Explore the vast range of titles available.

The striatum integrates excitatory inputs from the cortex and the thalamus to control diverse functions. Although the striatum is thought to consist of sensorimotor, associative and limbic domains, their precise demarcations and whether additional functional subdivisions exist remain unclear. How striatal inputs are differentially segregated into each domain is also poorly understood. This study presents a comprehensive map of the excitatory inputs to the mouse striatum. The input patterns reveal boundaries between the known striatal domains. The most posterior striatum likely represents the 4th functional subdivision, and the dorsomedial striatum integrates highly heterogeneous, multimodal inputs. The complete thalamo-cortico-striatal loop is also presented, which reveals that the thalamic subregions innervated by the basal ganglia preferentially interconnect with motor-related cortical areas. Optogenetic experiments show the subregion-specific heterogeneity in the synaptic properties of striatal inputs from both the cortex and the thalamus. This projectome will guide functional studies investigating diverse striatal functions. To fully understand how the brain works, we need to understand how different brain structures are organized and how information flows between these structures. For example, the cortex and thalamus communicate with another structure known as the basal ganglia, which is essential for controlling voluntary movement, emotions and reward behaviour in humans and other mammals. Information from the cortex and the thalamus enters the basal ganglia at an area called the striatum. This area is further divided into smaller functional regions known as domains that sort sensorimotor, emotion and executive information into the basal ganglia to control different types of behaviour. Three such domains have been identified in the striatum of mice. However, the boundaries between these domains are vague and it is not clear whether any other domains exist or if the domains can actually be divided into even smaller areas with more precise roles. Information entering the striatum from other parts of the brain can either stimulate activity in the striatum (known as an “excitatory input”) or alter existing excitatory inputs. Now, Hunnicutt et al. present the first comprehensive map of excitatory inputs into the striatum of mice. The experiments show that while many of the excitatory inputs flowing into the striatum from the cortex and thalamus are sorted into the three known domains, a unique combination of the excitatory inputs are sorted into a new domain instead. One of the original three domains of the striatum is known to relay information related to associative learning, for example, linking an emotion to a person or place. Hunnicutt et al. show that this domain has a more complex architecture than the other domains, being made up of many distinct areas. This complexity may help it to process the various types of information required to make such associations. The findings of Hunnicutt et al. provide a framework for understanding how the striatum works in healthy and diseased brains. Since faulty information processing in the striatum is a direct cause of Parkinson’s disease, Huntington’s disease and other neurological disorders in humans, this framework may aid the development of new treatments for these disorders.

Striatal projections from the lateral intermediate (LI) and posterior (Po) thalamic complexes were studied with the anterograde tracers wheat germ agglutinin-horseradish peroxidase and Phaseolus vulgaris leucoagglutinin. Projections to the lateral part of the head and body of the caudate nucleus (CN) and to the putamen (Pu) were found to arise from the ventral parts of the caudal subdivision of the LI besides the well established sources in the intralaminar and ventral thalamic nuclei. No projections to the CN and only a few to the Pu were found to arise from the medial division of the Po. The presence of terminal and intercalated varicosities in the thalamostriatal fibers suggests that they form both terminal and en passant synapses. Thalamostriatal fibers from these thalamic sectors were unevenly distributed within the CN, with patches of either low-density innervation or with no projections at all interspersed within irregular, more densely innervated areas. The former coincided with the acetylcholinesterase-poor striosomes and the latter areas of dense projection with the extrastriosomal matrix.

We have analyzed whether caudal regions of the caudate putamen receive direct projections from thalamic sensory relay nuclei such as the ventrobasal complex. To this aim, the delivery of the retrograde neuroanatomical tracer Fluoro-Gold into the caudal caudate putamen resulted in the appearance of retrogradely labeled neurons in the ventral posteromedial and ventral posterolateral thalamic nuclei. These projections were further confirmed with injections of the anterograde tracers biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin into these thalamic nuclei, by showing the existence of axonal terminal fields located in the caudal striatum. These results support the existence of direct projections linking the thalamic ventrobasal complex and the caudal striatum in the rat, probably via collateralization of thalamocortical axons when passing through the caudate putamen, and therefore supporting the putative involvement of the caudal striatum in sensory-related functions.

This paper provides an overview of the major organizational features of the basal ganglia and related thalamic centers, as delineated by the application of single-axon or single-cell labeling procedures in primates. These studies have revealed that the striatum, the external pallidum and the subthalamic nucleus harbor several types of projection neurons endowed with a highly collateralized axon that allows these neurons to interact with most components of the basal ganglia. In contrast, the internal pallidum, which is a major output structure of the basal ganglia, contains only two types of projection neurons. First, there is a minority of “limbic” pallidal neurons with a poorly branched axon that arborized profusely within the lateral habenula, which stands out as the most densely innervated pallidal target. Second, there is a majority of pallidal “motor” neurons with a long (total axonal length up to 27 cm) and highly branched axon that provides collaterals to the ventral tiers thalamic nuclei, the brainstem pedunculopontine nucleus and the centre médian/parafascicular thalamic complex. This type of axon allows internal pallidal neurons to send efferent copies of the same information to the thalamus and brainstem and hence influence various neuronal systems scattered throughout the neuraxis. Pallidal information is conveyed to the cerebral cortex and the striatum via the thalamus, while it is projected back to different components of the basal ganglia via the numerous reentrant pathways that arise from the pedunculopontine nucleus. Virtually all neurons in the centre médian thalamic nucleus innervate massively the striatum and less prominently the primary motor cortex, which in turn projects to the striatum directly or via a collateral from long-range corticofugal pyramidal axons. The results call for a reappraisal of our current concept of the anatomical and functional organization of basal ganglia, which play a crucial role in sensorimotor integration. Our data indicate that basal ganglia and related thalamic nuclei form a widely distributed neuronal network, whose elements are endowed with a highly patterned set of axon collaterals. This morphological feature allows a complex and exquisitely precise interaction between the various basal ganglia and related thalamic nuclei. The elucidation of this finely tuned network is needed to understand the complex spatiotemporal sequence of neural events that ensures the flow of cortical information through the basal ganglia and thalamus.

Synaptic inputs from cortex and thalamus were compared in electrophysiologically defined striatal cell classes: direct and indirect pathways’ striatal projection neurons (dSPNs and iSPNs), fast-spiking interneurons (FS), cholinergic interneurons (ChINs), and low-threshold spiking-like (LTS-like) interneurons. Our purpose was to observe whether stimulus from cortex or thalamus had equivalent synaptic strength to evoke prolonged suprathreshold synaptic responses in these neuron classes. Subthreshold responses showed that inputs from either source functionally mix up in their dendrites at similar electrotonic distances from their somata. Passive and active properties of striatal neuron classes were consistent with the previous studies. Cre-dependent adeno-associated viruses containing Td-Tomato or eYFP fluorescent proteins were used to identify target cells. Transfections with ChR2-eYFP driven by the promoters CamKII or EF1.DIO in intralaminar thalamic nuclei using Vglut-2-Cre mice, or CAMKII in the motor cortex were used to stimulate cortical or thalamic afferents optogenetically. Both field stimuli in the cortex or photostimulation of ChR2-YFP cortical fibers evoked similar prolonged suprathreshold responses in SPNs. Photostimulation of ChR2-YFP thalamic afferents also evoked suprathreshold responses. Differences previously described between responses of dSPNs and iSPNs were observed in both cases. Prolonged suprathreshold responses could also be evoked from both sources onto all other neuron classes studied. However, to evoke thalamostriatal suprathreshold responses, afferents from more than one thalamic nucleus had to be stimulated. In conclusion, both thalamus and cortex are capable to generate suprathreshold responses converging on diverse striatal cell classes. Postsynaptic properties appear to shape these responses.