Developmental Neuroscience

Decety, Jean

doi: 10.1159/000317771pmid: 20805682

Empathy, which implies a shared interpersonal experience, is implicated in many aspects of social cognition, notably prosocial behavior, morality and the regulation of aggression. The purpose of this paper is to critically examine the current knowledge in developmental and affective neuroscience with an emphasis on the perception of pain in others. It will be argued that human empathy involves several components: affective arousal, emotion understanding and emotion regulation, each with different developmental trajectories. These components are implemented by a complex network of distributed, often recursively connected, interacting neural regions including the superior temporal sulcus, insula, medial and orbitofrontal cortices, amygdala and anterior cingulate cortex, as well as autonomic and neuroendocrine processes implicated in social behaviors and emotional states. Decomposing the construct of empathy into subcomponents that operate in conjunction in the healthy brain and examining their developmental trajectory provides added value to our current approaches to understanding human development. It can also benefit our understanding of both typical and atypical development.

Keays, David A.; Cleak, James; Huang, Guo-Jen; Edwards, Andrew; Braun, Andreas; Treiber, Christoph D.; Pidsley, Ruth; Flint, Jonathan

doi: 10.1159/000319663pmid: 21041996

The multitubulin hypothesis holds that each tubulin isotype serves a unique role with respect to microtubule function. Here we investigate the role of the α-tubulin subunit Tuba1a in adult hippocampal neurogenesis and the formation of the dentate gyrus. Employing birth date labelling and immunohistological markers, we show that mice harbouring an S140G mutation in Tuba1a present with normal neurogenic potential, but that this neurogenesis is often ectopic. Morphological analysis of the dentate gyrus in adulthood revealed a disorganised subgranular zone and a dispersed granule cell layer. We have shown that these anatomical abnormalities are due to defective migration of prospero-homeobox-1-positive neurons and T-box-brain-2-positive progenitors during development. Such migratory defects may also be responsible for the cytoarchitectural defects observed in the dentate gyrus of patients with mutations in TUBA1A.

Hernandez, Melissa C.; Janušonis, Skirmantas

doi: 10.1159/000314723pmid: 20805681

The adrenergic β₂ receptor (β₂-AR) gene is embedded (nested) within the serotonin 5-HT₄ receptor (5-HT₄-R) gene and these two receptors can interact at the transcriptional and post-transcriptional levels. The mouse 5-HT₄-R gene contains a number of exons and codes at least four mRNA splice variants (5-HT_4(a)-R, 5-HT_4(b)-R, 5-HT_4(e)-R, 5-HT_4(f)-R), whereas the β₂-AR gene is intronless. Since 5-HT₄-Rs and β₂-ARs can form homodimers and heterodimers and they increase intracellular cAMP levels, these receptors may be important for integrating serotonergic and noradrenergic signals at the single-neuron level. Both 5-HT₄-R and β₂-AR have been implicated in autism spectrum disorders, depression, and Alzheimer’s disease. In the fetal brain, these receptors may mediate the effects of stress on neurodevelopmental processes. We used quantitative reverse-transcription PCR (qRT-PCR) to investigate the developmental expression of 5-HT₄-R and β₂-AR in the mouse telencephalon at embryonic days (E) 13–18. At E13–E14, the mRNA levels of all 5-HT₄-R splice variants were very low, but by E17–E18 they increased 7-fold (5- HT_4(a)-R), 5-fold (5-HT_4(b)-R), 9-fold (5-HT_4(e)-R), and 11-fold (5-HT_4(f)-R). The expression of 5-HT_4(a)-R and 5-HT_4(b)-R was rapidly upregulated between E14 and E15, at the time when the thalamocortical projections arrive in the telencephalon. This pattern was not observed in the expression of 5-HT_4(e)-R and 5-HT_4(f)-R, the mRNA levels of which showed a steady, gradual increase from E13 to E18. The β₂-AR mRNA levels were relatively high throughout the studied period of development and increased only by 70% from E13–E14 to E17–E18. These findings suggest that 5-HT₄-R splice variants and β₂-ARs are differentially regulated in the embryonic telencephalon and that their relative amounts may carry developmentally important information.

Milanovic, Desanka; Popic, Jelena; Pesic, Vesna; Loncarevic-Vasiljkovic, Natasa; Kanazir, Selma; Jevtovic-Todorovic, Vesna; Ruzdijic, Sabera

doi: 10.1159/000316970pmid: 20714114

Exposure of newborn rats to a variety of anesthetics has been shown to induce apoptotic neurodegeneration in the developing brain. We investigated the effect of the general anesthetic propofol on the brain of 7-day-old (P7) Wistar rats during the peak of synaptic growth. Caspase and calpain protease families most likely participate in neuronal cell death. Our objective was to examine regional and temporal patterns of caspase-3 and calpain activity following repeated propofol administration (20 mg/kg). P7 rats were exposed for 2, 4 or 6 h to propofol and killed 0, 4, 16 and 24 h after exposure. Relative caspase-3 and calpain activities were estimated by Western blot analysis of the proteolytic cleavage products of α-II-spectrin, protein kinase C and poly(ADP-ribose) polymerase 1. Caspase-3 activity and expression displayed a biphasic pattern of activation. Calpain activity changed in a region- and time-specific manner that was distinct from that observed for caspase-3. The time profile of calpain activity exhibited substrate specificity. Fluoro-Jade B staining revealed an immediate neurodegenerative response that was in direct relationship to the duration of anesthesia in the cortex and inversely related to the duration of anesthesia in the thalamus. At later post-treatment intervals, dead neurons were detected only in the thalamus 24 h following the 6-hour propofol exposure. Strong caspase-3 expression that was detected at 24 h was not followed by cell death after 2- and 4-hour exposures to propofol. These results revealed complex patterns of caspase-3 and calpain activities following prolonged propofol anesthesia and suggest that both are a manifestation of propofol neurotoxicity at a critical developmental stage.

Wallace, K.; Veerisetty, S.; Paul, I.; May, W.; Miguel-Hidalgo, J.J.; Bennett, W.

doi: 10.1159/000319506pmid: 20948182

The cerebellum is involved in the control of motor functions with Purkinje cells serving as the only output from the cerebellum. Purkinje cells are important targets for toxic substances and are vulnerable to prenatal insults. Intrauterine infection (IUI) has been shown to selectively target the developing cerebral white matter through lesioning, necrosis and inflammatory cytokine activation. Developmental and cognitive delays have been associated with animal models of IUI. The aim of this study was to determine if IUI leads to damage to Purkinje cells in the developing cerebellum and if any damage is associated with decreases in calbindin and motor behaviors in surviving pups. Pregnant rats were injected with Escherichia coli (1 × 10⁵ colony-forming units) or sterile saline at gestational day 17. Beginning at postnatal day (PND) 2, the pups were subjected to a series of developmental tests to examine developmental milestones. At PND 16, some pups were sacrificed and their brains extracted and processed for histology or protein studies. Hematoxylin and eosin (HE) staining was done to examine the general morphology of the Purkinje cells and to examine Purkinje cell density, area and volume. Calbindin expression was examined in the cerebellum via immunohistochemistry and Western blot techniques. The remaining rat pups were used to examine motor coordination and balance on a rotating rotarod at the prepubertal and adult ages. Prenatal E. coli injection did not significantly change birth weight or delivery time, but did delay surface righting and negative geotaxis in pups. Pups in the E. coli group also had a decrease in the number of Purkinje cells, as well as a decrease in Purkinje cell density and volume. HE staining demonstrated a change in Purkinje cell morphology. Calbindin expression was decreased in rats from the E. coli group as well. Locomotor tests indicated that while there were no significant changes in gross motor activity, motor coordination and balance was impaired in both prepubertal and adult rats from the E. coli group. In this model of IUI, we observed changes in Purkinje cell development which were associated with alterations in cerebellum-dependent motor behaviors. The decreases in calbindin and Purkinje cells were associated with developmental delays. These data further support the importance of IUI in brain development.

Pradhan, A.D.; Case, A.M.; Farrer, R.G.; Tsai, S.Y.; Cheatwood, J.L.; Martin, J.L.; Kartje, G.L.

doi: 10.1159/000309135pmid: 20938157

The myelin-associated protein Nogo-A is a well-known inhibitor of axonal regeneration and compensatory plasticity, yet functions of neuronal Nogo-A are not as clear. The present study examined the effects of decreased levels of neuronal Nogo-A on dendritic spines of developing neocortical neurons. Decreased Nogo-A levels in these neurons resulted in lowered spine density and an increase in filopodial type protrusions. These results suggest a role for neuronal Nogo-A in maintaining a spine phenotype in neocortical pyramidal cells.

Hernández-Benítez, Reyna; Pasantes-Morales, Herminia; Pinzón-Estrada, Enrique; Ramos-Mandujano, Gerardo

doi: 10.1159/000321583pmid: 21160187

Taurine addition to cultured embryonic neural precursor cells (NPC) significantly increased cell proliferation [Hernández-Benítez et al., 2010]. The medium used for NPC growing and proliferation is a fetal serum-free medium, and therefore, NPC become taurine depleted. Addition of taurine to the cultured medium fully replenished the cell taurine pool, suggesting the functional expression of a taurine transporter (TauT) in these cells. In the present study, TauT in NPC was functionally characterized and its protein expression and the subcellular distribution of immunoreactivity were determined. ³H-taurine uptake in NPC could be separated into a non-saturable component and a Na⁺/Cl^–-dependent, saturable component. The saturable component showed an apparent 2:1:1 Na⁺/Cl^–/taurine stoichiometry, a V_max of 0.39 ± 0.04 nmol/mg protein/min, and a K_m of 21.7 ± 2.6 µM. TauT in NPC was strongly inhibited by hypotaurine and β-alanine (92 and 79%, respectively) and reduced (71%) by γ-aminobutyric acid. TauT protein is expressed in NPC as a single band of about 70 kDa. Essentially all (98.8%) of the neurosphere-forming cells were positive to TauT immunoreactivity. Immunolocalization visualized by confocal microscopy localized TauT predominantly at the cell membrane. TauT was also found at the cytosol and only occasionally at the nuclear membrane. This study represents the first characterization of TauT in NPC.