RESUMEN
Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate on the neuromolecular mechanisms by which prenatal exposure may perturb neurocognitive development. Specifically, we explore the potential role of topiramate's pharmacological interactions with ligand- and voltage-gated ion channels, especially GABAergic signaling, its effects on DNA methylation and histone acetylation, whether topiramate induces oxidative stress, and its association with fetal growth restriction as possible mechanisms contributing to neurodevelopmental toxicity. Resolving this biology will be necessary to reduce the risk of adverse pregnancy outcomes caused by topiramate or other ASMs.
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Anticonvulsivantes , Topiramato , Topiramato/toxicidad , Humanos , Embarazo , Anticonvulsivantes/toxicidad , Femenino , Efectos Tardíos de la Exposición Prenatal , Trastornos del Neurodesarrollo/inducido químicamente , Animales , Fructosa/análogos & derivados , Fructosa/toxicidadRESUMEN
Emotion is represented in limbic and prefrontal brain areas, herein termed the affective salience network (ASN). Within the ASN, there are substantial unknowns about how valence and emotional intensity are processed-specifically, which nodes are associated with affective bias (a phenomenon in which participants interpret emotions in a manner consistent with their own mood). A recently developed feature detection approach ('specparam') was used to select dominant spectral features from human intracranial electrophysiological data, revealing affective specialization within specific nodes of the ASN. Spectral analysis of dominant features at the channel level suggests that dorsal anterior cingulate (dACC), anterior insula and ventral-medial prefrontal cortex (vmPFC) are sensitive to valence and intensity, while the amygdala is primarily sensitive to intensity. Akaike information criterion model comparisons corroborated the spectral analysis findings, suggesting all four nodes are more sensitive to intensity compared to valence. The data also revealed that activity in dACC and vmPFC were predictive of the extent of affective bias in the ratings of facial expressions-a proxy measure of instantaneous mood. To examine causality of the dACC in affective experience, 130 Hz continuous stimulation was applied to dACC while patients viewed and rated emotional faces. Faces were rated significantly happier during stimulation, even after accounting for differences in baseline ratings. Together the data suggest a causal role for dACC during the processing of external affective stimuli.
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Mapeo Encefálico , Encéfalo , Humanos , Encéfalo/fisiología , Emociones/fisiología , Afecto , Electroencefalografía , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVES: Disability in patients with epilepsy (PWEs) is multifactorial: beyond seizure frequency/severity, PWEs are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly affect quality of life. Here, we explored how variations in seizure severity and the burden of self-reported somatic/neuropsychiatric symptoms correlate with disruptions to 24 h activity patterns (rest-activity rhythms [RARs]), determined through wrist accelerometry/actigraphy. METHODS: Multiday wrist-actigraphy recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously responded to validated psychometric instruments to measure anxiety, depression, sleepiness, and somatic symptoms. We conducted a similar in silico psychometric-actigraphic correlation in a publicly available data set of 1747 Hispanic subjects (35% male, ages 18-65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying amplitude, steepness, acrophase, and robustness) and nonparametric measures to estimate RAR stability, fragmentation, and sleep. RESULTS: Compared with matched SOL subjects, RARs from PWE subjects featured a significantly lower amplitude, a wider rest phase, and significantly more total daily sleep. Within PWEs, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy, whereas high anxiety, depression, and somatic symptom scores were associated with lower RAR robustness and acrophase delay. We applied the SOL data set to train logistic regression models to dichotomously classify subjective anxiety, depression, and sleepiness symptoms using demographic and RAR parameters. When tested on PWEs, these models predicted prevalent anxiety and depression symptom burden (accuracy ~70%) but failed to predict subjective sleepiness. SIGNIFICANCE: Together these results demonstrate that RAR features may encode prevalent depression and anxiety symptoms in patients with focal epilepsy, potentially offering wearable-derived endpoints to adjunct clinical care and drug/device trials. With larger PWE-specific actigraphic-psychometric data sets, we may identify RAR signatures that may more precisely correlate with varying seizure frequency, the burden of anticonvulsant therapy, and prevalent mood/anxiety symptoms.
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Epilepsias Parciales , Epilepsia , Humanos , Masculino , Adulto , Femenino , Actigrafía , Anticonvulsivantes , Calidad de Vida , Somnolencia , Epilepsia/psicología , Convulsiones , Epilepsias Parciales/diagnóstico por imagenRESUMEN
Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Our results suggest that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.
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Trastorno Autístico/genética , Regulación hacia Abajo , Proteínas del Tejido Nervioso/deficiencia , Precursores de Proteínas/deficiencia , Convulsiones/psicología , Conducta Social , Ubiquitina-Proteína Ligasas/metabolismo , Área Tegmental Ventral/metabolismo , Animales , Trastorno Autístico/fisiopatología , Trastorno Autístico/psicología , Núcleo Celular/metabolismo , Femenino , Ácido Glutámico/metabolismo , Masculino , Ratones , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Precursores de Proteínas/biosíntesis , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Transmisión Sináptica , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
PURPOSE OF REVIEW: Depression and anxiety substantially contribute to interictal disability in patients with epilepsy (PWE). This review summarizes current studies that shed light on mechanisms of comorbidity. RECENT FINDINGS: Mounting epidemiological data implicate shared risk factors for anxiety/depression and seizure propensity, but these remain largely elusive and probably vary by epilepsy type. Within PWE, these symptoms appear to be associated with unique genetic, neuropathological, and connectivity profiles. Temporal lobe epilepsy has received enormous emphasis particularly in preclinical studies of comorbidity, where candidate neurobiological mechanisms underlying bidirectionality have been tested without psychopharmacological confounds. Depression and anxiety in epilepsy reflect dysfunction within broadly distributed limbic networks that may be the cause or consequence of epileptogenesis. In refractory epilepsy, seizures and/or certain anticonvulsants may distort central emotional homeostatic mechanisms that perpetually raise seizure risk. Developing future safe and effective combined anticonvulsant-antidepressant treatments will require a detailed understanding of anatomical and molecular nodes that pleiotropically enhance seizure risk and negatively alter emotionality.
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Depresión , Epilepsia , Ansiedad , Trastornos de Ansiedad/epidemiología , Comorbilidad , Depresión/epidemiología , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Humanos , Convulsiones/epidemiologíaRESUMEN
Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.
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Trastornos de Ansiedad/inmunología , Conducta Animal , Interleucina-6/inmunología , Estrés Psicológico/inmunología , Aloinjertos , Animales , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/patología , Trasplante de Médula Ósea , Susceptibilidad a Enfermedades/inmunología , Susceptibilidad a Enfermedades/patología , Interleucina-6/genética , Ratones , Ratones Noqueados , Estrés Psicológico/genética , Estrés Psicológico/patología , Factores de Tiempo , Quimera por Trasplante/genética , Quimera por Trasplante/inmunologíaRESUMEN
Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.
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Depresión , Neurobiología , Animales , Monoaminas Biogénicas/metabolismo , Depresión/genética , Depresión/inmunología , Depresión/fisiopatología , Depresión/terapia , Epigénesis Genética , Humanos , Factores de Crecimiento Nervioso/metabolismo , Neuroinmunomodulación , Sistemas Neurosecretores/metabolismoRESUMEN
Ultradian rhythms are physiological oscillations that resonate with period lengths shorter than 24â hours. This study examined the expression of ultradian rhythms in patients with epilepsy, a disease defined by an enduring seizure risk that may vary cyclically. Using a wearable device, we recorded heart rate, body temperature, electrodermal activity and limb accelerometry in patients admitted to the paediatric epilepsy monitoring unit. In our case-control design, we included recordings from 29 patients with tonic-clonic seizures and 29 non-seizing controls. We spectrally decomposed each signal to identify cycle lengths of interest and compared average spectral power- and period-related markers between groups. Additionally, we related seizure occurrence to the phase of ultradian rhythm in patients with recorded seizures. We observed prominent 2- and 4-hour-long ultradian rhythms of accelerometry, as well as 4-hour-long oscillations in heart rate. Patients with seizures displayed a higher peak power in the 2-hour accelerometry rhythm (U = 287, P = 0.038) and a period-lengthened 4-hour heart rate rhythm (U = 291.5, P = 0.037). Those that seized also displayed greater mean rhythmic electrodermal activity (U = 261; P = 0.013). Most seizures occurred during the falling-to-trough quarter phase of accelerometric rhythms (13 out of 27, χ2 = 8.41, P = 0.038). Fluctuations in seizure risk or the occurrence of seizures may interrelate with ultradian rhythms of movement and autonomic function. Longitudinal assessments of ultradian patterns in larger patient samples may enable us to understand how such rhythms may improve the temporal precision of seizure forecasting models.
RESUMEN
Importance: Wrist-worn activity monitors provide biomarkers of health by non-obtrusively measuring the timing and amount of rest and physical activity (rest-activity rhythms, RARs). The morphology and robustness of RARs vary by age, gender, and sociodemographic factors, and are perturbed in various chronic illnesses. However, these are cross-sectionally derived associations from recordings lasting 4-10 days, providing little insights into how RARs vary with time. Objective: To describe how RAR parameters can vary or evolve with time (~months). Design Setting and Participants: 48 very long actograms ("VLAs", ≥90 days in duration) were identified from subjects enrolled in the STAGES (Stanford Technology, Analytics and Genomics in Sleep) study, a prospective cross-sectional, multi-site assessment of individuals > 13 years of age that required diagnostic polysomnography to address a sleep complaint. A single 3-year long VLA (author GD) is also described. Exposures/Intervention: None planned. Main Outcomes and Measures: For each VLA, we assessed the following parameters in 14-day windows: circadian/ultradian spectrum, pseudo-F statistic ("F"), cosinor amplitude, intradaily variability, interdaily stability, acrophase and estimates of "sleep" and non-wearing. Results: Included STAGES subjects (n = 48, 30 female) had a median age of 51, BMI of 29.4kg/m2, Epworth Sleepiness Scale score (ESS) of 10/24 and a median recording duration of 120 days. We observed marked within-subject undulations in all six RAR parameters, with many subjects displaying ultradian rhythms of activity that waxed and waned in intensity. When appraised at the group level (nomothetic), averaged RAR parameters remained remarkably stable over a ~4 month recording period. Cohort-level deficits in average RAR robustness associated with unemployment or high BMI (>29.4) also remained stable over time. Conclusions and Relevance: Through an exemplary set of months-long wrist actigraphy recordings, this study quantitatively depicts the longitudinal stability and dynamic range of human rest-activity rhythms. We propose that continuous and long-term actigraphy may have broad potential as a holistic, transdiagnostic and ecologically valid monitoring biomarker of changes in chronobiological health. Prospective recordings from willing subjects will be necessary to precisely define contexts of use.
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Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, â¼6-7 months, and â¼12 months of age, malin-deficient mice ("KO") and wild-type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age-dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home-cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.
Asunto(s)
Conducta Animal , Enfermedad de Lafora , Ratones Noqueados , Ubiquitina-Proteína Ligasas , Animales , Enfermedad de Lafora/genética , Enfermedad de Lafora/patología , Ratones , Conducta Animal/fisiología , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Cuerpos de Inclusión/patología , Cuerpos de Inclusión/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas no Receptoras/deficiencia , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.
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It has been suggested for some time that circadian rhythm abnormalities underlie the development of multiple psychiatric disorders. However, it is unclear how disruptions in individual circadian genes might regulate mood and anxiety. Here we found that mice lacking functional mPeriod 1 (mPer1) or mPeriod 2 (mPer2) individually did not have consistent behavioral abnormalities in measures of anxiety-related behavior. However, mice deficient in both mPer1 and mPer2 had an increase in levels of anxiety-like behavior in multiple measures. Moreover, we found that mPer1 and mPer2 expression was reduced in the nucleus accumbens (NAc) after exposure to chronic social defeat stress, a paradigm that led to increased anxiety-related behavior. Following social defeat, chronic treatment with fluoxetine normalized Per gene expression towards wild-type levels. Knockdown of both mPer1 and mPer2 expression via RNA interference specifically in the NAc led to a similar increase in anxiety-like behavior as seen in the mutant animals. Taken together, these results implicate the Per genes in the NAc in response to stress and the development of anxiety.
Asunto(s)
Ansiedad/genética , Núcleo Accumbens/metabolismo , Proteínas Circadianas Period/metabolismo , Animales , Antidepresivos de Segunda Generación/farmacología , Ansiedad/metabolismo , Reacción de Prevención , Fluoxetina/farmacología , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación , Núcleo Accumbens/fisiología , Proteínas Circadianas Period/genética , ARN Interferente Pequeño , Estrés Psicológico , Transcripción Genética/efectos de los fármacosRESUMEN
Interictal electrocardiographic predictors of sudden unexpected death in epilepsy (SUDEP) are unknown. This study was designed to identify the unique features of the interictal 12-lead electrocardiogram (EKG) in patients with epileptic seizures. We conducted a retrospective chart review of adult patients below the age of 65 admitted to our epilepsy monitoring unit. Using EEG telemetry data, we classified patients as having nonepileptic seizures (NESs), probable epilepsy (PE), or definite epilepsy (DE) and analyzed 12-lead EKGs obtained on admission. Patients with NESs were assigned as the control group. We included patients taking antipsychotic and/or antidepressant medications but excluded patients with medical conditions or taking other medications that would otherwise confound EKG measurements. Out of the 1007 charts reviewed, 195 patients were included in our analysis, and extensive subgroup analyses were performed. We found that patients with definite localization-related epilepsy displayed a significantly longer average PR interval (162.1 ms) than patients with NESs (148.8 ms). This effect was pronounced in female patients and did not vary with the number of antiepileptic drugs (AEDs) prescribed. In contrast to previous studies, mean QTc intervals were not significantly different between DE (428 ms) and NESs (422.6 ms). However, within females, this difference reached statistical significance (DE: 434.6 ms, NESs: 424.6 ms). Antiepileptic drug polytherapy was associated with a significantly lower QTc interval (416 ms in patients on 4-6 drugs and 436.4 ms in patients on 0-1 drugs). Levetiracetam was the most commonly used AED and was associated with the longest average PR (163 ms) and QTc (432 ms) intervals. The mean QRS axis displayed a significant leftward shift in patients with localization-related epilepsy (35.6° versus 54.3° in patients with NESs) and also in female patients with DE (42.1° versus 55.4° in female patients with NESs). No differences were observed between patients with left versus right hemisphere seizure foci. Overall, these findings may reflect cardiac structural changes and/or alterations in autonomic tone that deserve closer study. Further, longer-term prospective studies are required to understand how these electrocardiographic signatures may predict sudden unexpected death in epilepsy.
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Muerte Súbita Cardíaca/etiología , Electrocardiografía/métodos , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Adulto , Anticonvulsivantes/uso terapéutico , Electroencefalografía , Procesamiento Automatizado de Datos , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores Sexuales , Adulto JovenRESUMEN
The long-term response to chronic stress is variable, with some individuals developing maladaptive functioning, although other "resilient" individuals do not. Stress reduces neurogenesis in the dentate gyrus subgranular zone (SGZ), but it is unknown if stress-induced changes in neurogenesis contribute to individual vulnerability. Using a chronic social defeat stress model, we explored whether the susceptibility to stress-induced social avoidance was related to changes in SGZ proliferation and neurogenesis. Immediately after social defeat, stress-exposed mice (irrespective of whether they displayed social avoidance) had fewer proliferating SGZ cells labeled with the S-phase marker BrdU. The decrease was transient, because BrdU cell numbers were normalized 24 h later. The survival of BrdU cells labeled before defeat stress was also not altered. However, 4 weeks later, mice that displayed social avoidance had more surviving dentate gyrus neurons. Thus, dentate gyrus neurogenesis is increased after social defeat stress selectively in mice that display persistent social avoidance. Supporting a functional role for adult-generated dentate gyrus neurons, ablation of neurogenesis via cranial ray irradiation robustly inhibited social avoidance. These data show that the time window after cessation of stress is a critical period for the establishment of persistent cellular and behavioral responses to stress and that a compensatory enhancement in neurogenesis is related to the long-term individual differences in maladaptive responses to stress.
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Reacción de Prevención , Hipocampo/patología , Neurogénesis , Estrés Psicológico/patología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Bromodesoxiuridina/metabolismo , Muerte Celular , Hipocampo/metabolismo , Masculino , Ratones , Fase S , Transducción de SeñalRESUMEN
Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ~6-7 months and ~12 months of age, malin deficient mice ("KO") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.
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The neurobiological underpinnings of mood and anxiety disorders have been linked to the nucleus accumbens (NAc), a region important in processing the rewarding and emotional salience of stimuli. Using chronic social defeat stress, an animal model of mood and anxiety disorders, we investigated whether alterations in synaptic plasticity are responsible for the long-lasting behavioral symptoms induced by this form of stress. We hypothesized that chronic social defeat stress alters synaptic strength or connectivity of medium spiny neurons (MSNs) in the NAc to induce social avoidance. To test this, we analyzed the synaptic profile of MSNs via confocal imaging of Lucifer-yellow-filled cells, ultrastructural analysis of the postsynaptic density, and electrophysiological recordings of miniature EPSCs (mEPSCs) in mice after social defeat. We found that NAc MSNs have more stubby spine structures with smaller postsynaptic densities and an increase in the frequency of mEPSCs after social defeat. In parallel to these structural changes, we observed significant increases in IκB kinase (IKK) in the NAc after social defeat, a molecular pathway that has been shown to regulate neuronal morphology. Indeed, we find using viral-mediated gene transfer of dominant-negative and constitutively active IKK mutants that activation of IKK signaling pathways during social defeat is both necessary and sufficient to induce synaptic alterations and behavioral effects of the stress. These studies establish a causal role for IKK in regulating stress-induced adaptive plasticity and may present a novel target for drug development in the treatment of mood and anxiety disorders in humans.
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Quinasa I-kappa B/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/patología , Núcleo Accumbens/patología , Estrés Psicológico/patología , Análisis de Varianza , Animales , Conducta Animal , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes/genética , Quinasa I-kappa B/genética , Relaciones Interpersonales , Isoquinolinas , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal/métodos , Microscopía Electrónica de Transmisión/métodos , Mutación/genética , Neuronas/fisiología , Neuronas/ultraestructura , Técnicas de Placa-Clamp , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Estadística como Asunto , Estrés Psicológico/fisiopatologíaRESUMEN
Sub-scalp electroencephalography (ssEEG) is emerging as a promising technology in ultra-long-term electroencephalography (EEG) recordings. Given the diversity of devices available in this nascent field, uncertainty persists about its utility in epilepsy evaluation. This review critically dissects the many proposed utilities of ssEEG devices including (1) seizure quantification, (2) seizure characterization, (3) seizure lateralization, (4) seizure localization, (5) seizure alarms, (6) seizure forecasting, (7) biomarker discovery, (8) sleep medicine, and (9) responsive stimulation. The different ssEEG devices in development have individual design philosophies with unique strengths and limitations. There are devices offering primarily unilateral recordings (24/7 EEGTM SubQ, NeuroviewTM, Soenia® UltimateEEG™), bilateral recordings (Minder™, Epios™), and even those with responsive stimulation capability (EASEE®). We synthesize the current knowledge of these ssEEG systems. We review the (1) ssEEG devices, (2) use case scenarios, (3) challenges and (4) suggest a roadmap for ideal ssEEG designs.
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Neurofisiología , Cuero Cabelludo , Electroencefalografía/métodos , Humanos , ConvulsionesRESUMEN
In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction, which limit traditional approaches to behavioral phenotyping. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented bouts of behaviorally defined "sleep", atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2.
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Ataxia Cerebelosa , Personas con Discapacidad , Epilepsia Tipo Ausencia , Trastornos Motores , Animales , Ataxia/genética , Ataxia Cerebelosa/genética , Humanos , Ratones , Convulsiones/genéticaRESUMEN
We analyzed the influence of the transcription factor DeltaFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces DeltaFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit-with the strongest DeltaFosB induction observed in the most resilient animals. Induction of DeltaFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for DeltaFosB, is downregulated upon DeltaFosB induction. Local overexpression of DeltaFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.
Asunto(s)
Reacción de Fuga/fisiología , Desamparo Adquirido , Sustancia Gris Periacueductal/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Psicológico/metabolismo , Adaptación Fisiológica , Adaptación Psicológica/fisiología , Análisis de Varianza , Animales , Regulación de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Núcleo Accumbens/metabolismo , Sustancia Gris Periacueductal/citología , Ratas , Ratas Sprague-Dawley , Sustancia P/metabolismoRESUMEN
Previous work has identified alterations in histone acetylation in animal models of drug addiction and depression. However, the mechanisms which integrate drugs and stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. Chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given stimulus and that disruption of this balance is involved in the transition from an acute adaptive response to a chronic psychiatric illness.