# Biophysical and Circuit Mechanisms of OXTR signaling

> **NIH NIH U19** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $405,452

## Abstract

Project Summary (Project 3, Co-PIs: Tsien, Froemke, Buzsaki)
Neuromodulators act across many timescales—a consequence of the dynamics of their release, receptor
activation and downstream signaling. Their actions target numerous subcellular compartments, shaping
synaptic transmission, intrinsic excitability and long-term plasticity. How, in turn, these phenomena translate to
behavior is a fundamental goal of neuroscience research. In Project 3, we grapple with this complexity by
deconstructing the actions of the peptide and hormone oxytocin. Famous for its roles in the periphery and in
social behavior, the biophysical and cellular consequences of oxytocin signaling in the central nervous system
are poorly described. A thorough understanding of how oxytocin’s role in the brain is further motivated by
disruption of oxytocin signaling in various neuropsychiatric disorders, including ASD and schizophrenia. To
address this gap in knowledge, we will study the cellular, synaptic and microcircuit signaling mechanisms of
oxytocin in the hippocampus, focusing on the CA2 subregion. Long overlooked, CA2 is enriched in OXTRs
and, intriguingly, has been implicated in social behavior. Our most recent efforts have focused on how
activation of the OXTR depolarizes CA2 pyramidal cells and causes them to enter into a burst firing mode. This
effect was attributable to inhibition of a Kv7-mediated potassium current (or M-current), downstream of a Gq-
coupled signaling pathway. In Project 3, we take these biophysical results into increasingly more physiological
contexts. In Aim 1, we ask how endogenous activity patterns of oxytocinergic fibers translate into oxytocin
release, receptor activation and changes in intrinsic excitability. In Aim 2, we test the strength of our model (in
which oxytocin’s effects in the hippocampus are primarily mediated by M-current inhibition), by developing
optical tools that test the sufficiency and necessity of M-current inhibition in oxytocin signaling. In Aim 3, we
ask how profound changes in hippocampal activity, specifically in CA2, are transmitted beyond the
hippocampus. We primarily focus our efforts on the lateral septum; a region long implicated in social behaviors,
densely innervated by the hippocampus and rich itself in OXTRs.
In sum, we propose a research plan that distills oxytocin signaling in the hippocampus into its most elementary
components: peptide release, receptor activation and cell-type specific modulation of the M-current. Then, as
an acid test of our understanding, we attempt to reconstruct oxytocin’s modulatory actions using our newly
developed optical tools. Finally, we consider how oxytocin signaling in the hippocampus may propagate to
downstream structures, ultimately influencing social behavior.

## Key facts

- **NIH application ID:** 10220158
- **Project number:** 5U19NS107616-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** RICHARD W TSIEN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,452
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220158

## Citation

> US National Institutes of Health, RePORTER application 10220158, Biophysical and Circuit Mechanisms of OXTR signaling (5U19NS107616-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10220158. Licensed CC0.

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