Thursday, March 13, 2025 3/13/2025

A high-throughput sequencing and imaging approach to understand the functional basis of olfaction

Award Number: R01DC017876
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY We propose to develop a strategy for understanding olfactory coding by linking the molecular identity of odorant receptors (OR) to their odor sensitivities in vivo and discovering the logic of neural circuits that process smell. Unlike for other sensory modalities (i.e. vision, audition), it is not understood what properties of odorants are important for olfaction, how these properties are processed by olfactory neural circuits, and how odorant receptor genes have evolved to optimize such an encoding. The relationship between odorant structure (chemical space), the sequence of odorant receptors, the underlying spatial-temporal patterns of activity in the brain (neuronal space) and the perceived odor quality (perceptual space) has been elusive. An efficient method for connecting the olfactory sensory spaces will have a paradigm-shifting effect on olfactory research. Our multidisciplinary approach will use cutting edge next-generation sequencing technologies (FISSEQ, MAPseq and RNAseq) together with functional widefield fluorescence and two photon imaging in vivo to define the functional properties of olfactory sensory neurons that express defined odorant receptors (ORs), to discover their connections to individual glomeruli olfactory bulb (OB), second order OB output (mitral/tufted) cells and map their projection statistics to the downstream olfactory processing brain areas. Using these tools, we will map the identity and spatial layout of all 3,500 glomeruli in the mouse olfactory bulb according to the OR types from which they receive inputs. We will further link the molecular identity of ORs to their glomerular responses to hundreds of odorants (>500) in the form of OR/odorant binding affinity matrices across hundreds of glomeruli (~500) that are optically accessible in vivo. In the same samples, we will track thousands (>1,000/experiment) of individual olfactory bulb projections to their input glomeruli and their target brain areas by RNA-barcoding in relation to their tuning to odorants via multiphoton imaging in vivo. Our approach will bridge the gap between the molecular biology of ORs and neurophysiology and will usher in a new era of understanding the functional basis of olfaction. It will allow unprecedented resolution and throughput for determining OR-ligand interactions across hundreds of odorants, and the connectivity of tens of thousands of single neurons at once in a single specimen. The data obtained will enable the study of OR- ligand interactions, relate the chemical identity of odorants to olfactory perception, and the construction of artificial nose devices for immediate biomedical applications, including disease diagnostics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$13,228 )
2025	2022	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Trans-NIH Research Support	000	5	1/7/2025	NON-COMPETING CONTINUATION	-$13,228
														Subtotal = -$13,228

Issue Date FY: 2022 ( Subtotal = $1,065,335 )
2022	2022	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Trans-NIH Research Support	000	5	8/19/2022	NON-COMPETING CONTINUATION	$1,065,335
														Subtotal = $1,065,335

Issue Date FY: 2021 ( Subtotal = $1,089,335 )
2021	2021	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Trans-NIH Research Support	000	4	8/11/2021	NON-COMPETING CONTINUATION	$1,089,335
														Subtotal = $1,089,335

Issue Date FY: 2020 ( Subtotal = $1,089,335 )
2020	2020	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Trans-NIH Research Support	000	3	8/11/2020	NON-COMPETING CONTINUATION	$1,089,335
														Subtotal = $1,089,335

Issue Date FY: 2019 ( Subtotal = $1,083,575 )
2019	2019	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Trans-NIH Research Support	000	2	8/14/2019	NON-COMPETING CONTINUATION	$1,083,575
														Subtotal = $1,083,575

Issue Date FY: 2018 ( Subtotal = $993,218 )
2018	2018	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Trans-NIH Research Support	000	1	9/11/2018	NEW	$993,218
														Subtotal = $993,218

Grand Total All Awards = $5,307,570

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A high-throughput sequencing and imaging approach to understand the functional basis of olfaction

Award Number: R01DC017876

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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