1 receptor (GLP-1R) expression across cerebellar lobes, layers, and deep nuclei, showing broad expression that is enriched in Purkinje cells, present in granule cells, and prominent on mossy fiber terminals. Electrophysiological recordings demonstrated that activation of these GLP-1Rs increases Purkinje cell firing and enhances granule cell excitation via pre- and postsynaptic mechanisms, indicating robust modulation of cerebellar glutamatergic circuits. Collectively, the work presented in this dissertation contributes to an updated model in which peripheral and central ‘bottom-up’ interoceptive pathways encode peripheral feeding signals and gives insight to how these brain regions can influence appetitive feeding behaviors. By revealing lateralized vagal signaling, characterizing distinct NTS-to-VTA pathways, and identifying cerebellar GLP-1R circuits as previously unrecognized contributors to feeding regulation, this work broadens our understanding of how the brain senses and responds to internal physiological state.

Anatomical and Functional Characteristics of Vagal, Brainstem, and Cerebellar Circuits: Novel Synaptic Modulation by Gut-Derived Peptides

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