# Oxytocin regulation of ion channels and canonical circuit operations

> **NIH NIH U19** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $591,798

## Abstract

Project Summary (Project 3, Co-PIs: Tsien, Buzsaki, Froemke, Lin)
Oxytocin is a neuropeptide that shapes vital behaviors such as pair bonding, parenting and social competition.
There are many pressing questions about how such behaviors are steered by brain circuits. Understanding
oxytocin’s actions in the brain is further motivated by possible disruption of oxytocin signaling in various
neuropsychiatric disorders. Oxytocin is widely seen as affecting cellular excitability, synaptic transmission, and
long-term plasticity in single neurons, but a mechanism-based understanding of behavior is still lacking. Project
3 and 4 have a suitable meeting ground for understanding modulatory mechanisms, examining circuits in
hippocampus and lateral septum (LS) that successively relay input from neocortical areas and send output to
other brain areas that control social behaviors. OXTRs are particularly enriched in the CA2 subregion of the
hippocampus. Hippocampal CA2 harbors pyramidal neurons (PYRs) that directly receive input from lateral
entorhinal cortex and are pivotal to generation of brain oscillations and establishment of social memory. The
lateral septum, a largely GABAergic structure, includes neurons in its dorsal quadrant that receive inputs from
CA2 and other neurons that connect to hypothalamic VMHvl to help control a range of behaviors including
aggression and competition.
 Here we will study the cellular, synaptic and microcircuit signaling mechanisms of oxytocin, focusing on
the CA2 subregion and the LS. Aim 1 builds on our recent discovery of how oxytocin alters excitability in CA2
PYRs: by diminishing inward rectifier potassium channels (IKir) (favoring membrane depolarization) and shutting
off hyperpolarization-activated cyclic-nucleotide-gated channels (Ih) (providing a hyperpolarizing drive). The
combined reduction in both IKir and Ih restrains membrane potential from quickly depolarizing from rest (thus
enabling oxytocin to “signal slow”) but synergistically elevates membrane resistance, favoring dendritic
integration. Indeed, we observe a new population of huge unitary synaptic currents. We will test whether these
giant events arise from distal dendritic inputs, impinging on local GluR clusters several times bigger than at
postsynaptic sites nearer the soma, potentially those arriving from entorhinal cortex. In Aim 2, we will pursue
new data showing that fast-spiking interneurons (FSIs) display an unusual synergy between oxytocin and
inhibitory transmission. A FSI driven to rapidly fire by OXTR stimulation can be persistently interrupted by brief
GABAergic inhibition. We will test whether such combinatorial “signaling fast” supports sudden switching of
circuits involved in social choice, as proposed by our Computational Modeling Core. In Aim 3, we will build on
our surprising observation that oxytocin hyperpolarizes certain inhibitory LS neurons, causing them to cease
their spontaneous firing (“signaling in reverse”), by heavily weighting...

## Key facts

- **NIH application ID:** 10912583
- **Project number:** 5U19NS107616-07
- **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:** 2024
- **Award amount:** $591,798
- **Award type:** 5
- **Project period:** 2018-09-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912583

## Citation

> US National Institutes of Health, RePORTER application 10912583, Oxytocin regulation of ion channels and canonical circuit operations (5U19NS107616-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10912583. Licensed CC0.

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