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Harnessing a noncanonical vestibular input in the head-direction network to rectify age-related navigational deficits

Nature Aging volume 5, pages 1079–1096 (2025)Cite this article

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Abstract

Navigational decline is a metric distinct from aging-related cognitive degradation, yet the affected circuits and synaptic changes remain elusive. This study identified a long-range excitatory projection from parvalbumin (PV) neurons in the brainstem medial vestibular nucleus (MVN) of mice that monosynaptically innervates the midbrain dorsal tegmental nucleus (DTN). This PVMVN→DTN projection exhibits high neuronal excitability and synaptic plasticity as electrophysiological traits. In vivo chemogenetic inhibition of the PVMVN→DTN projection impaired the navigational performance of adult mice. Navigational deficits in aged mice linked to both diminished innervation and synaptic drive of the PVMVN→DTN pathway were pinpointed as hallmarks of the aging process. Strikingly, targeted activation of this pathway mitigated navigational impairments in older mice. In sum, our results revealed an excitatory PVMVN→DTN pathway that impacts navigation. Rescue from aging-related navigational decline by activation of a spared projection pathway further highlights the potential for targeted therapies.

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Fig. 1: PV neurons from the MVN directly project to higher centers in HD networks.
Fig. 2: Projecting PVMVN neurons exert biased synaptic impact on DTN, SG and NPH.
Fig. 3: PVMVN→DTN projection innervates PV neurons in DTN via monosynaptic excitation and disynaptic inhibition.
Fig. 4: Projecting and local PVMVN neurons exhibit distinct electrophysiological properties.
Fig. 5: Inhibition of the PVMVN→DTN pathway impairs navigational function.
Fig. 6: Diminished synaptic innervation and excitatory drive from PVMVN→DTN projection associated with navigational deficits in aging.
Fig. 7: Chemogenetic activation of PVMVN→DTN pathway rescues navigational deficits in aged mice.

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Data availability

The Allen Brain Atlas database was used. Any other data reported in this paper are available from the corresponding authors upon reasonable request. Source data are provided within this paper.

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Acknowledgements

We are grateful to A. Y. Y. Lui, T. P. Y. Kwan and G. G. Lam for assisting mechanical setup, providing technical support and offering valuable insights. We acknowledge BioRender.com for providing materials used in schematic illustrations. This work was supported by State Key Laboratory of Brain and Cognitive Sciences, HKU Strategic Interdisciplinary Research Scheme, Sau Po Centre on Ageing, HKU COA JMK Dementia Care Scholarships and the Chi Lin Kok Ng BHL Foundation. This work was also funded by grants from Hong Kong Research Grants Council: GRF 17125115, 17131816 and 12113717, NSFC/RGC N_HKU735/14 to D.K.-Y.S. and Y.-S.C.; GRF 14115821 to K.Y.; CRF C4012-22G to W.-H.Y; and China Postdoctoral Science Foundation 2024M753760 to X.-Q.H.

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Authors and Affiliations

  1. Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xiao-Qian Hu

  2. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Xiao-Qian Hu, Kenneth Lap-Kei Wu, Daisy Kwok-Yan Shum & Ying-Shing Chan

  3. Neuroscience Research Centre, The University of Hong Kong, Hong Kong SAR, China

    Kenneth Lap-Kei Wu, Daisy Kwok-Yan Shum & Ying-Shing Chan

  4. MRC Laboratory of Molecular Biology, Cambridge, UK

    Kenneth Lap-Kei Wu

  5. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

    Kang-Lin Rong & Ke Ya

  6. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China

    Wing-Ho Yung

  7. State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China

    Daisy Kwok-Yan Shum & Ying-Shing Chan

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  1. Xiao-Qian Hu
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Contributions

X.-Q.H. and Y.-S.C. conceptualized the study. D.K.-Y.S. and Y.-S.C. acquired research funding. X.-Q.H. and Y.-S.C. designed the electrophysiological experiments. K.L.-K.W., D.K.-Y.S. and Y.-S.C. designed the behavioral experiments. X.-Q.H. and K.-L.R. performed electrophysiological recordings. X.-Q.H. and K.L.-K.W. performed rodent surgery and behavioral experiments. X.-Q.H., K.L.-K.W. and D.K.-Y.S. performed histology and acquired imaging data. X.-Q.H., K.-L.R., K.Y., W.-H.Y. and Y.-S.C. analyzed the electrophysiological data. X.-Q.H., K.L.-K.W., D.K.-Y.S. and Y.-S.C. analyzed the behavioral data. X.-Q.H., K.L.-K.W., W.-H.Y., D.K.-Y.S. and Y.-S.C. wrote and revised the paper with inputs from all authors.

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Correspondence to Daisy Kwok-Yan Shum or Ying-Shing Chan.

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Extended data

Extended Data Fig. 1 Details of PVMVN→DTN projection.

a, A tile-scan image (for Fig. 1b left) showed the injection site in MVN. Scale bar, 500 μm. b, Left, a tile-scan image (for Fig. 1c middle) showed the synaptic puncta in SG (red dotted areas) and PDTg (blue dotted areas) at Bregma - 5.80 mm. Right, a tile-scan image in low-magnification showed the synaptic puncta in DTg at Bregma - 5.20 mm. Abbreviations: c, contralateral; i, ipsilateral; SG, supragenual nucleus; PDTg, posterodorsal tegmental nucleus; DTg, dorsal tegmental nucleus. Scale bar, 200 μm. (from independent experiments on 3 mice). c, Schematic of injecting Cholera toxin subunit B (CTB) into the contralateral DTN (cDTN) to retrogradely label DTN-projecting neurons from ipsilateral MVN (iMVN). d, Left, schematic coronal brainstem at Bregma – 5.52 mm (adopted from Allen Brain Atlas) illustrating CTB retrograde tracing. Right, a representative image showing the CTB injection site in cDTN co-stained with NeuN. Scale bar, 80 μm. e, Representative confocal images at low (upper left panel) and high (upper right panel) resolution showing the co-labeling of NeuN and PV with CTB-labeled DTN-projecting cells in MVN (scale bar, 50 μm). DTN-projecting neurons in MVN (MVNDTN-pr°jecting) were labeled with CTB (magenta) and NeuN (green). PV neurons in MVN (MVNPV) were labeled with PV (red) and NeuN (green). DTN-projecting PV neurons in MVN (PVMVN→DTN) were labeled with CTB (magenta), NeuN (green) and PV (red). Separate panels of the zoom-in image indicated the identity of labeled neurons (lower panel; scale bar, 80 μm). f, Quantification of the averaged number and fraction of double-labeled neurons in MVN. PV neurons constituted a significant proportion of DTN-projecting neurons in MVN (PVMVN→DTN/ MVNDTN-pr°jecting = 85.23 ± 3.14 %), while DTN-projecting PV neurons account for one fifth of PV neurons in MVN (PVMVN→DTN/ MVNPV = 17.56 ± 1.41 %). Data were presented as mean ± s.e.m. Volin plot displayed all sample points, median and quartiles of the data. (c–f, n = 4 mice). g, Schematic sagittal (upper panel) and top (lower panel) view indicating the injection of CTB for cDTN and green Retrobeads for cMVN in the same animal to reveal MVN neurons that project to both cMVN and cDTN. h, Representative images showing the injection sites in cDTN with CTB (scale bar, 100 μm) and cMVN with green Retrobeads (scale bar, 80 μm). i, Representative images of MVN showing the segregated distribution of cMVN-projecting (green) and cDTN-projecting (red) neurons in MVN neurons, indicating the limited possibility of MVN neurons that project to both cMVN and cDTN (scale bar, 100 μm). (g-i, from independent experiments on 3 mice).

Source data

Extended Data Fig. 2 Distinct projecting patterns of PV and SST neurons in MVN.

a, Representative images (from n = 3 mice) of the injection sites for viral tracing (with AAV-DIO-eGFP-T2A-Synaptophysin-mRuby) in PV-Cre and SST-Cre mice to plot the projection pattern of PVMVN and SSTMVN neurons. b, Representative images (from n = 3 mice) showed that the axonal terminals from PVMVN but not SSTMVN neurons reach contralateral NPH, SG and DTN.

Extended Data Fig. 3 Validation of light-evoked responses from ChR2-expressing PVMVN neurons.

a, Schematic of using whole-cell patch-clamp recording to validate the functionality of PVMVN neurons transfected with AAV-DIO-ChR2-EGFP in acute slices containing MVN from PV-Cre::Ai9 mice (n = 3) for CRARM analysis. b, Representative images (from n = 5 neurons) showing PVMVN neurons with AAV-DIO-ChR2-EGFP expression in coronal section containing MVN (scale bar, 20 μm). c, Epifluoresecent (left), bright-field (middle) and overlay (right) images showing a labeled PV neuron in whole-cell patch-clamp recording configuration (scale bar, 10 μm). d, Upper panel, averaged normalized amplitude of light-evoked events in ChR2-expressing PV neurons in response to ten consecutive photo-stimulation (2 ms) of different frequencies. Lower panel, example traces of PVMVN neurons with ChR2 expression in response to ten consecutive photo-stimulation of 2, 5, 8, and 10 Hz. Neurons displayed ChR2 stimulation-failure at higher frequencies of 8 Hz (green) and 10 Hz (blue). Data were presented as mean ± s.e.m. (n = 3 neurons). e, Upper panel, averaged normalized amplitude of light-evoked events in ChR2-expressing PV neurons in response to five consecutive photo-stimulation (1 ms) of different frequencies. Lower panel, representative traces of PVMVN neurons with ChR2 expression in response to five consecutive photo-stimulation of 1, 2, 5, 8, 10, 20, 30, 40, and 50 Hz. Data were presented as mean ± s.e.m. (n = 3 neurons).

Source data

Extended Data Fig. 4 Supplementary data of different synaptic impacts exerted by PVMVN projection among DTN, SG and NPH.

a-b, Sum (a) and individual (b) data showing the amplitude of optic-evoked EPSC (oEPSC) and IPSC (oIPSC) recorded from neurons in DTN (n = 27 neurons), SG (n = 18 neurons) and NPH (n = 11 neurons). Amplitude of oEPSC vs oIPSC from the same neurons were: DTN (326.06 ± 45.02 vs 126.08 ± 31.77 pA, ***P = 9.0 × 10-4), SG (89.06 ± 23.51 vs 195.24 ± 44.12, *P = 0.0352) and NPH (54.53 ± 10.89 vs 93.97 ± 17.80, *P = 0.0304). Data were presented as mean ± s.e.m. and tested by paired two-tailed t-test. c-d, Sum (a) and individual (b) data showing the latency of oEPSC and oIPSC recorded from neurons in DTN (n = 27 neurons), SG (n = 18 neurons) and NPH (n = 11 neurons). Latency of oEPSC vs oIPSC from the same neurons were: DTN (3.45 ± 0.58 vs 6.10 ± 0.57, *P = 0.0259), SG (5.25 ± 1.19 vs 5.91 ± 0.52, P = 0.6721) and NPH (5.50 ± 1.34 vs 7.81 ± 0.96, P = 0.6184). Data were presented as mean ± s.e.m. and tested by paired two-tailed t-test. e-f, Sum (a) and individual (b) data showing the max rise slope of oEPSC and oIPSC recorded from neurons in DTN (n = 27 neurons), SG (n = 18 neurons) and NPH (n = 11 neurons). max rise slope of oEPSC vs oIPSC from the same neurons were: DTN (267.38 ± 55.13 vs 118.54 ± 28.29, *P = 0.0259), SG (77.54 ± 9.28 vs 114.93 ± 22.58, *P = 0.0468) and NPH (75.68 ± 6.08 vs 130.02 ± 27.16, *P = 0.039). Data were presented as mean ± s.e.m and tested by paired two-tailed t-test. g, A diagram summarizing the differentiated synaptic impacts exerted by PVMVN projection among DTN, SG and NPH.

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Extended Data Fig. 5 PVMVN→DTN neurons exert null control on non-PV neurons within the ipsilateral or contralateral MVN.

a, Schematic of using optogenetics-coupled whole-cell patch-clamp recording to assess whether PVMVN→DTN neurons directly innervate non-PV neurons in ipsilateral and contralateral MVN. PV-Cre mice were bilaterally injected with AAV5-DIO-FLP-mCherry in MVN to label PV neurons and unilateral injected with rAAV-fDIO-ChR2-EGFP in DTN to express optogenetic vector ChR2 in PVMVN→DTN neurons. b, Left, a representative image of DTN showing the injection site with rAAV-fDIO-ChR2-EGFP (green). Right, representative images of MVN showing PV neurons infected with both AAV5-DIO-mCherry (red) and rAAV-fDIO-ChR2-EGFP (green). c, Left, epifluorescence, bright-field and overlay images showing the configuration of whole-cell patch-clamp recording for DTN-projecting neurons in MVN with ChR2 expression (scale bar, 10 μm). Right, a representative current-clamp tracing from the sampled neuron (displayed in left) with ChR2 expression showed time-locked responses upon 1 Hz blue light stimulation. (c-e, representative recording traces from 5 neurons from 3 mice). d-e, Epifluorescence, bright-field and overlay images showing the configuration of whole-cell patch-clamp recording for non-PV neurons in the ipsilateral (d, left) and contralateral (e, left) MVN without mCherry expression (scale bar, 10 μm). Representative voltage-clamp tracings recorded from the sampled neuron (displayed in left) at 0 and −70 mV demonstrated absence of oIPSCs and oEPSCs responses upon 1 Hz blue light stimulation, indicating null recruitment from PVMVN→DTN neurons on non-PV neurons in the ipsilateral (d, right) and contralateral (e, right) MVN. Blue bars, optical stimulation.

Extended Data Fig. 6 Whole-brain mapping of inputs to PVDTN neurons via monosynaptic retrograde tracing.

a, Schematic of monosynaptic tracing strategy with rabies system to identify the inputs from MVN to PVDTN neurons (n = 3 mice). Helper virus AAV-DIO-TVA-RVG-GFP was injected in DTN of PV-Cre mice, followed by injection of RV-EvnA-dG-DsRed at the same coordinate three weeks later. b, Left, a representative image of the injection site in DTN showing starter neurons co-infected with both AAV-DIO-TVA-RVG-GFP (green) and Rabies-EvnA-dG-DsRed (red) (scale bar, 50 μm). Right, a representative image showing retrogradely labeled MVN neurons that innervated PVDTN neurons (scale bar, 100 μm). c, Representative images showing other brain regions possessing projections to PVDTN neurons (scale bar, 100 μm). MVN, medial vestibular nucleus; DTN, dorsal tegmental nucleus; PMn, paramedian reticular nucleus; 10Cb, lobule ten of the cerebellar vermis; DPGi, dorsal paragigantocellular nucleus; Med, medial cerebellar nucleus; SGN, supragenual nucleus; SVN, superior vestibular nucleus; PMnR, paramedian raphe nucleus; LDTg, laterodorsal tegmental nucleus; MnR, median raphe nucleus; InG, intermediate gray layer of the superior colliculus; InWh, intermediate white layer of the superior colliculus; IPR, interpeduncular nucleus, rostral subnucleus; 3 N, oculomotor nucleus; DK, nucleus of Darkschewitsch; IPC, interpeduncular nucleus, caudal subnucleus; LM, lateral mammillary nucleus; RI, rostral interstitial nucleus; ZI, zona incerta; RSD, retrosplenial dysgranular cortex; LHb, lateral habenular nucleus; TuLH, tuberal part of the lateral hypothalamus.

Extended Data Fig. 7 Vestibular stimulation via sinusoidal rotations activated DTN-projecting neurons in MVN and non-PV neurons in DTN.

a, Schematic of injecting green Retrobeads into contralateral DTN (cDTN) to label DTN-projecting neurons in ipsilateral MVN (iMVN) before vestibular stimulation. Created with BioRender.com. (a-f, results from n = 4 mice). b, Representative images of cDTN in green fluorescence (left) and overlay with bright field showing the injection site. Scale bar, 250 μm. c, Left, a representative image of iMVN with Retrobeads (green) labeling and Fos (magenta) staining (scale bar, 100 μm). Right, high-magnification images (scale bar, 20 μm) of the inset in left using separated fluorescent channels to show the overlay of Retrobeads with Fos, indicating the activation of DTN-projecting neurons in iMVN after vestibular stimulation. d, Schematic of using brain sections with DTN from PV::Ai9 mice for Fos staining after vestibular stimulation. Created with BioRender.com. e, Representative images of Fos staining (left, blue) and its overlay (right) with neuronal markers NeuN (green) and PV (red) after vestibular stimulation (scale bar, 20 μm). f, Box and whiskers (upper panel) and table (lower panel) showing the quantification of averaged number and fraction of Fos+ PV and non-PV neurons in DTN. Box and whisker plots displayed all sample points, with boxes indicating the interquartile range, central lines indicating the median and lower/upper whiskers extend to the minimum/maximum values. Fraction of Fos+ neurons was higher in PV (Fos+ PV/ PV = 83.33 ± 5.34 %) than non-PV (Fos+ non-PV/ non-PV = 41.28 ± 4.10 %) neurons, implying higher proportion of PV neurons in DTN were activated by vestibular stimulation. Data were presented as mean ± s.e.m and tested by paired two-tailed t-test, ***P = 4.0 × 10-4.

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Extended Data Fig. 8 Supplementary data from ex vivo optogenetic whole-cell patch-clamp recordings of PV and non-PV neurons in DTN.

a, Experiment design for injecting AAV-DIO-ChR2-EGFP into MVN of PV::Ai9 mice to compare the synaptic impact of PVMVN projection to PV and non-PV neurons in DTN via ex vivo optogenetics-coupled whole-cell patch-clamp recordings. b, A representative image showing the dense innervation of ChR2-expressing PVMVN terminals (green) in DTN (scale bar, 80 μm). c, Pairwise comparison of the amplitude of EPSC and IPSC recorded from the same PV (blue) and non-PV (grey) neurons upon photo-stimulation of PVMVN terminals in DTN. d-i, No statistically significant difference between PV and non-PV neurons was observed in other intrinsic and synaptic electrophysiological properties. Membrane resistance (d) and capacitance (e) of recorded PV (blue, n = 19) and non-PV (grey, n = 19) neurons. Latency (f), maximum rise slope (g), absolute peak voltage amplitude (h, left) and half-width (h, right) of optic-evoked EPSC recorded from PV (blue, n = 18) and non-PV (grey, n = 9) neurons in DTN upon blue-light stimulation of PVMVN axonal terminals. Absolute peak voltage amplitude (i, left) and half-width (i, right) of optic-evoked IPSCs recorded from PV (n = 18) and non-PV (n = 9) neurons in DTN upon blue-light stimulation of PVMVN axonal terminals. Volin plot displayed all sample points, median and quartiles of the data Bar charts presented data as mean ± s.e.m. Floating bars showed mean, minimal, and maximal value of the data.

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Extended Data Fig. 9 Post hoc verification of region-restricted expression of hM4Di and hM3Dq in PVMVN→DTN pathway.

a, Upper panel, representative images demonstrated restricted expression of retroAAV within the injection site (white dotted areas) while hM4Di (green) expression was absent in cell bodies of DTN neurons (scale bar, 100 μm). Lower panel, images of low-magnification (left; scale bar, 100 μm) and high-magnification (right; scale bar, 25 μm) showed cell bodies (yellow) of PVMVN→DTN neurons in MVN co-expressed with rAAV-fDIO-hM4Di-EGFP (green) and AAV5-DIO-FLP-mCherry (red). b, Quantification of the number and fraction of MVN neurons expressing rAAV-fDIO-hM4Di-EGFP (green) and AAV5-DIO-FLP-mCherry (red) by using 50-μm brain slices containing MVN sampled from mice in the experimental group (n = 7 mice). Averaged fraction of PVMVN neurons with hM4Di expression was 21.3 ± 3.83 % (mean ± s.e.m). c, Upper panel, representative images demonstrated the restricted expression of retroAAV within the injection site (white dotted areas) while hM3Dq (green) expression was absent in cell bodies of DTN neurons (scale bar, 100 μm). Lower panel, images of low-magnification (left; scale bar, 100 μm) and high-magnification (right; scale bar, 25 μm) showed cell bodies (yellow) of PVMVN→DTN neurons in MVN co-expressed with rAAV-fDIO-hM3Dq-EGFP (green) and AAV5-DIO-FLP-mCherry (red). d, Quantification of the number and fraction of MVN neurons expressing rAAV-fDIO-hM3Dq-EGFP (green) and AAV5-DIO-FLP-mCherry (red) by using 50-μm brain slices containing MVN sampled from mice in the aged group (n = 8 mice). Averaged fraction of PVMVN neurons with hM3Dq expression was 18.5 ± 4.05 % (mean ± s.e.m).

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Extended Data Fig. 10 Individual data of dead reckoning behavior tests and open field test upon chemogenetic inhibition.

a-d, Individual data of dead reckoning navigational tests from control (mCherry, n = 7 mice) and experimental (hM4Di, n = 8 mice) groups, showing search time (a), return time (b), heading angle (c), and error (d) from the same mice when treated with saline (left) and CNO (right). Bar charts displayed showed the mean. Paired two-tailed t-test. *P < 0.05, **P < 0.01. e-h, Performance of mice in both control (mCherry, n = 7 mice) and experimental (hM4Di, n = 8 mice) group showed no difference in open field test upon administration of saline and CNO, precluding the side effect of chemogenetic manipulation in locomotion. (e) Left, average speed of mice in control (Saline vs CNO = 8.61 ± 0.75 vs 9.32 ± 0.67 cm/s) and experimental group (saline vs CNO = 8.40 ± 0.60 vs 8.33 ± 0.82 cm/s). Middle, total distance of mice in control (Saline vs CNO = 51.56 ± 4.48 vs 55.90 ± 4.00 cm) and experimental group (Saline vs CNO = 50.42 ± 3.61vs 49.99 ± 4.96 cm). Right, time in center of mice in control (Saline vs CNO = 47.68 ± 7.69 vs 44.65 ± 6.31 s) and experimental group (Saline vs CNO = 42.09 ± 5.80 vs 37.48 ± 6.07 s). Bar chat showed the mean. Box and whisker plots displayed all sample points, with boxes indicating the interquartile range, central lines indicating the median and lower/upper whiskers extend to the minimum/maximum values. (f) Representative traces and heat maps in open field test from a mouse expressing chemogenetic vector hM4Di after treating with saline (left) and CNO (right). Individual comparison of total travel distance (g) and time spent in center area (h) in open field tests from the same mice treated with saline (left) or CNO (right) in both mCherry-expressing control group and hM4Di-expressing experimental group. Bar charts showed the mean of data. Statistics were tested by paired two-tailed t-test. Ctrl, n = 7 mice; hM4Di, n = 8 mice.

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Hu, XQ., Wu, K.LK., Rong, KL. et al. Harnessing a noncanonical vestibular input in the head-direction network to rectify age-related navigational deficits. Nat Aging 5, 1079–1096 (2025). https://doi.org/10.1038/s43587-025-00884-4

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