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Client Article | Cell Stem Cell | Team of Weixiang Guo at the Chinese Academy of Sciences Uncovers Key Neural Mechanisms Linking Auditory Loss to Cognitive Decline

Release time：2026-04-22 15:38:19

Hearing loss is a common condition in the elderly and has been recognized as one of the most important modifiable risk factors for cognitive decline, though the causal relationship between the two remains unclear. Adult hippocampal neurogenesis is critical for cognitive function and is sensitive to environmental factors, but it is unknown whether hearing loss contributes to cognitive impairment by affecting hippocampal neurogenesis.

On March 19, 2026, the team of Weixiang Guo from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, published their research in the journal Cell Stem Cell (IF=20.4), titled "Auditory activity sustains adult neurogenesis and cognition through the locus coeruleus-norepinephrine system." This study reveals for the first time that hearing loss impairs hippocampal neurogenesis by disrupting the neural pathway from the pontine nuclei to the locus coeruleus noradrenergic neurons (PnCᵛᴳˡᵘᵀ² → LC^NEergic), leading to decreased norepinephrine levels in the hippocampal dentate gyrus (DG), and ultimately contributing to cognitive decline. This research provides direct evidence of the causal relationship between hearing loss and dementia.

https://doi.org/10.1016/j.stem.2026.02.008

1. Cochlear Outer Hair Cell Gene Knockout Leads to Cognitive Decline

The study used Slc26a5^DTR/+ mice and specifically ablated cochlear outer hair cells (OHCs) with diphtheria toxin (DT), successfully creating a model of severe hearing loss without stress or central inflammation. Immunohistochemistry for c-fos indicated that selective ablation of outer hair cells specifically impaired neuronal activity in the auditory circuitry. To investigate the causal relationship between hearing loss and cognitive decline, a series of behavioral tests were performed on the DT-treated Slc26a5^DTR/+ mice (Figure 1A). The results showed that, compared to the control group, the DT-treated group displayed significant impairments in the Y-maze (Figures 1B, 1C), novel object location test (Figures 1D, 1E), novel object recognition test (Figures 1F, 1G), and contextual fear conditioning test (Figures 1H, 1I), indicating deficits in short-term memory, spatial memory, object recognition memory, and associative learning. However, no significant differences were observed between the two groups in the open field test (Figures 1J-L), elevated plus maze (Figures 1M-O), and tail suspension test (Figures 1P, 1Q). In summary, hearing loss specifically leads to cognitive dysfunction without affecting motor ability, anxiety-like behavior, or depression-like behavior.

Figure 1. Selective knockout of cochlear OHC genes causes cognitive dysfunction but does not affect motor ability or anxiety-like behavior.

2. Outer Hair Cell Gene Knockout Impairs Adult Hippocampal Neurogenesis

To explore the impact of hearing loss on adult hippocampal neurogenesis, researchers crossed Slc26a5^DTR/+ mice with Nestin-GFP mice to obtain Slc26a5^DTR/+::Nestin-GFP mice. The mice were injected with DT at 5 weeks of age, and three weeks later, it was found that the number of Nestin-GFP-positive cells and radial glia-like neural stem cells (RGLs) in the hippocampal dentate gyrus (DG) of the DT-treated group was significantly reduced (Figures 2A-D). The number of proliferating cells labeled with Mcm2 (proliferation marker) and Mcm2⁺Nestin-GFP⁺ double-positive proliferating neural stem cells was also significantly lower (Figures 2E, 2F). Caspase-3 analysis showed no significant change in apoptosis levels (Figure 2G). The number of newly generated neurons was assessed using EdU pulse labeling (Figure 2H), and the results showed that the DT-treated group had significantly fewer EdU⁺NeuN⁺ new neurons than the control group (Figures 2I, 2J). In summary, hearing loss reduces adult hippocampal neurogenesis by inhibiting neural stem cell proliferation.

Figure 2. Selective Knockout of Cochlear OHCs Impairs Adult Hippocampal Neurogenesis

3. LC^NEergic Neurons Receive Auditory Input from PnC^vGluT2 Neurons

It is known that the projection from the locus coeruleus (LC) to the dentate gyrus (DG) originates from noradrenergic neurons. To identify the synaptic projections from the auditory circuit to LC^NEergic neurons, the study used retrograde monosynaptic tracing techniques. AAV-DIO-TVA-GFP and AAV-DIO-RG were specifically used to label noradrenergic neurons in the LC region of DBH-Cre mice, and after three weeks, RV-mCherry was injected and analyzed one week later. The results showed that the viral injection sites were precisely localized to the LC (Figure 3D), and the afferent synapses to the LC mainly originated from the pontine nuclei (PnC) (Figures 3E–L). The cell bodies of RV-labeled PnC neurons were approximately 20μm in diameter and were not considered giant neurons (Figure 3M). In situ hybridization confirmed that these neurons primarily expressed^vGluT2 rather than GlyT2 (Figures 3N, 3O). Combined with retrograde AAV tracing and anterograde monosynaptic HSV tracing techniques, the study showed that PnC^vGluT2 neurons send excitatory projections to the LC, where the postsynaptic target cells are mainly noradrenergic neurons that are DBH-positive in the LC, rather than GABAergic neurons. In conclusion, LC^NEergic neurons directly receive auditory input from PnC^vGluT2 neurons.

Figure 3. Retrograde Monosynaptic Tracing of PnCvGluT2 to LCNEergic Neurons

4. PnC^vGluT2→LC^NEergic Pathway Directly Regulates Norepinephrine Release in the DG

To clarify the functional connection between PnC^vGluT2 neurons and LC^NEergic neurons, the study used retrograde AAV combined with chemogenetics and optogenetic fiber photometry recording strategies. RetroAAV2-hSyn-Flp and Cre-dependent calcium indicator GCaMP6f were injected into the LC of DBH-Cre mice, and Flp-dependent chemogenetic viruses hM3Dq/hM4Di-mCherry were injected into the PnC (Figure 4A). The results showed that activation of PnC^vGluT2 neurons significantly increased the GCaMP6f fluorescence signal in LC^NEergic neurons, while inhibition of these neurons decreased their fluorescence intensity (Figures 4B, 4C). Further, in ^vGluT2-Cre mice, retroAAV2-EF1α-DIO-Flp was injected into the LC, while Flp-dependent chemogenetic viruses hM3Dq/hM4Di-mCherry were injected into the PnC. Norepinephrine probes AAV-hSyn-GRAB-NE2h were injected into the hippocampal DG (Figure 4D). The fiber photometry results showed that activating or inhibiting PnC^vGluT2 neurons correspondingly increased or decreased norepinephrine signaling in the hippocampal DG, with no significant changes observed in the control group (Figures 4E, 4F). Further, in DBH-Cre mice, retrograde Cre-dependent optogenetic viruses (NpHR or hChR2) were injected into the DG, and retroAAV2-hSyn-Flp was injected into the LC, with Flp-dependent chemogenetic viruses injected into the PnC. Norepinephrine probes were also expressed in the DG to allow for multi-level manipulation and real-time monitoring of this pathway (Figures 4G, 4K). Optogenetic inhibition of this projection blocked CNO-induced increases in norepinephrine (Figures 4H-J), while optogenetic activation reversed the decreases (Figures 4L-N), demonstrating that the PnC^vGluT2→LC^NEergic pathway directly regulates norepinephrine release in the DG.

Figure 4. PnC^vGluT2→LC^NEergic Pathway Regulates Norepinephrine Release in the Hippocampal DG

5. Gene Knockout of OHCs Weakens the Auditory Input from PnC^vGluT2 to LC^NE Neurons

To assess the impact of hearing loss on neuronal activity, the study examined c-Fos expression in the brains of DT-induced Slc26a5ᴰᵀᴿ/⁺ mice following hearing loss. It was found that the activity of ^vGluT2⁺ positive neurons in the PnC was significantly reduced, while the activity of GlyT2⁺ positive neurons showed no significant changes (Figures 5A-E). At the same time, the activity of DBH⁺ noradrenergic neurons in the LC was significantly decreased, while the activity of GABA⁺ neurons showed no significant differences (Figures 5F-I). These results indicate that hearing loss simultaneously reduces the activity of PnC^vGluT2 neurons and LC^NE neurons. Further, AAV-EF1α-DIO-GCaMP6f was injected into the LC of Slc26a5ᴰᵀᴿ/⁺::DBH-Cre double-transgenic mice (Figure 5J). The results showed that LC^NE neurons in untreated mice could be significantly activated by white noise stimulation, while LC^NE neurons in hearing loss mice did not respond to sound stimuli (Figures 5K, 5L). Using GRAB_ne2h probes to record norepinephrine levels in the hippocampal DG region, it was found that sound stimulation significantly enhanced norepinephrine signals in the DG of untreated mice, while no significant changes were observed in hearing loss mice. This suggests that hearing loss reduces the activity of PnC^vGluT2 and LC^NEergic neurons, and consequently reduces norepinephrine levels in the hippocampal dentate gyrus.

Figure 5. Selective Knockout of OHCs Weakens Auditory Input from PnC^vGluT2 to LC^NE Neurons

6. Activation of PnC^vGluT2→LC^NE Auditory Input Rescues Neurogenesis Deficits and Cognitive Impairments in DT-Treated Slc26a5ᴰᵀᴿ/⁺ Mice

To explore whether activating the PnC^vGluT2→LC^NE neural input could rescue the adult hippocampal neurogenesis deficits caused by hearing loss, the study injected retroAVV2-EF1α-DIO-Flp into the LC of DT-induced ^vGluT2-Cre::Slc26a5ᴰᵀᴿ/⁺::Nestin-GFP mice, and AAV-fDIO-hM3Dq-mCherry into the PnC to specifically activate the PnC^vGluT2→LC^NE input (Figures 6A, 6B). After CNO treatment, the number of Nestin-GFP⁺ cells and Nestin-GFP⁺ radial glia-like stem cells (RGLs) did not change significantly (Figures 6C, 6D), but the number of Mcm2⁺ proliferating cells and double-positive proliferating RGLs significantly increased (Figures 6E, 6F), suggesting that activation of this pathway can reverse the inhibition of neural stem cell proliferation caused by hearing loss. The EdU pulse labeling experiment showed that CNO treatment significantly increased the number of EdU⁺NeuN⁺ adult-born neurons in the ^vGluT2-Cre::Slc26a5ᴰᵀᴿ/⁺ mice treated with DT (Figures 6G, 6H). Since neural stem cells can differentiate into intermediate progenitor cells and further into new neurons, it is hypothesized that long-term CNO treatment would lead to an increase in both neural stem cells and progenitor cells. In conclusion, activating the PnC^vGluT2→LC^NE neural input can rescue the adult hippocampal neurogenesis deficits caused by hearing loss.

Figure 6. Activation of PnC^vGluT2→LC^NE Neural Input Rescues Adult Hippocampal Neurogenesis Deficits in Hearing Loss Mice

To explore whether activation of the PnC^vGluT2→LC^NE neural input could improve the cognitive deficits caused by hearing loss, the study injected retroAAV2-EF1α-DIO-Flp into the LC of DT-treated ^vGluT2-Cre::Slc26a5ᴰᵀᴿ/⁺ mice and AAV-fDIO-hM3Dq-mCherry into the PnC. After 4 weeks of CNO treatment, behavioral tests were conducted (Figures 7A, 7B). The results showed that activation of the PnC^vGluT2→LC^NE neural input significantly improved the cognitive functions of the mice, as evidenced by increased spontaneous alternation in the Y-maze, improved preference for novel object location and recognition, and increased freezing behavior in the contextual fear conditioning test (Figures 7C-7F). However, hippocampal injection of the neurogenesis inhibitor AraC (a known mitotic inhibitor) completely blocked the above cognitive improvements (Figures 7C-7F). No significant changes were observed in the open field, elevated plus maze, or tail suspension tests (Figures 7G-7I), ruling out the involvement of motor dysfunction and anxiety-like behavior in this process. This confirms that activation of PnC^vGluT2→LC^NE neural input improves cognitive deficits by restoring adult hippocampal neurogenesis in hearing loss mice.

Figure 7. Activation of PnC^vGluT2→LC^NE Neural Input Improves Cognitive Deficits in Hearing Loss Mice

Conclusion

This study is the first to clarify the causal relationship between hearing loss and cognitive decline at the neural circuit level. By selectively knocking out cochlear outer hair cells to construct a hearing loss mouse model, it was found that both cognitive function and adult hippocampal neurogenesis were significantly impaired. Mechanistically, hearing loss weakened the PnC^vGluT2→LC^NE neural input, leading to a reduction in hippocampal norepinephrine levels. Activating this pathway was able to rescue these deficits, and this improvement was dependent on the hippocampal neurogenesis process. This discovery reveals the key neural mechanisms through which hearing loss leads to cognitive impairment, providing new targets for related interventions.

Figure 8. Summary Diagram

The tools used in this study are available from Brain Case:

Product Category	Product Number	Product Name
Fluorescent Protein	BC-0025	rAAV-hSyn-DIO-mCherry
	BC-0023	rAAV-hSyn-mCherry
	BC-0020	rAAV-hSyn-EGFP
	BC-0244	rAAV-hSyn-DIO-GFP
Recombinase	BC-0172	rAAV-hSyn-SV40 NLS-Flp
	BC-0178	rAAV-EF1α-DIO-Flp
	BC-0159	rAAV-hSyn-SV40 NLS-Cre
Chemogenetics	BC-5388	rAAV-hSyn-FDIO-hM4D(Gi)-P2A-mCherry
Chemogenetics	BC-4927	rAAV-hSyn-FDIO-hM3D(Gq)-P2A-mCherry
Optogenetics	BC-0101	rAAV-CaMKIIα-hChR2(H134R)-mCherry
Optogenetics	BC-4623	rAAV-hSyn-DIO-eNpHR3.0-P2A-mCherry
Calcium Imaging	BC-0088	rAAV-EF1α-DIO-GCaMP6f
Fluorescent Probe	BC-0268	rAAV-hSyn-NE2h
Retrograde Monosynaptic	BC-0041	rAAV-EF1α-DIO-EGFP-T2A-TVA
	BC-0442	rAAV-EF1α-DIO-N2cG
	BC-RV-EnvA844	RV-EnvA-ΔG-mCherry
Anterograde Monosynaptic	BC-0045	rAAV-EF1α-DIO-EGFP-T2A-TK(HSV)
Anterograde Monosynaptic	BC-HSVΔTK-tdT	H129ΔTK-hUbC-tdTomato

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Client Article | Cell Stem Cell | Team of Weixiang Guo at the Chinese Academy of Sciences Uncovers Key Neural Mechanisms Linking Auditory Loss to Cognitive Decline

2. Outer Hair Cell Gene Knockout Impairs Adult Hippocampal Neurogenesis

3. LC^NEergic Neurons Receive Auditory Input from PnC^vGluT2 Neurons

4. PnC^vGluT2→LC^NEergic Pathway Directly Regulates Norepinephrine Release in the DG

5. Gene Knockout of OHCs Weakens the Auditory Input from PnC^vGluT2 to LC^NE Neurons

6. Activation of PnC^vGluT2→LC^NE Auditory Input Rescues Neurogenesis Deficits and Cognitive Impairments in DT-Treated Slc26a5ᴰᵀᴿ/⁺ Mice

Conclusion

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Client Article | Cell Stem Cell | Team of Weixiang Guo at the Chinese Academy of Sciences Uncovers Key Neural Mechanisms Linking Auditory Loss to Cognitive Decline

2. Outer Hair Cell Gene Knockout Impairs Adult Hippocampal Neurogenesis

3. LCNEergic Neurons Receive Auditory Input from PnCvGluT2 Neurons

4. PnCvGluT2→LCNEergic Pathway Directly Regulates Norepinephrine Release in the DG

5. Gene Knockout of OHCs Weakens the Auditory Input from PnCvGluT2 to LCNE Neurons

6. Activation of PnCvGluT2→LCNE Auditory Input Rescues Neurogenesis Deficits and Cognitive Impairments in DT-Treated Slc26a5ᴰᵀᴿ/⁺ Mice

Conclusion

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