Abstract
Besides the main cortical inputs to the basal ganglia, via the corticostriatal projection, there is another input via the corticosubthalamic projection (CSTP), terminating in the subthalamic nucleus (STN). The present study investigated and compared the CSTPs originating from the premotor cortex (PM) or the primary motor cortex (M1) in two groups of adult macaque monkeys. The first group includes six intact monkeys, whereas the second group was made up of four monkeys subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication producing Parkinson’s disease (PD)-like symptoms and subsequently treated with an autologous neural cell ecosystem (ANCE) therapy. The CSTPs were labeled with the anterograde tracer biotinylated dextran amine (BDA), injected either in PM or in M1. BDA-labeled axonal terminal boutons in STN were charted, counted, and then normalized based on the number of labeled corticospinal axons in each monkey. In intact monkeys, the CSTP from PM was denser than that originating from M1. In two PD monkeys, the CSTP originating from PM or M1 were substantially increased, as compared to intact monkeys. In one other PD monkey, there was no obvious change, whereas the last PD monkey showed a decrease of the CSTP originating from M1. Interestingly, the linear relationship between CSTP density and PD symptoms yielded a possible dependence of the CSTP re-organization with the severity of the MPTP lesion. The higher the PD symptoms, the larger the CSTP densities, irrespective of the origin (from both M1 or PM). Plasticity of the CSTP in PD monkeys may be related to PD itself and/or to the ANCE treatment.
Highlights
MATERIALS AND METHODSIn parallel to the multiple descending motor pathways originating from cortical areas, such as the corticospinal (CST), the corticorubral, corticotectal, and the corticobulbar projections (Lemon, 2008), motor control is based on cortico-basal ganglia circuit loops
In four of such MPTP intoxicated monkeys subjected to autologous neural cell ecosystem (ANCE) therapy, tracing studies showed that the corticobulbar projections were significantly reduced as compared to intact monkeys (Fregosi et al, 2018), whereas the corticotectal projection was much less affected (Fregosi et al, 2019)
In the latter two studies, the evidence for a reduction of cortical inputs to subthalamic nucleus (STN) was derived from immunohistochemical detection of vesicular glutamate transporter type-1 terminals, making it impossible to discriminate the distinct origins of the corticosubthalamic projection (CSTP) inputs, for example, Primary motor cortex (M1) vs. premotor cortex (PM)
Summary
In parallel to the multiple descending motor pathways originating from cortical areas, such as the corticospinal (CST), the corticorubral, corticotectal, and the corticobulbar (corticoreticular) projections (Lemon, 2008), motor control is based on cortico-basal ganglia circuit loops. The corrected number of axonal boutons in STN was normalized, based on the number of corticospinal axons labeled with BDA in the same monkey (see “Materials and Methods” section). To compensate for variations in the size and location of the BDA injection sites, as well as differences in tracer uptake, the corrected numbers of boutons were divided by the number of corticospinal axons labeled just above the pyramidal decussation and multiplied by 1,000 to keep a realistic normalized number of boutons (Table 1). To assess the relationship between the number of BDA-labeled boutons with the interaction between motor impairment (PD symptoms based on manual dexterity in the modified-Brinkman board task post-ANCE transplantation (see above) and dopaminergic (tyrosine hydroxylase positive (TH+) neurons) loss in the substantia nigra pars compacta (SNpc), we performed a multivariable linear regression model test (MATLAB R2017b, function ‘‘fitlm’’; Contestabile et al, 2018). We considered Mk-LL being at 100% of its motor performance she had a hectic behavior in the modified-Brinkman board task (Table 1)
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