Brain Asymmetry in Evolution

In higher mammals, including primates and carnivores, the asymmetrical aspects of brain morphology and function have been shown to be species-related, sex-related, and subject to individual diversity, and are associated with cognition, emotion, language, preference of hand/paw use, and numerous other aspects. Disturbance of the brain lateralization is involved in human neurodevelopmental disorders with cognitive impairments, social deficits, and/or specific language impairments. Asymmetric development may be essential to the evolution of the brain in acquiring higher and/or more diverse functions. The purpose of this Special Issue on “Brain Asymmetry in Evolution” is to highlight morphological and functional lateralization of the brain in various species of mammals toward understanding the evolution of the brain

Molecular mechanisms underlying cortical (mal)formation: case studies of ESCO2 and EXOSC10

This work focuses on elucidating the molecular mechanisms that control the cortical development. Identification of genes and factors that direct the development of the cerebral cortex will both tell us about their disease-related importance and improve our understanding of the normal formation and malformation of the cortex. In the first part, we performed transcriptome analysis to determine the molecular profile of IPCs, which play a crucial role in cortical formation as they generate the majority of cortical neurons. Accordingly, we sorted TBR2+ IPCs from the embryonic mouse cortex and analysed gene expression profiles of TBR2+ IPCs versus TBR2- cell populations. We identified different levels of key genetic factors regulating chromatid segregation, cell-cycle progression, transcription, and cell signaling. Remarkably, in humans, mutations of several identified IPC genes are linked to various cortical malformations, like microcephaly and macrocephaly, corpus callosum defects, and neurological deficits. For example, mutations in the cohesin acetyltransferase ESCO2, one of the newly identified IPC genes, cause severe malformations including microcephaly. We showed that deficiency of ESCO2 in the developing mouse cortex leads to severe loss of IPCs, resulting in cortical malformation. We thereby demonstrate the identification of a central genetic factor of IPC genesis. Our molecular profiling data reveal novel molecular characteristics of IPCs and offer a resource for future investigations. Recent sequencing analyses of cortical malformations revealed a multifarious genetic landscape. In our pilot work, we identified novel microcephaly-related mutations in a gene encoding EXOSC10, a core subunit of the RNA-decay exosome complex. In the second part of this work, we characterized the cortical phenotypes of EXOSC10cKO mutants. We showed that EXOSC10 is essential for forebrain formation. EXOSC10 deficiency in the developing mouse cortex causes massive apoptosis in cortical cells resulting in cortical malformation. We found that EXOSC10 binds and degrades mRNA coding for P53 signaling-mediators, like AEN and BBC3. Additionally, our studies indicate that EXOSC10 plays a role in regulating the differentiation of cortical progenitors. It might do so via degrading transcripts of the SHH/WNT-β catenin signaling pathways. Further investigations are needed to illuminate this additional role of EXOSC10. In conclusion, our study reveals an essential role of EXOSC10 in suppressing the P53, SHH/WNT-β catenin pathways, which are indispensable for cell survival, neurogenesis and normal cortical formation. Our findings of the mouse model correspond to observations of humans with microcephaly linked to EXOSC10 mutations.2021-09-2

Organização e plasticidade sinápticas na amígdala medial póstero-dorsal de ratos : modulação ontológica e sexual dos espinhos dendríticos, expressão de conexinas e de fatores neurotróficos locais

A amígdala medial póstero-dorsal (MePD) é estrutura cerebral sexualmente dimórfica, dependente dos níveis de hormônios gonadais em circulação e relacionado com o comportamento reprodutivo em ratos. A plasticidade sináptica local se relaciona com os espinhos dendríticos, locais de modulação da atividade pós-sináptica, relacionados com o funcionamento dos neurônios da MePD e as diferenças entre machos e as fêmeas ao longo do ciclo ovulatório. Apesar da prevalência de sinapses químicas, discretas sinapses elétricas já foram reportadas entre células gliais, mas não entre neurônios, na MePD. Nem se sabe a variação de fatores neurotróficos que pode ocorrer entre machos e fêmeas ao longo do ciclo estral. Os objetivos deste trabalho foram: (1) comparar número e estrutura dos espinhos dendríticos na MePD de ratos machos e fêmeas prépúberes e, a seguir, entre machos pós-púberes com e sem experiência sexual empregando-se ténica com microscopia confocal; (2) estudar a ultraestrutura da MePD procurando pela presença de junções comunicantes e, a seguir, estudar a presença das conexinas 36, 43 e 45 por imunofluorescência nessa mesma estrutura; e, (3) estudar o possível dimorfismo sexual e variação ao longo do ciclo estral na expressão local de BDNF (fator neurotrófico derivado do encéfalo), IGF- 1 (fator de crescimento semelhante à insulina tipo 1), PSA-NCAM (forma policialidade da molécula de adesão celular neuronal) e Efrina-A4, fatores neurotróficos envolvidos com a plasticidade sináptica, empregando-se RT-PCR e técnica imunohistoquímica com fluorescência. Os resultados evidenciaram (1) um dimorfismo sexual em espinhos dendríticos da MePD em animais pré-púberes e um remodelamento dos espinhos causado pela puberdade e pela experiência sexual; (2) presença de escassas junções comunicantes entre dendritos e a expressão mais evidente de conexinas 36, 43 e 45 na MePD; e, (3) não haver diferença estatisticamente significativa na expressão de BDNF, IGF-1, PSANCAM e Efrina-A4, nem na expressão gênica de BDNF, NCAM e Efrina-A4, entre machos e fêmeas ao longo do ciclo estral. No entanto, há diferença estatisticamente significativa e maior quantidade de puncta imunorreativa para BDNF em fêmeas em proestro do que em machos e maior de IGF-1 em fêmeas em proestro de que em diestro. Os presentes dados indicam que, na MePD, há dimorfismo sexual e notável reorganização e plasticidade sináptica relacionada com os espinhos dendríticos, que conexinas são mais abundantes que junções comunicantes locais sugerindo haver forma de comunicação intercelular adicional à sinapse química e que duas neurotrofinas (BDNF e IGF-1) podem estar participando da modulação da forma neuronal e da plasticidade sináptica que ocorre em fêmeas especificamente na fase de proestro, quando estrógeno e progesterona estão nos maiores níveis circulantes.The postero-dorsal medial amygdala (MePD) is a sexually dimorphic cerebral structure, dependent on the levels of circulating gonadal hormones and related to the reproductive behavior in rats. Local synaptic plasticity is related to the dendritic spines, modulation sites of postsynaptic activity, related to the functioning of MePD neurons and the differences between males and females throughout the ovulatory cycle. Despite the prevalence of chemical synapses, discrete electrical synapses have been reported between glial cells, but not between neurons, in MePD. Nor is it known the variation of neurotrophic factors that can occur between males and females throughout the estrous cycle. The aims of this study were: 1) to compare number and structure of the dendritic spines in the MePD of prepubertal male and female rats, then between postpubertal males with and without sexual experience using confocal microscopy; 2) to study the ultrastructure of MePD looking for the presence of gap junctions and then to study the presence of connexins 36, 43 and 45 by immunofluorescence in the same structure; e, 3) to study possible sexual dimorphism and estrous cycle variation in local expression of BDNF (Brain-Derived Neurotrophic Factor), IGF-1 (insulin-like growth factors 1), PSA-NCAM (polysialylated neuronal cell adhesion molecule) and Ephrin-A4, neurotrophic factors involved in synaptic plasticity, using RT-PCR and fluorescence immunohistochemical technique. The results showed (1) a sexual dimorphism in MePD dendritic spines in prepubertal animals and a remodeling of the spines caused by puberty and sexual experience; (2) presence of sparse gap junctions between dendrites and the most evident expression of Cx36, Cx43 and Cx45 in MePD; and, (3) there was no statistically significant difference in the expression of BDNF, IGF-1, PSA-NCAM and Ephrin-A4, nor in the BDNF, NCAM and Ephrin-A4 gene expression between males and females throughout the estrus cycle. However, there is a statistically significant difference and a greater quantity of immunoreactive puncta for BDNF in females in proestrus than in males and higher in IGF-1 females in proestrus than in diestrus. The present data indicate that in MePD there is sexual dimorphism and remarkable reorganization and synaptic plasticity related to dendritic spines, connexins are more abundant than local gap junctions suggesting that there is a form of intercellular communication in addition to the chemical synapse and two neurotrophins (BDNF and IGF-1) may be involved in the modulation of neuronal form and synaptic plasticity that occurs in females specifically in the proestrus stage, when estrogen and progesterone are at the highest circulating levels

Gene expression underlying ferret hair growth initiation induced by melatonin and modified by steroids

Synchronised ferret winter pelage development induced by melatonin was utilised as an in vivo model for studying gene expression associated with the hair growth cycle. The effects of melatonin and steroids on hair follicle growth initiation in flank skin samples were monitored by histology and immunocytochemistry. Melatonin implantation initiated hair growth within 10 days. Exogenous steroids delivered by slow-release subcutaneous implants had mainly inhibitory effects on spontaneous and melatonin-initiated hair growth, either when given simultaneously or prior to melatonin administration. 17β-oestradiol totally suppressed hair follicle growth in all circumstances, while the inhibitory effects of dexamethasone, testosterone and deoxycorticosterone were weaker and attenuated by melatonin. Progesterone given simultaneously with melatonin inhibited hair growth in males, but did not significantly affect female hair growth initiated by melatonin. Gene expression underlying ferret hair growth was studied using an optimised differential display technique using two sets of complementary skin samples covering all growth initiation stages. The differential display band patterns for approximately 8% of all skin transcripts suggested that more than a thousand genes are required for hair follicle growth. Of the differentially expressed genes detected in a set of flank skin samples covering all proanagen stages, up to a half are likely to be specifically associated with hair growth. The 150 expressed sequence tags (ESTs) discovered represented 112 unique sequences. Forty-two of these were aligned by sequence homology to known genes, while the remainder are likely to represent novel genes. Differential expression through the follicle growth cycle or after the treatments was confirmed for 21 out of 23 genes whose mRNAs were detectable by Northern blot hybridisation. Overall, expression alteration for most of these ESTs occurred prior to morphological changes in the skin associated with hair follicle reactivation. All the ESTs whose expression sites were detected by in situ hybridisation were localised to hair follicles. Some were detected only in certain stages of the hair follicle cycle, others in all growth stages, but at different levels. Classification of the identified ESTs suggested that apoptosis as well as fatty acid synthesis and cholesterol metabolism were closely associated with hair growth initiation, while cell interaction and motility were also particular prominent processes in hair follicle regrowth. Additional DNA sequence information was obtained for ferret hair acidic keratin 8 (fHa8) and ferret cyclin D-interacting myb-like protein 1 (fDMP1). Both of these genes were expressed only in cortical cells in the keratogenous zone from mid-proanagen. fHa8 was expressed only in one side of the cortex, a feature has not previously been reported for other type I intermediate hair keratins. The restricted expression of fDMP1 and its smaller size suggested that it was an alternatively spliced form of the human and mouse homologues with a specialised function in the regulation of cortical cell proliferation and differentiation. Further studies on the expression regulation and function of the genes represented by the ESTs identified in this study promise to considerably advance our understanding of hair follicle growth control

A comparative analysis of play behaviour in primates and carnivores

This thesis considers the evolution of play behaviour, focusing on comparative analyses of extant primates and carnivores from various perspectives, including intra-specific analyses, life-history, socio-ecology, and brain anatomy, taking data from the existing literature, and using phylogenetic comparative techniques. Phylogenetic reconstructions suggest that each play category represents its own evolutionary trajectory, and support previous findings that social play, being the most ancient form of play in primates, may represent a distinct category of behaviour. Analyses of intra-specific play patterns proved difficult due to a lack of available data in the literature, but point to the importance of controlling for variables that differ between populations of the same species, such as group composition, and research effort. Comparative analyses of life-history variables and play demonstrate that precocial species play more than altricial species. Precocial species have a relatively shorter developmental period of postnatal brain development, and may therefore require the neurological and physiological benefits afforded by play behaviour in order to hone brain development prior to adulthood. Comparative analyses of socio-ecology and play suggest that larger groups require increased play time budgets, possibly because of a need to fulfil the social skills required to maintain group cohesion. Social networks of the population (clique size and network size) predict social play frequency in primates. Contrary to previous findings, I found no evidence that diet is a good indicator of time spent in play, although basal metabolic rate does correlate with play, suggesting that other socio-ecological factors contribute to the performance of play. Comparative analyses of brain components and play indicate that brain correlates are selective and do not apply to all regions. There are strong correlations between socio-cognitive, motor, emotional, and also visual areas of the brain and social play in primates, namely the neocortex, cerebellum, visual cortex and LGN, vestibular complex, striatum, medulla, amygdala, and hypothalamus. Although play is a difficult ethological topic, it appears to be vital to development and life in social groups

Mechanisms underlying postnatal development of primary somatosensory cortex

Layer IV of the mouse somatosensory cortex contains discrete cytoarchitectonic units called 'barrels', formed in response to thalamocortical axon invasion by two processes: translocation of cortical cells to form a cell-dense barrel wall and cell-sparse barrel hollow, and selective dendritic elaboration toward thalamocortical afferents to form oriented dendritic branch patterns. Interestingly gene knockout of several members of the N-Methyl-D-Aspartate (NMDA) receptor -complex (NRC) disrupts barrel formation, indicating that synaptic activity is critical for barrel formation. Little is known of the cellular processes initiated by glutamate receptor activation; however, recent evidence suggests an interaction between neuronal activity and Wnt signalling. Wnts are secreted glycoproteins, are powerful regulators of cell proliferation and differentiation, and their signalling pathway involves proteins that directly participate in both gene transcription and cell adhesion. Wnt7a and Dv11 knockout mice exhibit delays in glomerular rosette formation; a cerebellar structure similar to barrels whose development involves granule cell migration and dendritic rearrangement. Furthermore activity dependent Wnt release can regulate the enhancement of dendrite arborisation, raising the possibility that NRC components and Wnts may interact to regulate barrel development.Recent findings suggest that membrane association guanylyl kinases (MAGUKs) may be the key scaffolding molecules that mediate the interaction between glutamate receptor and Wnt signalling pathways. The MAGUK family includes Postsynaptic Density (PSD)-95 and Synapse Associated Protein (SAP)-102, two key molecules of the NRC during barrel formation. These MAGUKs also bind the Wnt receptor family Frizzled and SAP-102 binds to APC, a key Frizzled-signalling protein. As a first step in examining a role for Wnts in barrel formation, the gene expression patterns of members of the Wnt, Frizzleds and secreted Frizzled related protein (sFRPs) families during barrel cortex development were measured using degenerate primer RT-PCR, quantitative real-time PCR and in-situ hybridization. Wnts 2b, 3, 4, 5a, la, 7b, 9a, 11, 16 were found in the barrel cortex, suggesting that these members of the Wnt family may play a role in barrel development, and Wnt7b, Frizzled 4, Frizzled 9, and Frizzled 3 were conspicuously downregulated in mutant mice that lack barrels, namely Plc-ß1⁻/⁻, Pkar2ß⁻/⁻ and Mglur5⁻/⁻ mice.In order to determine whether Wnts, members of the Wnt signaling machinery and MAGUKs associated with Wnt signaling are essential for barrel formation, the barrel phenotype of all available postnatally viable Wnt gene knockouts, Wnt2b⁻/⁻, Wnt7a⁻/⁻, Wnt8b⁻/⁻, Wnt signaling component knockouts Dvl⁻/⁻, MAGUK knockouts Sap-102'1', Psd-95'1' and double knockouts of Wnt7a"Dvr'~ and of Sap-102⁻/⁻Psd-95⁻/⁻ were examined. Barrels appeared normal in all mutants, apart from compound Sap-102⁻/⁻Psd-95⁻/⁻ and Sap-102⁻/⁻Psd-95⁻/⁻ mice, which exhibited poorer barrel segregation compared to wild type.In order to achieve a detailed understanding of the mechanisms by which neuronal activity regulates barrel development, we need a detailed understanding of the intracellular pathways activated by NMDA receptors during development. In searching the literature, data concerning the developmental expression patterns of NRC components can be difficult to locate, as the prevailing database tools used either search only title, author and keyword abstract text (NCBI PubMed) potentially missing desired information, or as in the unique case of Google Scholar, search the full text of electronically published papers, but yield overwhelming numbers of results in the process.The Jackson Laboratories MGI suite offers an impressive way of mining the literature for such data, but the content is sparse, relying on author submission and attempting to map expression throughout the whole mouse. For example, the only gene present in MGI for postnatal layer IV cerebral cortex is Apc2.In order to bring together the data in the literature and from the mouse genome projects into a usable and accessible way, we decided to create a web-based centralised resource for the developmental neuroscience community, containing expression profiles of NRC components within mouse somatosensory cortex. By performing exhaustive literature searches utilising Google Scholar and PubMed, and linking to sequence and mutant mouse availability information elsewhere, BGI offers a portal for such information and also offers a forum for the notification of unpublished observations of transgenic animals displaying normal barrel formation, preventing duplication of experiments. Barrelgene.info should provide a key resource for any researcher interested in the molecular basis of cortical development

The Effects of Differential Maternal Environments Prior to Pregnancy on Future Offspring in Hooded Lister Rats

Central to any understanding of the nature of an organism is the examination of the relative contributions of heredity and environment to its development. Set within this framework are the literatures studying the environmental forces which interact with biological predispositions to produce the mature individual (Shaffer 1985). One such area of research which has provided evidence that the environment has a beneficial impact on an animal's neurochemistry, neuroanatomy and behaviour is the environmental enrichment literature (Rosenzweig 1984; Renner and Rosenzweig 1987; Rose 1988) where animals reared in socially and perceptually stimulating environments are compared with their litter mates raised in impoverished environments. Within this literature are a handful of studies which suggest that these beneficial effects are not only confined to those animals directly exposed to an enriching environment but also can be passed across generations. It is this intergenerational research which provides the focus of this thesis in which the effects of exposing female rats to differential environments prior to pregnancy on successive generations were investigated in Hooded Lister rats. Chapter one, the introduction to this present work, provides a historical background to the investigation of early experience, enrichment and its effect on the brain and reviews those few studies which have investigated the results of maternal enrichment on the offspring generation. Enrichment as an environmental manipulation has been extensively researched and those studies investigating the behavioural consequences of exposing animals directly to Enriched (EC) and Impoverished (IC) conditions are reviewed in chapter two, to provide a profile against which to compare the offspring generations investigated in this thesis. The impact of inter generational effects has of course been explored using manipulations other than enrichment. Indeed, it is now well established that various kinds of stressors imposed upon females of different species can affect both the physiology and behaviour of their offspring (Joffe 1969b; 1978; 1982; Thompson and Grusec 1970; Archer and Blackman 1971). Chapter three of this thesis provides an overview of the literature investigating the effects of manipulation of the maternal generation either prior to pregnancy, during pregnancy or postnatally on offspring and grandoffspring generations emphasising the diversity of manipulations other than enrichment that have been employed. Following chapter four, which describes the general methodology employed in this thesis, with details of the breeding programmes, the environmental manipulations and behavioural test apparatus used, are the four experimental studies designed to investigate the effects of enrichment on successive generations. In particular, chapter five (study one) provided a profile of animals exposed directly to environmental enrichment, impoverishment and standard housing (SC) against which to compare future generations’ behavioural patterns. Futhermore, this chapter also tested the efficacy of the enriched environment employed in this thesis, best described as a Superenriched environment (SEC) in male, female and postpartum female rats. The inclusion of the latter group was to ensure that the commonly found enrichment effects would continue postpartum despite undergoing pregnancy and litter-rearing. Moving on to successive generations, chapter six (study two) explored the effects of differential maternal environments prior to pregnancy on offspring and grandoffspring behaviour. Animals were put through a battery of tests to investigate their activity, perceptual and learning performances. From this work qualitatively different behavioural profiles were observed in both the offspring and grandoffspring of the three maternal conditions. Possible causes for the observed performance differences were discussed and it was suggested that they might reflect amongst other things, different learning capacities between the groups or differential arousal and/or stress levels. The last two studies of this thesis were designed to investigate these postulated causes further. Chapter seven (study three) analysed the effects of differential maternal environments prior to pregnancy on offspring performance in the Hebb-Williams maze and in an operant conditioning task, whilst chapter eight (study four) considered the hypothesis that offspring of SEC, SC and IC dams are differentially aroused, by artificially manipulating arousal levels with d-amphetamine sulphate. In the final chapter of this thesis (chapter nine) the main findings of the four studies are summarised and possible causes of the intergenerational transfer of effects discussed. In addition, the individual experiments are critically assessed and avenues for future research suggested

Change blindness: eradication of gestalt strategies

Arrays of eight, texture-defined rectangles were used as stimuli in a one-shot change blindness (CB) task where there was a 50% chance that one rectangle would change orientation between two successive presentations separated by an interval. CB was eliminated by cueing the target rectangle in the first stimulus, reduced by cueing in the interval and unaffected by cueing in the second presentation. This supports the idea that a representation was formed that persisted through the interval before being 'overwritten' by the second presentation (Landman et al, 2003 Vision Research 43149–164]. Another possibility is that participants used some kind of grouping or Gestalt strategy. To test this we changed the spatial position of the rectangles in the second presentation by shifting them along imaginary spokes (by ±1 degree) emanating from the central fixation point. There was no significant difference seen in performance between this and the standard task [F(1,4)=2.565, p=0.185]. This may suggest two things: (i) Gestalt grouping is not used as a strategy in these tasks, and (ii) it gives further weight to the argument that objects may be stored and retrieved from a pre-attentional store during this task

Investigating the role of orphan GPR50 in normal brain function and mental illness

G protein-coupled receptors (GPCRs) form a link between the cell and their environment when signaling pathways are activated upon ligand binding. However, the ligands and functions for many GPCRs remain to be determined. G protein-coupled receptor 50 (GPR50) is one such orphan, and its exact role is yet unknown. There is however emerging functional and genetic evidence suggesting a function for GPR50 in psychiatric illness and lipid metabolism. It was hypothesised that investigating GPR50’s protein-protein interactions would lead to a greater understanding of the role of GPR50 in normal brain functioning and in mental illness. Putative protein interactors were initially isolated by a yeast two-hybid study and were further tested here. To address GPR50’s links to mental illness, the GPR50∆502-505 deletion variant associated with mood disorders was also investigated. To test this hypothesis I sought to confirm some of the key yeast two-hybrid interactions. Using co-immunoprecipitation and immunocytochemistry the interaction of GPR50 with reticulon family members Nogo-A, Nogo-C and RTN3, and with cell-cell adhesion molecule CDH8 and lipid-associated protein ABCA2 were validated. In order to identify the location of interactions, subcellular fractionation of mouse brain and rt-PCR and immunohistochemistry in developing and adult mouse brain were performed. GPR50 and several interactors were found to be enriched at the synapse by subcellular fractionation of whole adult brain, and at embryonic day 18 (E18) and 5 weeks by rt-PCR. Colocalisation of GPR50 and interactors was found in the amygdala, hypothalamus, cortex and specific brain stem nuclei by immunohistochemistry. The discovery of GPR50 expression in noradrenergic, serotonergic and dopaminergic nuclei in the adult brain stem suggests a further role for GPR50 in neurotransmitter signaling and stress. To investigate the function of GPR50 two assays were performed that measure processes which are known to be affected by Nogo and RTN3: The first assay was a neurite outgrowth assay in Neuroscreen-1 cells, a PC12 cell clone. A significant increase in neurite length was detected after transient overexpression of GPR50 and this effect was increased in the GPR50∆502-505/T532A variant. Additionally GPR50-overexpression resulted in an increase in filopodia formation suggesting a role in actin dynamics. As a second functional assay in vitro BACE1 activity assays were performed in HEK293 cells. GPR50 but not GPR50∆502-505/T532A overexpression resulted in a significant increase in BACE1 activity. Lastly a final series of pilot experiments were performed to gain insight into the secondary structure of the C-terminal domain and the effects of the polymorphisms on structure. The 35kDa GPR50 C-terminal domain was purified and Circular Dichroism studies indicated a predominantly unstructured protein with increased a- helical content in the GPR50∆502-505 variant. The results in this thesis indicate a role for GPR50 in neuronal development and synaptic functioning. The results also strengthen an association with major mental illness, with links to several disease mechanisms

Crosstalk between Depression, Anxiety, and Dementia: Comorbidity in Behavioral Neurology and Neuropsychiatry

This Special Issue highlights the most recent research on depression, anxiety and dementia, with attention to comorbidity in a range of diseases. The symptoms of depression, anxiety and dementia are the most common comorbid manifestations present in patients suffering from neurodegenerative and psychiatric diseases. Together, these illnesses constitute an extremely complex and challenging research field due to their inherent multifactorial causative factors, heterogeneous pathogenesis, and mental and behavioral manifestations. This Special Issue covers laboratory, clinical and statistical studies on the crosstalk between depression, anxiety, dementia, Alzheimer’s disease, multiple sclerosis, schizophrenia, diabetes mellitus, Down’s syndrome, and/or compulsive disorders. It contains contributions from 71 authors, has been reviewed by 25 referees, and edited by three academic editors and one managing editor