Abstract
The subthalamic nucleus (STN) is a small, ovoid structure, and an important site of deep brain stimulation (DBS) for the treatment of Parkinson’s disease. Although the STN is a clinically important structure, there are many unresolved issues with regard to it. These issues are especially related to the anatomical subdivision, neuronal phenotype, neuronal composition, and spatial distribution. In this study, we have examined the expression pattern of 8 neuronal markers [nNOS, NeuN, parvalbumin (PV), calbindin (CB), calretinin (CR), FOXP2, NKX2.1, and PAX6] in the adult human STN. All of the examined markers, except CB, were present in the STN. To determine the neuronal density, we have performed stereological analysis on Nissl-stained and immunohistochemical slides of positive markers. The stereology data were also used to develop a three-dimensional map of the spatial distribution of neurons within the STN. The nNOS population exhibited the largest neuronal density. The estimated total number of nNOS STN neurons is 281,308 ± 38,967 (± 13.85%). The STN neuronal subpopulations can be divided into two groups: one with a neuronal density of approximately 3,300 neurons/mm3 and the other with a neuronal density of approximately 2,200 neurons/mm3. The largest density of STN neurons was observed along the ventromedial border of the STN and the density gradually decreased toward the dorsolateral border. In this study, we have demonstrated the presence of 7 neuronal markers in the STN, three of which were not previously described in the human STN. The human STN is a collection of diverse, intermixed neuronal subpopulations, and our data, as far as the cytoarchitectonics is concerned, did not support the tripartite STN subdivision.
Highlights
The phenotype and the number of subthalamic nucleus (STN) neurons are well documented in experimental animals, the data on the human STN are often lacking (Keuken et al, 2012; Emmi et al, 2020)
To estimate the number of STN neurons, we have used the nNOS-ir neurons as we believe nNOS to be the pan-neuronal marker in the STN
All data suggest that the most abundant neuronal marker in the STN is nNOS, constituting more than 90% of neurons in the STN (Nisbet et al, 1994; Dos Santos-Lobato et al, 2016). nNOS is a key enzyme in the production of NO, an atypical neurotransmitter in the human brain
Summary
The subthalamic nucleus (STN) is a small diencephalic structure, an important part of the basal ganglia circuitry involved in modulating information flow through basal ganglia (Parent and Hazrati, 1995; Shink et al, 1996; Nakano, 2000; Parent, 2002; Karachi et al, 2005; Benarroch, 2008; Keuken et al, 2012; Emmi et al, 2020). It is interesting to note the lack of studies analyzing the expression and spatial distribution of transcription factors (TFs) in the human STN, important for the proliferation and specification of neurons in the STN and adjacent structures in the brain of experimental animals (such as PAX6, NKX2.1, FOXP2, PITX2, and FOXA1) (Stoykova and Gruss, 1994; Puelles et al, 2000; Mastick and Andrews, 2001; Wolf et al, 2001; Martin et al, 2002, 2004; Ferland et al, 2003; Teramitsu et al, 2004; Pauly et al, 2014; Dodson et al, 2015; Gasser et al, 2016; Kee et al, 2017; Co et al, 2020; Wallén-Mackenzie et al, 2020). We have developed a spatial threedimensional map of STN and proposed the organizational model of STN based on the observed neuronal density and distribution
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