The role of competitive learning in the generation of DG fields from EC inputs

We follow up on a suggestion by Rolls and co-workers, that the effects of competitive learning should be assessed on the shape and number of spatial fields that dentate gyrus (DG) granule cells may form when receiving input from medial entorhinal cortex (mEC) grid units. We consider a simple non-dynamical model where DG units are described by a threshold-linear transfer function, and receive feedforward inputs from 1,000 mEC model grid units of various spacing, orientation and spatial phase. Feedforward weights are updated according to a Hebbian rule as the virtual rodent follows a long simulated trajectory through a single environment. Dentate activity is constrained to be very sparse. We find that indeed competitive Hebbian learning tends to result in a few active DG units with a single place field each, rounded in shape and made larger by iterative weight changes. These effects are more pronounced when produced with thousands of DG units and inputs per DG unit, which the realistic system has available, than with fewer units and inputs, in which case several DG units persists with multiple fields. The emergence of single-field units with learning is in contrast, however, to recent data indicating that most active DG units do have multiple fields. We show how multiple irregularly arranged fields can be produced by the addition of non-space selective lateral entorhinal cortex (lEC) units, which are modelled as simply providing an additional effective input specific to each DG unit. The mean number of such multiple DG fields is enhanced, in particular, when lEC and mEC inputs have overall similar variance across DG units. Finally, we show that in a restricted environment the mean size of the fields is unaltered, while their mean number is scaled down with the area of the environment.

Prediction, conservation analysis, and structural characterization of mammalian mucin-type O-glycosylation sites

O-GalNAc-glycosylation is one of the main types of glycosylation in mammalian cells. No consensus recognition sequence for the O-glycosyltransferases is known, making prediction methods necessary to bridge the gap between the large number of known protein sequences and the small number of proteins experimentally investigated with regard to glycosylation status. From O-GLYCBASE a total of 86 mammalian proteins experimentally investigated for in vivo O-GalNAc sites were extracted. Mammalian protein homolog comparisons showed that a glycosylated serine or threonine is less likely to be precisely conserved than a nonglycosylated one. The Protein Data Bank was analyzed for structural information, and 12 glycosylated structures were obtained. All positive sites were found in coil or turn regions. A method for predicting the location for mucin-type glycosylation sites was trained using a neural network approach. The best overall network used as input amino acid composition, averaged surface accessibility predictions together with substitution matrix profile encoding of the sequence. To improve prediction on isolated (single) sites, networks were trained on isolated sites only. The final method combines predictions from the best overall network and the best isolated site network; this prediction method correctly predicted 76% of the glycosylated residues and 93% of the nonglycosylated residues. NetOGlyc 3.1 can predict sites for completely new proteins without losing its performance. The fact that the sites could be predicted from averaged properties together with the fact that glycosylation sites are not precisely conserved indicates that mucin-type glycosylation in most cases is a bulk property and not a very site-specific one. NetOGlyc 3.1 is made available at www.cbs.dtu.dk/services/netoglyc.     

9-Methyl-β-carboline-induced cognitive enhancement is associated with elevated hippocampal dopamine levels and dendritic and synaptic proliferation

β-Carbolines (BCs) belong to the heterogenous family of carbolines, which have been found exogenously, that is, in various fruits, meats, tobacco smoke, alcohol and coffee, but also endogenously, that is, blood, brain and CSF. These exogenous and endogenous BCs and some of their metabolites can exert neurotoxic effects, however, an unexpected stimulatory effect of 9-methyl-β-carboline (9-me-BC) on dopaminergic neurons in primary mesencephalic cultures was recently discovered. The aim of the present study was to extend our knowledge on the stimulatory effects of 9-me-BC and to test the hypothesis that 9-me-BC may act as a cognitive enhancer. We found that 10 days (but not 5 days) of pharmacological treatment with 9-me-BC (i) improves spatial learning in the radial maze, (ii) elevates dopamine levels in the hippocampal formation, and (iii) results after 10 days of treatment in elongated, more complex dendritic trees and higher spine numbers on granule neurons in the dentate gyrus of 9-me-BC-treated rats. Our results demonstrate that beyond its neuroprotective/neurorestorative and anti-inflammatory effects, 9-me-BC acts as a cognitive enhancer in a hippocampus-dependent task, and that the behavioral effects may be associated with a stimulatory impact on hippocampal dopamine levels and dendritic and synaptic proliferation.     

Active and machine learning-based approaches to rapidly enhance microbial chemical production

In order to make renewable fuels and chemicals from microbes, new methods are required to engineer microbes more intelligently. Computational approaches, to engineer strains for enhanced chemical production typically rely on detailed mechanistic models (e.g., kinetic/stoichiometric models of metabolism)—requiring many experimental datasets for their parameterization—while experimental methods may require screening large mutant libraries to explore the design space for the few mutants with desired behaviors. To address these limitations, we developed an active and machine learning approach (ActiveOpt) to intelligently guide experiments to arrive at an optimal phenotype with minimal measured datasets. ActiveOpt was applied to two separate case studies to evaluate its potential to increase valine yields and neurosporene productivity in Escherichia coli. In both the cases, ActiveOpt identified the best performing strain in fewer experiments than the case studies used. This work demonstrates that machine and active learning approaches have the potential to greatly facilitate metabolic engineering efforts to rapidly achieve its objectives.     

The oviposition behavior ofAphidius ervi andMonoctonus paulensis (Hymenoptera: Aphididae) encountering different host species (Homoptera: Aphididae) in sequential patches

Two-day-old mated females ofAphidius ervi Haliday andMonoctonus paulensis (Ashmead) were each provided with two sequential host patches. Patches were comprised of plastic petri dishes containing either 15 pea aphids,Acyrthosiphum pisum (Harris), or 15 alfalfa aphids,Macrosiphum creelii Davis. Both wasp species parasitized more hosts in patches containing pea aphids than in those containing alfalfa aphids, regardless of sequence. Females ofA. ervi also laid more eggs per aphid in patches containing pea aphids than in patches containing alfalfa aphids. When both patches contained alfalfa aphids,M. paulensis females parsitized more aphids in the second patch than in the first. Fewer alfalfa aphids were parasitized in the second patch when the first patch contained pea aphids, and fewer eggs were laid per alfalfa aphid. Parasitoid females of both species exhibited consistently higher rates of oviposition into their preferred host species and adjusted their reproductive allocation to hosts and host patches as a function of their experience in previous patches.     

The bold and the shy: individual differences in rainbow trout

Boldness and shyness were investigated as 'personality' traits in hatchery-reared rainbow trout Oncorhynchus mykiss . Bold fish spent more time in an open area and were more active than shy fish and these behaviours could be used as indicators of boldness and shyness. These differences were related to learning ability in a simple conditioning task. Bold fish learned the task more quickly than shy fish.     

Developmental Lead Exposure and Two-Way Active Avoidance Training Alter the Distribution of Protein Kinase C Activity in the Rat Hippocampus

Long-term exposure to a low level of lead is associated with learning deficits. Several types of learning have been correlated to hippocampal protein kinase C (PKC) activation. This study was designed to determine if there is a correlation between the effects of lead on hippocampal PKC activation and those on learning performance. Rats were exposed to 0.2% (w/v) lead acetate at different developmental stages including a maternally exposed group, a postweaning exposed group, and a continuously exposed group. The continuously lead exposed rats tended to avoid less frequently and not respond more frequently in two-way active avoidance training than did controls. This training process was associated with translocation of hippocampal PKC activity from cytosol to membrane. Two-way analysis of variance of data indicates that there is a significant training and lead treatment interaction in the ratio of membrane to cytosolic PKC activity (F_3,32 = 3.013; p = 0.044). The interaction is attributable to the absence of the training-induced PKC translocation in the continuously lead exposed rats. In addition, no significant changes were observed in learning performance and training-induced hippocampal PKC activation after maternal and postweaning lead exposure. Continuous and longer duration of lead exposure appears to affect the learning performance and hippocampal PKC activation. These data suggest that a change in the activation of hippocampal PKC may be involved in the lead-induced deficit in learning.     

Possible aversion learning in the Pacific Coast wireworm

The effects of carbon dioxide and the induction of morbidity on aversion learning in larvae of the Pacific Coast wireworm Limonius canus LeConte (Coleoptera: Elateridae) are discussed. Wireworms preconditioned by exposing them one or four times to odour of Tefluthrin 20SC and Dividend XLRTA [Syngenta Crop Protection (Canada), Inc., Canada] during the induction of temporary morbidity subsequently contact tefluthrin‐treated wheat seeds in soil bioassays for as long as naïve (i.e. not preconditioned) larvae but are repelled four to five‐fold more frequently by Dividend‐treated seeds in soil bioassays than naïve wireworms, suggesting that wireworms are capable of associating a novel odour (i.e. Dividend) with morbidity but require a minimum of 10–15 min subsequent contact time with treated seeds before being repelled. Wireworms preconditioned by exposure to peppermint odour during the induction of morbidity are not subsequently repelled by peppermint odour in soil bioassays, suggesting that wireworms are either not capable of aversion learning or that the presence of a CO₂ source and/or a suitable host plant may override a negative cue (i.e. peppermint odour). In studies conducted in the absence of soil, a host plant and CO₂ production, wireworms are repelled slightly by droplets of 1.0% but not 0.1% peppermint oil. Previous exposure to peppermint odour or contact with peppermint oil‐treated filter paper during one induction of morbidity does not increase the repellency of wireworms to 1.0% peppermint oil significantly. Repellency to 1.0% peppermint oil is almost eliminated when morbidity is induced five times in the absence of peppermint odour but is restored when peppermint odour is present during preconditioning. These findings suggest that wireworm sensitivity to repellent compounds decreases when repeatedly made moribund, although the results are not sufficient to conclude that wireworms are capable of associative learning.     

Instrumental outcome devaluation with representation-mediated conditioning

In three experiments, rats were trained to perform two instrumental behaviours (R1 and R2) in the presence of discriminative stimuli (Sd1 and Sd2, respectively) to obtain a common food outcome (O1). Acquisition of the two discriminations was followed by switching the outcome accompanying R2 performance from O1 to a new one (O2). Experiment 1 showed paired presentations of O2 with a lithium chloride (LiCl) injection resulted in a reduction in the R2 performance. In the subsequent two experiments, each Sd was paired with LiCl injection and its effects on outcome consumption and instrumental performance were investigated. A reduction in the O2 consumption subsequent to the Sd devaluation was found in Experiments 2 and 3. Experiment 3 revealed a reduced R2 performance in an extinction test, following the animals’ consummatory access to the outcomes in training context. These results demonstrate representation-mediated outcome devaluation in the course of the Sd devaluation.     

Resistance to change and vulnerability to stress: autistic‐like features of GAP43‐deficient mice

There is an urgent need for animal models of autism spectrum disorder (ASD) to understand the underlying pathology and facilitate development and testing of new treatments. The synaptic growth‐associated protein‐43 (GAP43) has recently been identified as an autism candidate gene of interest. Our previous studies show many brain abnormalities in mice lacking one allele for GAP43 [GAP43 (+/?)] that are consistent with the disordered connectivity theory of ASD. Thus, we hypothesized that GAP43 (+/?) mice would show at least some autistic‐like behaviors. We found that GAP43 (+/?) mice, relative to wild‐type (+/+) littermates, displayed resistance to change, consistent with one of the diagnostic criteria for ASD. GAP43 (+/?) mice also displayed stress‐induced behavioral withdrawal and anxiety, as seen in many autistic individuals. In addition, both GAP43 (+/?) mice and (+/+) littermates showed low social approach and lack of preference for social novelty, consistent with another diagnostic criterion for ASD. This low sociability is likely because of the mixed C57BL/6J 129S3/SvImJ background. We conclude that GAP43 deficiency leads to the development of a subset of autistic‐like behaviors. As these behaviors occur in a mouse that displays disordered connectivity, we propose that future anatomical and functional studies in this mouse may help uncover underlying mechanisms for these specific behaviors. Strain‐specific low sociability may be advantageous in these studies, creating a more autistic‐like environment for study of the GAP43‐mediated deficits of resistance to change and vulnerability to stress.