Progressive Changes in Cortical Noradrenergic and Catecholaminergic Innervation in the MPTP treated non-human primate model of Parkinson’s Disease Restricted; Files Only
Gottipalli, Olivia (Summer 2026)
Abstract
Parkinson’s Disease (PD) is a common movement disorder characterized by motor symptoms such as tremor, rigidity, impaired balance, and slower movements induced by degeneration of the nigrostriatal dopamine system. However, non-motor symptoms –including executive dysfunction, depression, and working memory deficits – often precede motor onset and significantly impact quality of life. The chronic low-dose 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model of PD in non-human primates also presents with early cognitive deficits in executive functions prior to motor symptoms. In humans, some of these early onset non-motor PD symptoms may be due to dysfunction and/or loss of brainstem noradrenergic neurons in the locus coeruleus (LC). LC neurons, which innervate prefrontal and motor cortices, are key regulators of arousal, attention, and mood – functions often disrupted early in PD. This study aims to quantify changes in noradrenergic innervation of various cognitive and motor cortical regions in MPTP-treated monkeys with various degrees of striatal dopamine (DA) depletion (~30-50%, >70%). Brain tissue from 2 control, 3 MPTP-treated parkinsonian (>70% striatal DA loss), and 2 MPTP-treated motor asymptomatic monkeys (~30-50% striatal DA loss) were collected and immunostained for norepinephrine transporter (NET) and tyrosine hydroxylase (TH). Digital images of serial brain sections were taken to measure changes in the intensity of NET and TH immunostaining in different layers (layer I, II, III, Va, and Vb) of comparable cortical regions of MPTP-treated and control monkey cortices (Brodmann’s area 4, 6, 9, 46, 24, and 25). Initial analyses revealed a 60-80% decrease in NET and TH labeling intensity measurements from all 6 Brodmann’s areas in MPTP-treated parkinsonian monkeys compared to controls. Layers I, II, III, and Vb displayed the greatest decreases in NET and TH innervation as compared to controls. MPTP-treated motor asymptomatic monkeys presented with non-significant differences in NET and TH staining intensity as compared to control monkeys. Differences between asymptomatic and control monkeys were more variable depending on brain region and cortical layer, suggesting a more nuanced progression. Given evidence from the literature that TH immunostaining may not be detectable in noradrenergic axons in the monkey prefrontal cortex, double immunofluorescent staining for NET and TH was performed in control monkeys to assess the extent of TH expression in NET-positive cortical axons in cortical regions examined in this study. More than 80% of axons stained with NET colocalized with TH in all 6 Brodmann’s areas. Together, these preliminary results provide greater insights into the possible use of the MPTP-treated monkey model to understand the influence of norepinephrine on non-motor symptoms of PD and therefore provide insight into research on earlier therapeutics. Larger cohorts of monkeys are needed to extend these observations and provide more insight into the extent of NET-positive neuronal loss in the locus coeruleus in asymptomatic and symptomatic MPTP-treated monkeys.
Table of Contents
Hypothesis ……………...……………………………………………………………………… 1
Rationale ……………...……………………………………………………………...………… 2
Background and Introduction ………………………………………………………………….. 3
Parkinson’s Disease Overview 3
Non-motor symptoms of PD 5
Noradrenergic Involvement in non-motor symptoms of PD 6
Imaging and functional correlates of NE loss in human PD patients 9
The MPTP Non-Human Primate Model 11
Research Methods ……………………………………………………………………………… 14
Animals 14
MPTP Treatment and Perfusion 14
Brain Regions of Interest 16
Immunohistochemistry 16
Digital Image Analysis 18
Optical Density Statistics 20
Immunofluorescent Staining and Imaging 21
Results ……………...………………………………...………………………………………… 23
Tyrosine Hydroxylase Optical Density 23
Norepinephrine Transporter Optical Density 24
NET and TH Immunofluorescent Labeling 26
Discussion ……………...………………………………...………………………..………...…. 27
Limitations ……………...………………………………...…………………………….…...…. 34
Conclusions …………….………………………………...………………………..………...…. 37
Future Directions …………….…………...……………...………………………..………...…. 38
Figures ……………………….…………...……………...………………………..………...…. 39
Figure 5: NET and TH Stained Imaged 39
Figure 6 and Table 3: TH Results in Motor Cortices 40
Figure 7 and Table 4: TH Results in Prefrontal Cortices 41
Figure 8 and Table 5: TH Results in Limbic Cortices 42
Figure 9 and Table 6: NET Results in Motor Cortices 43
Figure 10 and Table 7: NET Results in Prefrontal Cortices 44
Figure 11 and Table 8: NET Results in Limbic Cortices 45
Table 9 and 10: Summary of Densitometry Statistics 46
Figure 12: NET and TH Immunofluorescent Labeling 47
Figure 13: NET and TH Colocalization Proportions 48
References …………….………………………………...………………………...………...…. 49
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File download under embargo until 28 May 2027 | 2026-04-16 14:28:25 -0400 | File download under embargo until 28 May 2027 |
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