Sex differences in autism-like behavior and dopaminergic neurons in substantia nigra of juvenile mice prenatally exposed to valproate.

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication and repetitive and restricted behaviors. Sex dimorphism in the brain, including midbrain dopaminergic circuits, can explain differences in social behavior impairment and stereotypic behaviors between male and female individuals with ASD. These abnormal patterns may be due to alterations in dopamine synthesis in the ventral tegmental area (VTA) and substantia nigra (SN). We used an autism-like mouse model by prenatal valproic acid (VPA) exposure. CD1 pregnant female mice were injected with 500 mg/kg VPA or 0.9% NaCl as a vehicle on gestational day 12.5. In the offspring, on postnatal day 31, we examined the social and repetitive behaviors and the number of tyrosine hydroxylase (TH)-positive cells in VTA and SN by sex. Male VPA mice showed impaired social behavior and increased repetitive behaviors when compared to male vehicles. In females, we did not find statistically significant differences in social or repetitive behaviors between the groups. Male VPA mice had fewer TH+ cells in the SN than control-vehicle mice. Interestingly, no cellular changes were observed between females. This study supports the notion that sex dimorphism of certain brain regions is involved in the etiopathogenesis and clinical presentation of ASD.

Therapeutic Approaches for ADHD by Developmental Stage and Clinical Presentation.

Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder with three presentations: inattentive, hyperactive/impulsive and combined. These may represent an independent disease entity. Therefore, the therapeutic approach must be focused on their neurobiological, psychological and social characteristics. To date, there is no comprehensive analysis of the efficacy of different treatments for each presentation of ADHD and each stage of development. This is as narrative overview of scientific papers that summarize the most recent findings and identify the most effective pharmacological and psychosocial treatments by ADHD presentation and age range. Evidence suggests that methylphenidate is the safest and most effective drug for the clinical management of children, adolescents and adults. Atomoxetine is effective in preschoolers and maintains similar efficacy to methylphenidate in adults, whereas guanfacine has proven to be an effective monotherapy for adults and is a worthy adjuvant for the management of cognitive symptoms. The psychosocial treatments with the best results in preschoolers are behavioral interventions that include training of primary caregivers. In adolescents, the combination of cognitive and cognitive-behavioral therapies has shown the best results, whereas cognitive-behavioral interventions are the most effective in adults. Pharmacological and psychosocial treatments must be adjusted to the ADHD presentation and its neurocognitive characteristics through the patient's development.

Phenytoin promotes the proliferation of oligodendrocytes and enhances the expression of myelin basic protein in the corpus callosum of mice demyelinated by cuprizone.

Oligodendrocyte loss and myelin sheet destruction are crucial characteristics of demyelinating diseases. Phenytoin promotes the proliferation of endogenous neural precursor cells in the ventricular-subventricular zone in the postnatal brain that help restore the oligodendroglial population. This study aimed to evaluate whether phenytoin promotes myelin recovery of the corpus callosum of demyelinated adult mice. CD1 male mice were exposed to a demyelinating agent (0.2% cuprizone) for 8 weeks. We assembled two groups: the phenytoin-treated group and the control-vehicle group. The treated group received oral phenytoin (10 mg/kg) for 4 weeks. We quantified the number of Olig2 + and NG2 + oligodendrocyte precursor cells (OPCs), Rip + oligodendrocytes, the expression level of myelin basic protein (MBP), and the muscle strength and motor coordination. The oligodendroglial lineage (Olig2 + cells, NG2 + cells, and RIP + cells) significantly increases by the phenytoin administration when compared to the control-vehicle group. The phenytoin-treated group also showed an increased expression of MBP in the corpus callosum and better functional scores in the horizontal bar test. These findings suggest that phenytoin stimulates the proliferation of OPCs, re-establishes the oligodendroglial population, promotes myelin recovery in the corpus callosum, and improves motor coordination and muscle strength.

Biopsychological correlates of repetitive and restricted behaviors in autism spectrum disorders.

BACKGROUND: Autism Spectrum Disorder (ASD) is considered a neurodevelopmental condition that is characterized by alterations in social interaction and communication, as well as patterns of restrictive and repetitive behaviors (RRBs). RRBs are defined as broad behaviors that comprise stereotypies, insistence on sameness, and attachment to objects or routines. RRBs can be divided into lower-level behaviors (motor, sensory, and object-manipulation behaviors) and higher-level behaviors (restrictive interests, insistence on sameness, and repetitive language). According to the DSM-5, the grade of severity in ASD partially depends on the frequency of RRBs and their consequences for disrupting the life of patients, affecting their adaptive skills, and increasing the need for parental support. METHODS: We conducted a systematic review to examine the biopsychological correlates of the symptomatic domains of RRBs according to the type of RRBs (lower- or higher-level). We searched for articles from the National Library of Medicine (PubMed) using the terms: autism spectrum disorders, ASD, and autism-related to executive functions, inhibitory control, inflexibility, cognitive flexibility, hyper or hypo connectivity, and behavioral approaches. For describing the pathophysiological mechanism of ASD, we also included animal models and followed PRISMA guidelines. RESULTS: One hundred and thirty-one articles were analyzed to explain the etiology, continuance, and clinical evolution of these behaviors observed in ASD patients throughout life. CONCLUSIONS: Biopsychological correlates involved in the origin of RRBs include alterations in a) neurotransmission system, b) brain volume, c) inadequate levels of growth factors, d) hypo- or hyper-neural connectivity, e) impairments in behavioral inhibition, cognitive flexibility, and monitoring and f) non-stimulating environments. Understanding these lower- and higher-level of RRBs can help professionals to improve or design novel therapeutic strategies.

Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

Melatonin modifies SOX2+ cell proliferation in dentate gyrus and modulates SIRT1 and MECP2 in long-term sleep deprivation.

Melatonin is a pleiotropic molecule that, after a short-term sleep deprivation, promotes the proliferation of neural stem cells in the adult hippocampus. However, this effect has not been observed in long-term sleep deprivation. The precise mechanism exerted by melatonin on the modulation of neural stem cells is not entirely elucidated, but evidence indicates that epigenetic regulators may be involved in this process. In this study, we investigated the effect of melatonin treatment during a 96-hour sleep deprivation and analyzed the expression of epigenetic modulators predicted by computational text mining and keyword clusterization. Our results showed that the administration of melatonin under sleep-deprived conditions increased the MECP2 expression and reduced the SIRT1 expression in the dentate gyrus. We observed that let-7b, mir-132, and mir-124 were highly expressed in the dentate gyrus after melatonin administration, but they were not modified by sleep deprivation. In addition, we found more Sox2+/5-bromo-2'-deoxyuridine (BrdU)+ cells in the subgranular zone of the sleep-deprived group treated with melatonin than in the untreated group. These findings may support the notion that melatonin modifies the expression of epigenetic mediators that, in turn, regulate the proliferation of neural progenitor cells in the adult dentate gyrus under long-term sleep-deprived conditions. All procedures performed in this study were approved by the Animal Ethics Committee of the University of Guadalajara, Mexico (approval No. CI-16610) on January 2, 2016.

Alterations of Growth Factors in Autism and Attention-Deficit/Hyperactivity Disorder.

Growth factors (GFs) are cytokines that regulate the neural development. Recent evidence indicates that alterations in the expression level of GFs during embryogenesis are linked to the pathophysiology and clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). In this concise review, we summarize the current evidence that supports the role of brain-derived neurotrophic factor, insulin-like growth factor 2, hepatocyte growth factor (HGF), glial-derived neurotrophic factor, nerve growth factor, neurotrophins 3 and 4, and epidermal growth factor in the pathogenesis of ADHD and ASD. We also highlight the potential use of these GFs as clinical markers for diagnosis and prognosis of these neurodevelopmental disorders.

Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders.

The psychiatric disorders are one of the most disabling illnesses in the world and represent a major problem for public health. These disorders are characterized by neuroanatomical or biochemical changes and it has been suggested that such changes may be due to inadequate neurodevelopment. Diverse alterations in the gene expression and/or serum level of specific growth factors have been implicated in the etiology, symptoms and progression of some psychiatric disorders. Herein, we summarize the latest information regarding the role of brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), fibroblast growth factor (FGF), Insulin-like growth factor (IGF-1), neuroregulin-1 (NGR-1), erythropoietin (EPO), vascular growth factor (VEGF), transforming growth factor beta (TGF-ß), nerve growth factor (NGF) and others cytokines in the pathogenesis of schizophrenia, depression, bipolar and anxiety disorders. Focusing on the role of these growth factors and their relationship with the main impairments (cognitive, emotional and social) of these pathologies. Some of these signaling molecules may be suitable biological markers for diagnosis and prognosis in cognitive, mood and social disabilities across different mental disorders.

Sex-related effects of sleep deprivation on depressive- and anxiety-like behaviors in mice.

Anxiety and depressive symptoms are generated after paradoxical sleep deprivation (PSD). However, it is not clear whether PSD produces differential effects between females and males. The aim of this study was to assess the effect of PSD on anxiety- and depressive-like behaviors between sexes. Male and female BALB/c mice were divided in three groups: the control group, the 48-h PSD group and the 96-h PSD group. Immediately after PSD protocols, the forced swimming and open field test were applied. Sucrose consumption test was used to evaluate the middle-term effect of PSD. We found that corticosterone serum levels showed significant differences in the 96-h PSD females as compared to 96-h PSD males. In the open-field test, the 48-h and 96-h PSD females spent more time at the periphery of the field, and showed high locomotion as compared to males. In the elevated plus maze, the 48-h PSD females spent more time in closed arms than males, which is compatible with anxiety-like behavior. The forced swim test indicated that the 96-h PSD males spent more time swimming as compared to the 96-h PSD females. Remarkably, the 96-h PSD males had lower sucrose intake than the 96-h PSD females, which suggest that male mice have proclivity to develop a persistent depressive-like behavior late after PSD. In conclusion, male mice showed a significant trend to depressive-like behaviors late after sleep deprivation. Conversely, female have a strong tendency to display anxiety- and depressive-like behaviors immediately after sleep deprivation.

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation.

Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular-subventricular zone (V-SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V-SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V-SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V-SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V-SVZ, and expanded the population of Olig2-expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V-SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.

Cyclohexane produces behavioral deficits associated with astrogliosis and microglial reactivity in the adult hippocampus mouse brain.

Cyclohexane is a volatile substance that has been utilized as a safe substitute of several organic solvents in diverse industrial processes, such as adhesives, paints, paint thinners, fingernail polish, lacquers, and rubber industry. A number of these commercial products are ordinarily used as inhaled drugs. However, it is not well known whether cyclohexane has noxious effects in the central nervous system. The aim of this study was to analyze the effects of cyclohexane inhalation on motor behavior, spatial memory, and reactive gliosis in the hippocampus of adult mice. We used a model that mimics recreational drug use in male Balb/C mice (P60), divided into two groups: controls and the cyclohexane group (exposed to 9,000 ppm of cyclohexane for 30 days). Both groups were then evaluated with a functional observational battery (FOB) and the Morris water maze (MWM). Furthermore, the relative expression of AP endonuclease 1 (APE1), and the number of astrocytes (GFAP+ cells) and microglia (Iba1+ cells) were quantified in the hippocampal CA1 and CA3 areas. Our findings indicated that cyclohexane produced severe functional deficits during a recreational exposure as assessed by the FOB. The MWM did not show statistically significant changes in the acquisition and retention of spatial memory. Remarkably, a significant increase in the number of astrocytes and microglia cells, as well as in the cytoplasmic processes of these cells were observed in the hippocampal CA1 and CA3 areas of cyclohexane-exposed mice. This cellular response was associated with an increase in the expression of APE1 in the same brain regions. In summary, cyclohexane exposure produces functional deficits that are associated with an important increase in the APE1 expression as well as the number of astrocytes and microglia cells and their cytoplasmic complexity in the CA1 and CA3 regions of the adult hippocampus.

The role of EGFR and ErbB family related proteins in the oligodendrocyte specification in germinal niches of the adult mammalian brain.

IN THE ADULT BRAIN, MULTIPOTENT PROGENITOR CELLS HAVE BEEN IDENTIFIED IN THREE AREAS: the ventricular-subventricular zone (VZ-SVZ), adjacent to the striatal wall of the lateral ventricles, the subgranular zone (SGZ), located at the dentate gyrus of the hippocampus and the subcallosal zone (SCZ), located between the corpus callosum and the CA1 and CA2 regions of the hippocampus. The neural progenitor cells of these regions express the epidermal growth factor receptor (EGFR, ErbB-1 or HER1). EGF, the most important ligand for the EGFR, is a potent mitogenic agent that stimulates proliferation, survival, migration and differentiation into the oligodendrocyte lineage. Other ErbB receptors also activate several intracellular pathways for oligodendrocyte specification, migration and survival. However, the specific downstream pathways related to oligodendrogenesis and the hierarchic interaction among intracellular signaling cascades is not well-known. We summarize the current data regarding the role of EGFR and ErbB family signaling on neural stem cells and the downstream cascades involved in oligodendrogenesis in the neurogenic niches of the adult brain. Understanding the mechanisms that regulate proliferation, differentiation, migration of oligodendrocytes and myelination is of critical importance for the field of neurobiology and constitutes a crucial step in the design of stem-cell-based therapies for demyelinating diseases.

Role of fibroblast growth factor receptors in astrocytic stem cells.

There are two well-defined neurogenic regions in the adult brain, the subventricular zone (SVZ) lining the lateral wall of the lateral ventricles and, the subgranular zone (SGZ) in the dentate gyrus at the hippocampus. Within these neurogenic regions, there are neural stem cells with astrocytic characteristics, which actively respond to the basic fibroblast growth factor (bFGF, FGF2 or FGF-ß) by increasing their proliferation, survival and differentiation, both in vivo and in vitro. FGF2 binds to fibroblast growth factor receptors 1 to 4 (FGFR1, FGFR2, FGFR3, FGFR4). Interestingly, these receptors are differentially expressed in neurogenic progenitors. During development, FGFR-1 and FGFR-2 drive oligodendrocytes and motor neuron specification. In particular, FGFR-1 determines oligodendroglial and neuronal cell fate, whereas FGFR-2 is related to oligodendrocyte specification. In the adult SVZ, FGF-2 promotes oligodendrogliogenesis and myelination. FGF-2 deficient mice show a reduction in the number of new neurons in the SGZ, which suggests that FGFR-1 is important for neuronal cell fate in the adult hippocampus. In human brain, FGF-2 appears to be an important component in the anti-depressive effect of drugs. In summary, FGF2 is an important modulator of the cell fate of neural precursor and, promotes oligodendrogenesis. In this review, we describe the expression pattern of FGFR2 and its role in neural precursors derived from the SVZ and the SGZ.

Diphenylhydantoin promotes proliferation in the subventricular zone and dentate gyrus.

PROBLEM STATEMENT: Diphenylhydantoin (phenytoin) is an antiepileptic drug that generates hyperplasia in some tissue by stimulating Epidermal Growth Factor (EGFR) and Platelet-Derived Growth Factor beta (PDGFR-ß) receptors and by increasing serum levels of basic fibroblast growth factor (bFGF, FGF2 or FGF-ß). Neural stem cells in the adult brain have been isolated from three regions: the Subventricular Zone (SVZ) lining the lateral wall of the lateral ventricles, the Subgranular Zone (SGZ) in the dentate gyrus at the hippocampus and the Subgranular Zone (SZC) lining between the hippocampus and the corpus callosum. Neural stem cells actively respond to bFGF, PDGFR-ß or EGF by increasing their proliferation, survival and differentiation. The aim of this study was to evaluate the effect of phenytoin on proliferation and apoptosis in the three neurogenic niches in the adult brain. APPROACH: We orally administrated phenytoin with an oropharyngeal cannula for 30 days: 0 mg kg-1 (controls), 1, 5, 10, 50 and 100 mg kg-1. To label proliferative cells, three injections of 100 mg kg-1 of BrdU was administrated every 12 h. Immunohistochemistry against BrdU or Caspase-3 active were performed to determine the number of proliferative or apoptotic cells. RESULTS: Our results showed that phenytoin induces proliferation in the SVZ and the SGZ in a dose-dependent manner. No statistically significant effects on cell proliferation in the SCZ neither in the apoptosis rate at the SVZ, SGZ and SCZ were found. CONCLUSION: These data indicate that phenytoin promotes a dose-dependent proliferation in the SVZ and SGZ of the adult brain. The clinical relevance of these findings remain to be elucidated.

Neurogenesis in Alzheimer´s disease: a realistic alternative to neuronal degeneration?

Neural stem cells (NSC) are cells that have the capacity to generate multiple types of differentiated brain cells. In conditions in which there is a loss of key functional cell groups, such as neurons, inducing or introducing neural stem cells to replace the function of those cells that were lost during the disease has the greatest potential therapeutic applications. Indeed, the achievement of one of the main objectives of various investigations is already on the horizon for some conditions, such as Alzheimer's disease. It is not known whether impaired neurogenesis contributes to neuronal depletion and cognitive dysfunction in Alzheimer's disease (AD). The results of the different investigations are controversial; some studies have found that neurogenesis is increased in AD brains, but others have not.