# Characterizing the Functional Architecture of the Necklace Olfactory System

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $508,166

## Abstract

Abstract
 A central goal of modern neurobiology is to understand the neural mechanisms that transform sensory
inputs from the outside world into appropriate and adaptive behavioral outputs. Here we propose to approach
this general problem by answering key questions regarding the organization and function of the olfactory
system, the main sensory modality used by most animals to interrogate the environment. In mammals, the
challenge of odor detection is addressed by multiple olfactory subsystems that each convey information about
a unique subset of odor space. In the two largest olfactory subsystems — the main and the vomeronasal
systems — sensory neurons detect odors through g-protein coupled receptors (GPCRs) expressed in a
characteristic one-receptor-per-neuron pattern; odor information is then organized into channels called
glomeruli in the olfactory bulb, and is relayed to higher brain centers responsible for odor processing and
behavior. However, not all olfactory subsystems follow this pattern: the mysterious olfactory “necklace” is
comprised of sensory neurons that innervate a string of glomeruli in the olfactory bulb, and which express the
single-pass transmembrane receptor guanylate cyclase-D (GC-D) rather than GPCRs. GC-D detects chemical
cues, including urinary peptides and carbon disulfide, that act as unconditioned stimuli during a specific form of
odor learning, the social transmission of food preferences (STFP). We have recently identified a new family of
4 transmembrane-containing odor receptors called the Membrane Spanning 4As (MS4As), which are co-
expressed in necklace sensory neurons, and which detect odors ranging from food scents to pheromones. This
co-expression of non-GPCR odor receptors in necklace sensory neurons suggests that the necklace system
plays a fundamentally different role in olfactory perception from the discriminative functions for which the main
and vomeronasal systems appear to be optimized. Here we will take advantage of new genetic tools we have
established, and novel neural tracing and behavioral techniques we have developed, to tease apart the unique
function of the necklace system in odor perception and behavior. We will first assess necklace sensory
responses in mice in which single Ms4a receptor genes are mutated or the entire Ms4a gene cluster is deleted,
and also ask whether MS4A and GC-D ligands, when presented simultaneously, activate necklace sensory
neurons synergistically, additively or in some other pattern (Aim I). We will then perform anterograde and
retrograde tracing (including cell type-specific trans-synaptic tracing) to identify brain areas and cell types that
receive information from the necklace system (Aim II). Finally, we will use genetics and optogenetics to
manipulate the necklace system, thereby establishing the roles of MS4A ligands, receptors and projections
from the necklace glomeruli to the brain in STFP-based odor learning. These experiments will lead to important
discoveri...

## Key facts

- **NIH application ID:** 9892001
- **Project number:** 5R01DC016222-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Sandeep R Datta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,166
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892001

## Citation

> US National Institutes of Health, RePORTER application 9892001, Characterizing the Functional Architecture of the Necklace Olfactory System (5R01DC016222-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9892001. Licensed CC0.

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