Motor deficits and beta oscillations are dissociable in an alpha‐synuclein model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterised by progressive motor symptoms resulting from chronic loss of dopaminergic neurons in the nigrostriatal pathway. The over expression of the protein alpha-synuclein in the substantia nigra has been used to induce progressive dopaminergic neuronal loss and to reproduce key histopathological and temporal features of PD in animal models. However, the neurophysiological aspects of the alpha-synuclein PD model have been poorly characterised. Hereby, we performed chronic in vivo electrophysiological recordings in the corticostriatal circuit of rats injected with viral vector to over express alpha-synuclein in the right substantia nigra. Our model, previously shown to exhibit mild motor deficits, presented moderate dopaminergic cell loss but did not present prominent local field potential oscillations in the beta frequency range (11-30 Hz), considered a hallmark of PD, during the 9 weeks after onset of alpha-synuclein over expression. Spinal cord stimulation, a potential PD symptomatic therapy, was applied regularly from sixth to ninth week after alpha-synuclein over expression onset and had an inhibitory effect on the firing rate of corticostriatal neurons in both control and alpha-synuclein hemispheres. Dopamine synthesis inhibition at the end of the experiment resulted in severe parkinsonian symptoms such as akinesia and increased beta and high-frequency (>90 Hz) oscillations. These results suggest that the alpha-synuclein PD model with moderate level of dopaminergic depletion does not reproduce the prominent corticostriatal beta oscillatory activity associated to parkinsonian conditions.

Striatal cholinergic receptor activation causes a rapid, selective and state‐dependent rise in cortico‐striatal β activity

“…Perhaps DBS amplifies intrinsic M1 mechanisms that prevent the propagation of elevated β oscillations around the CBT loop. Indeed, HFOs also appear in M1 after severe dopamine depletion in rats, with the amount of β correlating inversely with the amount of HFOs (Brys et al ., ), consistent with the idea that the HFOs may offer some protective or homeostatic effect against exaggerated β. Further research into the mechanisms and functions of HFOs is needed to shed light on these possibilities.…”

Striatal cholinergic receptor activation causes a rapid, selective, & state-dependent rise in corticostriatalβactivity

“…Perhaps DBS amplifies intrinsic M1 mechanisms that prevent the propagation of elevated β oscillations around the CBT loop. Indeed, HFOs also appear in M1 after severe dopamine depletion in rats, with the amount of β correlating inversely with the amount of HFOs [Brys et al (2017)], consistent with the idea that the HFOs may offer some protective effect against exaggerated β . Further research into the mechanisms and functions of these HFOs is needed to shed light on these possibilities.…”

Closed-loop spinal cord stimulation is superior in restoring locomotion in rodent models of Parkinson’s Disease

“…We showed that CLDCS, altogether, had both inhibitory and excitatory effects on the spiking activity of neurons in the motor cortex and striatum (Fig 3a, 3b). A similar effect of open loop stimulation has already been established in previous research (14, 31). In addition to that, by performing dimensionality reduction on the time-series population activity of all neurons before and during bouts of locomotion, we were able to represent aggregate neural activity using principal components (PC) as locomotion unfolded over time.…”