Neurons gating behavior-developmental, molecular and functional features of neurons in the Substantia Nigra pars reticulata

Abstract

The Substantia Nigra pars reticulata (SNpr) is the major information output site of the basal ganglia network and instrumental for the activation and adjustment of movement, regulation of the behavioral state and response to reward. Due to both overlapping and unique input and output connections, the SNpr might also have signal integration capacity and contribute to action selection. How the SNpr regulates these multiple functions remains incompletely understood. The SNpr is located in the ventral midbrain and is composed primarily of inhibitory GABAergic projection neurons that are heterogeneous in their properties. In addition, the SNpr contains smaller populations of other neurons, including glutamatergic neurons. Here, we discuss regionalization of the SNpr, in particular the division of the SNpr neurons to anterior (aSNpr) and posterior (pSNpr) subtypes, which display differences in many of their features. We hypothesize that unique developmental and molecular characteristics of the SNpr neuron subtypes correlate with both region-specific connections and notable functional specializations of the SNpr. Variation in both the genetic control of the SNpr neuron development as well as signals regulating cell migration and axon guidance may contribute to the functional diversity of the SNpr neurons. Therefore, insights into the various aspects of differentiation of the SNpr neurons can increase our understanding of fundamental brain functions and their defects in neurological and psychiatric disorders, including movement and mood disorders, as well as epilepsy.

Keywords: GABAergic neuron; Substantia Nigra pars reticulata; basal ganglia; movement; neurogenesis; reward; seizure; sleep.

FIGURE 1

The anatomical context and connectivity of Substantia Nigra. (A) Coronal view to the adult mouse brain at the level on midbrain (level indicated with arrows on the 3D image in left). The Substantia Nigra pars reticulata (SNpr), pars compacta (SNpc) and Ventral Tegmental Area (VTA) are highlighted. (B) Sagittal view to adult mouse brain, showing the positions of SNpr and its interconnected structures. Str, striatum; STN, Subthalamic nucleus; SC, Superior colliculus; pRF, pontine reticular formation. (C) Input and output structures of the SNpr and their interconnections in mature mouse brain. Black arrows represent inhibitory GABAergic (blunt arrowhead) and excitatory glutamatergic (triangular arrowhead) projections. The dopaminergic neuron projection from SNpc to striatum (Str) is shown in violet. Th, Thalamus; GPe, Globus Pallidus, external segment; MRF, midbrain reticular formation; MLR, midbrain locomotor region; DR, Dorsal Raphe nucleus; PPTn, pedunculopontine tegmental nucleus. The views in (A,B) are created using the Brain Explorer 2 app (Allen Institute for Brain Science, https://mouse.brain-map.org/static/brainexplorer).

FIGURE 2

The development, connectivity and function of the anterior and posterior SNpr neurons. (A) Developmental origin and differential gene expression in the aSNpr GABAergic neurons and the pSNpr GABAergic and glutamatergic neurons. The aSNpr GABAergic neurons originate in the Nkx6-2 expressing neuronal progenitors in the ventrolateral midbrain or posterior diencephalon (green), and are characterized by the expression of Six3 and Foxp1. aSNpr neurons require the function of the proneural genes Ascl1 and Helt and the selector genes Tal1 and Gata2 in order to acquire GABAergic neuron phenotype. In early precursors, Gata2 and Tal2 are activated independently of each other and can have both common and separate target genes. The pSNpr GABAergic neurons (violet) and glutamatergic neurons (blue) originate in the Nkx6-1 expressing neuronal progenitors in the anterior ventrolateral hindbrain. pSNpr progenitors express Foxn4, Ascl1 and Notch1. pSNpr GABAergic neurons are characterized by the expression of Pax5, Ctip2 and Pou6f2, and require the function of Tal1 and Gata2/Gata3 to acquire GABAergic neuron phenotype. Sox14, En1 and Zfpm1 expression marks further subtypes of pSNpr neurons, which are located in distinct spatial positions: lateral (l), dorsomedial (dm) or ventrolateral (vl) pSNpr. The transcription factors involved in the fate specification of pSNpr glutamatergic neurons are not known. The relatively minor populations of dopaminergic and cholinergic SNpr neurons are not shown. (B) Differences in the output connectivity of aSNpr and pSNpr neurons. One of the hallmarks of SNpr neurons are the axon-collaterals. The common targets of the aSNpr and pSNpr are thalamus, MRF (midbrain and pontine reticular formation) and PPTn (pedunculopontine nucleus. In addition to projections to the common targets, the aSNpr neuron axon-collaterals (green) project to superior colliculus (SC), while the pSNpr axon-collaterals (violet) more often project to brainstem. Thalamus is one of the major targets of the SNpr glutamatergic neurons (blue). SNpr glutamatergic neurons specifically project to the nucleus reticularis of thalamus (nRT, see text). (C) Variety of functions of the SNpr neuron subtypes. The table summarizes the known functions of the Pvalb- or Gad2-expressing SNpr GABAergic neurons in the control of motor activity and behavioral state, and the functions of the anterior and posterior parts of the SNpr in the seizure activity, motivation, and reward. How these functions are related to specific molecularly defined SNpr neuron subtypes remains to be shown.