The Thalamostriatal Pathway and the Hierarchical Control of Action
Authors: Laura A. Bradfield, Miriam Matamales, Jesus Bertran-Gonzalez
Journal: Neuron (2018)

Sequential ordering of motor commands is required for the simplest of our daily activities. In this issue of Neuron, Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar show that distinct thalamic inputs to different regions of the dorsal striatum critically modulate the initiation and execution of action sequences. Sequential ordering of motor commands is required for the simplest of our daily activities. In this issue of Neuron, Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar show that distinct thalamic inputs to different regions of the dorsal striatum critically modulate the initiation and execution of action sequences. The days of the thalamus being recognized as a simple relay of sensorimotor information are well and truly over, as more and more evidence points to the central role of direct thalamic projections to the striatum in major cognitive functions such as goal-directed learning, action selection, and flexible control of behavior. In the current issue of Neuron, Díaz-Hernández and colleagues (Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar) add to this rapidly growing body of work, reporting the dissociable roles of striatal afferent connections originating from two different thalamic territories in the performance of sequences of lever press actions. Notably, the circuitry identified by Díaz-Hernández et al. is unusual, as half of it is part of the well-documented thalamostriatal projection (including the parafascicular nucleus, PF), whereas the other half belongs to what has been traditionally classified as a pure somatosensory relay to the cortex (including the ventral posterior nucleus). Therefore, this study uncovers an intriguing thalamostriatal circuitry spanning medio-lateral territories that serves a previously unrecognized role in modulating elicitation and performance of sequences of actions, potentially shedding light on how animals engage and execute automatic action in a hierarchical manner. Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar first performed a series of anatomical analyses to test the connectivity between the thalamus and the striatum. Combining anterograde and retrograde tracing techniques, they showed that the parafascicular, posterior, and centrolateral thalamic nuclei (grouped as PFs) preferentially innervate the dorsomedial striatum (DMS), whereas the ventroposteromedial, ventromedial, and ventroposterolateral (grouped as VPs) nuclei target the dorsolateral striatum (DLS). In addition, ex vivo activation of thalamic terminals onto presumably spiny projection neurons in different striatal regions showed that intrastriatal stimulation of PFs inputs evoked EPSCs preferentially in cells of the DMS and not the DLS, whereas the opposite was true for VPs inputs. The authors then trained mice in a self-paced operant task which involved learning to press a lever on a fixed ratio schedule to earn a sucrose reward. Over days, animals progressively started pressing in bouts (four presses on average), increasing within-sequence press rate and reducing the time to start a new sequence (latency). After 11 days of training, Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar performed in vivo electrophysiological recordings in PFs and VPs and showed that neuronal activity in both correlated with sequence initiation, whereas only neurons in the VPs remained active during sequence execution. Each thalamostriatal circuit's preferential modulation of these different aspects of action elicitation/execution was further evidenced using a particularly elegant follow-up study, in which relevantly modulated thalamic neurons projecting to the striatum were distinguished through post hoc optogenetic phenotyping (antidromic photo-identification). The authors recorded from identified thalamostriatal neurons (PFs→DMS or VPs→DLS) and confirmed that the DMS-projecting PFs neurons were preferentially modulated immediately prior to action sequence initiation, whereas DLS-projecting VPs neurons showed preferential modulation during execution. Finally, to demonstrate the causality of PFs→DMS and/or VPs→DLS pathway contributions to the initiation/execution of actions, the authors performed optogenetic inhibition of thalamostriatal terminals while animals performed the action sequence task. When optogenetic inhibition occurred before the first lever press of each bout (i.e., when a mouse crossed an infrared beam to move toward the lever), inhibition of either PFs→DMS or VPs→DLS terminals increased the latency to initiate sequences. During a second optogenetic session in the same animals, however, when terminals were inhibited only after lever press sequences had been initiated (i.e., during execution), inhibition of VPs→DLS terminals increased the number of lever presses while leaving the duration of the sequence intact, whereas PFs→DMS inhibition had no effect. These results suggest that although PFs→DMS and VPs→DLS projections each contribute to the preparation to initiate action sequences, VPs→DLS projections in particular may be a key player in establishing performance rules during the execution of such sequences. The thalamus is a highly heterogeneous structure both at anatomical and functional levels. While classically considered a two-way relay of large-scale sensory and motor information to and from the cortex, several subsequent studies have identified thalamic regions whose projections show a marked preference toward different regions of the striatum (Cowan and Powell, 1956Cowan W.M. Powell T.P. A study of thalamo-striate relations in the monkey.Brain. 1956; 79: 364-390Crossref PubMed Scopus (143) Google Scholar). These nuclei form the intralaminar nuclear complex of the thalamus and are known to provide critical first-hand modulation to basal ganglia functions. It is not surprising, then, that Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar found that the parafascicular nucleus and neighboring intralaminar nuclei (labeled PFs) are densely connected with various striatal areas. Notably, their experiments reveal topographically organized projections between the PF and the striatum, with medial PF innervating the DMS and lateral PF, the DLS. What is surprising, however, is the discovery of a smaller but non-negligible thalamostriatal projection mostly originating in ventroposteromedial and ventroposterolateral nuclei (labeled VPs), which to date has been considered as strictly non-striatum projecting based on their almost exclusive connections with somatosensory cortices (S1/2) (Hunnicutt et al., 2016Hunnicutt B.J. Jongbloets B.C. Birdsong W.T. Gertz K.J. Zhong H. Mao T. A comprehensive excitatory input map of the striatum reveals novel functional organization.eLife. 2016; 5: 19103Crossref PubMed Scopus (223) Google Scholar). It is worth noting that most of the cells labeled using anterograde and retrograde tracing were close to the anterior intralaminar region, in proximity to the paracentral and centrolateral nuclei whose projections are well documented to target lateral territories of the dorsal striatum (Smith et al., 2004Smith Y. Raju D.V. Pare J.F. Sidibe M. The thalamostriatal system: a highly specific network of the basal ganglia circuitry.Trends Neurosci. 2004; 27: 520-527Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar). Clearly, although future research using highly restricted labeling of thalamic neurons should further confirm the exact circuitry involved, Díaz-Hernández and collaborators have uncovered a new role of the thalamostriatal system that directly relates to the control of sequence performance. Unlike lateral circuitry, the role of thalamostriatal projections targeting medial territories of the striatum has been thoroughly explored. Mounting evidence suggests that PF inputs, whether targeting cholinergic or projection systems in the DMS, provide an "internal state" or "context" signal that is critical for associative learning during goal-directed action (Bradfield et al., 2013Bradfield L.A. Bertran-Gonzalez J. Chieng B. Balleine B.W. The thalamostriatal pathway and cholinergic control of goal-directed action: interlacing new with existing learning in the striatum.Neuron. 2013; 79: 153-166Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, Bradfield and Balleine, 2017Bradfield L.A. Balleine B.W. Thalamic control of dorsomedial striatum regulates internal state to guide goal-directed action selection.J. Neurosci. 2017; 37: 3721-3733Crossref PubMed Scopus (25) Google Scholar, Matamales et al., 2016Matamales M. Skrbis Z. Hatch R.J. Balleine B.W. Götz J. Bertran-Gonzalez J. Aging-related dysfunction of striatal cholinergic interneurons produces conflict in action selection.Neuron. 2016; 90: 362-373Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar found that, in fully trained mice, PFs→DMS modulation is most relevant during the instances preceding action initiation, perhaps illustrating the confluence of "state" signals used to contextualise the end of one action sequence and the beginning of another (Figure 1). In contrast, the function of thalamostriatal projections in lateral striatum is not well documented. One particularly interesting result in Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar concerns the involvement of VPs→DLS in setting the speed of action execution. The authors found that optogenetically inhibiting VPs→DLS pathways either prior to or during the execution of the action sequence resulted in increased lever presses that were confined within the same total sequence durations. These results add to recent studies (including the authors' previous work) supporting the role of the DLS in controlling the pace of action (Tecuapetla et al., 2016Tecuapetla F. Jin X. Lima S.Q. Costa R.M. Complementary contributions of striatal projection pathways to action initiation and execution.Cell. 2016; 166: 703-715Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, Matamales et al., 2017Matamales M. Skrbis Z. Bailey M.R. Balsam P.D. Balleine B.W. Götz J. Bertran-Gonzalez J. A corticostriatal deficit promotes temporal distortion of automatic action in ageing.eLife. 2017; 6: 29908Crossref Scopus (6) Google Scholar) and may provide critical new information on the microcircuitry responsible for the temporal scaling of action sequences. Finally, it is worth considering the possibility that once action sequences are well learned, they might be initiated intentionally, but then performed automatically, in a hierarchical manner in line with the ideas put forward by Dezfouli and Balleine, 2012Dezfouli A. Balleine B.W. Habits, action sequences and reinforcement learning.Eur. J. Neurosci. 2012; 35: 1036-1051Crossref PubMed Scopus (180) Google Scholar and as illustrated in Figure 1. Indeed, it is well established that action control becomes automatic as sequences are well practiced, and that the striatal control of actions during this process tends to move from its dorsomedial to its more dorsolateral sections. Thus, in the current paper, it is attractive to think that all PFs→DMS and VPs→DLS inputs are necessary for the intentional, first-tier selection of the incoming action sequence (possibly via state contextualisation as outlined above), and once pre-loaded, the VPs→DLS inputs remain under the second-tier of the hierarchy at which point actions are performed automatically. This interpretation is, of course, entirely speculative, and more accurate behavioral dissections are necessary to confirm thalamic involvement in this process. In summary, these exciting new findings from Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The thalamostriatal projections contribute to the initiation and execution of a sequence of movements.Neuron. 2018; (Published online October 13, 2018)https://doi.org/10.1016/j.neuron.2018.09.052Scopus (36) Google Scholar add to a significant and increasing body of evidence espousing a more cognitive role for thalamic nuclei in action initiation and execution. This is important, because when these processes go awry, they can have implications for a number of diseases, including disorders of compulsivity as well as Parkinson's disease which feature strong dysregulations of various thalamic nuclei. Thus, providing new targets for study—such as novel thalamic modulations in the DLS—will potentially lead to new discoveries about their neurophysiological mechanisms and possibly even new ways to treat such disorders. The authors' work was funded by grants from the National Health and Medical Research Council of Australia (GNT1087689) to L.A.B. and the Australian Research Council (DE160101275) to J. B.-G. The Thalamostriatal Projections Contribute to the Initiation and Execution of a Sequence of MovementsDíaz-Hernández et al.NeuronOctober 18, 2018In BriefDiaz-Hernández et al. performed electrophysiological recordings of antidromically photo-identified thalamostriatal neurons and optogenetic inhibition of the thalamostriatal terminals to probe their contribution to the smooth initiation and execution of a sequence of movements. Their data support a model in which different thalamostriatal projections provide differential control of distinct phases of initiating/executing a sequence of movements. Full-Text PDF Open Archive