Modern views on thalamus structure and function are the outcome of a long process of scientific discovery that started centuries ago and is still ongoing. As for other brain systems, strides along this path followed, to a large extent, from the introduction of new research tools capable of providing increasingly accurate delineations of neuronal connections and functional properties. These discoveries, in turn, expanded or corrected previous theories about thalamus operation and the contributions of the thalamus to behavior. Here, I summarize the key steps of this process, from the early descriptions of macroscopic anatomy and lesion effects through electrophysiological, neurochemical, and pathway-tracing studies to current connectomic, functional, and transcriptome investigations at the single-cell and brain-wide level.

The motor thalamus is a complex system made of several subnuclei that together play a pivotal role in the planning and execution of movement. Some subnuclei were considered to form the “classical motor thalamus” (ventroanterior, ventrolateral, and ventromedial nuclei), and other thalamic subnuclei (centrolateral, parafascicular, and centromedian nuclei) innervate sensorimotor cortical areas. The cerebellum innervates all motor thalamus nuclei, with axons from all four different cerebellar nuclei. Decades of neuroanatomical tracer experiments have revealed that the cerebellar nuclei axons form excitatory synapses in the thalamus, thus creating somototopically organized cerebello-thalamo-cortical networks. Electrophysiological data at the synaptic, cellular, and network levels reveal how the action-potential firing patterns of cerebellar and cerebral cortical inputs are integrated in the motor thalamus to synergistically drive its output. In the current chapter, we provide a review of the anatomical and electrophysiological data and share our opinion on how the cerebellum regulates the precise timing of thalamo-cortical activity. We conclude our chapter with a discussion of the role of the cerebello-thalamo-cortical tract in the pathophysiology and treatment of movement disorders, autism spectrum disorders, and epilepsy.

Once thought to be a simple relay, the thalamus is now seen as a more dynamic player in overall cortical functioning. Several relatively recent observations created led to this new understanding: (1) Glutamatergic inputs can be classified as drivers (e.g., main conveyors of information) or modulators. Most inputs in the thalamus and cortex are modulators, and identifying the driver subset has provided insights into thalamocortical circuit functioning. (2) Much of the modulator input to the thalamus relates to control of the response mode of relay cells–tonic or burst. Which mode operates at any time affects the significance of the message conveyed to the cortex. (3) We now appreciate that most of thalamus, called higher order (e.g., pulvinar and medial dorsal nucleus), serves as a central relay in a transthalamic corticocortical information route organized in parallel with direct connections. First-order nuclei (e.g., lateral geniculate and ventral posterior nuclei) instead relay peripheral information to the cortex. Thus, the thalamus not only provides a behaviorally relevant, dynamic control over the nature of the information relayed, but it also plays a key role in basic corticocortical communication. These findings are reviewed, along with speculations regarding the functional significance of transthalamic pathways.

Projection neurons are both the main target of inputs to the thalamus and the only conduit for thalamic outputs. Projection neurons show similar somatodendritic morphologies, electrotonic properties, and membrane conductances, and they are all glutamatergic. Moreover, their axons never cross the midline and always target both the prethalamic reticular nucleus and one or more forebrain structures, chiefly the cerebral cortex and/or striatum. Despite these similarities, however, new anatomical, electrophysiological, and transcriptomic methods with single-cell resolution have in recent years revealed that thalamic projection neurons are remarkably diverse. Differences prominently involve axon arborization and gene-expression patterns, but significant variations in somatodendritic morphology and membrane conductances are also evident. Here, I first review the structural, functional, and gene-expression single-cell level variation observed among thalamic projection neurons. Then, based on evidence currently available for rodents, I propose a tentative catalog of six high-level cell classes. This catalog provides a consistent and cellularly accurate framework for the analysis of classic, large-scale thalamic output pathways such as the thalamocortical, thalamostriatal, and thalamoamygdaloid, among others. Moreover, developmental studies suggest that the neuron classes identified here may reflect a fundamental level of cell-lineage diversity that precedes nuclei formation or the establishment of thalamus connection systems.

Inputs to the thalamus display perplexing heterogeneity in source, transmitter, and the complexity of axon terminals. Almost the entire neuraxis provides excitatory and/or inhibitory terminals to the thalamus. The structure of both glutamatergic and GABAergic inputs varies from simple unisynaptic to highly complex multisynaptic terminals. Variable bouton structures support neurotransmission with different kinetics. In contrast to earlier accounts that proposed the dominance of a single type of input on thalamocortical activity (“relay cell”), in the majority of the thalamus, integration of inputs with different origins, transmitters, and complexities is the rule. Because most thalamic inputs are confined to only a portion of the structure, the emerging picture is that inputs can be integrated in many distinct ways in different thalamic territories. As a consequence, unlike in modular networks, where, however complex the input space is, it is homogeneous across the structure (e.g., the striatum, cerebellum, or cortex), no canonical thalamic module can be defined. The reason for this unique complexity is presently unclear, but the lack of canonical input organization in the thalamus certainly limits the opportunity of generalizing thalamic transfer function between territories. Deciphering the role of the thalamus requires an understanding of the diversity in thalamic input integration in each region.

The higher-order thalamus (e.g., the pulvinar) is widely thought to play a critical role in its interactions with the neocortex, but identifying precisely what that role is has been somewhat challenging.Here, we describe how a computational approach to understanding the nature of learning and memory in the neocortex suggests three distinct, well-defined contributions of the thalamus: (1) attention, which is perhaps the most widely discussed function of the pulvinar, is supported by a pooled inhibition dynamic involving the thalamic reticular nucleus; (2) predictive learning, where the pulvinar serves as a kind of screen on which predictions are projected, and a temporal difference between predictions and subsequent outcomes can drive error-driven learning throughout the thalamocortical system; and (3) executive function in the circuits involving the frontal cortex, where the mediodorsal (MD) thalamus is largely similar anatomically to the pulvinar and could thus support similar attentional and predictive learning functions, whereas ventral thalamic nuclei receive inhibitory modulation from the basal ganglia, supporting a gating function to regulate action based on a strong competition of Go versus No Go informed by reinforcement learning.Taken together, these important modulatory and learning contributions of the thalamus suggest that a full computational understanding of the neocortex is significantly incomplete without an integration of the thalamic circuitry.

Selective attention is a cognitive process that enables the preferential routing of behaviorally relevant information through the brain.The associated large-scale network includes regions in all major lobes as well as subcortical structures such as the thalamus. There is mounting evidence that the visual thalamus–the lateral geniculate nucleus (LGN), thalamic reticular nucleus (TRN), and pulvinar–plays an important functional role in this process. The LGN has been traditionally viewed to be a relay of retinal information to the cortex. However, it has been shown that neural gain is amplified in LGN neurons, possibly in pathway-specific ways and via TRN-regulated inhibitory control, to amplify neural representations in the focus of attention at the expense of those that are unattended, thereby boosting attention-related information and filtering unwanted distracter information at the earliest possible processing stage of the visual pathway. The pulvinar is the largest nucleus of the primate thalamus and is almost exclusively interconnected with the cortex. Its function has remained elusive for many decades. Recent evidence suggests at least two functions that may be interdependent. First, pulvinar influences on the cortex are necessary to enable regular cortical function so that information can be processed from one area to the next. Second, the pulvinar coordinates information processing across the cortical attention network by synchronizing local population activity, thereby optimizing information transfer. Taken together, emerging views suggest roles for the LGN–TRN circuit as the gatekeeper and for the pulvinar as the timekeeper of the cortex.

GABAergic interneurons are present in the thalamus of amniotes to provide local inhibition and potentially contribute to the pacing of thalamocortical network activity. However, it has long been known that the density of GABAergic interneurons varies greatly between thalamocortical subdivisions among animal species. In mammals, the GABAergic interneurons that are invariantly found in the visual areas of the thalamus are very rare in other sensory and associative regions in rodents but not in carnivores and primates. Are GABAergic interneurons dispensable for the faithful relay of sensory information? Are there different interneuron types allocated to thalamocortical hierarchies and sensory modalities? Are thalamic interneurons the product of evolutionarily conserved differentiation programmes, or do they represent examples of convergence and novelty in evolution? Important clues for answering these open questions may come from an understanding of the genesis of thalamic GABAergic neurons in different species. Neuronal cell fate in the embryonic thalamic primordium is overwhelmingly of the glutamatergic type. Recent research identified multiple extra-thalamic sources of thalamic interneurons, suggesting that the correct cellular assembly of the thalamus also depends on the species-specific maturation of other regions of the brain.

The rodent somatic sensory system is characterized by a prominent representation of the mystacial vibrissae, which form an orderly array of low-threshold mechanoreceptors. Centrally, the arrangement of the vibrissal pad is maintained in arrays of cellular aggregates referred to as barrelettes (brainstem), barreloids (thalamus), and barrels (primary sensory cortex). Trigeminal brainstem nuclei that receive vibrissal primary afferents give rise to two main streams of information, the lemniscal and paralemniscal pathways. The lemniscal pathway arises from the trigeminal nucleus principalis, transits through the ventral posterior medial nucleus of the thalamus, and projects to the primary somatosensory cortex. The paralemniscal pathway arises from the rostral part of trigeminal spinal nucleus interpolaris, transits through the posterior group of the thalamus, and projects to the somatosensory cortical areas and the vibrissa motor cortex. In this chapter, we review the anatomical organization of these pathways and propose that whereas the lemniscal pathway encodes both touch and whisking kinematics, the paralemniscal pathway signals the valence of orofacial inputs. Lastly, we call attention to the importance of understanding sensory processing in the brainstem trigeminal nuclei to understand their role in regulating behavior. These nuclei are richly interconnected and contain inhibitory circuits that operate both pre- and postsynaptically.

Sensory information enters the cerebral cortex through separate thalamocortical pathways that originate in different senses. One of these pathways links the dorsal lateral geniculate nucleus of the thalamus to the primary visual cortex and is crucial for mammalian vision. Over the past decades, there has been tremendous progress in understanding its functional organization, and new tools are allowing us to isolate, with increasing precision, its different components. Just as different senses remain segregated on their way to the cerebral cortex, the different properties of the visual stimulus also reach the primary visual cortex through separate geniculocortical pathways. On the one hand, these separate pathways underlie the parallel processing of stimulus position, eye of origin, light–dark polarity, and temporal dynamics, a strategy that is well preserved across species. On the other hand, the convergence of the different geniculocortical pathways in the visual cortex enables cortical neurons to extract features of the visual world that are not encoded by any geniculocortical pathway individually. This chapter reviews the current knowledge on the functional organization of this prominent thalamocortical pathway and concludes by raising key questions to be addressed in the future.