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.

Progenitor Hyperpolarization Regulates the Sequential Generation of Neuronal Subtypes in the Developing Neocortex

“…Finally, we examined whether hyperpolarization APs at E12.5, a time at which deep-layer neurons are normally born, also led to the generation of normally later-born neurons. As previously reported (Telley et al, 2016; Jabaudon, 2017), early born neurons have an broader radial distribution than later born neurons, yet neurons born from Kir2.1-hyperpolarized APs at E12.5 were located more superficially within deep layers than their control counterparts, and showed a corresponding change in their molecular identity when using CTIP2 (BCL11B) as a marker of L5B neurons (Figure 4F,G) (Arlotta et al, 2005). In contrast to deep-layer neurons, the position of superficial layer neurons was unaltered, consistent with progressive plasmid dilution and a dose-dependent effect of hyperpolarization.…”

“…In the mouse, each embryonic day (E) sees the peak of birth of one laminar subtype of neurons. Layer (L) 6 neurons are born first, at E12.5, followed by L5 neurons (E13.5), L4 neurons (E14.5) and finally L3 (E15.5) and L2 (E16.5) neurons (reviewed in Jabaudon, 2017). While the cell-intrinsic molecular mechanisms controlling AP divisions are increasingly understood (Dehay and Kennedy, 2007; Govindan and Jabaudon, 2017; Taverna et al, 2014), the mechanisms which drive the progression in AP neurogenic competence are not, since molecular distinction across APs are not readily apparent (Toma et al, 2016, Okamoto et al, 2016).…”

Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis

“…Hence, brain development and maturation is not just a linear expansion of the existing building blocks, but also a sequential increase in the diversity of functional modules and cell types. In the cortex for example, individual layers are born at different time points, with deep layers being born earlier than superficial layers (Angevine and Sidman, 1961;Lein et al, 2017;Luskin and Shatz, 1985), creating a diversity in the cytoarchitecture of cortical layers, cell types and regions with distinct functions (Donato et al, 2017;Jabaudon, 2017;Sur and Leamey, 2001). The maturation and refinement of the developing brain relies on neural activity, which can be evoked by sensory inputs (Penn and Shatz, 1999;Wiesel and Hubel, 1965), or spontaneously generated (Galli and Maffei, 1988;Moreno-Juan et al, 2017;O'Donovan, 1989;Penn and Shatz, 1999;Yuste, 1997).…”

Coupling progenitor and neuronal diversity in the developing neocortex

“…In mice, neurogenesis starts on the tenth embryonic day (E10.5) and proceeds for about a week, until E18.5, after which astrogliogenesis occurs (see Ref. for a recent review). Early born neurons migrate to form the deepest cortical layers (layers 6 and 5) while later born neurons migrate past them to reside more superficially and form upper layers (layer 2, 3 and 4).…”

“…Deep layer neurons mostly send their axons to subcortical targets such as the thalamus, hindbrain or spinal cord, while superficial layer neurons mostly project intracortically, either locally (layer 4 neurons), or by forming long‐range intracortical and interhemispheric projections. Numerous subtypes of neurons exist within each of the broad classes of subcortically projecting and intracortically projecting neurons, such that at least several dozens of different excitatory cell types ultimately compose neocortical circuits .…”