Abstract
Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB.
Highlights
Parkinson’s disease (PD) is one of the most prevalent progressive neurodegenerative disorders characterized by the loss of dopaminergic terminals in the striatum and neurons in the substantia nigra pars compacta (SNpc), resulting in cardinal motor symptoms, such as resting tremors, rigidity, bradykinesia, and postural instability [1,2,3,4]
In the 6-OHDA animal model used here, dopaminergic deafferentation caused a compensatory increase in D2/D3 receptor (D2/D3R) availability in the right caudate nucleus and putamen (CPu) of hemi-PD rats by 23% [58]
When right and left D2/D3R availability in the olfactory bulb (OB) were measured, the right OB of botulinum neurotoxin-A (BoNT-A)-treated hemi-PD rats 6 weeks, 3 months, and 6 months (PET/CT 1-3) after BoNT-A injection showed significant, about 8.5% higher, BPnd values in the right OB compared with both Sham + Sham and 6-OHDA + Sham rats
Summary
Parkinson’s disease (PD) is one of the most prevalent progressive neurodegenerative disorders characterized by the loss of dopaminergic terminals in the striatum and neurons in the substantia nigra pars compacta (SNpc), resulting in cardinal motor symptoms, such as resting tremors, rigidity, bradykinesia, and postural instability [1,2,3,4]. As a prominent non-motor symptom, especially, olfactory deficits (hyposmia, anosmia) occur in more than 90% of PD patients [5,6,7,8,9]. The clinically dominant motor/stature failure is attributed primarily to the lack of dopaminergic neurons in the SNpc that normally project to the basal ganglia complex of caudate nucleus and putamen (CPu) via the medial forebrain bundle (MFB) [27,28,29,30]. In a well-established animal model, SNpc dopaminergic neurons are destroyed by injection of 6-hydroxydopamine (6-OHDA) into the MFB, causing hemiparkinsonian (hemi-PD) conditions [31,32,33,34]
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