Striatal topographical organization: Bridging the gap between molecules, connectivity and behavior

Abstract

The striatum represents the major hub of the basal ganglia, receiving projections from the entire cerebral cortex and it is assumed to play a key role in a wide array of complex behavioral tasks. Despite being extensively investigated during the last decades, the topographical organization of the striatum is not well understood yet. Ongoing efforts in neuroscience are focused on analyzing striatal anatomy at different spatial scales, to understand how structure relates to function and how derangements of this organization are involved in various neuropsychiatric diseases. While being subdivided at the macroscale level into dorsal and ventral divisions, at a mesoscale level the striatum represents an anatomical continuum sharing the same cellular makeup. At the same time, it is now increasingly ascertained that different striatal compartments show subtle histochemical differences, and their neurons exhibit peculiar patterns of gene expression, supporting functional diversity across the whole basal ganglia circuitry. Such diversity is further supported by afferent connections which are heterogenous both anatomically, as they originate from distributed cortical areas and subcortical structures, and biochemically, as they involve a variety of neurotransmitters. Specifically, the cortico-striatal projection system is topographically organized delineating a functional organization which is maintained throughout the basal ganglia, subserving motor, cognitive and affective behavioral functions. While such functional heterogeneity has been firstly conceptualized as a tripartite organization, with sharply defined limbic, associative and sensorimotor territories within the striatum, it has been proposed that such territories are more likely to fade into one another, delineating a gradient-like organization along medio-lateral and ventro-dorsal axes. However, the molecular and cellular underpinnings of such organization are less understood, and their relations to behavior remains an open question, especially in humans. In this review we aimed at summarizing the available knowledge on striatal organization, especially focusing on how it links structure to function and its alterations in neuropsychiatric diseases. We examined studies conducted on different species, covering a wide array of different methodologies: from tract-tracing and immunohistochemistry to neuroimaging and transcriptomic experiments, aimed at bridging the gap between macroscopic and molecular levels.

Figure 1.

Subcortical connectivity of the striatum. Widespread cortical projections reach the striatal neurons which are engaged in direct (blue) and indirect (red) pathways before reaching the thalamus which in turn projects back to the cortex. The former engages neurons which project to GPi and SNr, the latter involves neurons and detours through two synaptic stations, namely the GPe and the STN, prior to reach the GPi/SNr complex. Neurons involved in the direct pathway co-express dopamine receptor D1, substance P and dynorphin while those engaged in the indirect pathway co-express dopamine receptor D2 and enkephalin. These subsets of neurons demonstrated characteristic patterns of gene expression.

Figure 2.

Molecular diversity of striatal subterritories. Some examples of molecular markers which show differential expression across different territories of the striatum. Dotted borders encompass putative functional striatal territories defined by cortical connections; red, limbic-ventral; green, associative-dorsal; blue, sensorimotor-caudal. Boundaries of limbic, associative and sensorimotor territories have been drawn manually for schematic visualization purpose considering the evidence of available studies in literature. Among molecular markers, some show a graded expression across the rostral-caudal (e.g., DAT, dopamine receptors) or medial-lateral axis (e.g, CRYM; GPR155; DLK1); other discriminate between dorsal and ventral striatum (PDYN; PENK1; GABRA4; GABRA5) and other are increased in specific subterritories which are less clearly related to cortical topography (e.g., CHAT, SERT). Additionally, it has been suggested that D2-expressing projection neurons (not showed) show topographically specific expression patterns.

Figure 3.

Striatal topography according to structural and functional connectivity. Right: Striatal functional territories obtained by diffusion tractography are arranged along the ventro-dorsal and rostro-caudal axes. The ventral striatum (red) is mainly connected to ventromedial prefrontal cortices, the antero-dorsal territory (green) or the central striatum has stronger connectivity with prefrontal areas related to cognition, the postero-dorsal territory (blue) or the posterior striatum is mainly connected to sensorimotor areas. Left: Striatal territories defined using resting-state functional MRI, classified according corresponding cortical networks as follows: limbic (cream), default mode (red), frontoparietal (orange), somatomotor (light blue), dorsal attention (green), ventral attention (purple) and visual (violet). Behavioral labeling follows task-based activation of selected striatal territories.

Figure 4.

Molecular correlates of striatal structural and functional organization. Left: Gene expression correlates of structural connectivity based-parcellation. Genes showing enrichment for dopamine receptor signaling process (dopamine receptors D1, D2, D3, endocannabinoid system) are correlated to the dorsoventral axis and identify dorsal and ventral striatum, while genes showing enrichment for glutamate secretion identify the caudal striatum; GO, gene ontology. Right: Gene expression correlates of functional connectivity based-parcellation: Genes for prodynorfin (PDYN), oxitocyn (OXT), somatostatin (SST) and others (not mentioned) are preferentially expressed in the limbic network-related striatum, while genes for parvalbumin (PVALB) are preferentially expressed in the ventral attention network-related and somatomotor striatum.