A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice.

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.

Network meta-analysis of transcriptome expression changes in different manifestations of dengue virus infection.

BACKGROUND: Several studies have been performed to study transcriptome profiles after dengue virus infections with partly different results. Due to slightly different settings of the individual studies, different genes and enriched gene sets are reported in these studies. The main aim of this network meta-analysis was to aggregate a selection of these studies to identify genes and gene sets that are more generally associated with dengue virus infection, i.e. with less dependence on the individual study settings. METHODS: We performed network meta-analysis by different approaches using publicly available gene expression data of five selected studies from the Gene Expression Omnibus database. The study network includes dengue fever (DF), hemorrhagic fever (DHF), shock syndrome (DSS) patients as well as convalescent and healthy control individuals. After data merging and missing value imputation, study-specific batch effects were removed. Pairwise differential expression analysis and subsequent gene-set enrichment analysis were performed between the five study groups. Furthermore, mutual information networks were derived from the top genes of each group comparison, and the separability between the three patient groups was studied by machine learning models. RESULTS: From the 10 possible pairwise group comparisons in the study network, six genes (IFI27, TPX2, CDT1, DTL, KCTD14 and CDCA3) occur with a noticeable frequency among the top listed genes of each comparison. Thus, there is an increased evidence that these genes play a general role in dengue virus infections. IFI27 and TPX2 have also been highlighted in the context of dengue virus infection by other studies. A few of the identified gene sets from the network meta-analysis overlap with findings from the original studies. Mutual information networks yield additional genes for which the observed pairwise correlation is different between the patient groups. Machine learning analysis shows a moderate separability of samples from the DF, DHF and DSS groups (accuracy about 80%). CONCLUSIONS: Due to an increased sample size, the network meta-analysis could reveal additional genes which are called differentially expressed between the studied groups and that may help to better understand the molecular basis of this disease.

Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapeutic principle in Parkinson's disease, but the underlying mechanisms, particularly mediating non-motor actions, remain largely enigmatic. OBJECTIVE/HYPOTHESIS: The delayed onset of neuropsychiatric actions in conjunction with first experimental evidence that STN-DBS causes disease-modifying effects prompted our investigation on how cellular plasticity in midbrain dopaminergic systems is affected by STN-DBS. METHODS: We applied unilateral or bilateral STN-DBS in two independent cohorts of 6-hydroxydopamine hemiparkinsonian rats four to eight weeks after dopaminergic lesioning to allow for the development of a stable dopaminergic dysfunction prior to DBS electrode implantation. RESULTS: After 5 weeks of STN-DBS, stimulated animals had significantly more TH+ dopaminergic neurons and fibres in both the nigrostriatal and the mesolimbic systems compared to sham controls with large effect sizes of gHedges = 1.9-3.4. DBS of the entopeduncular nucleus as the homologue of the human Globus pallidus internus did not alter the dopaminergic systems. STN-DBS effects on mesolimbic dopaminergic neurons were largely confirmed in an independent animal cohort with unilateral STN stimulation for 6 weeks or for 3 weeks followed by a 3 weeks washout period. The latter subgroup even demonstrated persistent mesolimbic dopaminergic plasticity after washout. Pilot behavioural testing showed that augmentative dopaminergic effects on the mesolimbic system by STN-DBS might translate into improvement of sensorimotor neglect. CONCLUSIONS: Our data support sustained neurorestorative effects of STN-DBS not only in the nigrostriatal but also in the mesolimbic system as a potential factor mediating long-latency neuropsychiatric effects of STN-DBS in Parkinson's disease.

Prevention of schizophrenia deficits via non-invasive adolescent frontal cortex stimulation in rats.

Schizophrenia is a severe neurodevelopmental psychiatric affliction manifested behaviorally at late adolescence/early adulthood. Current treatments comprise antipsychotics which act solely symptomatic, are limited in their effectiveness and often associated with side-effects. We here report that application of non-invasive transcranial direct current stimulation (tDCS) during adolescence, prior to schizophrenia-relevant behavioral manifestation, prevents the development of positive symptoms and related neurobiological alterations in the maternal immune stimulation (MIS) model of schizophrenia.

Starting ambulance care professionals and critical incidents: a qualitative study on experiences, consequences and coping strategies.

BACKGROUND: Ambulance care professionals are regularly confronted with critical incidents that increase risks for mental health disorders. To minimize these risks, it is important that ambulance care professionals adequately cope with critical incidents. Especially from the perspective of starting ambulance care professionals it is unknown which coping styles they use when experiencing a critical incident and how they are trained to cope with critical incidents. The aim of this study was to gain insight in (a) what starting ambulance care professionals describe as critical incidents, (b) how they experience these critical incidents and their consequences, (c) how they cope with these incidents, and (d) how they are trained and guided to cope with these incidents. METHODS: A qualitative design with individual, semi-structured interviews was used. The data was analyzed by using inductive thematic analysis. RESULTS: Twenty-two starting ambulance care professionals were interviewed of which, 11 were male. The age ranged from 23 to 31 years, with 11 participants being 27 years or younger. Three key-themes emerged that make an incident critical: (1) emotional connection versus emotional detachment, (2) feeling loss of control, and (3) incomprehension. All participants experienced several short to middle term physical, psychological and social consequences after encountering a critical incident. Starting ambulance care professionals applied different coping strategies during different phases of the ambulance care process: a mix of depersonification, focus on the medical task, support from colleagues and their own network, seeking confirmation, and distraction. Most starting ambulance care professionals don't actively remember they received education about coping with critical incidents during their initial educational program. During and after traineeships, the workplace preceptor has a crucial role for starting ambulance care professionals to learn them how to cope with critical incidents. CONCLUSIONS: Three key-themes interact to make an incident more critical for starting ambulance care professionals. To cope with these critical incidents, starting ambulance care professionals use a variety of coping strategies. These results can be used to develop training and coaching for starting ambulance care professionals so they can adequately cope with critical incidents.

Basophils enhance immunological memory responses.

The cellular basis of immunological memory remains a controversial issue. Here we show that basophils bound large amounts of intact antigens on their surface and were the main source of interleukins 6 and 4 in the spleen and bone marrow after restimulation with a soluble antigen. Depletion of basophils resulted in a much lower humoral memory response and greater susceptibility of immunized mice to sepsis induced by Streptococcus pneumoniae. Adoptive transfer of antigen-reactive basophils significantly increased specific antibody production, and activated basophils, together with CD4(+) T cells, profoundly enhanced B cell proliferation and immunoglobulin production. These basophil-dependent effects on B cells required interleukins 6 and 4 and increased the capacity of CD4(+) T cells to provide B cell help. Thus, basophils are important contributors to humoral memory immune responses.

Addiction Research Consortium: Losing and regaining control over drug intake (ReCoDe)-From trajectories to mechanisms and interventions.

One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12-year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism-based interventions. These goals will be achieved by: (i) using mobile health (m-health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real-life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal-directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.

Abdominal Vagal Afferents Modulate the Brain Transcriptome and Behaviors Relevant to Schizophrenia.

Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions.SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions.

Network meta-analysis correlates with analysis of merged independent transcriptome expression data.

BACKGROUND: Using meta-analysis, high-dimensional transcriptome expression data from public repositories can be merged to make group comparisons that have not been considered in the original studies. Merging of high-dimensional expression data can, however, implicate batch effects that are sometimes difficult to be removed. Removing batch effects becomes even more difficult when expression data was taken using different technologies in the individual studies (e.g. merging of microarray and RNA-seq data). Network meta-analysis has so far not been considered to make indirect comparisons in transcriptome expression data, when data merging appears to yield biased results. RESULTS: We demonstrate in a simulation study that the results from analyzing merged data sets and the results from network meta-analysis are highly correlated in simple study networks. In the case that an edge in the network is supported by multiple independent studies, network meta-analysis produces fold changes that are closer to the simulated ones than those obtained from analyzing merged data sets. Finally, we also demonstrate the practicability of network meta-analysis on a real-world data example from neuroinfection research. CONCLUSIONS: Network meta-analysis is a useful means to make new inferences when combining multiple independent studies of molecular, high-throughput expression data. This method is especially advantageous when batch effects between studies are hard to get removed.

Deep brain stimulation during early adolescence prevents microglial alterations in a model of maternal immune activation.

In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease.

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.

Gut vagal afferents differentially modulate innate anxiety and learned fear.

Vagal afferents are an important neuronal component of the gut-brain axis allowing bottom-up information flow from the viscera to the CNS. In addition to its role in ingestive behavior, vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear. Here, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on innate anxiety, conditioned fear, and neurochemical parameters in the limbic system. We found that compared with Sham controls, SDA rats consistently displayed reduced innate anxiety-like behavior in three procedures commonly used in preclinical rodent models of anxiety, namely the elevated plus maze test, open field test, and food neophobia test. On the other hand, SDA rats exhibited increased expression of auditory-cued fear conditioning, which specifically emerged as attenuated extinction of conditioned fear during the tone re-exposure test. The behavioral manifestations in SDA rats were associated with region-dependent changes in noradrenaline and GABA levels in key areas of the limbic system, but not with functional alterations in the hypothalamus-pituitary-adrenal grand stress. Our study demonstrates that innate anxiety and learned fear are both subjected to visceral modulation through abdominal vagal afferents, possibly via changing limbic neurotransmitter systems. These data add further weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior.

Human metapneumovirus SH and G glycoproteins inhibit macropinocytosis-mediated entry into human dendritic cells and reduce CD4+ T cell activation.

UNLABELLED: Human metapneumovirus (HMPV) is a major etiologic agent of respiratory disease worldwide. HMPV reinfections are common in healthy adults and children, suggesting that the protective immune response to HMPV is incomplete and short-lived. We used gene-deletion viruses to evaluate the role of the attachment G and small hydrophobic SH glycoproteins on virus uptake by primary human monocyte-derived dendritic cells (MDDC) in vitro and on subsequent MDDC maturation and activation of autologous T cells. HMPV with deletion of G and SH (ΔSHG) exhibited increased infectivity but had little effect on MDDC maturation. However, MDDC stimulated with ΔSHG induced increased proliferation of autologous Th1-polarized CD4(+) T cells. This effect was independent of virus replication. Increased T cell proliferation was strictly dependent on contact between virus-stimulated MDDC and CD4(+) T cells. Confocal microscopy revealed that deletion of SH and G was associated with an increased number of immunological synapses between memory CD4(+) T cells and virus-stimulated MDDC. Uptake of HMPV by MDDC was found to be primarily by macropinocytosis. Uptake of wild-type (WT) virus was reduced compared to that of ΔSHG, indicative of inhibition by the SH and G glycoproteins. In addition, DC-SIGN-mediated endocytosis provided a minor alternative pathway that depended on SH and/or G and thus operated only for WT. Altogether, our results show that SH and G glycoproteins reduce the ability of HMPV to be internalized by MDDC, resulting in a reduced ability of the HMPV-stimulated MDDC to activate CD4(+) T cells. This study describes a previously unknown mechanism of virus immune evasion. IMPORTANCE: Human metapneumovirus (HMPV) is a major etiologic agent of respiratory disease worldwide. HMPV reinfections are common in healthy adults and children, suggesting that the protective immune response to HMPV is incomplete and short-lived. We found that HMPV attachment G and small hydrophobic SH glycoproteins reduce the ability of HMPV to be internalized by macropinocytosis into human dendritic cells (DC). This results in a reduced ability of the HMPV-stimulated DC to activate Th1-polarized CD4(+) T cells. These results contribute to a better understanding of the nature of incomplete protection against this important human respiratory virus, provide new information on the entry of HMPV into human cells, and describe a new mechanism of virus immune evasion.

Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning.

BACKGROUND AIMS: In Parkinson's disease (PD), neurogenesis in the subventricular zone (SVZ)-olfactory bulb (OB) axis is affected as the result of the lack of dopaminergic innervations reaching the SVZ. This aberrant network has been related to the hyposmia of PD patients, which is an early diagnostic marker of the disease. Consequently, much interest arose in finding mechanisms to modulate the SVZ-OB axis. Direct modulation of this axis could be achieved by transplantation of mesenchymal stromal cells (MSC), as it has been shown in rat and mouse PD models. However, the neurogenic effect of MSC in PD was thus far only analyzed weeks after transplantation, and little is known about effects immediately after transplantation. METHODS: We assessed the acute neuroprotective and neurogenic effects of adipose-derived MSC transplanted into the rat substantia nigra in the 6-hydroxydopamine model of PD. RESULTS: Three days after transplantation, subventricular neurogenesis was significantly increased in MSC-transplanted versus non-transplanted animals. Most MSC were found in the region of the substantia nigra and the surrounding arachnoid mater, expressing S100ß and brain-derived neurotrophic factor, whereas some MSC showed an endothelial phenotype and localized around blood vessels. CONCLUSIONS: The acute neurogenic effects and neurotrophic factor expression of MSC could help to restore the SVZ-OB axis in PD.

A Review of Transcranial Magnetic Stimulation as a Treatment for Post-Traumatic Stress Disorder.

Patients with post-traumatic stress disorder (PTSD) may fail to achieve adequate relief despite treatment with psychotherapy, pharmacotherapy, or complementary medicine treatments. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation procedure that can alter neuronal activity through administration of various pulse sequences and frequencies. TMS may theoretically have promise in correcting alterations observed in patients with PTSD. While the precise treatment location and pulse sequences remain undefined, current evidence suggests two promising targets, the right dorsolateral prefrontal cortex and the medial prefrontal cortex. The beneficial effects may be due to the secondary or indirect regulation of other brain structures that may be involved in the mood regulatory network. TMS may be an effective part of a comprehensive treatment program for PTSD, although significant work remains to define optimal treatment parameters and clarify how it fits within a broader traditional treatment program.

Social experience modulates ocular dominance plasticity differentially in adult male and female mice.

Environmental factors have long been known to regulate brain plasticity. We investigated the potential influence of social experience on ocular dominance plasticity. Fully adult female or male mice were monocularly deprived for four days and kept a) either alone or in pairs of the same sex and b) either in a small cage or a large, featureless arena. While mice kept alone did not show ocular dominance plasticity, no matter whether in a cage or in an arena, paired female mice in both environmental conditions displayed a shift of ocular dominance towards the open eye. Paired male mice, in contrast, showed no plasticity in the cage, but a very strong ocular dominance shift in the arena. This effect was not due to increased locomotion, since the covered distance was similar in single and paired male mice in the arena, and furnishing cages with a running wheel did not enable ocular dominance plasticity in cage-housed mice. Confirming recent results in rats, the plasticity-enhancing effect of the social environment was shown to be mediated by serotonin. Our results demonstrate that social experience has a strong effect on cortical plasticity that is sex-dependent. This has potential consequences both for animal research and for human education and rehabilitation.

Respiratory syncytial virus modified by deletions of the NS2 gene and amino acid S1313 of the L polymerase protein is a temperature-sensitive, live-attenuated vaccine candidate that is phenotypically stable at physiological temperature.

Human respiratory syncytial virus (RSV) is the leading viral cause of lower respiratory tract disease in infants and children worldwide. In previous work to develop point mutations in RSV with improved genetic stability, we observed that an attenuating mutation at amino acid position 1321 in the L polymerase protein was subject to deattenuation by a spontaneous second-site compensatory mutation at position 1313 (C. Luongo, C. C. Winter, P. L. Collins, and U. J. Buchholz, J. Virol. 86:10792-10804, 2012). In the present study, we found that deletion of position 1313 (Δ1313), irrespective of the presence of an attenuating mutation at position 1321, provided a new attenuating mutation. RSV bearing Δ1313 replicated in cell culture as efficiently as wild-type virus at 32°C, was restricted for replication at 37°C, and was restricted 50-fold and 150-fold in the upper and lower respiratory tracts, respectively, of mice. We combined the Δ1313 deletion with the previously described, attenuating NS2 gene deletion (ΔNS2) to produce the recombinant live-attenuated RSV vaccine candidate ΔNS2/Δ1313. During in vitro stress tests involving serial passage at incrementally increasing temperatures, a second-site compensatory mutation was detected in close proximity of Δ1313, namely, I1314T. This site was genetically and phenotypically stabilized by an I1314L substitution. Combination of I1314L with ΔNS2/Δ1313 yielded a virus, ΔNS2/Δ1313/1314L, with genetic stability at physiological temperature. This stabilized vaccine candidate was moderately temperature sensitive and had a level of restriction in chimpanzees comparable to that of MEDI-559, a promising RSV vaccine candidate that presently is in clinical trials but lacks stabilized attenuating mutations. The level of attenuation and genetic stability identify ΔNS2/Δ1313/1314L as a promising candidate for evaluation in pediatric phase I studies.

Surface glycoproteins of an African henipavirus induce syncytium formation in a cell line derived from an African fruit bat, Hypsignathus monstrosus.

Serological screening and detection of genomic RNA indicates that members of the genus Henipavirus are present not only in Southeast Asia but also in African fruit bats. We demonstrate that the surface glycoproteins F and G of an African henipavirus (M74) induce syncytium formation in a kidney cell line derived from an African fruit bat, Hypsignathus monstrosus. Despite a less broad cell tropism, the M74 glycoproteins show functional similarities to glycoproteins of Nipah virus.

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia.

Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia. We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1ß and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1ß production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.

Differences in the tissue tropism to chicken oviduct epithelial cells between avian coronavirus IBV strains QX and B1648 are not related to the sialic acid binding properties of their spike proteins.

The avian coronavirus (AvCoV) infectious bronchitis virus (IBV) is a major poultry pathogen. A characteristic feature of IBV is the occurrence of many different strains belonging to different serotypes, which makes a complete control of the disease by vaccinations a challenging task. Reasons for differences in the tissue tropism and pathogenicity between IBV strains, e.g. a predilection for the kidneys or the oviduct are still an open question. Strains of the QX genotype have been major pathogens in poultry flocks in Asia, Europe and other parts of the world. They are the cause of severe problems with kidney disease and reproductive tract disorders. We analysed infectivity and binding properties of the QX strain and compared them with those of the nephropathogenic strain B1648. As most IBV strains do not infect permanent cell lines and show infection only in primary chicken cells of the target organs, we developed a culture system for chicken oviduct explants. The epithelial cells of the oviduct showed a high susceptibility to infection by the QX strain and were almost resistant to infection by the nephropathogenic B1648 strain. Binding tests with isolated primary oviduct epithelial cells and soluble S1 proteins revealed that S1 proteins of two IBV strains bound with the same efficiency to oviduct epithelial cells. This attachment was sialic acid dependent, indicating that the sugar binding property of IBV spike proteins is not the limiting factor for differences in infection efficiency for the oviduct of the corresponding viruses.