# Hormonal Tuning of Specific Circuit States from a Well-Defined Connectome > **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $592,055 ## Abstract Project Summary We aim to establish that only specific circuit states of an identified connectome are modulated by circulating hormones. Different circuit states are ones with at least some circuit neurons expressing modified cellular (ionic currents) and synaptic properties. Most cellular-level mechanistic studies of circuit state modulation have come from in vitro studies using arbitrary parameters or concentrations to stimulate individual modulatory neurons or apply one or two neuromodulators. Thus far, little is known about the full complement of effective modulators, such as within a population of hormones, during a specific behavioral state and whether they influence all circuit states of a given connectome. We aim to bridge this gap by merging access to two defined circuits in the isolated nervous system with our ability to deliver a natural source of hormones. We will determine the response of different gastric mill (chewing)- and pyloric (passage of chewed food) circuit states, configured by different applied neuromodulators, in the isolated crab (Cancer borealis) stomatogastric ganglion (STG) to hemolymph ('blood') obtained from an unfed crab. By using the fully functional circuits in the isolated STG, the direct influence of hormones can be determined without a background of variable, spontaneous projection neuron influences. Our pilot data support the hypothesis that hormones from a single behavioral state tune the output of only certain circuit states. Specifically, hemolymph from unfed crabs strengthens the gastric mill rhythm and its regulation of the pyloric rhythm when configured by the peptide Gly1-SIFamide [G- SIFamide] or CabTRP Ia [CabTRP]. These effects of unfed hemolymph occurred without any qualitative change in circuit activity. In contrast, unfed hemolymph did not alter the STG circuit states configured by the peptide proctolin or the muscarinic acetylcholine agonist oxotremorine. Using these four applied modulators and hemolymph from unfed crabs, we aim to (a) fully characterize each circuit state response, (b) identify each hormone influencing a particular circuit state, including determining their hemolymph concentration and comparing their separate and combined influence to whole hemolymph, and (c) determine the underlying cellular and synaptic mechanisms. To these ends, we will use electrophysiology to monitor and manipulate circuit neuron activity, and mass spectrometric (MS) analyses for hormone identification and hemolymph concentration. Because unfed hemolymph enhances without otherwise altering the G-SIFamide and CabTRP actions, we hypothesize that the active hormone(s) either activate the same ionic current(s) as the applied peptide, or they enhance the effective concentration of each peptide by inhibiting their cleavage. We will use voltage- and dynamic clamp to test the ionic current hypothesis, and MS analysis to identify each peptide's cleavage products and determine if their amount is reduced in hemolymph... ## Key facts - **NIH application ID:** 10867400 - **Project number:** 5R01NS029436-32 - **Recipient organization:** UNIVERSITY OF PENNSYLVANIA - **Principal Investigator:** MICHAEL P NUSBAUM - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $592,055 - **Award type:** 5 - **Project period:** 1991-05-01 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10867400 ## Citation > US National Institutes of Health, RePORTER application 10867400, Hormonal Tuning of Specific Circuit States from a Well-Defined Connectome (5R01NS029436-32). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867400. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*