Reactive astrogliosis contributes to neurodegeneration in a regionally heterogeneous manner in a body-first rodent model of environmental parkinsonism

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the loss of dopaminergic (DAergic) neurons in the Substantia Nigra pars compacta (SNpc) and the accumulation of α-synuclein aggregates (Lewy bodies) in the surviving neurons. These cellular hallmarks result in motor impairments along with some common non-motor symptoms which include gastrointestinal dysfunctions that decrease the patient’s quality of life, and precede the onset of motor symptoms. Previous work from our lab has described an environmental model of parkinsonism in rats that results from oral administration of subthreshold doses of paraquat (P) and lectin (L). This “bottom-up” (i.e., gut-brain) model results in synucleinopathy that is transported from the gut to the brainstem via the efferent vagus nerve, and then to the SNpc where it induces neuronal loss and motor deficits. Strikingly, in this model, although the dorsal motor nucleus of the vagus (DMV) cholinergic neurons in the brainstem are exposed to the same ascending pathogens, they remain relatively intact, whereas SNpc DAergic neurons undergo profound degeneration.Astrocytes are important for neuronal survival but recent research has shown that in PD, the shift toward neurotoxic reactive astrocytes contributes to DAergic neuron vulnerability. This study hypothesized that neurotoxic astrocytes are critically important in the pathogenesis of parkinsonism in multiple brain regions and inhibition of astrocytes will prevent loss of SNpc DAergic neurons and delay the onset of motor deficits.Male Sprague-Dawley rats were orally gavaged with P+L (1.5mg/kg and 0.75mg/kg, respectively, in 10% sucrose; N=18) or vehicle (10% sucrose; N=18) for 7 days. Immunohistochemical assessment of midbrain and brainstem sections were performed for localization of glial fibrillary protein (GFAP) and tyrosine hydroxylase (TH) or choline acetyltransferase (ChAT) immunoreactivity (-IR) at 1-4 weeks post-gavage. Astrocytes in the SNpc showed an increased intensity of GFAP-IR in P+L (mean pixel density/mm2 = 31.1 ± 3.065) compared to control rats (mean = 8.69 ± 1.584, p< 0.001). Astrocyte morphology, as assessed with Sholl analysis, showed that development of parkinsonism increased SNpc astrocyte branching and morphological complexity (N=30 for control; N=37 for P+L; p< 0.05) as well as DMV astrocyte branching and morphological complexity (N=8 for control; N=14 for P+L; p< 0.05). SNpc or DMV astrocytes were chemogenetically inhibited via unilateral microinjection of hM4D(Gi)-GFAP DREADD and application of the DREADD agonist JHU37152 in drinking water for 8 weeks post P+L gavage. Unilateral SNpc astrocyte inhibition resulted in sided sensorimotor deficits assessed with vibrissae testing (N=7; p< 0.05) and preservation of dopaminergic SNpc neurons, compared to an almost complete loss of TH-IR on the contralateral (non-inhibited) side. In contrast, unilateral inhibition of DMV astrocytes did not alter progression of motor deficits (N=3; p >0.05) and had no effect on ChAT-IR DMV neuronal number. These data suggest that astrocyte reactivity within the SNpc precedes the appearance of parkinsonian motor deficits. While chemogenetic inhibition of SNpc astrocytes delayed the progression of motor deficits, inhibition of DMV astrocytes were without effect, suggesting that astrocyte reactivity may contribute to neurodegeneration in a regionally heterogeneous manner in this rodent model. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.