Development of the brain functional connectome follows puberty-dependent nonlinear trajectories.

Adolescence is a developmental period that dramatically impacts body and behavior, with pubertal hormones playing an important role not only in the morphological changes in the body but also in brain structure and function. Understanding brain development during adolescence has become a priority in neuroscience because it coincides with the onset of many psychiatric and behavioral disorders. However, little is known about how puberty influences the brain functional connectome. In this study, taking a longitudinal human sample of typically developing children and adolescents (of both sexes), we demonstrate that the development of the brain functional connectome better fits pubertal status than chronological age. In particular, centrality, segregation, efficiency, and integration of the brain functional connectome increase after the onset of the pubertal markers. We found that these effects are stronger in attention and task control networks. Lastly, after controlling for this effect, we showed that functional connectivity between these networks is related to better performance in cognitive flexibility. This study points out the importance of considering longitudinal nonlinear trends when exploring developmental trajectories, and emphasizes the impact of puberty on the functional organization of the brain in adolescence.

Altered Functional Brain Network Integration, Segregation, and Modularity in Infants Born Very Preterm at Term-Equivalent Age.

OBJECTIVES: To determine the functional network organization of the brain in infants born very preterm at term-equivalent age and to relate network alterations to known clinical risk factors for poor neurologic outcomes in prematurity. STUDY DESIGN: Resting-state functional magnetic resonance imaging data from 66 infants born very preterm (gestational age <32 weeks and birth weight <1500 g) and 66 healthy neonates born at full term, acquired as part of a prospective, cross-sectional study, were compared at term age using graph theory. Features of resting-state networks, including integration, segregation, and modularity, were derived from correlated hemodynamic activity arising from 93 cortical and subcortical regions of interest and compared between groups. RESULTS: Despite preserved small-world topology and modular organization, resting-state networks of infants born very preterm at term-equivalent age were less segregated and less integrated than those of infants born full term. Chronic respiratory illness (ie, bronchopulmonary dysplasia and the length of oxygen support) was associated with decreased global efficiency and increased path lengths (P < .05). In both cohorts, 4 functional modules with similar composition were observed (parietal/temporal, frontal, subcortical/limbic, and occipital). The density of connections in 3 of the 4 modules was decreased in the very preterm network (P < .01); however, in the occipital/visual cortex module, connectivity was increased in infants born very preterm relative to control infants (P < .0001). CONCLUSIONS: Early exposure to the ex utero environment is associated with altered resting-state network functional organization in infants born very preterm at term-equivalent age, likely reflecting disrupted brain maturational processes.

The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM.

The formation of synaptic connections during nervous system development requires the precise control of dendrite growth and synapse formation. Although glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 are expressed in the forebrain, the role of this system in the hippocampus remains unclear. Here, we investigated the consequences of GFRα1 deficiency for the development of hippocampal connections. Analysis of conditional Gfra1 knockout mice shows a reduction in dendritic length and complexity, as well as a decrease in postsynaptic density specializations and in the synaptic localization of postsynaptic proteins in hippocampal neurons. Gain- and loss-of-function assays demonstrate that the GDNF-GFRα1 complex promotes dendritic growth and postsynaptic differentiation in cultured hippocampal neurons. Finally, in vitro assays revealed that GDNF-GFRα1-induced dendrite growth and spine formation are mediated by NCAM signaling. Taken together, our results indicate that the GDNF-GFRα1 complex is essential for proper hippocampal circuit development.

Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein.

Neuronal connectivity and synaptic remodeling are fundamental substrates for higher brain functions. Understanding their dynamics in the mammalian allocortex emerges as a critical step to tackle the cellular basis of cognitive decline that occurs during normal aging and in neurodegenerative disorders. In this work we have designed a novel approach to assess alterations in the dynamics of functional and structural connectivity elicited by chronic cell-autonomous overexpression of the human amyloid precursor protein (hAPP). We have taken advantage of the fact that the hippocampus continuously generates new dentate granule cells (GCs) to probe morphofunctional development of GCs expressing different variants of hAPP in a healthy background. hAPP was expressed together with a fluorescent reporter in neural progenitor cells of the dentate gyrus of juvenile mice by retroviral delivery. Neuronal progeny was analyzed several days post infection (dpi). Amyloidogenic cleavage products of hAPP such as the ß-C terminal fragment (ß-CTF) induced a substantial reduction in glutamatergic connectivity at 21 dpi, at which time new GCs undergo active growth and synaptogenesis. Interestingly, this effect was transient, since the strength of glutamatergic inputs was normal by 35 dpi. This delay in glutamatergic synaptogenesis was paralleled by a decrease in dendritic length with no changes in spine density, consistent with a protracted dendritic development without alterations in synapse formation. Finally, similar defects in newborn GC development were observed by overexpression of α-CTF, a non-amyloidogenic cleavage product of hAPP. These results indicate that hAPP can elicit protracted dendritic development independently of the amyloidogenic processing pathway.

Calbindin-D28k and calretinin in chicken inner retina during postnatal development and neuroplasticity by dim red light.

Members of the family of calcium binding proteins (CBPs) are involved in the buffering of calcium (Ca2+) by regulating how Ca2+ can operate within synapses or more globally in the entire cytoplasm and they are present in a particular arrangement in all types of retinal neurons. Calbindin D28k and calretinin belong to the family of CBPs and they are mainly co-expressed with other CBPs. Calbindin D28k is expressed in doubles cones, bipolar cells and in a subpopulation of amacrine and ganglion neurons. Calretinin is present in horizontal cells as well as in a subpopulation of amacrine and ganglion neurons. Both proteins fill the soma at the inner nuclear layer and the neuronal projections at the inner plexiform layer. Moreover, calbindin D28k and calretinin have been associated with neuronal plasticity in the central nervous system. During pre and early postnatal visual development, the visual system shows high responsiveness to environmental influences. In this work we observed modifications in the pattern of stratification of calbindin immunoreactive neurons, as well as in the total amount of calbindin through the early postnatal development. In order to test whether or not calbindin is involved in retinal plasticity we analyzed phosphorylated p38 MAPK expression, which showed a decrease in p-p38 MAPK, concomitant to the observed decrease of calbindin D28k. Results showed in this study suggest that calbindin is a molecule related with neuroplasticity, and we suggest that calbindin D28k has significant roles in neuroplastic changes in the retina, when retinas are stimulated with different light conditions.

The timing for neuronal maturation in the adult hippocampus is modulated by local network activity.

The adult hippocampus continuously generates new cohorts of immature neurons with increased excitability and plasticity. The window for the expression of those unique properties in each cohort is determined by the time required to acquire a mature neuronal phenotype. Here, we show that local network activity regulates the rate of maturation of adult-born neurons along the septotemporal axis of the hippocampus. Confocal microscopy and patch-clamp recordings were combined to assess marker expression, morphological development, and functional properties in retrovirally labeled neurons over time. The septal dentate gyrus displayed higher levels of basal network activity and faster rates of newborn neuron maturation than the temporal region. Voluntary exercise enhanced network activity only in the temporal region and, in turn, accelerated neuronal development. Finally, neurons developing within a highly active environment exhibited a delayed maturation when their intrinsic electrical activity was reduced by the cell-autonomous overexpression of Kir2.1, an inward-rectifying potassium channel. Our findings reveal a novel type of activity-dependent plasticity acting on the timing of neuronal maturation and functional integration of newly generated neurons along the longitudinal axis of the adult hippocampus.

Robust artificial intelligence tool for automatic start-up of the supplementary medium feeding in recombinant E. colicultivations

One of the most important events in fed-batch fermentations is the definition of the moment to start the feeding. This paper presents a methodology for a rational selection of the architecture of an artificial intelligence (AI)system, based on a neural network committee (NNC),which identifies the end of the batch phase. The AI systemwas successfully used during high cell density cultivations of recombinant Escherichia coli. The AI algorithm wasvalidated for different systems, expressing three antigens to be used in human and animal vaccines: fragments of surface proteins of Streptococcus pneumoniae (PspA), clades 1 and 3, and of Erysipelothrix rhusiopathiae (SpaA). Standard feed-forward neural networks (NNs), with a single hidden layer, were the basis for the NNC. The NN architecture with best performance had the following inputs: stirrer speed, inlet air, and oxygen flow rates, carbon dioxide evolution rate, and CO2 molar fraction in the exhaust gas.

Nutritional tryptophan restriction impairs plasticity of retinotectal axons during the critical period.

The use-dependent specification of neural circuits occurs during post-natal development with a conspicuous influence of environmental factors, such as malnutrition that interferes with the major steps of brain maturation. Serotonin (5-HT), derived exclusively from the essential aminoacid tryptophan, is involved in mechanisms of development and use-dependent plasticity of the central nervous system. We studied the effects of the nutritional restriction of tryptophan in the plasticity of uncrossed retinotectal axons following a retinal lesion to the contralateral retina during the critical period in pigmented rats. Litters were fed through their mothers with a low tryptophan content diet, based on corn and gelatin, a complemented diet with standard tryptophan requirements for rodents or standard laboratory diet. The results suggest a marked reduction in the plasticity of intact axons into denervated territories in the tryptophan restricted group in comparison to control groups. Tryptophan complementation between PND10-21 completely restored retinotectal plasticity. However, the re-introduction of tryptophan after the end of the critical period (between PND28-P41) did not restore the sprouting ability of uncrossed axons suggesting a time-dependent effect to the reversion of plasticity deficits. Tryptophan-restricted animals showed a reduced activity of matrix metalloproteinase-9 and altered expressions of phosphorylated forms of ERK1/2 and AKT. Our results demonstrate the influence of this essential aminoacid as a modulator of neural plasticity during the critical period through the reduction of serotonin content which alters plasticity-related signaling pathways and matrix degradation.

Neonatal tryptophan dietary restriction alters development of retinotectal projections in rats.

The specification of sensory neural circuits includes the elimination of transitory axon collaterals/synapses that takes place during early post natal life, an important step for the acquisition of topographical order of sensory systems. Serotonin has been implicated in the patterning of connections in subcortical and cortical circuits. We investigated the effects of the dietary restriction of the only serotonin precursor, tryptophan, on the development of the uncrossed retinotectal pathway in pigmented rats. Litters were fed through their mothers with either a tryptophan restricted, corn and gelatin based diet or a similar control diet complemented with tryptophan during the lactation period. The developmental status of the uncrossed retinotectal terminal fields was studied after the anterograde transport of horseradish peroxidase injected into one eye. We also studied the effects of tryptophan restriction on 5-HT immunoreactivity of raphe neurons, on cAMP levels in the visual layers of the superior colliculus and on protein synthesis among retinal neurons. We found that tryptophan restriction resulted in reduced weight gain among tryptophan restricted rats, without differences in protein synthesis between tryptophan complemented and restricted groups. Tryptophan restriction was also associated with a reduction of serotonin immunoreactive cells in the raphe nuclei and increased cAMP levels in the superior colliculus. Finally we found that neonatal tryptophan restriction resulted in an abnormal patterning of retinotectal topography, which was consistent with a developmental delay in axonal elimination and fine tuning of central connections. These results suggest, therefore, that dietary tryptophan is crucial for the influence of serotonin in the maturation of central visual connections.

Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo.

The pre-Bötzinger complex (PBC), part of the ventral respiratory group that is responsible for inspiratory rhythm generation, contains at least two types of pacemaker neurons. In vitro studies have shown that bursting properties of one type of pacemaker relies on a riluzole-sensitive persistent sodium current, whereas bursting of a second type is sensitive to flufenamic acid (FFA), a calcium-dependent nonspecific cationic current blocker. In vitro, under control conditions, the PBC generates fictive eupneic activity that depends on both riluzole-sensitive and FFA-sensitive pacemaker neurons. During hypoxia the PBC generates fictive gasping activity and only riluzole-sensitive pacemaker neurons appear to be necessary for this rhythm. We carried out pharmacological experiments to test the role of respiratory pacemaker neurons in vivo by performing plethysmographic recordings on neonate mice. As reported in vitro, eupnea activity in vivo is abolished only if both FFA and riluzole are coadministered intracisternally, but not when either of them is administered independently. On the other hand riluzole, but not FFA, drastically reduced gasping generation and compromised the ability of mice to autoresucitate. Neither substance P nor forskolin was able to reestablish respiratory activity after riluzole and FFA coapplication. Our results confirm in vitro reports and suggest that eupnea generation in neonates requires a complex neuronal network that includes riluzole- and FFA-sensitive elements and that gasping activity depends mostly on a riluzole-sensitive mechanism.

Optimal pruning in neural networks.

We study pruning strategies in simple perceptrons subjected to supervised learning. Our analytical results, obtained through the statistical mechanics approach to learning theory, are independent of the learning algorithm used in the training process. We calculate the post-training distribution P(J) of synaptic weights, which depends only on the overlap rho(0) achieved by the learning algorithm before pruning and the fraction kappa of relevant weights in the teacher network. From this distribution, we calculate the optimal pruning strategy for deleting small weights. The optimal pruning threshold grows from zero as straight theta(opt)(rho(0), kappa) approximately [rho(0)-rho(c)(kappa)](1/2) above some critical value rho(c)(kappa). Thus, the elimination of weak synapses enhances the network performance only after a critical learning period. Possible implications for biological pruning phenomena are discussed.