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

Xiao-Qian Hu; Kenneth Lap-Kei Wu; Kang-Lin Rong; Ya Ke; Wing-Ho Yung; Daisy Kwok-Yan Shum; Ying-Shing Chan

doi:10.1038/s43587-025-00884-4

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

Xiao-Qian Hu
, Kenneth Lap-Kei Wu
, Kang-Lin Rong
, Ya Ke
, Wing-Ho Yung
, Daisy Kwok-Yan Shum^*
, Ying-Shing Chan^*

^*Corresponding author for this work

Department of Neuroscience

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

3 Citations (Scopus)

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 PV^MVN→DTN projection exhibits high neuronal excitability and synaptic plasticity as electrophysiological traits. In vivo chemogenetic inhibition of the PVM^VN→DTN projection impaired the navigational performance of adult mice. Navigational deficits in aged mice linked to both diminished innervation and synaptic drive of the PV^MVN→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 PV^MVN→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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025

Original language	English
Pages (from-to)	1079-1096
Number of pages	18
Journal	Nature Aging
Volume	5
Online published	28 May 2025
DOIs	https://doi.org/10.1038/s43587-025-00884-4
Publication status	Published - Jun 2025

Funding

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 Y.K.; CRF C4012-22G to W.-H.Y; and China Postdoctoral Science Foundation 2024M753760 to X.-Q.H.

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

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. {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025",

author = "Xiao-Qian Hu and Wu, \{Kenneth Lap-Kei\} and Kang-Lin Rong and Ya Ke and Wing-Ho Yung and Shum, \{Daisy Kwok-Yan\} and Ying-Shing Chan",

year = "2025",

month = jun,

doi = "10.1038/s43587-025-00884-4",

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T1 - Harnessing a noncanonical vestibular input in the head-direction network to rectify age-related navigational deficits

AU - Hu, Xiao-Qian

AU - Wu, Kenneth Lap-Kei

AU - Rong, Kang-Lin

AU - Ke, Ya

AU - Yung, Wing-Ho

AU - Shum, Daisy Kwok-Yan

AU - Chan, Ying-Shing

PY - 2025/6

Y1 - 2025/6

N2 - 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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025

AB - 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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025

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U2 - 10.1038/s43587-025-00884-4

DO - 10.1038/s43587-025-00884-4

M3 - RGC 21 - Publication in refereed journal

SN - 2662-8465

VL - 5

SP - 1079

EP - 1096

JO - Nature Aging

JF - Nature Aging

ER -

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

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

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