Scientific Understanding of Consciousness
Entorhinal-Hippocampal Circuit Maturation driven by Stellate Cells
Science 02 Feb 2017: eaai8178, DOI: 10.1126/science.aai8178
Stellate cells drive maturation of the entorhinal-hippocampal circuit
Kavli Institute for Systems Neuroscience and Centre for the Biology of Memory, Norwegian University of Science and Technology, Olav Kyrres gate 9, MTFS, 7491 Trondheim, Norway
The neural representation of space relies on a network of entorhinal-hippocampal cell types with firing patterns tuned to different abstract features of the environment. To determine how this network is set up during early postnatal development, we monitored markers of structural maturation in developing mice, both in naïve animals and after temporally restricted pharmacogenetic silencing of specific cell populations. We found that entorhinal stellate cells provide an activity-dependent instructive signal that drives maturation sequentially and unidirectionally through the intrinsic circuits of the entorhinal-hippocampal network The findings raise the possibility that a small number of autonomously developing neuronal populations operate as intrinsic drivers of maturation across widespread regions of cortex.
To create a neural representation of the external world, sensory stimuli are topographically mapped onto highly organized neural networks spanning multiple sensory areas in the neocortex. The early development of such topographical sensory representations depends strongly on spontaneous and sensory-driven neural activity spreading bottom-up from sensory receptors to sensory cortices.
Like in the sensory systems, the brain’s representation of space relies on an extended network of specialized cell types spanning multiple interconnected brain regions. Cell types involved in the representation of space include place cells in the hippocampus, and grid, border, head direction and speed cells in the medial entorhinal cortex (MEC). Properties of these cells are thought to reflect the intrinsic connectivity of the MEC as well as the unique unidirectional organization of entorhinal projections through the hippocampus. However, in contrast to the primary sensory cortices, little is known about how the entorhinal-hippocampal microcircuit is assembled during development, or what role neural activity has in refining the connectivity and maturation of the circuit. Place, border and head direction cells exhibit adult-like features from the onset of spatial navigation at 2-3 weeks of age,, while the periodic firing pattern of grid cells emerges later, at approximately 4 weeks. The spatial accuracy of place cells evolves with a similarly protracted time course, suggesting that early interactions between subregions of the network might be crucial for the eventual emergence of spatially specific firing.
With these parallels in mind, we sought to determine how structural elements of the entorhinal-hippocampal circuit are wired together during development. We monitored network-wide developmental changes in the expression of maturation-related anatomical markers, taking advantage of targeted pharmacogenetic silencing methods to determine whether activity in any elements of the circuit had particular functions in organizing maturation across the network as a whole. Our data show that the entorhinal-hippocampal circuit matures in a linear sequence that recapitulates excitatory information flow through the adult hippocampal network. Excitatory activity at each stage of the circuit was necessary for the development of the following stages. Stellate cells in MEC-L2 were at the top of this developmental hierarchy, providing an instructive signal that drove maturation across the entire entorhinal-hippocampal network.
To determine the temporal profile of maturation among identified populations of neurons in the entorhinal-hippocampal network, we first monitored the expression of doublecortin (DCX) in each area of the network during the first postnatal month. DCX is a microtubule-associated protein that is present in neuronal precursors and immature neurons, where it promotes dendritic growth, and is downregulated during the stabilization of synaptic connectivity at late developmental stages. In adults, the protein is expressed only in immature neurons in areas with ongoing neurogenesis. Because of this unique association with immature neurons, we used DCX as a marker of the maturational state of different classes of entorhinal and hippocampal neurons. For each region or cell class, we quantified for every third day the fraction of neurons in which DCX expression had declined to undetectable levels. We subsequently identified for each region or cell type the first day on which this fraction constituted 80% or more of the NeuN+ cells. The quantification was validated by testing it on entorhinal-hippocampal sections from adult mice (P90-P120). As expected, there were virtually no DCX+ neurons in any of the areas analyzed, in line with published values, except for the dentate gyrus, where adult neurogenesis accounts for DCX expression in progenitors and immature neurons.
Taken together, the data suggest that maturation of the hippocampal-entorhinal network follows a stereotyped sequence that recapitulates the stagewise unidirectional flow of information through the intrinsic hippocampal microcircuit. DG provided the only exception to this scheme. The temporal profile of maturation in dentate granule cells was closer to that of cells in the deep layers of the entorhinal cortex than to downstream CA3. This exceptional time profile is in line with the late peak of neurogenesis in DG, which extends through the first postnatal week.
We have shown that the entorhinal-hippocampal network matures in a stereotyped and directional sequence that, with the exception of the dentate gyrus, recapitulates the intrinsic excitatory connectivity of the hippocampal transverse circuit. At every level of the circuit, maturation and synaptogenesis rely on an excitatory activity-dependent instructive signal that originates in stellate cells of the MEC and spreads directionally throughout the circuit over the course of the first month of postnatal life. Stellate cells, being the first to mature, initiate maturation of the network by providing excitatory drive to their synaptic targets. These, in turn, subsequently exert a driving effect on areas further downstream, resulting in successive, stagewise maturation of the transverse entorhinal-hippocampal circuit. Maturation of stellate cells themselves is independent of local and incoming excitatory activity but correlates with birthdate, pointing to cell-autonomous molecular, genetic or epigenetic pathways, set up before birth, as potential sources of stellate-cell-initiated maturation in the entorhinal-hippocampal circuit.
In line with the role that sensory-driven activity exerts in the primary sensory cortices, stellate cells might influence computation in the entorhinal-hippocampal network by orchestrating the refinement of connectivity within MEC and hippocampus, as well as between these structures. By driving structural maturation of the interneuron network and of the backprojections from the hippocampus, stellate cells might serve as a developmental teaching layer to ensure strong coupling among cells that exhibit correlated neural activity in stimulus space. This may be crucial for the development of attractor network topologies thought to underlie the formation of grid patterns.
Our data show that stellate cells are at the top of the developmental hierarchy that instructs the linear sequence of maturation of the entorhinal-hippocampal circuit. Peripheral sensory organs have long been studied as the source of instructive signals driving the early development of the forebrain. For example, the olfactory organ instructs the central nervous system to reach its mature states, and in a similar fashion, thalamocortical axons are involved in cortical regionalization and the refinement of dendritic arborization and connectivity in the visual, somatosensory and auditory systems. While activity from sensory organs provides a clear directionality to the maturation of cortical columns in sensory areas, we show here that in the entorhinal-hippocampal circuit, it is activity from stellate cells that drives the maturation of the entire circuit. Our data identify a network where such instructive excitatory activity does not originate from sensory neurons, but is provided by a subpopulation of neurons that functions as an “autonomous” intrinsic driver in a neurogenesis-dependent manner. The presence of a few of these intrinsic drivers in the brain during development might be particularly influential for the coordinated maturation of networks that are positioned at a great synaptic distance from sensory signals and extend across multiple areas in the associative cortices, thereby shaping network topologies supporting higher cognitive function.
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