Biology subjects

Hilliard, J. D.

Publications and source records attributed to Hilliard, J. D..

3 recordsLinked to original sources

bioRxiv2023

Cerebellar Activity in Hemi-Parkinsonian Rats during Volitional Gait and Freezing

Parkinsons disease is a neurodegenerative disease characterized by gait dysfunction in the advanced stages of the disease. The unilateral 6-OHDA toxin-induced model is the most studied animal model of Parkinsons disease, which reproduces gait dysfunction after greater than 68% dopamine (DA) loss in the substantia nigra pars compacta (SNc). The extent to which the neural activity in hemi-parkinsonian rats correlates to gait dysfunction and DAergic cell loss is not clear. In this paper we report the effects of unilateral DA depletion on cerebellar vermis activity using micro-electrocorticography (ECoG) during walking and freezing on a runway. Gait and neural activity were measured in 6-OHDA lesioned and sham lesioned rats at 14d, 21d, and 28d after infusion of 6-OHDA or control vehicle into the medial forebrain bundle (MFB) (n=20). Gait deficits in 6-OHDA rats were different from sham rats at 14d (p<0.05). Gait deficits in 6-OHDA rats improved at 21d and 28d except for run speed, which decreased at 28d (p=0.018). No differences in gait deficits were observed in sham lesioned rats at any time points. Hemiparkinsonian rats showed hyperactivity in the cerebellar vermis at 21d (p<0.05), but not at 14d and 28d, and the activity was reduced during freezing epochs in lobules VIa, VIb, and VIc (p<0.05). These results suggest that DAergic cell loss causes pathological cerebellar activity at 21d postlesion and suggests that compensatory mechanisms from the intact hemisphere contribute to normalized cerebellar activity at 28d. The decrease in cerebellar oscillatory activity during freezing may be indicative of neurological changes during freezing of gait in Parkinsons disease patients making this region a potential location for biomarker detection. Although the unilateral 6-OHDA model presents gait deficits that parallel clinical presentations of Parkinsons disease, further studies in animal models of bilateral DA loss are needed to understand the role of the cerebellar vermis in Parkinsons disease.

neuroscience↗

bioRxiv2023

Cerebellar Activity in PINK1 Knockout Rats during Volitional Gait

Preclinical models of Parkinsons disease are imperative to gain insight into the neural circuits that contribute to gait dysfunction in advanced stages of the disease. The PTEN-induced putative kinase 1 (P1) knockout (KO) early onset model of Parkinsons disease may be a useful rodent model to study the effects of neurotransmitter degeneration caused by loss of P1 function on brain activity during volitional gait. The goal of this study was to measure changes in neural activity at the cerebellar vermis (CBLv) at 8 months of age. Gait deficits, except run speed, were not significantly different from age-matched wild-type (WT) controls as previously reported. P1KO (n=4) and WT (n=4) rats were implanted with a micro-electrocorticographic array placed over CBLv lobules VI (a, b, and c) and VII. Local field potential recordings were obtained during volitional gait across a runway. Power spectral analysis and coherence analysis were used to quantify network oscillatory activity in frequency bands of interest. CBLv power was hypoactive in the beta (VIb, VIc, and VII) and alpha (VII) bands at CBLv lobules VIb, VIc, and VII in P1KO rats compared to WT controls during gait (p<0.05). These results suggest that gait improvement in P1KO rats at 8 months may be a compensatory mechanism attributed to movement corrections caused by decreased inhibition of the alpha band of CBLv lobule VII and beta band of lobules VIb, VIc, and VII. The P1KO model may be a valuable tool for understanding the circuit mechanisms underlying gait dysfunction in early-onset Parkinsons disease patients with functional loss of P1. Future studies investigating the CBLv as a potential biomarker and therapeutic target for the treatment of gait dysfunction in Parkinsons disease are warranted.

neuroscience↗

bioRxiv2021

Dopaminergic but not Cholinergic Neurodegeneration is Correlated with Gait Disturbances in PINK1 Knockout Rats

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by gait dysfunction in later stages of the disease. PD hallmarks include a decrease in stride length, run speed, and swing time; an increase in stride time, stance time, and base of support; dopaminergic degeneration in the basal ganglia; and cholinergic degeneration in the pedunculopontine nucleus (PPN). A progressive animal model of PD is needed to identify treatments for gait dysfunction. The goal of this study was to quantify progressive gait degeneration in PTEN-induced putative kinase 1 knockout (P1KO) rats and investigate neurodegeneration as potential underlying mechanisms. Gait analysis was performed in male P1KO and wild-type rats at 5 and 8 months of age and immunohistochemical analysis at 8 months. Multiple parameters of volitional gait were measured using a runway system. P1KO rats exhibited significant gait deficits at 5 months, but not 8 months. Gait abnormalities improved over time suggesting compensation during behavioral testing. At 8 months a 15% loss of tyrosine hydroxylase (TH) in the striatum, a 27% loss of TH-positive cells in the substantia nigra pars compacta, and no significant loss of choline acetyltransferase-positive cells in the PPN was found. Dopaminergic cell loss may contribute to gait deficits in the P1KO model, but not cholinergic cell loss. The P1KO rat with the greatest dopamine loss exhibited the most pronounced PD-like gait deficits, highlighting variability within the model. Further analysis is required to determine the suitability of the P1KO rat as a progressive model of gait abnormalities in PD.

neuroscience↗