Strongly polyphenic social insects provide excellent models to examine the neurobiological basis of division of labor. Turtle ants, Cephalotes varians, have distinct minor worker, soldier, and reproductive (gyne/queen) morphologies associated with their behavioral profiles: small-bodied task-generalist minors lack the phragmotic shield-shaped heads of soldiers, which are specialized to block and guard the nest entrance. Gynes found new colonies and during early stages of colony growth overlap behaviorally with soldiers. Here we describe patterns of brain structure and synaptic organization associated with division of labor in C. varians minor workers, soldiers, and gynes. We quantified brain volumes, determined scaling relationships among brain regions, and quantified the density and size of microglomeruli, synaptic complexes in the mushroom body calyxes important to higher-order processing abilities that may underpin behavioral performance. We found that brain volume was significantly larger in gynes; minor workers and soldiers had similar brain sizes. Consistent with their larger behavioral repertoire, minors had disproportionately larger mushroom bodies than soldiers and gynes. Soldiers and gynes had larger optic lobes, which may be important for flight and navigation in gynes, but serve different functions in soldiers. Microglomeruli were larger and less dense in minor workers; soldiers and gynes did not differ. Correspondence in brain structure despite differences in soldiers and gyne behavior may reflect developmental integration, suggesting that neurobiological metrics not only advance our understanding of brain evolution in social insects, but may also help resolve questions of the origin of novel castes.

High percentage of human cancers involves alteration or mutation in Ras proteins, including the most aggressive malignancies, such as lung, colon and pancreatic cancers. FTS (Salirasib) is a farnesylcysteine mimetic, which acts as a functional Ras inhibitor, and was shown to exert anti-tumorigenic effects in vitro and in vivo. Previously, we have demonstrated that short-term treatment with FTS also induces protective autophagy in several cancer cell lines. Drug resistance is frequently observed in cancer cells exposed to prolonged treatment, and is considered a major cause for therapy inefficiency. Therefore, in the present study, we examined the effect of a prolonged treatment with FTS on drug resistance of HCT-116 human colon cancer cells, and the involvement of autophagy in this process. We found that cells grown in the presence of FTS for 6 months have become resistant to FTS-induced cell growth inhibition and cell death. Furthermore, we discovered that the resistant cells exhibit altered autophagy, reduced apoptosis and changes in Ras-related signaling pathways following treatment with FTS. Moreover we found that while FTS induces an apoptosis-related cleavage of p62, the FTS-resistant cells were more resistant to apoptosis and p62 cleavage.

Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death.

The ErbB receptor tyrosine kinases are major contributors to malignant transformation. These receptors are frequently overexpressed in a variety of human carcinomas. The role of the ErbB receptors and their ligands in carcinomas and the mechanism by which their overexpression leads to cancer development is still unclear. Ligand binding to specific ErbB receptor is followed by receptor dimerization, phosphorylation and recruitment of SH2 containing cytoplasmic proteins, which initiate the cascade of signaling events. Nevertheless, increasing data suggest that there are non-phosphorylated receptor-substrate interactions that may affect ErbB-mediated responses.

Neurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer's disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.

GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep-wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO) mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM) sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM) sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep.

Cephalopoda are a class of Mollusca species found in all the world's oceans. They are an important model organism in neurobiology. Unfortunately, the lack of neuronal molecular sequences, such as ESTs, transcriptomic or genomic information, has limited the development of molecular neurobiology research in this unique model organism.

Visual environments may simultaneously comprise stimuli of different significance. Often such stimuli require incompatible responses. Selective visual attention allows an animal to respond exclusively to the stimuli at a certain location in the visual field. In the process of establishing its focus of attention the animal can be influenced by external cues. Here we characterize the behavioral properties and neural mechanism of cueing in the fly Drosophila melanogaster. A cue can be attractive, repulsive or ineffective depending upon (e.g.) its visual properties and location in the visual field. Dopamine signaling in the brain is required to maintain the effect of cueing once the cue has disappeared. Raising or lowering dopamine at the synapse abolishes this after-effect. Specifically, dopamine is necessary and sufficient in the αβ-lobes of the mushroom bodies. Evidence is provided for an involvement of the αβposterior Kenyon cells.

The ErbB receptor tyrosine kinases and nucleolin are major contributors to malignant transformation. Recently we have found that cell-surface ErbB receptors interact with nucleolin via their cytoplasmic tail. Overexpression of ErbB1 and nucleolin leads to receptor phosphorylation, dimerization and anchorage independent growth.

The ErbB receptors, Ras proteins and nucleolin are major contributors to malignant transformation. The pleiotropic protein nucleolin can bind to both Ras protein and ErbB receptors. Previously, we have demonstrated a crosstalk between Ras, nucleolin and the ErbB1 receptor. Activated Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 levels. The three oncogenes synergistically facilitate anchorage independent growth and tumor growth in nude mice.

Preterm children often have language problems. This atypical language development is probably due to atypical brain development. We conducted a systematic review to provide an overview of the extensive and diverse scientific literature on the relations between language outcome and underlying brain structures in school-aged preterm-born children. Embase, Medline Ovid, Web of Science, Cochrane central and Google scholar were searched for relevant studies. Inclusion criteria were: cases are school-aged preterm children; structural MRI (T1- and T2-weighted sequences) or DTI used in combination with a neurocognitive language test; publication in an English-language peer-reviewed journal. Correlational measures between language scores and brain volume or fractional anisotropy of a brain structure were extracted. 23 studies were included. The relations between oral language, verbal fluency and/or written language and MRI/DTI measurements of white matter, gray matter, cerebellum, corpus callosum and/or the fasciculi are presented. Oral language skills and verbal fluency appear to be related to the corpus callosum. Oral language skills are also related to the uncinate fasciculus. There seems to be no clear relation between cerebellar development and verbal fluency skills. Not one single brain area is responsible for atypical language development, but several brain areas and their connections are essential. For future research it is recommended to relate brain areas to oral language skills on a microstructural level in preterm children. We also recommend to use language tests in which it is possible to distinguish between several language domains, such as perceptive and expressive language.

Synchronized oscillation in cortical networks has been suggested as a mechanism for diverse functions ranging from perceptual binding to memory formation to sensorimotor integration. Concomitant with synchronization is the occurrence of near-zero phase-lag often observed between network components. Recent theories have considered the importance of this phenomenon in establishing an effective communication framework among neuronal ensembles.

Mouse lemurs (Microcebus spp.) are an exciting new primate model for understanding human aging and disease. In captivity, Microcebus murinus develops human-like ailments of old age after five years (e.g., neurodegeneration analogous to Alzheimer's disease) but can live beyond 12 years. It is believed that wild Microcebus follow a similar pattern of senescence observed in captive animals, but that predation limits their lifespan to four years, thus preventing observance of these diseases in the wild. Testing whether this assumption is true is informative about both Microcebus natural history and environmental influences on senescence, leading to interpretation of findings for models of human aging. Additionally, the study of Microcebus longevity provides an opportunity to better understand mechanisms of sex-biased longevity. Longevity is often shorter in males of species with high male-male competition, such as Microcebus, but mouse lemurs are sexually monomorphic, suggesting similar lifespans. We collected individual-based observations of wild brown mouse lemurs (Microcebus rufus) from 2003-2010 to investigate sex-differences in survival and longevity. Fecal testosterone was measured as a potential mechanism of sex-based differences in survival. We used a combination of high-resolution tooth wear techniques, mark-recapture, and hormone enzyme immunoassays. We found no dental or physical signs of senescence in M. rufus as old as eight years (N = 189, ages 1-8, mean = 2.59 ± 1.63 SE), three years older than captive, senescent congeners (M. murinus). Unlike other polygynandrous vertebrates, we found no sex difference in age-dependent survival, nor sex or age differences in testosterone levels. While elevated male testosterone levels have been implicated in shorter lifespans in several species, this is one of the first studies to show equivalent testosterone levels accompanying equivalent lifespans. Future research on captive aged individuals can determine if senescence is partially a condition of their captive environment, and studies controlling for various environmental factors will further our understanding of senescence.

Sensorimotor learning typically shows generalization from one context to another. Models of sensorimotor learning characterize this with a fixed generalization function that couples learning between contexts. Here we examine whether such coupling is indeed fixed or changes with experience. We examine the interaction between motor memories for novel dynamics during reciprocating, back and forth reaching movements. Subjects first experienced a force field for one movement direction and we used channel trials to assess generalization on the reciprocal movements. This showed minimal coupling such that errors experienced for one movement direction did not lead to adaptation for the other. However, after subjects had experienced a force field for both movement directions concurrently, a coupling developed between the corresponding motor memories. That is, on re-exposure for one direction there was a significant adaptation for movements in the other direction. The coupling was specific to the errors experienced, with minimal coupling when the errors had the opposite sign to those experienced during adaptation. We developed a state-space model in which the states for the two movement directions are represented by separate, yet potentially coupled learning processes. The coupling in the model controlled the extent to which each learning process was updated by the errors experienced on the other movement direction. We show that the coupling relies on a memory trace of the consecutive errors experienced for both movement directions. Our results suggest that the generalization of motor learning is an adaptive process, reflecting the relation between errors experienced across different movements.

Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.

Individuals that initiate alcohol use at younger ages and binge drink during adolescence are more susceptible to developing alcohol use disorder. Adolescents are relatively insensitive to the aversive effects of alcohol and tend to consume significantly more alcohol per occasion than adults, an effect that is conserved in rodent models. Adolescent typical insensitivity to the aversive effects of alcohol may promote greater alcohol intake by attenuating internal cues that curb its consumption. Attenuated sensitivity to the aversive effects of alcohol is also retained into adulthood following protracted abstinence from adolescent intermittent ethanol (AIE) exposure. Despite these effects, much remains unknown regarding the neural contributors. In the present study, we used a conditioned taste aversion (CTA) paradigm to investigate neuronal activation in late-developing forebrain structures of male adolescents and adult cFos-LacZ transgenic rats as well as in AIE adults following consumption of 0.9% sodium chloride previously paired with an intraperitoneal injection of 0, 1.5 or 2.5 g/kg of ethanol. Adults that were non-manipulated or received water exposure during adolescence showed CTA to both ethanol doses, whereas adolescents displayed CTA only to the 2.5 g/kg ethanol dose. Adults who experienced AIE did not show CTA. Adults displayed increased neuronal activation indexed via number of β-galactosidase positive (β-gal+) cells in the prefrontal and insular cortex that was absent in adolescents, whereas adolescents but not adults had a reduced number of β-gal+ cells in the central amygdala. Adults also displayed greater cortical-insular functional connectivity than adolescents as well as insular-amygdalar and prefrontal cortex-accumbens core functional connectivity. Like adolescents, adults previously exposed to AIE displayed reduced prefrontal-insular cortex and prefrontal-accumbal core functional connectivity. Taken together, these results suggest that attenuated sensitivity to the aversive effects of ethanol is related to a loss of an insular-prefrontal cortex-accumbens core circuit.

During the course of a differential screen to identify transcripts specific for chick heart/hemangioblast precursor cells, we have identified Ccbe1 (Collagen and calcium-binding EGF-like domain 1). While the importance of Ccbe1 for the development of the lymphatic system is now well demonstrated, its role in cardiac formation remained unknown. Here we show by whole-mount in situ hybridization analysis that cCcbe1 mRNA is initially detected in early cardiac progenitors of the two bilateral cardiogenic fields (HH4), and at later stages on the second heart field (HH9-18). Furthermore, cCcbe1 is expressed in multipotent and highly proliferative cardiac progenitors. We characterized the role of cCcbe1 during early cardiogenesis by performing functional studies. Upon morpholino-induced cCcbe1 knockdown, the chick embryos displayed heart malformations, which include aberrant fusion of the heart fields, leading to incomplete terminal differentiation of the cardiomyocytes. cCcbe1 overexpression also resulted in severe heart defects, including cardia bifida. Altogether, our data demonstrate that although cardiac progenitors cells are specified in cCcbe1 morphants, the migration and proliferation of cardiac precursors cells are impaired, suggesting that cCcbe1 is a key gene during early heart development.

Accumulating evidence suggests that basic visual information processing is impaired in schizophrenia. However, deficits in peripheral vision remain largely unexplored. Here we hypothesized that sensory processing of information in the visual periphery would be impaired in schizophrenia patients and, as a result, crowding - the breakdown in target recognition that occurs in cluttered visual environments - would be stronger. Therefore, we assessed visual crowding in the peripheral vision of schizophrenia patients and healthy controls. Subjects were asked to identify a target letter that was surrounded by distracter letters of similar appearance. Targets and distracters were displayed at 8° and 10° of visual angle from the fixation point (eccentricity), and target-distracter spacing was 2°, 3°, 4°, 5°, 6°, 7° or 8° of visual angle. Eccentricity and target-distracter spacing were randomly varied. Accuracy was defined as the proportion of correctly identified targets. Critical spacing was defined as the spacing at which target identification accuracy began to deteriorate, and was assessed at viewing eccentricities of 8° and 10°. Schizophrenia patients were less accurate and showed a larger critical spacing than healthy individuals. These results indicate that crowding is stronger and sensory processing of information in the visual periphery is impaired in schizophrenia. This is in line with previous reports of preferential magnocellular dysfunction in schizophrenia. Thus, deficits in peripheral vision may account for perceptual alterations and contribute to cognitive dysfunction in schizophrenia.

Performance in most complex cognitive and psychomotor tasks improves with training, yet the extent of improvement varies among individuals. Is it possible to forecast the benefit that a person might reap from training? Several behavioral measures have been used to predict individual differences in task improvement, but their predictive power is limited. Here we show that individual differences in patterns of time-averaged T2*-weighted MRI images in the dorsal striatum recorded at the initial stage of training predict subsequent learning success in a complex video game with high accuracy. These predictions explained more than half of the variance in learning success among individuals, suggesting that individual differences in neuroanatomy or persistent physiology predict whether and to what extent people will benefit from training in a complex task. Surprisingly, predictions from white matter were highly accurate, while voxels in the gray matter of the dorsal striatum did not contain any information about future training success. Prediction accuracy was higher in the anterior than the posterior half of the dorsal striatum. The link between trainability and the time-averaged T2*-weighted signal in the dorsal striatum reaffirms the role of this part of the basal ganglia in learning and executive functions, such as task-switching and task coordination processes. The ability to predict who will benefit from training by using neuroimaging data collected in the early training phase may have far-reaching implications for the assessment of candidates for specific training programs as well as the study of populations that show deficiencies in learning new skills.

With the increased knowledge of biological risk factors, interest in including this information in forensic assessments is growing. Currently, forensic assessments are predominantly focused on psychosocial factors. A better understanding of the neurobiology of violent criminal behaviour and biological risk factors could improve forensic assessments.