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Fragile X syndrome (FXS) is a genetic disorder caused by a trinucleotide (CGG) expansion mutation in the Fmr1 gene located on the X chromosome. It is characterized by hyperactivity, increased anxiety, repetitive-stereotyped behaviors, and impaired language development. Many children diagnosed with FXS also experience seizures during their lifetime. However, the underlying etiology of the relationship between FXS and epilepsy is not fully understood. Ultrasonic vocalizations (UVs) are one tool that may be used to measure early behavioral changes in mouse pups. In the present study, neonatal UVs were analyzed as a measure of communicative behavior in a mouse model of FXS, both with and without early-life seizures (ELSs). On postnatal day (PD) 10, status epilepticus (SE) was induced via intraperitoneal injections of 0.5% kainic acid (2.0â¯mg/kg) in male Fmr1 knockout (KO) and wild-type (WT) mice. On PD 12, all pups were temporarily isolated from their dam and UVs were recorded. Significant alterations were found in both spectral and temporal measures across genotype and seizure groups. Early-life seizure experience resulted in a significant increase in the quantity of UVs only in WT animals (pâ¯<â¯0.05). We also found that while there was no difference between genotypes in the total number of vocalizations made, calls produced by Fmr1 KO mice were significantly shorter and had a higher peak frequency compared with WT mice. Overall, these findings support the use of vocalization behavior as an early phenotypic marker and highlight the importance of utilizing double-hit models to better understand comorbid disorders.
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Proteína do X Frágil da Deficiência Intelectual/genética , Estado Epiléptico/genética , Estado Epiléptico/fisiopatologia , Ondas Ultrassônicas , Vocalização Animal/fisiologia , Animais , Animais Recém-Nascidos , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Distribuição AleatóriaRESUMO
There is increasing evidence that seizures during early development can impact ultrasonic vocalizations (USVs) emitted from neonatal mice. However, most of the effects of early-life seizures have been reported using chemoconvulsants that produce continuous seizures (status epilepticus). In the present study, we evaluated the impact of different seizure frequency loads during early-life vocalization development in C57BL/6J male and female mice. For the high seizure load (HSL) paradigm, we administered 3 flurothyl seizures to mice on postnatal day (PD) 7 through PD11, and recorded USVs on PD12. We found that the induction of seizures across PD7-11 resulted in increased average duration (Pâ¯<â¯0.05) and cumulative duration (Pâ¯<â¯0.05) of USVs across both sexes. Call-type analyses indicated several call-type changes, including reduced production of complex call-types from males' HSL condition. For the low seizure load (LSL) paradigm, we induced 3 flurothyl seizures only on PD10 and recorded USVs on PD12. We found no change in any spectral or temporal features of USVs. However, call-type production analyses indicated that both male and female animals from the LSL paradigm also produced changes in call-types. This study provides evidence that the magnitude of communication impairment following seizures is significantly impacted by seizure frequency load early in development.
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Crescimento e Desenvolvimento , Convulsões/psicologia , Ondas Ultrassônicas , Vocalização Animal , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Índice de Gravidade de DoençaRESUMO
Early-life seizures are known to cause long-term deficits in social behavior, learning, and memory, however little is known regarding their acute impact. Ultrasonic vocalization (USV) recordings have been developed as a tool for investigating early communicative deficits in mice. Previous investigation from our lab found that postnatal day (PD) 10 seizures cause male-specific suppression of 50-kHz USVs on PD12 in 129 SvEvTac mouse pups. The present study extends these findings by spectrographic characterization of USVs following neonatal seizures. On PD10, male C57BL/6 pups were administered intraperitoneal injections of kainic acid or physiological saline. On PD12, isolation-induced recordings were captured using a broad-spectrum ultrasonic microphone. Status epilepticus significantly suppressed USV quantity (p=0.001) and total duration (p<0.05). Seizure pups also utilized fewer complex calls than controls (p<0.05). There were no changes in call latency or inter-call intervals. Spectrographic analysis revealed increased peak amplitude for complex, downward, short, two-syllable, and upward calls, as well as reduced mean duration for short and two-syllable calls in seizure mice. This investigation provides the first known spectrographic characterization of USVs following early-life seizures. These findings also enhance evidence for USVs as an indicator of select communicative impairment.
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Espectrografia do Som/métodos , Estado Epiléptico/fisiopatologia , Vocalização Animal/fisiologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estado Epiléptico/induzido quimicamente , Fatores de TempoRESUMO
OBJECTIVE: Infant crying is a series of innate vocal patterns intended to elicit the attention of adult caregivers for fulfillment of specific needs such as pain, hunger, or hypostimulation. It is one of the earliest forms of observable communication. In neonatal rodents, this behavior has recently been investigated as a potential early behavioral marker of neural deficits in neurodevelopmental disorders. However, few studies have examined the effects of seizures on vocalization behavior during the neonatal period. The purpose of this study is to investigate the effect of a single kainate-induced early life seizure on vocalization behavior in mice. This study also investigates the subsequent effect of seizures on two pathways critical for early neural development and epileptogenesis: the phosphoinositide 3-kinase|serine/threonine kinase|mammalian target of rapamycin (PI3K-Akt-mTOR) and canonical (Wingless-Int Wnt) intracellular signaling pathways. METHODS: On postnatal day 10, male and female 129SvEvTac mice received a single intraperitoneal injection of kainic acid (2.5 mg/kg) or vehicle injection. The kainate administration resulted in 1-2 h of status epilepticus. On postnatal days 11 and 12, the quantity and duration of isolation-induced ultrasonic vocalizations were recorded. Western blotting analyses were performed using male and female pups on postnatal day 12. RESULTS: There was significant, male-specific suppression in the quantity and total duration of 50-kHz calls on postnatal day 12 following seizures. The hippocampi of male mice on this postnatal day also revealed male-specific changes in the PI3K-Akt-mTOR intracellular signaling pathway, as well as changes in phosphorylated fragile × mental retardation protein. SIGNIFICANCE: These findings demonstrate that early life seizures can disrupt communication behavior in neonatal mice.
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Transdução de Sinais/fisiologia , Estado Epiléptico/fisiopatologia , Vocalização Animal/fisiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Ácido Caínico/toxicidade , Masculino , Camundongos , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Caracteres Sexuais , Estado Epiléptico/induzido quimicamente , Serina-Treonina Quinases TOR/metabolismoRESUMO
Primary intracranial gliomas are a heterogeneous class of lesions that rarely metastasize. Even more infrequently, they may spread caudally into the spinal cord causing spinal gliomatosis. In this case, we discuss an 18-year-old male patient with a diagnosis of grade IV astrocytoma with spinal gliomatosis, specifically detailing the radiographic progression of the disease over 38 months. We also discuss the significance of the change in the WHO classification of central nervous system tumors, as this patient's survival duration is inconsistent with the low survival rates expected of glioblastoma, and rather more consistent with a grade IV astrocytoma.
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The mechanistic target of rapamycin (mTOR) pathway is a signaling system integral to neural growth and migration. In both patients and rodent models, mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviors. Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS-Pten KO) mice, but its impact on behavior is not known. To determine the behavioral effects of rapamycin, male and female NS-Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioral testing. Rapamycin improved social behavior in both genotypes and stereotypic behaviors in NS-Pten KO mice. Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes. Rapamycin did not reverse the reduced anxiety behavior in KO mice. These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic-like behaviors in NS-Pten KO mice.
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Epilepsia , Sirolimo , Masculino , Feminino , Animais , Camundongos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais , Epilepsia/genética , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/farmacologiaRESUMO
BACKGROUND: Pediatric spinal arteriovenous shunts (SAVS) are rare lesions with heterogeneous pathogenesis and clinical manifestations. OBJECTIVE: To evaluate the clinical characteristics, angioarchitecture, and technical/clinical outcomes in SAVS through a large single-center cohort analysis and meta-analysis of individual patient data. METHODS: A retrospective institutional database identified children (aged 0-21 years) who underwent digital subtraction spinal angiography (DSA) for SAVS between January 1996 and July 2021. Clinical data were recorded to evaluate angioarchitecture, generate modified Aminoff-Logue gait disturbance scores (AL) and McCormick grades (MC), and assess outcomes. We then performed a systematic literature review following PRISMA-IPD (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for individual patient data) guidelines, extracting similar data on individual patients for meta-analysis. RESULTS: The cohort consisted of 28 children (M:F=11:17) with 32 SAVS lesions, with a mean age of 12.8±1.1 years at diagnosis. At presentation, SAVS were most highly concentrated in the cervical region (40.6%). Children had a median AL=2 and MC=2, with thoracolumbar AVS carrying the greatest disability. Among treated cases, complete obliteration was achieved in 48% of cases and median AL scores and MC grades both improved by one point. Systematic literature review identified 161 children (M:F=96:65) with 166 SAVS lesions with a mean age of 8.7±0.4 years. Among studies describing symptom chronicity, 37/51 (72.5%) of children presented acutely. At presentation, children had a median AL=4 and MC=3, with thoracolumbar AVS carrying the highest MC grades. After intervention, median AL and MC both improved by one point. CONCLUSIONS: This study provides epidemiologic information on the location, onset, and presentation of the full spectrum of pediatric SAVS, highlighting the role of targeted treatment of high-risk features.
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Embolização Terapêutica , Medula Espinal , Humanos , Criança , Adolescente , Estudos Retrospectivos , Estudos de Coortes , Pescoço , Resultado do TratamentoRESUMO
Pseudolipomas are an uncommon clinical manifestation appearing as a non-encapsulated prominence of subcutaneous fat on MRI. Post-traumatic pseudolipomas (PTLs) are thought to arise from neoadipogenesis following acute or chronic trauma. These are most commonly located on the lower extremities, gluteal, and trochanteric regions. Here, we report a case of PTL in a high school athlete, arising in the posterior neck after weight training with performing barbell squats without neck padding. To our knowledge, this case represents a novel association between PTLs and weight training exercises.
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BACKGROUND: Individuals on immunosuppressive therapies experience greater morbidity and mortality due to vaccine-preventable illnesses, but there are low rates of adherence to immunization guidelines within this population. OBJECTIVE: To determine the effectiveness of clinician-led education, patient-centered dialogue, and immediately available immunization on influenza vaccination uptake in patients taking immunosuppressive therapies. METHOD: We used a controlled before-and-after quasi-experimental design to evaluate our quality improvement intervention occurring from September 2019 to March 2020, with follow-up through July 2020. The study included 2 dermatology practices wherein nursing staff offered influenza vaccination during patient rooming (standard care). Within each practice, clinicians either implemented the intervention or provided only standard care. Patients received the intervention or standard care depending on the clinician they visited. Patients seen at the 2 clinics during the intervention period were included in analyses if they were taking or newly prescribed immunosuppressant medication at the time of their visit. We examined influenza immunization status for 3 flu seasons: 2017-2018 (preintervention), 2018-2019 (preintervention), and 2019-2020 (intervention). INTERVENTION: Immunosuppressed patients initially declining an influenza vaccine were provided dermatologist-led education on the benefits of immunization. Dermatologists explored and addressed individual patients' immunization concerns. Influenza vaccination was then offered immediately postdialogue. RESULTS: Analyses included 201 dermatology patients who were prescribed or currently taking immunosuppressive medication (intervention group [72.6%], comparison group [27.4%]). During the intervention period, 91.1% of the intervention group received influenza vaccination compared to 56.4% of the comparison group. Vaccination trends from 2018-2019 (preintervention) to 2019-2020 (intervention) differed significantly between groups (χ2 = 22.92, P < .001), with greater improvement in the intervention group. In 2019-2020, influenza vaccination was more likely in the intervention group relative to the comparison group (odds ratio: 16.22, 95% confidence interval: 5.55-47.38). In the subset of patients that had never received an influenza vaccine, influenza immunization in 2019-2020 was more common in the intervention group (75.8%, 25/33) relative to the comparison group (13.3%, 2/15, P < .001). CONCLUSION: The intervention successfully addressed vaccine hesitancy and improved influenza immunization rates in an immunosuppressed population receiving care from a specialty clinic. Implementing a similar model across specialty clinics may improve vaccination rates for influenza, coronavirus disease 2019, and other vaccine-preventable illnesses in other populations.
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COVID-19 , Vacinas contra Influenza , Influenza Humana , Humanos , Vacinas contra Influenza/uso terapêutico , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Vacinação , Hesitação VacinalRESUMO
Preventable healthcare-associated harm results in significant morbidity and mortality in the United States, costing nearly 400 000 patient lives annually. The Institute for Healthcare Improvement provides high-quality educational resources tailored for working healthcare professionals. One such resource is the Certified Professional in Patient Safety (CPPS™) review course, which equips professionals with advanced proficiency in 5 core patient safety domains. The CPPS™ certification is the only interprofessional, patient safety science credential recognized worldwide. In 2010, the Lucian Leape Institute at the National Patient Safety Foundation described the critical need for medical students to participate in patient safety solutions as well. However, equivalent patient safety credentialing remains challenging for students in the preclinical and clinical stages of training to obtain. To address this growing dilemma, the Texas College of Osteopathic Medicine (TCOM) piloted the first-of-its-kind CPPS™ course with 10 medical students to test a novel, academic-level approach to patient safety curriculum. Medical students showed large gains in performance on the post-test (83.18% ± 26.12%) compared to the pre-test (46.46% ± 27.18%) (P < .001, η2 p = .368), representing increased knowledge across all learning domains. On the national certification examination, students had a 90% first-time pass rate, exceeding the current national average of 70% for first-time examinees. In satisfaction surveys, students expressed the value of pilot curriculum for their medical training, the importance of similar Patient Safety Education and CPPS certification for all medical students, their confidence as future healthcare change agents. Content analysis of open response questions revealed 3 key areas of strength and opportunity for guiding future iterations of the course. This pilot generates a future vision of patient safety, equipping students with critical knowledge to systematically improve healthcare quality.
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Metformin is the safest and the most widely prescribed first-line therapy for managing hyperglycemia due to different underlying causes, primarily type 2 diabetes mellitus. In addition to its euglycemic properties, metformin has stimulated a wave of clinical trials to investigate benefits on aging-related diseases and longevity. Such an impact on the lifespan extension would undoubtedly expand the therapeutic utility of metformin regardless of glycemic status. However, there is a scarcity of studies evaluating whether metformin has differential cognitive effects across age, sex, glycemic status, metformin dose, and duration of metformin treatment and associated pathological conditions. By scrutinizing the available literature on animal and human studies for metformin and brain function, we expect to shed light on the potential impact of metformin on cognition across age, sex, and pathological conditions. This review aims to provide readers with a broader insight of (a) how metformin differentially affects cognition and (b) why there is a need for more translational and clinical studies examining multifactorial interactions. The outcomes of such comprehensive studies will streamline precision medicine practices, avoiding "fit for all" approach, and optimizing metformin use for longevity benefit irrespective of hyperglycemia.
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Diabetes Mellitus Tipo 2 , Metformina , Animais , Cognição , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Longevidade , Metformina/uso terapêuticoRESUMO
OBJECTIVE: Focal cortical dysplasia (FCD) accounts for nearly half of all cases of medically refractory epilepsy in the pediatric and adult patient populations. This neurological disorder stems from localized malformations in cortical brain tissue due to impaired neuronal proliferation, differentiation, and migration patterns. Recent studies in animal models have highlighted the potential role of the Fragile X mental retardation protein (FMRP) levels in FCD. The purpose of this study was to investigate the status of FMRP activation in cortical brain tissues surgically resected from patients with FCD. In parallel, this study also investigated protein levels within the PI3K/AKT/mTOR and canonical Wnt signaling pathways. METHODS: Pathologic tissue from malformative lesions of FCD patients with medically refractory epilepsy was compared to relatively normal control non-epileptic tissue from patients with intracranial neoplasms. A series of western blotting assays were performed to assess key proteins in the PI3K/AKT/mTOR, canonical Wnt signaling pathways, and FMRP. RESULTS: There was suppression of S235/236-phosphorylated S6, GSK3α, and GSK3ß protein levels in samples derived from FCD patients, compared to non-epileptic controls. FCD samples also had significantly greater levels of total and S499-phosphorylated FMRP. CONCLUSION: These findings support our hypothesis that malformative lesions associated with FCD are characterized by high levels of FMRP activation along with dysregulation of both PI3K/AKT/mTOR and canonical Wnt signaling. These novel clinical findings extend previous work in animal models, further suggesting a potential unforeseen role of GSK3α and GSK3ß in the pathophysiology of FCD and refractory epilepsy.
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Córtex Cerebral/metabolismo , Epilepsia Resistente a Medicamentos/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Malformações do Desenvolvimento Cortical/metabolismo , Western Blotting , Estudos de Casos e Controles , Córtex Cerebral/cirurgia , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/cirurgia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Malformações do Desenvolvimento Cortical/complicações , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína S6 Ribossômica/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Via de Sinalização WntRESUMO
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and a significant genetic contributor to Autism spectrum disorder. In addition to autistic-like phenotypes, individuals with FXS are subject to developing numerous comorbidities, one of the most prevalent being seizures. In the present study, we investigated how a single early-life seizure superimposed on a genetic condition impacts the autistic-like behavioral phenotype of the mouse. We induced status epilepticus (SE) on postnatal day (PD) 10 in Fmr1 wild type (WT) and knockout (KO) mice. We then tested the mice in a battery of behavioral tests during adulthood (PD90) to examine the long-term impact of an early-life seizure. Our findings replicated prior work that reported a single instance of SE results in behavioral deficits, including increases in repetitive behavior, enhanced hippocampal-dependent learning, and reduced sociability and prepulse inhibition (pâ¯<⯠0.05). We also observed genotypic differences characteristic of the FXS phenotype in Fmr1 KO mice, such as enhanced prepulse inhibition and repetitive behavior, hyperactivity, and reduced startle responses (pâ¯<⯠0.05). Superimposing a seizure on deletion of Fmr1 significantly impacted repetitive behavior in a nosepoke task. Specifically, a single early-life seizure increased consecutive nose poking behavior in the task in WT mice (pâ¯<⯠0.05), yet seizures did not exacerbate the elevated stereotypy observed in Fmr1 KO mice (pâ¯>⯠0.05). Overall, these findings help to elucidate how seizures in a critical period of development can impact long-term behavioral manifestations caused by underlying gene mutations in Fmr1. Utilizing double-hit models, such as superimposing seizures on the Fmr1 mutation, can help to enhance our understanding of comorbidities in disease models.
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Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Proteína do X Frágil da Deficiência Intelectual/genética , Convulsões/fisiopatologia , Comportamento Social , Estado Epiléptico/fisiopatologia , Animais , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Modelos Animais de Doenças , Ácido Caínico , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Convulsões/induzido quimicamente , Convulsões/complicações , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/complicaçõesRESUMO
The purpose of this investigation was to examine cerebellar levels of several molecular signaling pathways, including PI3K/AKT/mammalian target of rapamycin (mTOR) signaling and markers of neuronal migration, following loss of the phosphatase and tensin homolog (PTEN) gene in a subset of neurons, as well as the accompanying behavior phenotype in mice. Motor coordination and learning were measured by the sticker removal task and the accelerating rotarod. Western blots were conducted on cerebellar tissue samples. We demonstrated that neuron subset-specific deletion of PTEN in mice led to deficits in motor coordination. These changes were accompanied by alterations in many different proteins, including the PI3K/AKT/mTOR signaling pathway, FMRP, glutamate receptors, and neuronal migration markers. These data firstly support a role for hyperactivation of mTOR in the cerebellum following the loss of PTEN, accompanied by behavioral deficits. Moreover, the results of the current study support a broader role for PTEN signaling in early neuronal migration and organization of the cerebellum, and point to a putative role for PTEN in many neuropsychiatric conditions.
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Cerebelo/metabolismo , Aprendizagem/fisiologia , Atividade Motora , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Animais , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , Teste de Desempenho do Rota-Rod , Serina-Treonina Quinases TOR/metabolismoRESUMO
Dysregulation of the PI3K/Akt/mTOR signaling cascade has been associated with the pathology of neurodegenerative disorders, specifically Alzheimer's disease (AD). Both in-vivo models and post-mortem brain samples of individuals with AD have commonly shown hyperactivation of the pathway. In the present study, we examine how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactive mammalian target of rapamycin (mTOR) activity, affects the hippocampal protein levels of key neuropathological hallmarks of AD. We found NS-Pten knockout (KO) mice to have elevated levels of amyloid-ß, α-synuclein, neurofilament-L, and pGSK3α in the hippocampal synaptosome compared with NS-Pten wild type mice. In contrast, there was a decreased expression of amyloid precursor protein, tau, GSK3α, and GSK3ß in NS-Pten KO hippocampi. Overall, there were significant alterations in levels of proteins associated with AD pathology in NS-Pten KO mice. This study provides novel insight into how altered mTOR signaling is linked to AD pathology, without the use of an in-vivo AD model that already displays neuropathological hallmarks of the disease.
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Doença de Alzheimer/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , Transdução de Sinais , Sinaptossomos/metabolismo , Proteínas tau/metabolismoRESUMO
The canonical Wnt and PI3K/Akt/mTOR pathways both play critical roles in brain development early in life. There is extensive evidence of how each pathway is involved in neuronal and synaptic maturation, however, how these molecular networks interact requires further investigation. The present study examines the effect of neuronal subset-specific deletion of phosphatase and tensin homolog (Pten) in mice on Wnt signaling protein levels and associated cognitive impairments. PTEN functions as a negative regulator of the PI3K/Akt/mTOR pathway, and mutations in Pten can result in cognitive and behavioral impairments. We found that deletion of Pten resulted in elevated Dvl2, Wnt5a/b, and Naked2, along with decreased GSK3ß hippocampal synaptosome protein expression compared to wild type mice. Aberrations in the canonical Wnt pathway were associated with learning and memory deficits in Pten knockout mice, specifically in novel object recognition and the Lashley maze. This study demonstrates that deletion of Pten not only significantly impacts PI3K/Akt/mTOR signaling, but affects proper functioning of the Wnt signaling pathway. Overall, these findings will help elucidate how the PI3K/Akt/mTOR pathway intersects with Wnt signaling to result in cognitive impairments, specifically in memory.
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Transtornos da Memória/metabolismo , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Via de Sinalização Wnt/fisiologia , Animais , Encéfalo/metabolismo , Feminino , Expressão Gênica , Deficiências da Aprendizagem/metabolismo , Masculino , Memória/fisiologia , Camundongos Knockout , PTEN Fosfo-Hidrolase/genéticaRESUMO
The Fmr1 knockout (KO) mouse has commonly been used to investigate communication impairments, one of the key diagnostic symptoms observed in Fragile X syndrome (FXS) and Autism spectrum disorder (ASD). Many studies have found alterations in ultrasonic vocalizations (USVs) in neonatal Fmr1 KO mice, however, there is limited research investigating whether these deficits continue into adulthood. In the present study, we examine differences in female urine-induced ultrasonic vocalizations, scent marking behavior, odor discrimination, and open field activity in adult male Fmr1 KO and wildtype (WT) mice. Overall, we found extensive alterations between genotypes in both spectral and temporal properties of ultrasonic vocalizations. There was no difference in the average number of calls emitted by both genotypes, however, Fmr1 KO mice emitted calls of a higher frequency, decreased amplitude, and shorter duration than WT mice. Spectrographic analyses revealed statistically significant differences between genotypes in the types of calls emitted. Contrastingly, we found no differences in scent marking behavior, a form of social communication, or in odor discrimination and activity levels of the mice. The results corroborate previous studies emphasizing the importance of qualitative differences observed in vocalization behavior of Fmr1 KO mice, rather than quantitative measurements such as number of calls emitted. Overall, the study confirms the presence of abnormalities in vocalization behavior in adult Fmr1 KO mice that we believe are consistent with communication deficits seen in the syndrome.
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Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Vocalização Animal , Análise de Variância , Animais , Discriminação Psicológica/fisiologia , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Masculino , Camundongos Knockout , Percepção Olfatória/fisiologia , Fenótipo , Comportamento Sexual Animal/fisiologia , Espectrografia do Som , Fatores de Tempo , Urina , Vocalização Animal/fisiologiaRESUMO
Background: The piracetam analog, aniracetam, has recently received attention for its cognition enhancing potential, with minimal reported side effects. Previous studies report the drug to be effective in both human and non-human models with pre-existing cognitive dysfunction, but few studies have evaluated its efficacy in healthy subjects. A previous study performed in our laboratory found no cognitive enhancing effects of oral aniracetam administration 1-hour prior to behavioral testing in naïve C57BL/6J mice. Methods: The current study aims to further evaluate this drug by administration of aniracetam 30 minutes prior to testing in order to optimize any cognitive enhancing effects. In this study, all naïve C57BL/6J mice were tested in tasks of delayed fear conditioning, novel object recognition, rotarod, open field, elevated plus maze, and marble burying. Results: Across all tasks, animals in the treatment group failed to show enhanced learning when compared to controls. Conclusions: These results provide further evidence suggesting that aniracetam conveys no therapeutic benefit to subjects without pre-existing cognitive dysfunction.
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OBJECTIVE: In this study, we used a systemic Fmr1 knockout in order to investigate both genotype- and sex-specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear-related learning and memory. BACKGROUND: Fragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes. METHODS: Using wild-type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose-poke assay, accelerating rotarod, social partition task, three-chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects. RESULTS: Our results indicate several sex-specific changes in Fmr1 knockout mice, including male-specific increases in activity levels, and female-specific increases in repetitive behaviors on both the nose-poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks. CONCLUSION: These findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex-specific therapeutics.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil , Animais , Ansiedade/genética , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Medo/fisiologia , Feminino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fatores Sexuais , Comportamento SocialRESUMO
Fragile X syndrome is a neurodevelopmental disorder caused by a trinucleotide (CGG) hyperexpansion in the FMR1 gene, functionally silencing transcription of the fragile X mental retardation protein (FMRP). This disorder is characterized by impaired cognition, communication, and social behavior. The aim of this study was to investigate the development of ultrasonic vocalization (USV) behavior in a Fmr1-deficient mouse model. On postnatal days (PD) 9-14, separate cohorts of FVB/NJ pups were removed from their homecage and isolation-induced USVs were recorded. There were significant genotype-dependent and sex-dependent differences in USV behavior across the different testing days. Fmr1 knockout (KO) mice showed a significant reduction in vocalizations across all days. There was also a significant difference in vocalizations between male and female mice. We found a significant decrease in the total number of calls for KO males on PD9 and PD13 as well as an increase in the total number of calls for KO males on PD12. The KO males also showed a significant increase in the total call duration on PD12 and a reduction on PD13. The KO female showed a significant decrease in the total number of calls on PD9 and PD10. They also showed a significant decrease in the total call duration on PD9 and a marginal decrease in the total call duration on PD10. These results provide additional evidence for communication deficits in Fmr1 deficient mice and provide new insight suggesting sexually dimorphic vocalizations during the neonatal period.