Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated

Ariel - Volume 10 Number 3

Executive Editors Madalyn Schaefgen David Reich Business Manager David Reich News Editors Medical College Edward Zurad CAHS John Guardiani World Mark Zwanger Features Editors Meg Trexler Jim O\u27Brien Editorials Editor Jeffrey Banyas Photography and Sports Editor Stuart Singer Commons Editor Brenda Peterso

Better data for teachers, better data for learners, better patient care: college-wide assessment at Michigan State University's College of Human Medicine

When our school organized the curriculum around a core set of medical student competencies in 2004, it was clear that more numerous and more varied student assessments were needed. To oversee a systematic approach to the assessment of medical student competencies, the Office of College-wide Assessment was established, led by the Associate Dean of College-wide Assessment. The mission of the Office is to ‘facilitate the development of a seamless assessment system that drives a nimble, competency-based curriculum across the spectrum of our educational enterprise.’ The Associate Dean coordinates educational initiatives, developing partnerships to solve common problems, and enhancing synergy within the College. The Office also works to establish data collection and feedback loops to guide rational intervention and continuous curricular improvement. Aside from feedback, implementing a systems approach to assessment provides a means for identifying performance gaps, promotes continuity from undergraduate medical education to practice, and offers a rationale for some assessments to be located outside of courses and clerkships. Assessment system design, data analysis, and feedback require leadership, a cooperative faculty team with medical education expertise, and institutional support. The guiding principle is ‘Better Data for Teachers, Better Data for Learners, Better Patient Care.’ Better data empowers faculty to become change agents, learners to create evidence-based improvement plans and increases accountability to our most important stakeholders, our patients

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature

Substitution of corn grain for dehydrated lemon bagasse in rearing heifer´s diets

El objetivo de este trabajo fue evaluar la sustitución del grano de maíz (GM) por niveles crecientes de bagazo de limón deshidratado (BLD) en dietas de recría de vaquillonas. Se utilizaron 40 vaquillonas Braford (158 ± 3,5 kg PV inicial) asignadas aleatoriamente en 20 corrales, siendo cada corral la unidad experimental. Se generaron cuatro tratamientos a partir de la inclusión de proporciones crecientes de BLD en la dieta (0, 15, 30 y 45 % MS) en reemplazo del GM. La duración del ensayo fue de 90 d. Se evaluó el peso vivo final (PVf), el aumento medio diario (AMD), el consumo de ración (CMS), la conversión alimenticia (EC), el espesor de grasa dorsal (EGD) y el área de ojo de bife (AOB). Se recolectaron muestras individuales de cada ingrediente y muestras compuestas de las raciones ofrecidas para la determinación de la composición química. El diseño experimental fue completamente aleatorizado con 5 repeticiones por tratamiento. Los resultados fueron analizados utilizando el procedimiento GLM de SAS, siendo declaradas diferencias con P < 0,05. La sustitución parcial o total del GM por el BLD no generó diferencias significativas sobre el PVf (P = 0,61), CMS (P = 0,59), AMD (P = 0,35), EC (P = 0,29), AOB (P = 0,19) y EGD (P = 0,17). Se concluye que el bagazo de limón es un sub-producto que puede sustituir en forma parcial o total al grano de maíz en dietas de recría sin afectar el desempeño animal.The objective of this study was to evaluate the substitution of corn grain (CG) for increasing levels of dehydrated lemon bagasse (DLB) in rearing heifer ́s diets. Forty Braford heifers (158 ± 3.5 kg LW) were randomly assigned in 20 pens, considering each pen as an experimental unit. Four treatments were generated from the inclusion of increasing proportions of DLB in the diet (0, 15, 30, and 45% DM) in replacement of the corn grain. The experiment lasted 90 d. Final live weight (FLW), average daily gain (ADG), dry matter intake (DMI), feed conversion (feed:gain), backfat thickness (BFT), and rib eye area (REA) were evaluated. Individual samples of each ingredient and composite samples of the offered rations were collected for the determination of the chemical composition. The experimental design was completely randomized with 5 repetitions per treatment. The results were analyzed using the GLM procedure of SAS, being declared differences with P < 0.05. The partial or total substitution of the GM for the DLB did not generate significant differences on the FLW (P = 0.61), DMI (P = 0.59), ADG (P = 0.35), feed conversion (P = 0.29), REA (P = 0.19), and BFT (P = 0.17). It is concluded that DLB is a co-product that can partially or totally replace the corn grain in rearing diets without affecting animal performance.Fil: Lopez, Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Santiago del Estero. Universidad Nacional de Santiago del Estero. Centro de Investigaciones y Transferencia de Santiago del Estero; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Tucumán-Santiago del Estero. Estación Experimental Agropecuaria Santiago del Estero; Argentina. Universidad Nacional de Santiago del Estero. Facultad de Agronomía y Agroindustrias; ArgentinaFil: Nasca, Jose Andres. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Hernandez, Olegario. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Tucumán-Santiago del Estero. Estación Experimental Agropecuaria Santiago del Estero; ArgentinaFil: Fissolo, H.. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Tucumán-Santiago del Estero. Estación Experimental Agropecuaria Santiago del Estero; ArgentinaFil: Zimerman, María. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Bottegal, Diego Nicolas. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Molina, A.. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Royo, V.. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Franck, C.. No especifíca;Fil: Arroquy, Jose Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Cesáreo Naredo; Argentin

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults

Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. Design, Setting, and Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient\u27s neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016. Main Outcomes and Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies. Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation. Conclusions and Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020

Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy we identified 5 de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue

Sustitución del grano de maíz por bagazo de limón deshidratado en dietas de recría de vaquillonas = Substitution of corn grain for dehydrated lemon bagasse in rearing heifer´ s diets

El objetivo de este trabajo fue evaluar la sustitución del grano de maíz (GM) por niveles crecientes de bagazo de limón deshidratado (BLD) en dietas de recría de vaquillonas. Se utilizaron 40 vaquillonas Braford (158 ± 3,5 kg PV inicial) asignadas aleatoriamente en 20 corrales, siendo cada corral la unidad experimental. Se generaron cuatro tratamientos a partir de la inclusión de proporciones crecientes de BLD en la dieta (0, 15, 30 y 45 % MS) en reemplazo del GM. La duración del ensayo fue de 90 d. Se evaluó el peso vivo final (PVf), el aumento medio diario (AMD), el consumo de ración (CMS), la conversión alimenticia (EC), el espesor de grasa dorsal (EGD) y el área de ojo de bife (AOB). Se recolectaron muestras individuales de cada ingrediente y muestras compuestas de las raciones ofrecidas para la determinación de la composición química. El diseño experimental fue completamente aleatorizado con 5 repeticiones por tratamiento. Los resultados fueron analizados utilizando el procedimiento GLM de SAS, siendo declaradas diferencias con P < 0,05. La sustitución parcial o total del GM por el BLD no generó diferencias significativas sobre el PVf (P = 0,61), CMS (P = 0,59), AMD (P = 0,35), EC (P = 0,29), AOB (P = 0,19) y EGD (P = 0,17). Se concluye que el bagazo de limón es un sub-producto que puede sustituir en forma parcial o total al grano de maíz en dietas de recría sin afectar el desempeño animal.The objective of this study was to evaluate the substitution of corn grain (CG) for increasing levels of dehydrated lemon bagasse (DLB) in rearing heifer ́s diets. Forty Braford heifers (158 ± 3.5 kg LW) were randomly assigned in 20 pens, considering each pen as an experimental unit. Four treatments were generated from the inclusion of increasing proportions of DLB in the diet (0, 15, 30, and 45% DM) in replacement of the corn grain. The experiment lasted 90 d. Final live weight (FLW), average daily gain (ADG), dry matter intake (DMI), feed conversion (feed:gain), backfat thickness (BFT), and rib eye area (REA) were evaluated. Individual samples of each ingredient and composite samples of the offered rations were collected for the determination of the chemical composition. The experimental design was completely randomized with 5 repetitions per treatment. The results were analyzed using the GLM procedure of SAS, being declared differences with P < 0.05. The partial or total substitution of the GM for the DLB did not generate significant differences on the FLW (P = 0.61), DMI (P = 0.59), ADG (P = 0.35), feed conversion (P = 0.29), REA (P = 0.19), and BFT (P = 0.17). It is concluded that DLB is a co-product that can partially or totally replace the corn grain in rearing diets without affecting animal performance.EEA Santiago del EsteroFil: López, Agustín. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santiago del Estero; Argentina.Fil: López, Agustín. Universidad Nacional de Santiago del Estero. Facultad de Agronomía y Agroindustrias; Argentina.Fil: Nasca, Jose Andres. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Hernandez, Olegario. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santiago del Estero; ArgentinaFil: Fissolo, Hector Miguel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santiago del Estero; ArgentinaFil: Zimerman, María. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Bottegal, Diego Nicolas. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Molina Arias, Alvaro Marcelo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Royo, Victoria. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido; ArgentinaFil: Franck, C. Asesor privado; ArgentinaFil: Arroquy, Jose Ignacio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Cesareo Naredo; Argentina.Fil: Arroquy, Jose Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Arroquy, Jose Ignacio. Universidad Nacional del Sur. Departamento de Agronomía; Argentina