# Determining the role of noradrenergic heterogeneity in innate threat response

> **NIH NIH K08** · YALE UNIVERSITY · 2020 · $194,940

## Abstract

PROJECT SUMMARY / ABSTRACT
Studying the circuit basis of fear in psychiatric disorders has relied on learned associations
between stimuli and threatening experiences. Stimuli which are innately threatening represent
an alternative approach to this problem, and may elicit different neural circuit mechanisms to
promote survival. The neurotransmitter norepinephrine serves an important role in threat
response, and recent studies have demonstrated the existence of multiple subtypes of
norepinephrine cells within the locus coeruleus (LC). The scientific objective of this project is to
determine how subtypes of norepinephrine neurons in LC contribute to the encoding of threat,
so that in the future we can develop improved therapies for trauma-related disorders based on
that knowledge.
Our specific aims employ fluorescent biosensors of norepinephrine, miniature head-mounted
microscopes for recording LC norepinephrine cells, optogenetics, and single cell
transcriptomics. In our preliminary data, we identify a computational framework in which to
consider the problem of learning from innate threat, then show the feasibility of these
approaches. By employing these methods, we can collectively identify the relationship between
norepinephrine cell-types and the encoding of threat at molecular, cellular, and circuit scales.
This will generate a parts list for future studies into the nature of threat processing.
In addition to the proposed studies, this proposal develops a plan to train Dr. Kaye for an
independent research career as a circuit psychiatrist. This plan is mentored by Dr. Alex Kwan,
an expert in optical approaches to neural circuit dissection and computational approaches to
behavior, with the co-mentorship of Dr. Kerry Ressler, an expert in the neurobiology of
posttraumatic stress disorder and Dr. Ronald Duman, an expert in the neurobiology of stress.
This proposal relies on additional training in transcriptomics from Dr. Nenad Sestan, in
optogenetics from Dr. Ralph DiLeone, and in the physiology of the norepinephrine system from
Dr. Gary Aston-Jones.

## Key facts

- **NIH application ID:** 9953483
- **Project number:** 1K08MH122733-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Alfred P Kaye
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,940
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953483

## Citation

> US National Institutes of Health, RePORTER application 9953483, Determining the role of noradrenergic heterogeneity in innate threat response (1K08MH122733-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953483. Licensed CC0.

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