Deep Brain Stimulation of the Center Median-Parafascicular Complex of the Thalamus Has Efficient Anti-Parkinsonian Action Associated with Widespread Cellular Responses in the Basal Ganglia Network in a Rat Model of Parkinson's Disease

Abstract

The thalamic centromedian-parafascicular (CM/Pf) complex, mainly represented by Pf in rodents, is proposed as an interesting target for the neurosurgical treatment of movement disorders, including Parkinson's disease. In this study, we examined the functional impact of subchronic high-frequency stimulation (HFS) of Pf in the 6-hydroxydopamine-lesioned hemiparkinsonian rat model. Pf-HFS had significant anti-akinetic action, evidenced by alleviation of limb use asymmetry (cylinder test). Whereas this anti-akinetic action was moderate, Pf-HFS totally reversed lateralized neglect (corridor task), suggesting potent action on sensorimotor integration. At the cellular level, Pf-HFS partially reversed the dopamine denervation-induced increase in striatal preproenkephalin A mRNA levels, a marker of the neurons of the indirect pathway, without interfering with the markers of the direct pathway (preprotachykinin and preprodynorphin). Pf-HFS totally reversed the lesion-induced changes in the gene expression of cytochrome oxidase subunit I in the subthalamic nucleus, the globus pallidus, and the substantia nigra pars reticulata, and partially in the entopeduncular nucleus. Unlike HFS of the subthalamic nucleus, Pf-HFS did not induce per se dyskinesias and directly, although partially, alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced forelimb dyskinesia. Conversely, L-DOPA treatment negatively interfered with the antiparkinsonian effect of Pf-HFS. Altogether, these data show that Pf-DBS, by recruiting a large basal ganglia circuitry, provides moderate to strong anti-parkinsonian benefits that might, however, be affected by L-DOPA. The widespread behavioral and cellular outcomes of Pf-HFS evidenced here demonstrate that CM/Pf is an important node for modulating the pathophysiological functioning of basal ganglia and related disorders.

Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice

“…Given the reported increase in firing of thalamic CM/Pf neurons in PD models (Jouve et al, 2010; Magnin et al, 2000; Orieux et al, 2000; Parr-Brownlie et al, 2009; Yan et al, 2008), and the decrease in thalamic connectivity with dMSNs after chronic dopamine depletion, we hypothesized that thalamostriatal inputs might be actively contributing to decreased spontaneous motor activity in parkinsonian mice through selective drive of the indirect pathway, relative to the direct pathway. We reasoned that disconnection of this pathway could rescue motor behavior.…”

Dopamine deficiency increases synchronized activity in the rat subthalamic nucleus

“…It is generally adviced to inject desipramine or pargyline prior to 6-OHDA administration to protect noradrenergic neurons (Breese and Traylor, 1971) but this practice has been questioned (Debeir et al, 2005). There is a nonlinear dose dependent effect of 6-OHDA on noradrenergic neurons, and more recent work has shown that desipramine is not needed at the lower doses of 6-OHDA used in current study (Jouve et al, 2010). Notice that even in case of minor noradrenergic degeneration following 6-OHDA injection, the animal model would be closer to human PD where same degeneration of catecholaminergic cells is likely to be associated to the pathological state (Delaville et al, 2011;Mavridis et al, 1991;Pillon et al, 1989).…”

“…The injected solution contained 12 μl 6-OHDA hydrobromide (Sigma, Paris, France) dissolved in 6 μl of 0.9% NaCl with 0.1% ascorbic acid (Jouve et al, 2010). It is generally adviced to inject desipramine or pargyline prior to 6-OHDA administration to protect noradrenergic neurons (Breese and Traylor, 1971) but this practice has been questioned (Debeir et al, 2005).…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…However, the mechanism of action, specific target sites and stimulation parameters of this surgical approach must be further characterized. Recent studies indicate widespread basal ganglia cellular responses associated with efficient anti-parkinsonian effects of Pf DBS in rat models of PD (Goff et al, 2009;Jouve et al, 2010). Another DBS target that has recently generated some interest is the pedunculopontine nucleus (PPN), a conglomerate of cholinergic, glutamatergic and GABAergic neurons in the upper brainstem, tightly linked with the basal ganglia, thalamus and lower tegmental regions (MenaSegovia et al, 2004).…”