Neuronal Hypertrophy Research Articles

Partial depletion of septohippocampal cholinergic cells reduces seizure susceptibility, but does not mitigate hippocampal neurodegeneration in the kainate model of epilepsy

The brain cholinergic system may undergo structural and functional alterations both in human epilepsy and in respective animal models, but the causal relationships between these alterations and epilepsy remain to be established. In this study, we attempted to examine how the inhibition of epilepsy-related cholinergic plasticity may be reflected in seizure susceptibility and/or in the development of chronic epilepsy and its neurological consequences. For this purpose, adult Wistar rats received intrahippocampal injections of low doses of 192-IgG-saporin (SAP) to produce a moderate, but significant loss of septohippocampal cholinergic cells and to suppress their plasticity. Then, animals were treated with kainic acid to induce status epilepticus, which leads to the development of chronic epilepsy later in life. It was found that SAP-pretreatment was associated with longer latency to the onset of status epilepticus and with reduced mortality rate, suggesting that increased activity of septal cholinergic cells may potentiate seizures. Interestingly, months later, a greater percentage of rats with intact septohippocampal cholinergic connections showed spontaneous seizures, when compared to SAP-pretreated rats. Treatment with kainic acid produced death of 40–50% of hippocampal neurons and this effect was not ameliorated by prior cholinergic depletion. Moreover, the kainate induced cognitive deficits were detected in both SAP-pretreated and sham-pretreated groups. These data suggest that seizure-induced plasticity of cholinergic cells may indeed enhance seizure susceptibility and contribute to epileptogenic processes. They do not support the hypothesis that epilepsy-related hypertrophy of cholinergic neurons may potentiate hippocampal cell loss and respective behavioral impairments.

Behavioral Compensations and Neuronal Remodeling in a Rodent Model of Chronic Intervertebral Disc Degeneration

Low back pain is associated with degeneration of the intervertebral disc, but specific mechanisms of pain generation in this pathology remain unknown. Sensory afferent nerve fiber growth into the intervertebral disc after injury-induced inflammation may contribute to discogenic pain. We describe a clinically relevant behavioral phenotype in a rodent model of chronic intervertebral disc degeneration which provides a means to map sensory neuron changes to a single affected lumbar intervertebral disc. Unilateral disc puncture of one lumbar intervertebral disc revealed a bilateral behavioral phenotype characterized by gait changes and decreased activity. Moreover, neurons extracted from the dorsal root ganglia in animals with intervertebral disc injury demonstrated altered TRPV1 activation in vitro independent of exogenous NGF administration. Finally, neuronal nuclear hypertrophy and elevated expression of p75NTR provide evidence of active adaptation of innervating sensory neurons in chronic intervertebral disc degeneration. Therefore, this model and findings provide the template for future studies to establish specific mechanisms of nociceptive pain in chronic intervertebral disc degeneration.

Prenatal immune challenge induces behavioral deficits, neuronal remodeling, and increases brain nitric oxide and zinc levels in the male rat offspring

Schizophrenia is a severe mental disorder with numerous etiological susceptibilities. Maternal infection is a key risk factor for schizophrenia. Prenatal lipopolysaccharide (LPS) infection stimulates cytokine production that affects brain development. In the present study, we aimed to investigate the effect of prenatal LPS injection at gestational day (GD) 14–16 on behavioral paradigms, and neuronal morphology in the prefrontal cortex (PFC), basolateral amygdala (BLA), nucleus accumbens (NAcc) and ventral hippocampus (VH) at two critical ages of development: pre-pubertal (postnatal day 35, PD35) and post-pubertal (PD60) age in male rats. We also evaluated the effects of LPS on nitric oxide (NO) and zinc (Zn) levels in seven brain areas (PFC, VH, amygdala, brainstem, striatum and dorsal hippocampus) at PD35 and PD60. LPS induced hyperlocomotion in a novel environment and reduced social contact as well as increased the levels of NO and Zn in the PFC, brainstem and amygdala as observed in other animal models of schizophrenia-related behavior. Furthermore, we found that LPS-treated rats presented post-pubertal neuronal hypertrophy in the PFC and BLA and decreased spine density in the NAcc. The neuronal morphology of neurons in the VH in LPS-treated rats remained unaltered. Interestingly, the anxiogenic-related behavior correlated with neuronal hypertrophy observed in the BLA. Our findings suggest that the behavioral and neural modifications observed in our model could be mediated by the long-lasting alterations in Zn and NO levels in the brain.

Identification and immunophenotype of abnormal cells present in focal cortical dysplasia type IIb

BackgroundFocal cortical dysplasias (FCDs) are malformations of cortical development that present cortical dyslamination and abnormal cell morphology and are frequently associated with refractory epilepsy. FCD type IIb presents dysmorphic neurons (DNs) and balloon cells (BCs), which are the hallmarks of this dysplasia. Moreover, hypertrophic neurons (HyNs) may be present in FCD types I, II and III. The objective of this study was to perform a detailed morphology and immunophenotype study of BCs, DNs, and HyNs in a cohort of FCD IIb patients.MethodsCortices resected as a treatment for refractory epilepsy from 18 cases of FCD type IIb were analysed using Bielschowsky method and haematoxylin and eosin as routine stains. Immunophenotype was performed using specific antibodies to detect epitopes differentially expressed by abnormal cells.ResultsAll cases showed cortical dyslamination, BCs, DNs, and HyNs. No cell layer or column could be identified, except for cortical layer I. Lesions predominated in the frontal cortex (11 cases). DNs were large neurons and presented a clumped and or displaced Nissl substance towards the cell membrane, and a cytoplasm accumulation of neurofilament that displaced the nucleus to the cell periphery, as shown by Bielschowsky staining and immunohistochemistry. HyNs were as large as DNs, but without alterations of Nissl substance or dense neurofilament accumulation, with a central nucleus. BCs were identified as large, oval-shaped and pale eosinophilic cells, which lacked the Nissl substance, and presented an eccentric nucleus. BCs and DNs expressed epitopes of both undifferentiated and mature cells, detected using antibodies against nestin, vimentin, class III β-tubulin, pan-neuronal filaments, neurofilament proteins, β-tubulin and NeuN. Only BCs expressed GFAP.ConclusionFCDs present with disorganization of the cerebral cortex architecture, abnormal cell morphology, are frequently associated with refractory epilepsy, and their post-surgical prognosis depends on the type of FCD. The diagnosis of focal cortical dysplasia in a surgical specimen relies on the identification of the abnormal cells present in a dysplastic cortex specimen. The current report contributes to the identification of balloon cells, dysmorphic and hypertrophic neurons in the context of focal cortical dysplasia type IIb.

Tooth pulp injury induces sex-dependent neuronal reshaping in the ventral posterolateral nucleus of the rat thalamus

Orofacial injuries often result in persistent pain and are therefore considered a common health problem worldwide. Considerable evidence suggests that peripheral sensory nerve injury results in diverse plastic changes in the central nervous system (CNS). Tooth pulp is innervated by trigeminal afferents which extend to the trigeminal brainstem sensory nuclear complex and send input to higher level neurons in the CNS, including the ventral posterolateral nucleus of the thalamus (VPL). In the present study, we examined the long term effects of pulpal injury on neuronal arborization in the VPL using morphological analysis via Golgi-Cox staining. In addition, we examined these effects in both male and female rats due to the major prevalence of oral pain in women. Quantitative morphological analysis revealed that pulpal injury induced neuronal hypertrophy in VPL neurons of female rats. In clear contrast, pulpal injury increased arborization close to the soma and reduced arborization distal to the soma without modification of total dendritic length in male rats. As a result, we show, for the first time, sex-dependent morphological alterations in VPL neurons after orofacial peripheral injury. Since dental injuries are readily reproducible in rat dental molars and closely mimic the clinical setting in humans, this model represents a useful tool to further understand mechanisms of orofacial pain.

Self-reinforcing effects of mTOR hyperactive neurons on dendritic growth

Loss of the mTOR pathway negative regulator PTEN from hippocampal dentate granule cells leads to neuronal hypertrophy, increased dendritic branching and aberrant basal dendrite formation in animal models. Similar changes are evident in humans with mTOR pathway mutations. These genetic conditions are associated with autism, cognitive dysfunction and epilepsy. Interestingly, humans with mTOR pathway mutations often present with mosaic disruptions of gene function, producing lesions that range from focal cortical dysplasia to hemimegalanecephaly. Whether mTOR-mediated neuronal dysmorphogenesis is impacted by the number of affected cells, however, is not known. mTOR mutations can produce secondary comorbidities, including brain hypertrophy and seizures, which could exacerbate dysmorphogenesis among mutant cells. To determine whether the percentage or “load” of PTEN knockout granule cells impacts the morphological development of these same cells, we generated two groups of PTEN knockout mice. In the first, PTEN deletion rates were held constant, at about 5%, and knockout cell growth over time was assessed. Knockout cells exhibited significant dendritic growth between 7 and 18 weeks, demonstrating that aberrant dendritic growth continues even after the cells reach maturity. In the second group of mice, PTEN was deleted from 2 to 37% of granule cells to determine whether deletion rate was a factor in driving this continued growth. Multivariate analysis revealed that both age and knockout cell load contributed to knockout cell dendritic growth. Although the mechanism remains to be determined, these findings demonstrate that large numbers of mutant neurons can produce self-reinforcing effects on their own growth.

Hypertrophy of nigral neurons in Torsin1A deletion (DYT1) carriers manifesting dystonia

ObjectiveTo individuate morphometric changes and prevalent types of intraneuronal inclusions in nigral neurons of DYT1 dystonia autopsy-brains. MethodsUsing precise methods of quantification, such as unbiased stereology, we measured cellular and subcellular volumes of neuromelanin-containing (pigmented) neurons in the substantia nigra (SN) of DYT1 carriers with and without manifestation of generalized dystonia (manif-DYT1 and non-manif-DYT1, respectively), non-DYT1 carriers manifesting generalized dystonia (manif-non-DYT1) patients, and age-matched control subjects (controls). A total of four DYT1 carriers (two manif-DYT1 and two non-manif-DYT1), six manif-non-DYT1 carriers, and six controls autopsy-brains were available for these neuropathological-morphometric analyses. The search of brain lesions was performed for: tau neurofibrillary tangles and neurites, extracellular β-amyloid deposits, Lewy bodies and neurites, TorsinA, Laminin A + C, Ubiquitin, p62, pTDP43 intraneuronal inclusions; and Negri, Bunina, Hirano, Marinesco, Nissl, and Buscaino bodies. ResultsAn increased mean cell body, nuclear, and nucleolar volume of nigral neurons in manif-DYT1 vs. non-manif-DYT1 (p < 0.0001), manif-non-DYT1 (p < 0.0001), and controls (p < 0.00001) was found. Increased nuclear and nucleolar volumes in manif-non-DYT1 vs. controls were also found. None of the considered possible intraneuronal lesions were more frequent or prevalent in nigral neurons of manif-DYT1 vs. all the other groups. ConclusionsUnbiased stereology-based measurements of nigral neurons enlargement in manif-DYT1 in the absence of intraneuronal inclusions or neurodegenerative processes, is novel. These findings suggest distinct pathogenetic mechanisms between manif-DYT1 vs. non-manif-DYT1 and manif-non-DYT1 dystonia, especially in terms of possible nigral dopaminergic abnormalities. These data could open new pathophysiologic views on specific dopamino-associated pathomechanisms related to the clinical manifestation of generalized dystonia.

Resveratrol promotes neuroprotection and attenuates oxidative and nitrosative stress in the small intestine in diabetic rats

Damages to the enteric nervous system caused by diabetes mellitus (DM) are frequently attributed to oxidative and nitrosative stress. We aimed to investigate the effect of Resveratrol (RSV) (10 mg/kg) on oxidative and nitrosative stress in the intestinal wall and morphoquantitative aspects of the myenteric plexus of the duodenum, jejunum and ileum in diabetic rats. Twenty-four rats were distributed into four groups (n = 6/group): control (C group), control treated with RSV (CR group), diabetic (D group), and diabetic treated with RSV (DR group) for 120 days. Immunohistochemical staining techniques for the general neuronal population, nitrergic and calretinin neuronal subpopulations, enteric glial cells and glial fibrillary acid protein were performed in the myenteric plexus. Furthermore, parameters of oxidative and nitrosative stress were analyzed in the intestinal wall. RSV attenuated oxidative and nitrosative stress and prevented neuronal loss and hypertrophy of the HuC/D-IR, nNOS-IR and CALR-IR neuronal subpopulations in the DR group compared with the D group (P < 0.05). In addition, RSV prevented the increase in glial fibrillary acid protein fluorescence in the DR group compared with the D (P < 0.05). These results suggest that RSV has antioxidant and neuroprotective effects in myenteric plexus in rats with experimental DM.

The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia

The prevalence of vascular dementia is increasing at an alarming rate. The Confirmation of the clinical diagnosis of vascular dementia depends on post-mortem examination of the brain. In our study, we investigated the vascular disease and neuroinflammation during vascular dementia. Our results showed a β-amyloid deposits, neovascularization, neuronal hypertrophy and neuroinflammation in the hippocampus tissue. Interestingly, the neuroinflammation was characterized by a higher expression of TNF-α, IL-1β, TGF-β and iNOS which are TLR4/RelA pathway dependent. Finally, the finding of necroptosis by impaired blood supply and inflammation state suggests that the cognitive impairment was caused by vascular disease and neuroinflammation.

New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a heterogeneous syndrome. Surgery results in seizure freedom for most pharmacoresistant patients, but the epileptic and cognitive prognosis remains variable. The 2013 International League Against Epilepsy (ILAE) histopathological classification of hippocampal sclerosis (HS) has fostered research to understand MTLE-HS heterogeneity. We investigated the associations between histopathological features (ILAE types, hypertrophic CA4 neurons, granule cell layer alterations, CD34 immunopositive cells) and clinical features (presurgical history, postsurgical outcome) in a monocentric series of 247 MTLE-HS patients treated by surgery. NeuN, GFAP and CD34 immunostainings and a double independent pathological examination were performed. 186 samples were type 1, 47 type 2, 7 type 3 and 7 samples were gliosis only but no neuronal loss (noHS). In the type 1, hypertrophic CA4 neurons were associated with a worse postsurgical outcome and granule cell layer duplication was associated with generalized seizures and episodes of status epilepticus. In the type 2, granule cell layer duplication was associated with generalized seizures. CD34+ stellate cells were more frequent in the type 2, type 3 and in noHS. These cells had a Nestin and SOX2 positive, immature neural immunophenotype. Patients with nodules of CD34+ cells had more frequent dysmnesic auras. CD34+ stellate cells in scarce pattern were associated with higher ratio of normal MRI and of stereo-electroencephalographic studies. CD34+ cells were associated with a trend for a better postsurgical outcome. Among CD34+ cases, we proposed a new entity of BRAF V600E positive HS and we described three hippocampal multinodular and vacuolating neuronal tumors. To conclude, our data identified new clinicopathological associations with ILAE types. They showed the prognostic value of CA4 hypertrophic neurons. They highlighted CD34+ stellate cells and BRAF V600E as biomarkers to further decipher MTLE-HS heterogeneity.

Toxoplasmic Infection-induced Injury in the Ileal Myenteric Plexus in Rats Depends on the Dose of Toxoplasma gondii Oocysts

Introduction The present study evaluated the effects of different inocula of Toxoplasma gondii oocysts on the ileal myenteric plexus in rats. Materials and Methods Male Wistar rats, 60 days old, were distributed into four groups: control group (CG; which received saline solution) and groups that were infected with 100 (TG100), 1000 (TG1000), and 5000 (TG5000) T. gondii oocysts. Thirty days after infection, the rats were sacrificed, and the ileum was collected to make whole-mount preparations that were subjected to immunofluorescence staining to observe the general neuronal population (HuC/D), nitrergic neurons (nNOS), and enteric glial cells (S100). Morphometric and quantitative analyses of myenteric neurons were performed. Results The infections with different T. gondii inocula did not cause neuronal or glial loss, but cause neuronal hypertrophy in general population and nitrergic subpopulation in infected groups. Conclusion: Changes in neuronal morphology were observed in the TG5000 group, including the presence of vacuoles, translocation of Hu protein to the nucleus, and dendritic distortions, suggesting functional alterations in these cells.

Chronic stress leads to long-lasting deficits in olfactory-guided behaviors, and to neuroplastic changes in the nucleus of the lateral olfactory tract

A recent study reported that the integrity of the nucleus of the lateral olfactory tract (nLOT) is required for normal olfaction and for the display of odor-driven behaviors that are critical for species survival and reproduction. In addition to being bi-directionally connected with a key element of the neural circuitry that mediates stress response, the basolateral nucleus of the amygdala, the nLOT is a potential target for glucocorticoids as its cells express glucocorticoid receptors. Herein, we have addressed this hypothesis by exploring, first, if chronic variable stress (CVS) disrupts odor detection and discrimination, and innate olfactory-driven behaviors, namely predator avoidance, sexual behavior and aggression in male rats. Next, we examined if CVS alters the nLOT structure and if such changes can be ascribed to stress-induced effects on the activity of the main output neurons, which are glutamatergic, and/or of local GABAergic interneurons. Finally, we analyzed if the stress-induced changes are transient or, conversely, persist after cessation of CVS exposure. Our data demonstrate that CVS leads to severe olfactory deficits with inability to detect and discriminate between odors and to innately avoid predator odors. No effects of CVS on sexual and aggressive behaviors were observed. Results also showed that CVS leads to somatic hypertrophy of pyramidal glutamatergic neurons, which likely results from neuronal disinhibition consequent to the loss of inhibitory inputs mediated by GABAergic interneurons. Most of the CVS-induced effects persist beyond a 4-week stress-free period, suggesting long-lasting effects of chronic stress on the structure and function of the olfactory system.

Kolaviron Protects the Prefrontal Cortex and Hippocampus against Histomorphological and Neurobehavioural Changes in Cuprizone Model of Multiple Sclerosis.

BackgroundThis study explored the efficacy of kolaviron—a biflavonoid complex isolated from the seeds of Garcinia kola—in protecting against cuprizone (CPZ)-induced demyelination in both the prefrontal cortex and the hippocampus of Wistar rats.MethodologyThirty rats were treated to receive 0.5 mL phosphate-buffered saline (group A, control), 0.5 mL corn oil (group B), 0.2% CPZ (group C), for 6 weeks, 0.2% CPZ for 3 weeks and then 200 mg/kg of Kv for 3 weeks (group D), or 200 mg/kg of Kv for 3 weeks followed by 0.2% CPZ for 3 weeks (group E). Rats were assessed for exploratory functions and anxiety-like behaviour before being euthanised and perfused transcardially with 4% paraformaldehyde. Prefrontal and hippocampal thin sections were stained in hematoxylin and eosin and cresyl fast violet stains.ResultsCPZ-induced demyelination resulted in behavioural impairment as seen by reduced exploratory activities, rearing behaviour, stretch attend posture, center square entry, and anxiogenic characteristics. Degenerative changes including pyknosis, karyorrhexis, neuronal hypertrophy, and reduced Nissl integrity were also seen. Animals treated with Kv showed significant improvement in behavioural outcomes and a comparatively normal cytoarchitectural profile.ConclusionKv provides protective roles against CPZ-induced neurotoxicity through prevention of ribosomal protein degradation.

Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth

BackgroundPhosphatase and tensin homolog (PTEN) negatively regulates downstream protein kinase B signaling, resulting in decreased cellular growth and proliferation. PTEN is mutated in a subset of children with autism spectrum disorder (ASD); however, the mechanism by which specific point mutations alter PTEN function is largely unknown. Here, we assessed how ASD-associated single-nucleotide variations in PTEN (ASD-PTEN) affect function. MethodsWe used viral-mediated molecular substitution of human PTEN into Pten knockout mouse neurons and assessed neuronal morphology to determine the functional impact of ASD-PTEN. We employed molecular cloning to examine how PTEN’s stability, subcellular localization, and catalytic activity affect neuronal growth. ResultsWe identified a set of ASD-PTEN mutations displaying altered lipid phosphatase function and subcellular localization. We demonstrated that wild-type PTEN can rescue the neuronal hypertrophy, while PTEN H93R, F241S, D252G, W274L, N276S, and D326N failed to rescue this hypertrophy. A subset of these mutations lacked nuclear localization, prompting us to examine the role of nuclear PTEN in regulating neuronal growth. We found that nuclear PTEN alone is sufficient to regulate soma size. Furthermore, forced localization of the D252G and W274L mutations into the nucleus partially restores regulation of soma size. ConclusionsASD-PTEN mutations display decreased stability, catalytic activity, and/or altered subcellular localization. Mutations lacking nuclear localization uncover a novel mechanism whereby lipid phosphatase activity in the nucleus can regulate mammalian target of rapamycin signaling and neuronal growth.

Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes

Context: NK3 receptor (“NK3”; TACR3) signaling is implicated in the etiology of hot flashes by the clinical pharmacology of neurokinin B (NKB) [ [1] Jayasena C.N. et al. Sci Rep. 2015; 5https://doi.org/10.1038/srep08466 Crossref PubMed Scopus (85) Google Scholar ], neuroanatomical evidence for hypertrophy of NKB-expressing neurons in menopausal women [ [2] Rance N.E. Peptides. 2009; 30: 111-122https://doi.org/10.106/j.peptides.2008.05.016 Crossref PubMed Scopus (0) Google Scholar ], and association between risk of vasomotor symptoms and genetic variation in TACR3 [ [3] Crandall C.J. et al. Menopause. 2016; https://doi.org/10.1097/GME.0000000000000763 Crossref Scopus (43) Google Scholar ]. Fezolinetant is an NK3 antagonist demonstrated to safely modulate hormone biomarkers in premenopausal women [ [4] Fraser G.L. et al. J Clin Endocrinol Metab. 2016; https://doi.org/10.1210/jc.2015-3621 Crossref Scopus (54) Google Scholar ]. Here, we present clinical trial results for fezolinetant in the treatment of menopausal hot flashes (“HF”).

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRasG12V/G12V mice. HRasG12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRasG12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRasG12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments.

Differential roles for Akt and mTORC1 in the hypertrophy of Pten mutant neurons, a cellular model of brain overgrowth disorders

Mutations in the PI3K/Akt/mTOR signaling pathway or in the upstream negative regulator Pten cause human brain overgrowth disorders, such as focal cortical dysplasia and megalencephaly, and are characterized by the presence of hypertrophic neurons. These disorders often have a pediatric onset and a high comorbidity with drug-resistant epilepsy; however, effective pharmacological treatments are lacking. We established forebrain excitatory neuron-specific Pten-deficient cultures as an in vitro model of brain overgrowth disorders, and investigated the effects of this Pten mutation on PI3K/Akt/mTOR signaling and neuronal growth. Mutant neurons exhibit excessive PI3K/Akt/mTOR signaling activity, enlarged somas and increased dendritic arborization. To understand the contributions of Akt and mTORC1 kinases to the hypertrophy phenotype, we evaluated the effects of short-term treatment with the Akt inhibitor MK-2206, and the mTORC1 inhibitor RAD001, which have shown safety and efficacy in human cancer clinical trials. We found that RAD001 treatment only partially reversed the morphological abnormalities of Pten mutant neurons, whereas MK-2206 treatment completely rescued the phenotype. Interestingly, neither treatment altered the size or morphology of normal neurons. Our results suggest that Akt is a major determinant of neuronal growth, and that Akt inhibition may be an effective strategy for pharmacological intervention in brain overgrowth disorders.

Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.

SummaryTuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients.

Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: Implications for psychopathology

Stress exposure causes a structural reorganization in neurons of the amygdala. In particular, animal models have repeatedly shown that both acute and chronic stress induce neuronal hypertrophy and volumetric increase in the lateral and basolateral nuclei of amygdala. These effects are visible on the behavioral level, where stress enhances anxiety behaviors and provokes greater fear learning. We assessed stress and anxiety levels in a group of 18 healthy human trauma-exposed individuals (TR group) compared to 18 non-exposed matched controls (HC group), and related these measurements to amygdala volume. Traumas included unexpected adverse experiences such as vehicle accidents or sudden loss of a loved one. As a measure of aversive learning, we implemented a cued fear conditioning paradigm. Additionally, to provide a biological marker of chronic stress, we measured the sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis using a dexamethasone suppression test. Compared to the HC, the TR group showed significantly higher levels of chronic stress, current stress and trait anxiety, as well as increased volume of the left amygdala. Specifically, we observed a focal enlargement in its lateral portion, in line with previous animal data. Compared to HC, the TR group also showed enhanced late acquisition of conditioned fear and deficient extinction learning, as well as salivary cortisol hypo-suppression to dexamethasone. Left amygdala volumes positively correlated with suppressed morning salivary cortisol. Our results indicate differences in trauma-exposed individuals which resemble those previously reported in animals exposed to stress and in patients with post-traumatic stress disorder and depression. These data provide new insights into the mechanisms through which traumatic stress might prompt vulnerability for psychopathology.

Trypanosoma cruzi (CEPA CL) Promove Perda Neuronal no Plexo Mioentérico do Cólon de Ratos

Trypanosoma cruzi, um protozoário parasita, é o agente etiológico da doença de Chagas. A infecção chagásica apresenta duas fases: aguda e crônica. Na fase aguda a mortalidade é mais frequente, sendo que o organismo que consegue sobreviver a ela passa para a fase crônica indeterminada. No trato gastrointestinal o T. gondii pode parasitar o sistema nervoso intramural formando os megaesôfago e o megacólon. Não existem trabalhos que relacionam a perda neuronal do plexo mientérico com a infecção com a cepa CL do T. cruzi. Portanto, o objetivo deste trabalho foi verificar alterações morfoquantitativas no plexo mioentérico no colo distal de ratos infectados com a cepa CL durante a fase aguda e crônica da doença. Foram utilizados 20 ratos divididos em quatro grupos: infectado com a cepa CL durante 7 dias (grupo IA) do T. cruzi e seu controle (grupo CA), ambos sacrificados após sete dias do início do experimento, outro grupo infectado (IC) e sacrificado após trinta dias e seu controle (CC). Foi realizada a estimativa da densidade neuronal e a morfometria das áreas do perfil dos corpos celulares dos neurônios através da técnica de Giemsa. A análise quantitativa demonstrou uma redução significativa no número de neurônios nos grupos infectados IA e IC. Em relação ao perfil neuronal foi observada uma atrofia dos neurônios do grupo IC em relação ao controle. Portanto, a cepa CL do T. cruzi provoca uma denervação do plexo mioentérico do colo sem contudo ocasionar hipertrofia neuronal no tempo experimental de trinta dias.