Fate and freedom in developing neocortical circuits

Abstract

The activity of neuronal circuits of the neocortex underlies our ability to perceive the world and interact with our environment. During development, these circuits emerge from dynamic interactions between cell-intrinsic, genetically determined programs and input/activity-dependent signals, which together shape these circuits into adulthood. Building on a large body of experimental work, several recent technological developments now allow us to interrogate these nature–nurture interactions with single gene/single input/single-cell resolution. Focusing on excitatory glutamatergic neurons, this review discusses the genetic and input-dependent mechanisms controlling how individual cortical neurons differentiate into specialized cells to assemble into stereotypical local circuits within global, large-scale networks.

Figure 1. Areal and laminar organization of the neocortex.

(a) Schematic representation of the distinct primary cortical areas in the mouse, and cell-type specific connectivity of glutamatergic cortical neurons. A1: primary auditory cortex, M1 primary motor cortex, S1: primary somatosensory cortex, V1: primary visual cortex. (b) Laminar organization of the neocortex (S1). CUX1 specifically labels intracortical projection neurons while CTIP2 labels corticospinal neurons in layer (L) 5. (c) Laminar organization of the neocortex in mammals and reptiles. Mya: millions of year ago.

Figure 2. Cortical information flow.

(a) Exteroceptive, first-order thalamic nuclei (filled in blue) project to primary cortical areas (e.g.S1, V1). Higher-order thalamic nuclei and secondary cortical areas are outlined in blue. POm: posteromedial thalamic nucleus; LG: dorsolateral geniculate nucleus; LP: lateroposterior nucleus; VB: ventrobasalis nucleus. (b) Two main pathways allow inter-areal communications: an intracortical pathway (green) and a cortico-thalamo-cortical pathway (purple), originating from L5B corticospinal neurons and which transits through higher-order thalamic nuclei.

Figure 3. Direct and indirect neurogenic pathways during corticogenesis.

(a) The neocortex is built in an inside-out manner in which neurons born from deeply located germinal zone migrate past earlier-born neurons to reside in more superficial layers. Note that initially, the preplate (PP) is split into a subplate (SP) and superficially located marginal zone (MZ) by incoming L6 neurons, such that early born neurons are later found in L1. Direct neurogenesis from the ventricular zone (VZ) predominates at early developmental stages, while indirect neurogenesis from the subventricular zone (SVZ) progressively increases during corticogenesis. E: Embryonic day; MZ: marginal zone; PP: preplate; SP: subplate. (b) FlashTag (FT) labelling highlights neurons born in the VZ through direct neurogenesis (ref. 55).

Figure 4. Self-organizing properties of neocortical neurons.

The assembly of neurons into circuits may to some extent be independent of the spatial relationships between these neurons, due to the existence of conserved, location-independent molecular controls. Input neurons (in black) connect to intracortically projecting neurons (in green), which project to output neurons (in blue). A current limitation in testing this hypothesis is our generally limited ability to establish unambiguous correspondences in cell types across species/conditions. Reeler mouse, see ref. ; L4 FEZF2 overexpression, see ref. .