A hierarchical development of cortical areas was suggested over a century ago, but the diversity and complexity of cortical hierarchy properties have so far prevented a formal demonstration. The aim ...of this review is to clarify the similarities and differences in the developmental processes underlying cortical development of primary and higher-order areas. We start by recapitulating the historical and recent advances underlying the biological principle of cortical hierarchy in adults. We then revisit the arguments for a hierarchical maturation of cortical areas, and further integrate the principles of cortical areas specification during embryonic and postnatal development. We highlight how the dramatic expansion in cortical size might have contributed to the increased number of association areas sustaining cognitive complexification in evolution. Finally, we summarize the recent observations of an alteration of cortical hierarchy in neuropsychiatric disorders and discuss their potential developmental origins.
Changing serotonin (5-hydroxytryptamine, 5-HT) brain levels during critical periods in development has long-lasting effects on brain function, particularly on later anxiety/depression-related ...behaviors in adulthood. A large part of the known developmental effects of 5-HT occur during critical periods of postnatal life, when activity-dependent mechanisms remodel neural circuits. This was first demonstrated for the maturation of sensory brain maps in the barrel cortex and the visual system. More recently this has been extended to the 5-HT raphe circuits themselves and to limbic circuits. Recent studies overviewed here used new genetic models in mice and rats and combined physiological and structural approaches to provide new insights on the cellular and molecular mechanisms controlled by 5-HT during late stages of neural circuit maturation in the raphe projections, the somatosensory cortex and the visual system. Similar mechanisms appear to be also involved in the maturation of limbic circuits such as prefrontal circuits. The latter are of particular relevance to understand the impact of transient 5-HT dysfunction during postnatal life on psychiatric illnesses and emotional disorders in adult life.
GABA-containing (GABAergic) interneurons comprise a very heterogeneous group of cells that are crucial for cortical function. Different classes of interneurons specialize in targeting specific ...subcellular domains of excitatory pyramidal cells or other interneurons, which provides cortical circuits with an enormous capability for information processing. As in other regions of the CNS, cortical interneuron diversity is thought to emerge from the genetic specification of different groups of progenitor cells within the subpallium. Most cortical interneurons originate from two main regions, the medial and the caudal ganglionic eminences (MGE and CGE, respectively). In addition, it has been shown that progenitors in the embryonic preoptic area (POA) also produce a small population of cortical GABAergic interneurons. Here, we show that the contribution of the POA to the complement of cortical GABAergic interneurons is larger than previously believed. Using genetic fate mapping and in utero transplantation experiments, we demonstrate that Dbx1-expressing progenitor cells in the POA give rise to a small but highly diverse cohort of cortical interneurons, with some neurochemical and electrophysiological characteristics that were previously attributed to MGE- or CGE-derived interneurons. There are, however, some features that seem to distinguish POA-derived interneurons from MGE- or CGE-derived cells, such as their preferential laminar location. These results indicate that the mechanisms controlling the specification of different classes of cortical interneurons might be more complex than previously expected. Together with earlier findings, our results also suggest that the POA generates nearly 10% of the GABAergic interneurons in the cerebral cortex of the mouse.
Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic ...approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.
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•Increasing 5-HT neuronal activity increases anxiety-like behavior•Low DR/MR 5-HTergic activity correlates with altered emotional behavior in PNFLX mice•Reducing 5-HT neuronal activity normalizes emotional behavior in PNFLX mice•MR and DR 5-HT neuronal activity exert opposing consequences on floating behavior
Teissier et al. report that acute activation of serotonergic neurons is anxiogenic. Inhibition has no effect in naive mice but restores normal behavior in a developmental model of anxiety and depression. Normalization of unbalanced serotonergic activity between the median and dorsal raphé nuclei likely underlies this beneficial effect.
Early-life serotonin 5-hydroxytryptamine (5-HT) signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain ...poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2-P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2-P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors.
The generation of a precise number of neural cells and the determination of their laminar fate are tightly controlled processes during development of the cerebral cortex. Using genetic tracing in ...mice, we have identified a population of glutamatergic neurons generated by Dbx1-expressing progenitors at the pallial-subpallial boundary predominantly at embryonic day 12.5 (E12.5) and subsequent to Cajal-Retzius cells. We show that these neurons migrate tangentially to populate the cortical plate (CP) at all rostrocaudal and mediolateral levels by E14.5. At birth, they homogeneously populate cortical areas and represent <5% of cortical cells. However, they are distributed into neocortical layers according to their birthdates and express the corresponding markers of glutamatergic differentiation (Tbr1, ER81, Cux2, Ctip2). Notably, this population dies massively by apoptosis at the completion of corticogenesis and represents 50% of dying neurons in the postnatal day 0 cortex. Specific genetic ablation of these transient Dbx1-derived CP neurons leads to a 20% decrease in neocortical cell numbers in perinatal animals. Our results show that a previously unidentified transient population of glutamatergic neurons migrates from extraneocortical regions over long distance from their generation site and participates in neocortical radial growth in a non-cell-autonomous manner.
Short interspersed repetitive elements (SINEs) are highly repeated sequences that account for a significant proportion of many eukaryotic genomes and are usually considered "junk DNA". However, we ...previously discovered that many AmnSINE1 loci are evolutionarily conserved across mammalian genomes, suggesting that they may have acquired significant functions involved in controlling mammalian-specific traits. Notably, we identified the AS021 SINE locus, located 390 kbp upstream of Satb2. Using transgenic mice, we showed that this SINE displays specific enhancer activity in the developing cerebral cortex. The transcription factor Satb2 is expressed by cortical neurons extending axons through the corpus callosum and is a determinant of callosal versus subcortical projection. Mouse mutants reveal a crucial function for Sabt2 in corpus callosum formation. In this study, we compared the enhancer activity of the AS021 locus with Satb2 expression during telencephalic development in the mouse. First, we showed that the AS021 enhancer is specifically activated in early-born Satb2(+) neurons. Second, we demonstrated that the activity of the AS021 enhancer recapitulates the expression of Satb2 at later embryonic and postnatal stages in deep-layer but not superficial-layer neurons, suggesting the possibility that the expression of Satb2 in these two subpopulations of cortical neurons is under genetically distinct transcriptional control. Third, we showed that the AS021 enhancer is activated in neurons projecting through the corpus callosum, as described for Satb2(+) neurons. Notably, AS021 drives specific expression in axons crossing through the ventral (TAG1(-)/NPY(+)) portion of the corpus callosum, confirming that it is active in a subpopulation of callosal neurons. These data suggest that exaptation of the AS021 SINE locus might be involved in enhancement of Satb2 expression, leading to the establishment of interhemispheric communication via the corpus callosum, a eutherian-specific brain structure.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Development of the vertebrate forebrain and craniofacial structures are intimately linked processes, the coordinated growth of these tissues being required to ensure normal head formation. In this ...study, we identify five small subsets of progenitors expressing the transcription factor dbx1 in the cephalic region of developing mouse embryos at E8.5. Using genetic tracing we show that dbx1-expressing cells and their progeny have a modest contribution to the forebrain and face tissues. However, their genetic ablation triggers extensive and non cell-autonomous apoptosis as well as a decrease in proliferation in surrounding tissues, resulting in the progressive loss of most of the forebrain and frontonasal structures. Targeted ablation of the different subsets reveals that the very first dbx1-expressing progenitors are critically required for the survival of anterior neural tissues, the production and/or migration of cephalic neural crest cells and, ultimately, forebrain formation. In addition, we find that the other subsets, generated at slightly later stages, each play a specific function during head development and that their coordinated activity is required for accurate craniofacial morphogenesis. Our results demonstrate that dbx1-expressing cells have a unique function during head development, notably by controlling cell survival in a non cell-autonomous manner.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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