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. 2025 Jul 23:17:1573906.
doi: 10.3389/fnagi.2025.1573906. eCollection 2025.

Vulnerability of long-range inputome of basal forebrain in normal aging mice

Tingting Sun #  1 , Jiale Chen #  1 , Bimin Liu  2 , Anan Li  1 , Hui Gong  3 , Xiangning Li  2   3
Affiliations

Vulnerability of long-range inputome of basal forebrain in normal aging mice

Tingting Sun et al. Front Aging Neurosci. .

Abstract

Introduction: As the human undergoes the process of aging, it becomes evident that the elderly population exhibits age-related cognitive decline. The basal forebrain (BF) has been shown to have complex connections with the hippocampus (Hip) and medial prefrontal cortex (mPFC) through circuits, and is involved in cognitive functions. However, which circuit is most vulnerable during normal aging remains unclear.

Methods: Utilizing a combination of viral tracing and fluorescence Micro-Optical sectioning tomography (fMOST), we performed quantitative analyses on the whole-brain inputs of the BF, Hip, and mPFC during normal aging.

Results and discussion: The long-range inputome revealed that the nucleus of the diagonal band (NDB) of BF was vulnerability to damage, especially the connection strength of the vCA3-NDB circuit is significantly reduced, which may be related to decision making. A comparison of the 3D continuous data of BF subregions revealed that aging resulted in a weakened connection strength between each region and the olfactory areas (OLF), which obeyed a topological relationship, which might be related to the learning and memory. These results provide an anatomical foundation for understanding the selective vulnerability of BF circuit during normal aging and offer a novel perspective for future research into the treatment of age-related cognitive decline.

Keywords: basal forebrain; long-range input; normal aging; three-dimensional; whole brain.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Diagram with multiple panels illustrating brain input mapping. Panel A shows the experimental setup and process for injecting and imaging in young and old mice. Panels B, C, and D present sagittal, coronal, and horizontal brain sections with labeled inputs: NDB (blue), CA3 (red), and PL (yellow), indicating distinct brain regions targeted in the study. Directions (anterior, posterior, lateral, medial, dorsal, ventral) are indicated on some sections.
FIGURE 1
Acquisition of whole-brain input data of nucleus of the diagonal band (NDB), CA3 and PL. (A) Pipeline for obtaining input whole-brain data. (B–D) Typical sagittal, horizontal and coronal input patterns of NDB, CA3 and prelimbic area (PL) in young mice. The primarily input brain regions are indicated by black font.
Three panels are shown. Panel A depicts three transparent brain models with green dots representing neuron inputs for young subjects in NDB, CA3, and PL regions. Panel B shows similar models with orange dots for old subjects, highlighting areas like CA3, MEZ, and RSP. Panel C presents three scatter plots comparing neuron input numbers between young and old subjects across different brain regions, with annotations and a key explaining color coding for various brain areas.
FIGURE 2
The changes of inputome of NDB, CA3 and PL during normal aging. (A) The 3D displays of input neuron of NDB, CA3 and PL in young mice. (B) The 3D displays of input neuron of NDB, CA3 and PL in old mice. (C) The variation trend of whole-brain input pattern of NDB, CA3 and PL during normal aging. The red boxes indicate areas with significant changes in the number of input neurons. n = 3. To mark the names of different brain regions, the bars have been added without meaning.
Diagrams and bar graph showing neuronal input differences between young and old mice in brain regions: NDB, CA3, and PL. A) Young, represented in green, shows neuron distribution in CA1/2, CA3, and DG. B) Old, represented in brown. C) Bar graph compares neuron counts, indicating significant differences marked with asterisks.
FIGURE 3
The changes of inputome of NDB, CA3 and PL in each subregion of Hip. (A) The 3D displays of the Hip of NDB, CA3 and PL input neurons in young mice. (B) The 3D displays of the Hip input neuron of NDB, CA3 and PL in old mice. (C) Quantitative statistics of input neurons in each subregion of the Hip during normal aging. n = 3. *p < 0.05, **p < 0.01.
Bar charts and brain images compare neuronal inputs to different brain regions in young and old subjects. Sections A, C, and E display bar graphs of neuron counts with orange and green bars representing old and young subjects, respectively. Sections B, D, and F are brain images with green and brown dots indicating neuron distributions for MS, NDB, and SI input.
FIGURE 4
The changes of inputome of medial septal nucleus (MS), NDB, substantia innominata (SI) in olfactory areas (OLF). (A) Statistical analysis of input neurons of MS. n = 3. (B) The whole-brain distribution pattern of input neurons of MS. (C) Statistical analysis of input neurons of NDB. n = 3. (D) The whole-brain distribution pattern of input neurons of NDB. (E) Statistical analysis of input neurons of SI. n = 3. (F) The whole-brain distribution pattern of input neurons of SI. The shadows are subregions of the OLF. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
Diagram depicting input neurons in basal forebrain (BF) subregions for young and old subjects. A: Scatter plots show neural inputs to medial septum (MS), nucleus of the diagonal band (NDB), and substantia innominata (SI) with anterior-posterior orientation. Young neurons are green, old are brown. B: Bar graphs display absolute number of input neurons to MS, NDB, and SI labeled as MOB, AON, TT, DP, PIR, NLOT, COA, PAA, TR. C: Illustrates normal aging effects from anterior to posterior in different brain sections, indicating a shift in input distribution.
FIGURE 5
The variation of 3D distribution of input pattern of MS, NDB, SI in OLF. (A) The 3D displays of the OLF of MS, NDB, SI input neurons during normal aging. (B) Statistical analysis of input neurons of MS, NDB and SI in the OLF. n = 3. (C) Schematic diagram of changes of MS, NDB, SI input pattern in OLF. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
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