Identification of FoxP circuits involved in locomotion and object fixation in Drosophila.

The FoxP family of transcription factors is necessary for operant self-learning, an evolutionary conserved form of motor learning. The expression pattern, molecular function and mechanisms of action of the Drosophila FoxP orthologue remain to be elucidated. By editing the genomic locus of FoxP with CRISPR/Cas9, we find that the three different FoxP isoforms are expressed in neurons, but not in glia and that not all neurons express all isoforms. Furthermore, we detect FoxP expression in, e.g. the protocerebral bridge, the fan-shaped body and in motor neurons, but not in the mushroom bodies. Finally, we discover that FoxP expression during development, but not adulthood, is required for normal locomotion and landmark fixation in walking flies. While FoxP expression in the protocerebral bridge and motor neurons is involved in locomotion and landmark fixation, the FoxP gene can be excised from dorsal cluster neurons and mushroom-body Kenyon cells without affecting these behaviours.

High neural activity accelerates the decline of cognitive plasticity with age in Caenorhabditis elegans.

The ability to learn progressively declines with age. Neural hyperactivity has been implicated in impairing cognitive plasticity with age, but the molecular mechanisms remain elusive. Here, we show that chronic excitation of the Caenorhabditis elegans O2-sensing neurons during ageing causes a rapid decline of experience-dependent plasticity in response to environmental O2 concentration, whereas sustaining lower activity of O2-sensing neurons retains plasticity with age. We demonstrate that neural activity alters the ageing trajectory in the transcriptome of O2-sensing neurons, and our data suggest that high-activity neurons redirect resources from maintaining plasticity to sustaining continuous firing. Sustaining plasticity with age requires the K+-dependent Na+/Ca2+ (NCKX) exchanger, whereas the decline of plasticity with age in high-activity neurons acts through calmodulin and the scaffold protein Kidins220. Our findings demonstrate directly that the activity of neurons alters neuronal homeostasis to govern the age-related decline of neural plasticity and throw light on the mechanisms involved.

Clusters of DCX+ cells "trapped" in the subcortical white matter of early postnatal Cetartiodactyla (Tursiops truncatus, Stenella coeruloalba and Ovis aries).

The cytoskeletal protein doublecortin (DCX) is a marker for neuronal cells retaining high potential for structural plasticity, originating from both embryonic and adult neurogenic processes. Some of these cells have been described in the subcortical white matter of neonatal and postnatal mammals. In mice and humans it has been shown they are young neurons migrating through the white matter after birth, reaching the cortex in a sort of protracted neurogenesis. Here we show that DCX+ cells in the white matter of neonatal and young Cetartiodactyla (dolphin and sheep) form large clusters which are not newly generated (in sheep, and likely neither in dolphins) and do not reach the cortical layers, rather appearing "trapped" in the white matter tissue. No direct contact or continuity can be observed between the subventricular zone region and the DCX+ clusters, thus indicating their independence from any neurogenic source (in dolphins further confirmed by the recent demonstration that periventricular neurogenesis is inactive since birth). Cetartiodactyla include two orders of large-brained, relatively long-living mammals (cetaceans and artiodactyls) which were recognized as two separate monophyletic clades until recently, yet, despite the evident morphological distinctions, they are monophyletic in origin. The brain of Cetartiodactyla is characterized by an advanced stage of development at birth, a feature that might explain the occurrence of "static" cell clusters confined within their white matter. These results further confirm the existence of high heterogeneity in the occurrence, distribution and types of structural plasticity among mammals, supporting the emerging view that multiple populations of DCX+, non-newly generated cells can be abundant in large-brained, long-living species.

Non-Newly Generated, "Immature" Neurons in the Sheep Brain Are Not Restricted to Cerebral Cortex.

A newly proposed form of brain structural plasticity consists of non-newly generated, "immature" neurons of the adult cerebral cortex. Similar to newly generated neurons, these cells express the cytoskeletal protein Doublecortin (DCX), yet they are generated prenatally and then remain in a state of immaturity for long periods. In rodents, the immature neurons are restricted to the paleocortex, whereas in other mammals, they are also found in neocortex. Here, we analyzed the DCX-expressing cells in the whole sheep brain of both sexes to search for an indicator of structural plasticity at a cellular level in a relatively large-brained, long-living mammal. Brains from adult and newborn sheep (injected with BrdU and analyzed at different survival times) were processed for DCX, cell proliferation markers (Ki-67, BrdU), pallial/subpallial developmental origin (Tbr1, Sp8), and neuronal/glial antigens for phenotype characterization. We found immature-like neurons in the whole sheep cortex and in large populations of DCX-expressing cells within the external capsule and the surrounding gray matter (claustrum and amygdala). BrdU and Ki-67 detection at neonatal and adult ages showed that all of these DCX+ cells were generated during embryogenesis, not after birth. These results show that the adult sheep, unlike rodents, is largely endowed with non-newly generated neurons retaining immature features, suggesting that such plasticity might be particularly important in large-brained, long-living mammals.SIGNIFICANCE STATEMENT Brain plasticity is important in adaptation and brain repair. Structural changes span from synaptic plasticity to adult neurogenesis, the latter being highly reduced in large-brained, long-living mammals (e.g., humans). The cerebral cortex contains "immature" neurons, which are generated prenatally and then remain in an undifferentiated state for long periods, being detectable with markers of immaturity. We studied the distribution and developmental origin of these cells in the whole brain of sheep, relatively large-brained, long-living mammals. In addition to the expected cortical location, we also found populations of non-newly generated neurons in several subcortical regions (external capsule, claustrum, and amygdala). These results suggests that non-neurogenic, parenchymal structural plasticity might be more important in large mammals with respect to adult neurogenesis.