R01AG084036
Project Grant
Overview
Grant Description
Sexual dimorphic cell type and connectivity atlases of the aging and AD mouse brains - Project abstract
In response to NOT-21-039 and related PAR-22-093, we propose this project to address several urgent needs in the field. Mouse models spanning different ages and sexes are routinely used to quantify anatomic, molecular, and pathologic changes in neurodegenerative diseases like Alzheimer's disease (AD). Yet, the only available standard mouse brain atlases are constructed from 2-month-old adult male mice.
Furthermore, although both normal aging and AD neurodegeneration display sexually dimorphic features, the scientific community lacks the sexually differentiated rodent brain atlases necessary to study these attributes. By applying cutting-edge technologies, we have developed for Brain Initiative connectomic and cell type mapping projects, we will:
(1) Generate sexually dimorphic 3D aging and AD brain atlases with granular hippocampus (HPF) molecular domains, that can be used as standard atlas templates for all HPF work.
(2) We will comprehensively characterize morphological dystrophies, as well as connectional and synaptic disruptions, in aging and AD.
In Specific Aim 1, publicly available standard 3D HPF atlases of aging and AD brains will be created. Data will be generated in 2-, 9-, and 18-month-old wildtype (WT), 5XFAD (early AD onset), and MAPT(H1)*N279K (late AD onset) male and female mice. Fine HPF domain delineations will be facilitated by 3D volumetric images of cyto- and myeloarchitecture, while additional histopathological markers (ASS plaques/tau tangles) and chemoarchitectural details (glutamate, GABA, PV, SST, CALB1) will be mapped to create comprehensive histopathological and chemoarchitectural HPF atlases.
In Specific Aim 2, we will systematically apply a genetic MORF3 sparse labeling approach to label, reconstruct, and analyze cell type-specific neuronal morphology of all HPF regions at the granular level of their domains in WT, VGLUT1.MORF3/5XFAD, PV.MORF3/5XFAD, VGLUT1.MORF3/MAPT(H1)*N279K, and PV.MORF3/MAPT(H1)*N279K mice across age and sex. Our whole brain 3D clearing, immunostaining, imaging, and 3D neuronal reconstruction pipeline will be applied.
Given that an etiology of AD-related cognitive decline is selective HPF synaptic disruptions, with dorsal HPF nodes being some of the earliest affected in AD, in Specific Aim 3, we will examine progressive connectional disruptions along amyloid and tau pathology progression. Male and female MORF3 and double transgenic mice, MORF3/5XFAD and MORF3/MAPT(H1)*N279K, at 2M, 9M, and 18M of age will be used to reveal potential connectivity changes across aging and AD. The same groups will be used to determine synaptic-level HPF disruptions with the application of expansion microscopy that will capture super-resolution images of synaptic connections.
In Specific Aim 4, we will create a web-based data portal that enables visualization, comparison, and analysis of neural circuits and cell types in 3D aging and AD brains. Our team, with decades of experience in connectomics, brain atlas-ing, and online visualization, is sure to deliver standard HPF atlas templates for all neuroscience research and to determine sexually dimorphic anatomic regions vulnerable across age and AD progression.
In response to NOT-21-039 and related PAR-22-093, we propose this project to address several urgent needs in the field. Mouse models spanning different ages and sexes are routinely used to quantify anatomic, molecular, and pathologic changes in neurodegenerative diseases like Alzheimer's disease (AD). Yet, the only available standard mouse brain atlases are constructed from 2-month-old adult male mice.
Furthermore, although both normal aging and AD neurodegeneration display sexually dimorphic features, the scientific community lacks the sexually differentiated rodent brain atlases necessary to study these attributes. By applying cutting-edge technologies, we have developed for Brain Initiative connectomic and cell type mapping projects, we will:
(1) Generate sexually dimorphic 3D aging and AD brain atlases with granular hippocampus (HPF) molecular domains, that can be used as standard atlas templates for all HPF work.
(2) We will comprehensively characterize morphological dystrophies, as well as connectional and synaptic disruptions, in aging and AD.
In Specific Aim 1, publicly available standard 3D HPF atlases of aging and AD brains will be created. Data will be generated in 2-, 9-, and 18-month-old wildtype (WT), 5XFAD (early AD onset), and MAPT(H1)*N279K (late AD onset) male and female mice. Fine HPF domain delineations will be facilitated by 3D volumetric images of cyto- and myeloarchitecture, while additional histopathological markers (ASS plaques/tau tangles) and chemoarchitectural details (glutamate, GABA, PV, SST, CALB1) will be mapped to create comprehensive histopathological and chemoarchitectural HPF atlases.
In Specific Aim 2, we will systematically apply a genetic MORF3 sparse labeling approach to label, reconstruct, and analyze cell type-specific neuronal morphology of all HPF regions at the granular level of their domains in WT, VGLUT1.MORF3/5XFAD, PV.MORF3/5XFAD, VGLUT1.MORF3/MAPT(H1)*N279K, and PV.MORF3/MAPT(H1)*N279K mice across age and sex. Our whole brain 3D clearing, immunostaining, imaging, and 3D neuronal reconstruction pipeline will be applied.
Given that an etiology of AD-related cognitive decline is selective HPF synaptic disruptions, with dorsal HPF nodes being some of the earliest affected in AD, in Specific Aim 3, we will examine progressive connectional disruptions along amyloid and tau pathology progression. Male and female MORF3 and double transgenic mice, MORF3/5XFAD and MORF3/MAPT(H1)*N279K, at 2M, 9M, and 18M of age will be used to reveal potential connectivity changes across aging and AD. The same groups will be used to determine synaptic-level HPF disruptions with the application of expansion microscopy that will capture super-resolution images of synaptic connections.
In Specific Aim 4, we will create a web-based data portal that enables visualization, comparison, and analysis of neural circuits and cell types in 3D aging and AD brains. Our team, with decades of experience in connectomics, brain atlas-ing, and online visualization, is sure to deliver standard HPF atlas templates for all neuroscience research and to determine sexually dimorphic anatomic regions vulnerable across age and AD progression.
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Los Angeles,
California
90095
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 329% from $1,450,667 to $6,225,324.
Los Angeles University Of California was awarded
Sexually Dimorphic Aging & AD Mouse Brain Atlases Neurodegeneration Research
Project Grant R01AG084036
worth $6,225,324
from National Institute on Aging in September 2023 with work to be completed primarily in Los Angeles California United States.
The grant
has a duration of 4 years 8 months and
was awarded through assistance program 93.866 Aging Research.
The Project Grant was awarded through grant opportunity Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 6/5/26
Period of Performance
9/1/23
Start Date
5/31/28
End Date
Funding Split
$6.2M
Federal Obligation
$0.0
Non-Federal Obligation
$6.2M
Total Obligated
Activity Timeline
Transaction History
Modifications to R01AG084036
Additional Detail
Award ID FAIN
R01AG084036
SAI Number
R01AG084036-1968288494
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NN00 NIH National Insitute on Aging
Funding Office
75NN00 NIH National Insitute on Aging
Awardee UEI
RN64EPNH8JC6
Awardee CAGE
4B557
Performance District
CA-36
Senators
Dianne Feinstein
Alejandro Padilla
Alejandro Padilla
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute on Aging, National Institutes of Health, Health and Human Services (075-0843) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,450,667 | 100% |
Modified: 6/5/26