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.

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models.

The ventricular-subventricular, subgranular and subcallosal zones: three niches of neural stem cells in the postnatal brain.

In the postnatal brain, three regions show high mitotic activity. These brain areas are neurogenic niches, and each niche harbors a microenvironment favorable for the proliferation and differentiation of neural stem cells. These multipotential cells maintain the capacity to self-renew and generate intermediate precursors that will differentiate into neuronal and glial lineages (astrocytes and oligodendrocytes). The most well-studied niches are the ventricular-subventricular zone (V-SVZ) of the lateral ventricles, the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, and the subcallosal zone (SCZ), located in the limit between the corpus callosum and the hippocampal formation. The discovery of these three neurogenic niches has gained much interest in the field because they may be a therapeutic alternative in neural regeneration and neurodegenerative disorders. In this review, we describe in brief all these regions and explain their potential impact on solving some neurological conditions.

Normal pressure hydrocephalus decreases the proliferation of oligodendrocyte progenitor cells and the expression of CNPase and MOG proteins in the corpus callosum before behavioral deficits occur.

Normal pressure hydrocephalus (NPH) compromises the morphology of the corpus callosum (CC). This study aims to determine whether 60- or 120-day NPH disrupts the cytoarchitecture and functioning of white matter (WM) and oligodendrocyte precursor cells (OPCs) and establish whether these changes are reversible after hydrocephalus treatment. NPH was induced in CD1 adult mice by inserting an obstructive lamina in the atrium of the aqueduct of Sylvius. Five groups were assembled: sham-operated controls (60 and 120 days), NPH groups (60 and 120 days), and the hydrocephalus-treated group (obstruction removal after 60-d hydrocephalus). We analyzed the cellular integrity of the CC by immunohistochemistry, TUNEL analysis, Western blot assays, and transmission electron microscopy (TEM). We found a reduction in the width of the CC at 60 and 120 days of NPH. TEM analysis demonstrated myelin abnormalities, degenerative changes in the WM, and an increase in the number of hyperdense (dark) axons that were associated with significant astrogliosis, and microglial reactivity. Hydrocephalus also caused a decrease in the expression of myelin-related proteins (MOG and CNPase) and reduced proliferation and population of OPCs, resulting in fewer mature oligodendrocytes. Hydrocephalus resolution only recovers the OPC proliferation and MOG protein density, but the rest of the WM abnormalities persisted. Interestingly, all these cellular and molecular anomalies occur in the absence of behavioral changes. The results suggest that NPH severely disrupts the myelin integrity and affects the OPC turnover in the CC. Remarkably, most of these deleterious events persist after hydrocephalus treatment, which suggests that a late treatment conveys irreversible changes in the WM of CC.

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.

Tactile information from the vibrissal system modulates hippocampal functioning.

Most mammals have sensory tactile hairs, also known as whiskers or vibrissae. Traditionally, whiskers are associated with diverse survival skills, including tactile discrimination, distance assessment, food acquisition, gap crossing, and social interaction. Vibrissae functions are processed in the somatosensorial cortex, commonly referred to as the barrel cortex. Hence, most of the whisker-related research has been focused on this cortical region. However, increasing evidence indicates that the vibrissal system modulates several aspects of hippocampal physiology. This graphical review aims to summarize cumulative evidence indicating that whiskers regulate the neural function and cellularity in several hippocampal subfields. Interestingly, lack of whiskers notably affects neuronal firing in CA1 and CA3 hippocampal subfields, alters spatial mapping, impairs navigational skills, modifies cytoarchitecture, and reduces the adult neurogenesis in the dentate gyrus. This evidence extends our understanding of how whiskers are related to hippocampal function and offers insights to explore novel associations between whisker functions and neural plasticity in the hippocampus.

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.

EGF-Coupled Gold Nanoparticles Increase the Expression of CNPase and the Myelin-Associated Proteins MAG, MOG, and MBP in the Septal Nucleus Demyelinated by Cuprizone.

Current pharmacological therapies against demyelinating diseases are not quite satisfactory to promote remyelination. Epidermal growth factor (EGF) can expand the population of oligodendrocyte precursor cells (OPCs) that may help with the remyelination process, but its delivery into the injured tissue is still a biomedical challenge. Gold nanoparticles (GNPs) may be a useful tool for drug delivery into the brain. To evaluate remyelination in the septal nucleus, we administered intracerebral GNPs coupled with EGF (EGF-GNPs). C57BL6/J mice were demyelinated with 0.4% cuprizone (CPZ) and divided into several groups: Sham, Ctrl, GNPs, EGF, and EGF-GNPs. We evaluated the remyelination process at two time-points: 2 weeks and 3 weeks post-injection (WPI) of each treatment. We used the rotarod for evaluating motor coordination. Then, we did a Western blot analysis myelin-associated proteins: CNPase, MAG, MOG, and MBP. EGF-GNPs increase the expression of CNPase, MAG, and MOG at 2 WPI. At 3 WPI, we found that the EGF-GNPs treatment improves motor coordination and increases MAG, MOG, and MBP. EGF-GNPs enhance the expression of myelin-associated proteins and improve the motor coordination in mice. Thus, EGF-associated GNPs may be a promising pharmacological vehicle for delivering long-lasting drugs into the brain.

Chronic exposure to cyclohexane induces stereotypic circling, hyperlocomotion, and anxiety-like behavior associated with atypical c-Fos expression in motor- and anxiety-related brain regions.

Recreational abuse of solvents continues, despite cyclohexane (CHX) is used as a safe replacement in gasoline or adhesive formulations. Increasing evidence indicates that CHX inhalation affects brain functioning; however, scanty information is available about its effects on behavior and brain activity upon drug removal. In this study, we used CD1 adult mice to mimic an intoxication period of recreational drugs for 30 days. During the CHX exposure (~30,000 ppm), we analyzed exploratory and biphasic behaviors, stereotypic circling, and locomotion. After CHX removal (24 h or a month later), we assessed anxiety-like behaviors and quantified c-Fos cells in motor- and anxiety-related brain regions. Our findings indicate that the repeated inhalation of CHX produced steady hyperactivity and reduced ataxia, sedation, and seizures as the exposure to CHX progressed. Also, CHX decreased grooming and rearing behaviors. In the first week of CHX inhalation, a stereotypic circling behavior emerged, and locomotion increased gradually. One month after CHX withdrawal, mice showed low activity in the center zone of the open field and more buried marbles. Twenty-four hours after CHX removal, c-Fos expression was low in the dorsal striatum, ventral striatum, motor cortex, dorsomedial prefrontal cortex, basolateral amygdala, lateral hypothalamus, and ventral hippocampus. One month later, c-Fos expression remained low in the ventral striatum and lateral hypothalamus but increased in the dorsomedial prefrontal cortex and primary motor cortex. This study provides a comprehensive behavioral characterization and novel histological evidence of the CHX effects on the brain when is administered in a recreational-like mode.

A high-fat diet during pregnancy impairs memory acquisition and increases leptin receptor expression in the hippocampus of rat offspring.

A high-fat diet (HFD) during pregnancy influences the neurodevelopment of progeny, particularly in the hippocampus, a brain region involved in cognitive processes. The hippocampus has high levels of leptin receptors (Ob-R) that participate in synaptic plasticity. This study examined the effect of maternal HFD during gestation on Ob-R expression in the CA1 and CA3 hippocampal regions, and its relationship with spatial learning and memory in the offspring. We used 48 rat pups: 24 from dams fed a balanced diet (BD, 6.2% fat) and 24 from those fed an HFD (42% fat) during pregnancy. We recorded weight gain and food intake in each pup every day beginning on postnatal day 3 (PND 3). Memory acquisition was assessed on PND 28 and memory retention on PND 42 in the Morris water maze (MWM). Then, 12 pups per group were selected randomly and subjected to bioimpedance spectroscopy. The remaining offspring was perfused to determine Ob-R expression levels in the CA1 and CA3 hippocampal regions. Interestingly, HFD pups had significantly higher weight gain, food intake, and fat mass than BD offspring. Interestingly, the HFD group showed poor memory performance, which correlated with changes in the Ob-R expression in both hippocampal regions. These data indicate that maternal exposure to HFD impacts neurodevelopmental and cognitive functions of the offspring.

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.

Neurobiological approaches of high-fat diet intake in early development and their impact on mood disorders in adulthood: A systematic review.

The early stage of development is a vulnerable period for progeny neurodevelopment, altering cytogenetic and correct cerebral functionality. The exposure High-Fat Diet (HFD) is a factor that impacts the future mental health of individuals. This review analyzes possible mechanisms involved in the development of mood disorders in adulthood because of maternal HFD intake during gestation and lactation, considering previously reported findings in the last five years, both in humans and animal models. Maternal HFD could induce alterations in mood regulation, reported as increased stress response, anxiety-like behavior, and depressive-like behavior. These changes were mostly related to HPA axis dysregulations and neuroinflammatory responses. In conclusion, there could be a relationship between HFD consumption during the early stages of life and the development of psychopathologies during adulthood. These findings provide guidelines for the understanding of possible mechanisms involved in mood disorders, however, there is still a need for more human clinical studies that provide evidence to improve the understanding of maternal nutrition and future mental health outcomes in the offspring.

Characterization of a mouse model of chronic hydrocephalus induced by partial occlusion of the aqueduct of Sylvius in the adult brain.

BACKGROUND: Hydrocephalus is a neurologic disturbance produced by the abnormal production, circulation, and absorption of cerebrospinal fluid (CSF). Late-onset idiopathic aqueductal stenosis induces normal pressure hydrocephalus (NPH) in adults. To date, no animal model replicating chronic NPH is available to study the pathophysiological changes observed in these subjects. NEW METHOD: We performed and characterized a model that induces chronic hydrocephalus in the adult mouse brain by producing a pre-aqueductal semiobstruction using an acetate lamina inserted into the atrium of the aqueduct of Sylvius. After surgical procedure, we analyzed the hydrocephalus development on days 60 and 120 and sham-operated animals were used as controls. We included an additional group of hydrocephalus resolution in which we removed the obstruction and analyzed the morphological changes in the brain. RESULTS: The hydrocephalus was fully established on day 60 after the obstruction and remained stable for 120 days. In all animals, the intracranial pressure remained ~4.08 mmHg and we did not find statistically significant differences between the hydrocephalus groups and controls. We did not find motor impairments and anxiety-like behaviors among groups and the analysis of microglia and astrogliosis revealed mild glial reactivity. COMPARISON WITH EXISTING METHODS: This model generates a long-term ventricular enlargement with normal intracranial pressure and moderate glial reactivity. Importantly, this model allows the reversibility of ventricular enlargement after the removal of the obstructive film from the brain. CONCLUSIONS: This mouse model may be useful to study the long-term cerebral alterations that occur during NPH or after its surgical resolution.

Gold nanoparticles produce transient reactive gliosis in the adult brain.

Gold nanoparticles (GNPs) have unique physical and chemical properties that allow them to function as a drug-delivery system for several tissues: skin, eye, liver, and others. However, information about the biological response of brain tissue against GNPs is limited. Astrocytes and microglia cells are the first line of defense against brain insults and proper indicators of the level of brain damage. This study was aimed to evaluate the astrocytic and microglia response after an intracerebral injection of polyethylene-glycol-coupled GNPs (PEGylated GNPs). We injected spherical PEGylated GNPs (85 × 106 nanoparticles /nl) with a glass micropipette (inner diameter =35 µm) into the striatum of P60 CD1 mice. We evaluated the cellular response of astrocytes and microglia on days 3, 7, 14, 30, and 90 after intracerebral injection. For both astrocytes and microglia cells, our findings indicated that the glial response was transient and mainly circumscribed to the injection site. This evidence suggests that PEGylated GNPs are well-tolerated by the neural tissue. Understanding the effects of GNPs in the adult brain is a crucial step to design proper pharmacological vehicles to deliver long-lasting drugs.

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.

Cyclohexane Inhalation Produces Long-Lasting Alterations in the Hippocampal Integrity and Reward-Seeking Behavior in the Adult Mouse.

Cyclohexane (CHX) is an organic solvent commonly used as a drug-of-abuse. This drug increases the oxidative stress and glial reactivity in the hippocampus, which suggests that this brain region is vulnerable to CHX effects. This study aimed to establish the behavioral changes and the pathological alterations that occur in the Cornu Ammonis 3 (CA3) and Dentate Gyrus (DG) after a long-lasting exposure to CHX. We exposed CD1 mice to a recreational-like dose of CHX (~ 30,000 ppm) for 30 days and explored its consequences in motor skills, reward-seeking behavior, and the CA3 and DG hippocampal subfields. Twenty-four hours after the last administration of CHX, we found a significant decrease in the number of c-Fos+ cells in the hippocampal CA3 and DG regions. This event coincided with an increased in NMDAR1 expression and apoptotic cells in the CA3 region. At day 13th without CHX, we found a persistent reduction in the number of c-Fos+ and TUNEL+ cells in DG. At both time points, the CHX-exposed mice showed a strong overexpression of neuropeptide Y (NPY) in the CA3 stratum lucidum and the hippocampal hilus. In parallel, we used an operant-based task to assess motor performance and operant conditioning learning. The behavioral analysis indicated that CHX did not modify the acquisition of operant conditioning tasks, but affected some motor skills and increased the reward-seeking behavior. Altogether, this evidence reveals that CHX exposure provokes long-lasting changes in the hippocampal subfields, induces motor impairments and increases the motivation-guided behavior. These findings can help understand the deleterious effect of CHX into the adult hippocampus and unveil its potential to trigger addiction-like behaviors.

Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases.

INTRODUCTION: Demyelinating diseases of the central nervous system (CNS) comprise a group of neurological disorders characterized by progressive (and eventually irreversible) loss of oligodendrocytes and myelin sheaths in the white matter tracts. Some of myelin disorders include: Multiple sclerosis, Guillain-Barré syndrome, peripheral nerve polyneuropathy and others. To date, the etiology of these disorders is not well known and no effective treatments are currently available against them. Therefore, further research is needed to gain a better understand and treat these patients. To accomplish this goal, it is necessary to have appropriate animal models that closely resemble the pathophysiology and clinical signs of these diseases. Herein, we describe the model of toxic demyelination induced by cuprizone (CPZ), a copper chelator that reduces the cytochrome and monoamine oxidase activity into the brain, produces mitochondrial stress and triggers the local immune response. These biochemical and cellular responses ultimately result in selective loss of oligodendrocytes and microglia accumulation, which conveys to extensive areas of demyelination and gliosis in corpus callosum, superior cerebellar peduncles and cerebral cortex. Remarkably, some aspects of the histological pattern induced by CPZ are similar to those found in multiple sclerosis. CPZ exposure provokes behavioral changes, impairs motor skills and affects mood as that observed in several demyelinating diseases. Upon CPZ removal, the pathological and histological changes gradually revert. Therefore, some authors have postulated that the CPZ model allows to partially mimic the disease relapses observed in some demyelinating diseases. CONCLUSION: for five decades, the model of CPZ-induced demyelination is a good experimental approach to study demyelinating diseases that has maintained its validity, and is a suitable pharmacological model for reproducing some key features of demyelinating diseases, including multiple sclerosis.

Permanent Whisker Removal Reduces the Density of c-Fos+ Cells and the Expression of Calbindin Protein, Disrupts Hippocampal Neurogenesis and Affects Spatial-Memory-Related Tasks.

Facial vibrissae, commonly known as whiskers, are the main sensitive tactile system in rodents. Whisker stimulation triggers neuronal activity that promotes neural plasticity in the barrel cortex (BC) and helps create spatial maps in the adult hippocampus. Moreover, activity-dependent inputs and calcium homeostasis modulate adult neurogenesis. Therefore, the neuronal activity of the BC possibly regulates hippocampal functions and neurogenesis. To assess whether tactile information from facial whiskers may modulate hippocampal functions and neurogenesis, we permanently eliminated whiskers in CD1 male mice and analyzed the effects in cellular composition, molecular expression and memory processing in the adult hippocampus. Our data indicated that the permanent deprivation of whiskers reduced in 4-fold the density of c-Fos+ cells (a calcium-dependent immediate early gene) in cornu ammonis subfields (CA1, CA2 and CA3) and 4.5-fold the dentate gyrus (DG). A significant reduction in the expression of calcium-binding proteincalbindin-D28k was also observed in granule cells of the DG. Notably, these changes coincided with an increase in apoptosis and a decrease in the proliferation of neural precursor cells in the DG, which ultimately reduced the number of Bromodeoxyuridine (BrdU)+NeuN+ mature neurons generated after whisker elimination. These abnormalities in the hippocampus were associated with a significant impairment of spatial memory and navigation skills. This is the first evidence indicating that tactile inputs from vibrissal follicles strongly modify the expression of c-Fos and calbindin in the DG, disrupt different aspects of hippocampal neurogenesis, and support the notion that spatial memory and navigation skills strongly require tactile information in the hippocampus.

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.