The thalamus is at the heart of the pathways that allow us to perceive the world and interact meaningfully with our surroundings. Centrally located in the brain, this structure acts as a bridge between the exteroceptors at the surface of our bodies and the neocortex, where activation of these receptors becomes a conscious perception. Also, as increasingly recognized, the thalamus acts to bridge together distinct cortical areas (Theyel et al., 2010), and to control cortical states in a behaviorally relevant manner (Cruikshank et al., 2010; Minlebaev et al., 2011; Poulet et al., 2012). Despite the central functional and anatomical position of the thalamus, the development of the circuits that connect the distinct mechano-, photo- and chemo-receptors to their respective thalamic nuclei, and the neurons within these nuclei to their proper area- and cell-type-specific cortical target, is understood only in broad terms. Although the general mechanisms that guide the growth cones of thalamic axons from the diencephalon into the telencephalon have been identified with a reasonable level of detail, how neurons in the distinct thalamic nuclei are able to identify their areal and cell-type-specific partners is largely unknown. Furthermore, how intrinsic spontaneous activity and the pattern of activity generated by these exteroceptors (e.g. the retina, or the whiskers) act to guide afferent and efferent thalamic axons to their proper targets is still an intense area of investigation, driven by the use of elegant optogenetic and cell-type-specific genetic approaches (for recent examples, see Koch et al., 2011; Zhang et al., 2012). ‘The thalamus has not had good press in the recent past’. About 15 years ago, Sherman and Guillery began a now classical review of thalamic function with this sentence (Sherman & Guillery, 1996). They follow by regretting that after an initial phase of excitement (‘years of glory’), as the structure was recognized as a major source of input to the cortex, it has been hard to convince the neuroscientific community that the thalamus is more than a simple relay. In February 2011, scientists assembled in Arolla, a picturesque village in the Swiss Alps, to discuss aspects of thalamocortical development and function. In this special issue of European Journal of Neuroscience, we recapitulate some of the topics discussed at the meeting and argue that the years of glory may be back; with the ever-expanding availability of molecular approaches that enable cell-type-specific manipulation of cell identity and activity, the field is poised to bloom with new discoveries. The areas of interest that can now be investigated range from embryonic day 10 to adulthood, and from the specification of distinct subtypes of thalamocortical neuronal subtypes to the mechanisms controlling the experience-dependent pruning of thalamocortical axons. There is much ground to be covered. While the neocortex is 250 millions years younger than the thalamus (Butler, 2008; Butler et al., 2011) and has a tremendous diversity of cell types compared with the thalamus, our understanding of the molecular mechanisms that control the generation, migration and specification of neocortical neurons is much more detailed than in the thalamus (Lui et al., 2011). Similarly, on a larger anatomical scale, while the molecular controls over cortical area formation are increasingly understood, very little is known on how the thalamus becomes parcelled into functionally distinct nuclei. Nakagawa and Shimogori open this special feature of EJN by describing the molecular and morphological organization of the developing thalamus, and highlight some of the key molecular players that are responsible for the generation of distinct thalamic domains. After being born and having reached their target location in the thalamus, thalamocortical neurons have to send axons to the cerebral cortex through specific paths. Our understanding of forebrain patterning has increased tremendously over the past few years, bringing with it a better understanding of the guidance mechanisms that allow axons to bridge together the thalamus and the cortex. Molnár et al. review recent results in thalamic patterning, in the cellular and molecular mechanisms of axon guidance from the thalamus to the cortex, with emphasis on the current theories that are thought to account for the maintenance of topographic order in the thalamocortical projections. The classical view is that genetic programs control the early wiring of the forebrain while activity-dependent mechanisms take over at a later stage (Sur & Rubenstein, 2005). However, an increasing number of observations demonstrate that neural activity and genetic programs actually interact to specify the composition and organization of neural circuits at all stages of development. Moreover, evidence has been accumulating that electrical activity, including spontaneous firing, plays a crucial role not only in late developmental stages but also in earlier stages (De Marco Garcia et al., 2011). In their review of this active field, Yamamoto and López-Bendito describe the various forms of early neural activity displayed by the developing brain, and their potential roles in neuronal wiring. During critical periods, the developing cortical maps are vulnerable to deleterious effects of sensory organ damage or sensory deprivation. Recent advances in molecular genetics and analyses of genetically altered mice have provided new insight into neural pattern formation in the neocortex and the mechanisms underlying critical period plasticity. Erzurumlu and Gaspar review the development and patterning of the somatosensory barrel cortex and the critical period plasticity, with a particular emphasis on the importance of the timing of the events that allow patterning to be transmitted from the periphery to the cortex. The mechanisms that determine how axons from the periphery reach the thalamus, identify their specific target nucleus and distribute topographically within it are poorly understood. Pouchelon et al. summarize the state of the field, taking the somatosensory system as a model system. They emphasize the broad diversity in somatosensory afferent pathways that underlie different functional properties. Remarkably, most developmental studies have focused on just one of these pathways, the lemniscal pathway, while the development and plasticity of paralemniscal and associated pathways remain largely unexplored. Although the diversity of the thalamus is generally thought of in terms of nuclei, where one nucleus is assumed to contain only one cell type, recent findings indicate that cellular diversity in the thalamus is much wider than previously thought, and that most nuclei are actually cellularly heterogeneous. Most of the research has focused on two nuclei, the ventrobasal complex (somatosensory) and the dorsal lateral geniculate nucleus (visual), which indeed are relatively homogeneous. Jabaudon and Clasca review cellular diversity within more ‘typical’ thalamic nuclei, and discuss how our understanding of this diversity may inform our perception of thalamic functions. One of the first molecules to have been shown to play a central role in thalamocortical patterning is serotonin, and since the seminal study of Cases et al. (1996), there has been tremendous interest in the role of this neurotransmitter in patterning somatosensory thalamocortical axons. van Kleef and collaborators discuss how changes in extracellular serotonin levels can modulate axonal pathfinding in the system and address some of the apparent paradoxes in the field. Finally, Blakey et al. provide an original research contribution on the role of vesicular release in thalamocortical axon target recognition in the cortex. They show that branching is independent of vesicular release in SNAP25−/− mice (which lack vesicular release). In summary, as the articles in this issue show, there are still many questions to be addressed before we can understand how the multifaceted structure that bridges our thoughts with the reality of the outside world is built. However, the ability to manipulate distinct thalamic input and thalamocortical pathways with high spatial and temporal control carries the potential to provide new insights into these developmental mechanisms, and should provide us with exciting discoveries in the years to come.
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Nov 16, 2023
Shuxue Liu + 6