Whether the computational systems in language perception involve specific abilities in humans is debated. The vocalizations of songbirds share many features with human speech, but whether songbirds ...possess a similar computational ability to process auditory information as humans is unknown. We analyzed their spontaneous discrimination of auditory stimuli and found that the Bengalese finch (Lonchura striata var. domestica) can use the syntactical information processing of syllables to discriminate songs). These finches were also able to acquire artificial grammatical rules from synthesized syllable strings and to discriminate novel auditory information according to them. We found that a specific brain region was involved in such discrimination and that this ability was acquired postnatally through the encounter with various conspecific songs. Our results indicate that passerine songbirds spontaneously acquire the ability to process hierarchical structures, an ability that was previously supposed to be specific to humans.
Termites have colonized many habitats and are among the most abundant animals in tropical ecosystems, which they modify considerably through their actions. The timing of their rise in abundance and ...of the dispersal events that gave rise to modern termite lineages is not well understood. To shed light on termite origins and diversification, we sequenced the mitochondrial genome of 48 termite species and combined them with 18 previously sequenced termite mitochondrial genomes for phylogenetic and molecular clock analyses using multiple fossil calibrations. The 66 genomes represent most major clades of termites. Unlike previous phylogenetic studies based on fewer molecular data, our phylogenetic tree is fully resolved for the lower termites. The phylogenetic positions of Macrotermitinae and Apicotermitinae are also resolved as the basal groups in the higher termites, but in the crown termitid groups, including Termitinae + Syntermitinae + Nasutitermitinae + Cubitermitinae, the position of some nodes remains uncertain. Our molecular clock tree indicates that the lineages leading to termites and Cryptocercus roaches diverged 170 Ma (153-196 Ma 95% confidence interval CI), that modern Termitidae arose 54 Ma (46-66 Ma 95% CI), and that the crown termitid group arose 40 Ma (35-49 Ma 95% CI). This indicates that the distribution of basal termite clades was influenced by the final stages of the breakup of Pangaea. Our inference of ancestral geographic ranges shows that the Termitidae, which includes more than 75% of extant termite species, most likely originated in Africa or Asia, and acquired their pantropical distribution after a series of dispersal and subsequent diversification events.
Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ...ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (
). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (
) or repeat expansions in
Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an
mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.
MicroRNA-124a (miR-124a) is the most abundant microRNA expressed in the vertebrate CNS. Despite past investigations into the role of miR-124a, inconsistent results have left the in vivo function of ...miR-124a unclear. We examined the in vivo function of miR-124a by targeted disruption of Rncr3 (retinal non-coding RNA 3), the dominant source of miR-124a. Rncr3(-/-) mice exhibited abnormalities in the CNS, including small brain size, axonal mis-sprouting of dentate gyrus granule cells and retinal cone cell death. We found that Lhx2 is an in vivo target mRNA of miR-124a. We also observed that LHX2 downregulation by miR-124a is required for the prevention of apoptosis in the developing retina and proper axonal development of hippocampal neurons. These results suggest that miR-124a is essential for the maturation and survival of dentate gyrus neurons and retinal cones, as it represses Lhx2 translation.
•Avian adeno-associated virus (A3V) transcellularly transduces postsynaptic neurons.•Injecting A3V into sensory organs labeled neurons in sensory pathways.•Injecting A3V into an auditory nucleus ...labeled neurons in the ascending pathway.•A3V transsynaptic transport is at least preferentially anterograde.
Retrograde and anterograde transsynaptic viral vectors are useful tools for studying the input and output organization of neuronal circuitry, respectively. While retrograde transsynaptic viral vectors are widely used, viral vectors that show anterograde transsynaptic transduction are not common.
We chose recombinant avian adeno-associated virus (A3V) carrying the mCherry gene and injected it into the eyeball, cochlear duct, and midbrain auditory center of chickens. We observed different survival times to examine the virus transcellular transport and the resulting mCherry expression. To confirm the transcellular transduction mode, we co-injected A3V and cholera toxin B subunit.
Injecting A3V into the eyeball and cochlea labeled neurons in the visual and auditory pathways, respectively. Second-, and third-order labeling occurred approximately two and seven days, respectively, after injection into the midbrain. The distribution of labeled neurons strongly suggests that A3V transport is preferentially anterograde and transduces postsynaptic neurons.
A3V displays no extrasynaptic leakage and moderate speed of synapse passage, which is better than other viruses previously reported. Compared with AAV1&9, which have been shown to pass one synapse anterogradely, A3V passes several synapses in the anterograde direction.
A3V would be a good tool to study the topographic organization of projection axons and their target neurons.
The direct cortico-motoneuronal connection is believed to be essential for the control of dexterous hand movements, such as precision grip in primates. It was reported, however, that even after ...lesion of the corticospinal tract (CST) at the C4–C5 segment, precision grip largely recovered within 1–3 mo, suggesting that the recovery depends on transmission through intercalated neurons rostral to the lesion, such as the propriospinal neurons (PNs) in the midcervical segments. To obtain direct evidence for the contribution of PNs to recovery after CST lesion, we applied a pathway-selective and reversible blocking method using double viral vectors to the PNs in six monkeys after CST lesions at C4–C5. In four monkeys that showed nearly full or partial recovery, transient blockade of PN transmission after recovery caused partial impairment of precision grip. In the other two monkeys, CST lesions were made under continuous blockade of PN transmission that outlasted the entire period of postoperative observation (3–4.5 mo). In these monkeys, precision grip recovery was not achieved. These results provide evidence for causal contribution of the PNs to recovery of hand dexterity after CST lesions; PN transmission is necessary for promoting the initial stage recovery; however, their contribution is only partial once the recovery is achieved.
It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates. However, the role of the 'phylogenetically ...older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex–PN–motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.
A simulation model was developed to better understand the mechanisms of brain injuries in sports. A three-dimensional model comprising approximately 1.22 million elements was constructed from cranial ...computed tomography images of adult male volunteers by the voxel method. To simulate contact sports that permit actions such as tackling, a sinusoidal wave with duration of 10 ms and maximum acceleration of 2000 m/s2 was applied to the lowest point of the model to apply rotational acceleration to the head from different directions. The von Mises stress was then observed at five points in the coronal plane of the brain: cingulate gyrus (CG), corpus callosum (CC), brain stem (BS), lateral temporal lobe (LT), and medial temporal lobe (MT). LS-DYNA universal finite element analysis software with explicit time integration was used for the analysis. Concentrations of stress started to appear in the CC and BS at 10 ms post-impact, after which they also became evident in the CG and MT. The maximum changes in stress at each location occurred 10–15 ms post-impact. The von Mises stress was 9–14 kPa in the CG, 8–24 kPa in the CC, 12–24 kPa in the BS, 7–12 kPa in the LT, and 12–18 kPa in the MT. The highest stress in every part of the brain occurred after lateral impact, followed by oblique impact and sagittal impact. Such simulations may help elucidate the mechanisms of brain injuries in sports and help develop measures to prevent chronic traumatic encephalopathy.
Songbirds postnatally develop their skill to utter and to perceive a vocal signal for communication. How genetic and environmental influences act in concert to regulate the development of such skill ...is not fully understood. Here, we report the phenotype of transgenic songbirds with altered intrinsic activity of cAMP response element-binding protein (CREB) transcription factor. By viral vector-mediated modification of genomic DNA, we established germ line-transmitted lines of zebra finches, which exhibited enhanced or suppressed activity of CREB. Although intrinsically acquired vocalizations or their hearing ability were not affected, the transgenic birds showed reduced vocal learning quality of their own songs and impaired audio-memory formation against conspecific songs. These results thus demonstrate that appropriate activity of CREB is necessary for the postnatal acquisition of learned behavior in songbirds, and the CREB transgenic birds offer a unique opportunity to separately manipulate both genetic and environmental factors that impinge on the postnatal song learning.
Significance In highly socialized animals such as humans or songbirds, individuals postnatally develop their skills to communicate with conspecifics under the social influence. Both genetic and environmental influences play a crucial role in the development of such abilities, but dissection of the influences has been difficult, because genetic manipulation of avian species is still a challenging issue. In this study, we applied transgenic technology to songbirds along with an experimental song-training paradigm to separately manipulate both genes and social environment, and found that appropriate activity of cAMP response element-binding protein (CREB) is necessary for the postnatal song learning in songbirds.
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