Abstract
The entopeduncular nucleus (EPN) in rodents is one of the two major output nuclei of the basal ganglia and corresponds to the internal segment of the globus pallidus in primates. Previous studies have shown that the EPN contains three types of neurons that project to different targets, namely, parvalbumin (PV)-, somatostatin (SOM)-, and choline acetyltransferase-positive neurons. However, we have recently reported that neurons lacking immunoreactivities for these substances are present in the EPN. Here, we demonstrate that 27.7% of all EPN neurons showed immunoreactivity for nitric oxide synthase (NOS). Among them, NOS-only positive and NOS/SOM double-positive neurons accounted for 20.1% and 6.8%, respectively, whereas NOS/PV double-positive neurons were rarely observed. NOS-containing neurons were distributed in a shell region surrounding the thalamus-targeting, PV-rich core region of the EPN, especially in the ventromedial part of the shell. The retrograde tracer fluoro-gold (FG) was injected into several target regions of EPN neurons. Among FG-labeled EPN neurons after injection into the lateral habenula (LHb), NOS-only positive, NOS/SOM double-positive, and SOM-only positive neurons accounted for 25.7%, 15.2%, and 59.1%, respectively. We conclude that NOS-positive neurons are the second major population of LHb-targeting EPN neurons, suggesting their possible involvement in behaviors in response to aversive stimuli.
Highlights
An influential concept of the neural circuits in the basal ganglia is expressed as the direct/indirect pathway scheme (Albin et al 1989; Alexander and Crutcher 1990), to which another important pathway, called hyperdirect, has been added (Nambu et al 2000, 2002)
A large number of nitric oxide synthase (NOS)-negative/FG-positive neurons were further identified in the middle and caudal parts of the entopeduncular nucleus (EPN). These neurons showed a core-like distribution pattern, which corresponded well to the distribution of PV neurons. These findings further demonstrate that the two populations of NOS neurons projecting to the different targets, lateral habenula (LHb) and ventral anterior-ventral lateral thalamus (VA-VL), intermingled with each other in the rostral part of the EPN, it cannot be determined whether axon collaterals toward the LHb and VA-VL originate from the same neurons
NOS-only positive and NOS/SOM double-positive neurons account for 20.1% and 6.5% of all EPN neurons, respectively
Summary
An influential concept of the neural circuits in the basal ganglia is expressed as the direct/indirect pathway scheme (Albin et al 1989; Alexander and Crutcher 1990), to which another important pathway, called hyperdirect, has been added (Nambu et al 2000, 2002). The main targets of the EPN/GPi are the ventral anterior-ventral lateral thalamus (VA-VL), the parafasicular-center median complex (PF-CM), the pedunculo-pontine tegmental nucleus (PPN) of the brainstem, and the lateral habenula (LHb) Kooy and Carter 1981; Parent and De Bellefeuille 1982; Ilinsky and Kultas-Ilinsky 1987; Parent et al 1999). These areas are targeted in a separable manner by two types of EPN/GPi neurons with different morphological characteristics (Kha et al 2000; Parent et al 2001). GABAergic EPN neurons containing the calcium-binding protein parvalbumin (PV) target the VA-VL, PF-CM, and PPN (Rajakumar et al 1994), whereas somatostatin (SOM)-containing neurons project to the LHb (Vincent and Brown 1986). The projection to the LHb has gained much attention, because it is critically involved in the evaluation of action outcomes and the avoidance of aversive stimuli (Matsumoto and Hikosaka 2007; Proulx et al 2014; Stephenson-Jones et al 2016), a mechanism antagonistic to the well-established circuitry for reinforcement learning through activation of midbrain dopaminergic neurons
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