Microglia senescence occurs in both substantia nigra and ventral tegmental area
Fatemeh Shaerzadeh1, Leah Phan1, Douglas Miller1
1Department of Neuroscience, University of Florida College of Medicine, Gainesville, Florida, USA.
Abstract:
During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging-related changes in microglia and neurons occur in the vulnerable substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA). We conducted stereological analyses to enumerate microglia and dopaminergic neurons in the SNc and VTA of 1-, 6-, 9-, 18-, and 24-month-old C57BL/J6 mice using sections double-stained with tyrosine hydroxylase (TH) and Iba1. Both brain regions show an increase in microglia with aging, whereas numbers of TH+ cells show no significant change after 9 months of age in SNc and 6 months in VTA. Morphometric analyses reveal reduced microglial complexity and projection area while cell body size increases with aging. Contact sites between microglia and dopaminergic neurons in both regions increase with aging, suggesting increased microglial support/surveillance of dopamine neurons. To assess neurotrophin expression in dopaminergic neurons, BDNF and TH mRNA were quantified. Results show that the ratio of BDNF to TH decreases in the SNc, but not the VTA. Gait analysis indicates subtle, aging-dependent changes in gait indices. In conclusion, increases in microglial cell number, ratio of microglia to dopamine neurons, and contact sites suggest that innate biological mechanisms compensate for the aging-dependent decline in microglia morphological complexity (senescence) to ensure continued neuronal support in the SNc and VTA.
Insights
Aging brains show increased microglia in dopamine regions, compensating for reduced complexity to support neurons. This occurs in vulnerable areas like the substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA).
Area of Science:
- Neuroscience
- Aging Research
- Neuroimmunology
Background:
- Aging leads to dopamine neuron loss, particularly in the substantia nigra pars compacta (SNc), a key factor in Parkinson's disease.
- Microglia, essential for brain homeostasis, undergo senescence with aging, potentially impairing their supportive functions.
- Differential vulnerability of dopamine neuron populations (SNc vs. VTA) to aging suggests region-specific mechanisms.
Purpose of the Study:
- To investigate age-related changes in microglia and dopaminergic neurons in the SNc and VTA.
- To test the hypothesis that aging impacts microglia and neurons differently in vulnerable (SNc) versus non-vulnerable (VTA) dopamine regions.
- To explore compensatory mechanisms involving microglia in response to aging.
Main Methods:
- Stereological analysis of microglia (Iba1+) and dopaminergic neurons (TH+) in aged C57BL/J6 mice (1-24 months).
- Morphometric analysis of microglial complexity, cell body size, and contact sites with neurons.
- Quantification of BDNF and TH mRNA in dopaminergic neurons; assessment of gait parameters.
Main Results:
- Microglial numbers increased with age in both SNc and VTA, while dopaminergic neuron numbers remained stable.
- Aging reduced microglial complexity but increased their cell body size and contact with neurons, suggesting enhanced surveillance.
- The BDNF/TH mRNA ratio decreased in the SNc but not VTA; subtle age-dependent gait changes were observed.
Conclusions:
- Aging triggers compensatory increases in microglial number and interaction with dopamine neurons to maintain homeostasis.
- Despite microglial senescence, these compensatory mechanisms likely preserve dopaminergic neuron function in both SNc and VTA.
- Region-specific changes in neurotrophin expression (BDNF/TH ratio) in the SNc suggest differential aging impacts.
