A modification to the Kuramoto model to simulate epileptic seizures as synchronization.

The Kuramoto model was developed to describe the coupling of oscillators, motivated by the natural synchronization phenomena. We are interested in modeling an epileptic seizure considering it as the synchronization of action potentials using and modifying this model. In this article, we propose to modify this model, changing the constant coupling force for a function with logistic growth to simulate the onset and epileptic seizure level in an adult male rat caused by the administration of lithium-pilocarpine. Later, we select some frequencies and their respective amplitude values using an algorithm based on the fast Fourier transform (FFT) from an electroencephalography signal when the rat is in basal conditions. Then, we take these values as the natural frequencies of the oscillators in the modified Kuramoto model, considering every oscillator as a single neuron to simulate the emergence of an epileptic seizure numerically by increasing the synchronization value in the coupling function. Finally, using Dynamic Time Warping algorithm, we compare the simulated signal by the Kuramoto model with an FFT approximation of the epileptic seizure.

Oxidative stress: a common imbalance in diabetes and epilepsy.

The brain requires a large amount of energy. Its function can be altered when energy demand exceeds supply or during metabolic disturbances such as diabetes mellitus. Diabetes, a chronic disease with a high incidence worldwide, is characterized by high glucose levels (hyperglycemia); however, hypoglycemic states may also occur due to insulin treatment or poor control of the disease. These alterations in glucose levels affect the brain and could cause epileptic seizures and status epilepticus. In addition, it is known that oxidative stress states emerge as diabetes progresses, contributing to the development of diseases secondary to diabetes, including retinopathy, nephropathy, cardiovascular alterations, and alterations in the central nervous system, such as epileptic seizures. Seizures are a complex of transient signs and symptoms resulting from abnormal, simultaneous, and excessive activity of a population of neurons, and they can be both a cause and a consequence of oxidative stress. This review aims to outline studies linking diabetes mellitus and seizures to oxidative stress, a condition that may be relevant to the development of severe seizures in diabetes mellitus patients.

Advances and Challenges of Cannabidiol as an Anti-Seizure Strategy: Preclinical Evidence.

The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from Cannabis sativa, cannabidiol (CBD), has emerged over the last few years as a promising molecule with anti-seizure potential. Here, we present an overview of recent literature pointing out CBD's pharmacological profile (solubility, metabolism, drug-drug interactions, etc.,), CBD's interactions with multiple molecular targets as well as advances in preclinical research concerning its anti-seizure effect on both acute seizure models and chronic models of epilepsy. We also highlight the recent attention that has been given to other natural cannabinoids and to synthetic derivatives of CBD as possible compounds with therapeutic anti-seizure potential. All the scientific research reviewed here encourages to continue to investigate the probable therapeutic efficacy of CBD and its related compounds not only in epilepsy but also and specially in drug-resistant epilepsy, since there is a dire need for new and effective drugs to treat this disease.

Enhanced D2 Agonism Induces Conditioned Appetitive Sexual Responses Toward Non-reproductive Conspecifics.

Brain mechanisms of sexual attraction toward reproductive partners develop from a systematic interrelationship between biology (nature) and learning (nurture). However, the causes of attraction toward non-reproductive partners are poorly understood. Here, we explored the role of Pavlovian learning under dopaminergic agonism on the development of sexual preference and brain activation for young male rats. During conditioning, adult sexually naïve males received either Saline (Saline-Paired) or the D2-receptor agonist quinpirole (QNP-Paired) and cohabited in contingency, or out of contingency (QNP-Unpaired) during 24 h with an almond-scented prepubertal juvenile male (PD25). Conditioning occurred every 4 days for three trials. Social and sexual responses were assessed four days after the last conditioning trial in a drug-free test, and males chose freely between a scented young male (PD37) and a novel receptive female. Four days later, males were exposed to the conditioned odor only and brain Fos-IR and serum testosterone were analyzed. Saline-Paired and QNP-Unpaired males displayed more non-contact erections (NCEs) and genital investigations for females, whereas QNP-Paired males expressed more NCEs and genital investigations for young males. In the QNP-Paired group, exposure to the young male-paired odor evoked more Fos-IR in limbic, hypothalamic and cortical areas, but no differences in serum testosterone were observed. Cohabitation with juvenile males during enhanced D2 agonism results in atypical appetitive sexual responses and a higher pattern of brain response for the young male-paired odor, with no changes in serum testosterone. We discuss the potential implications for the development of pedophilic disorder and perhaps other paraphilias.

Brain and plasma amino acid concentration in infant rats prenatally exposed to valproic acid.

Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA, glutamate, glutamine, aspartate, taurine, and glycine in brain tissue and plasma of rats prenatally exposed to valproic acid (VPA), a well-characterized experimental model of autism. Pregnant rats were injected with VPA (600mg/Kg) during the twelfth-embryonic-day. Control rats were injected with saline. On the fourteen-postnatal-day, rats from both groups (males and females) were anesthetized, euthanized by decapitation and their brain dissected out. The frontal cortex, hippocampus, amygdala, brain stem and cerebellum were dissected and homogenized. Homogenates were centrifuged and supernatants were used to quantify amino acid concentrations by HPLC coupled with fluorometric detection. Blood samples were obtained by a cardiac puncture; plasma was separated and deproteinized to quantify amino acid concentration by HPLC. We found that, in VPA rats, glutamate and glutamine concentrations were increased in hippocampus and glycine concentration was increased in cortex. We did not find changes in other regions or in plasma amino acid concentration in the VPA group with respect to control group. Our results suggest that VPA exposure in utero may impair inhibitory and excitatory amino acid transmission in the infant brain.

Status Epilepticus Increases Cell Proliferation and Neurogenesis in the Developing Rat Cerebellum.

Status epilepticus (SE) promotes neuronal proliferation and differentiation in the adult and developing rodent hippocampus. However, the effect of SE on other neurogenic brain regions such as the cerebellum has been less explored. To determine whether SE induced by pentylentetrazole (PTZ-SE) and lithium-pilocarpine (Li-Pilo-SE) increases cell proliferation and neurogenesis in the developing rat cerebellum. SE was induced in 14-day-old (P14) Wistar rat pups (both sexes). One hour after SE and the following day rats were injected intraperitoneally with 5-bromo-2'-deoxyuridine (BrdU, 50 mg/kg). Seven days after SE, immunohistochemistry was performed to detect BrdU-positive (BrdU+) cells or BrdU/NeuN+ cells in the cerebellar vermis. SE induced by PTZ or Li-Pilo statistically significant increased the number of cerebellar BrdU+ cells when compared with the control group (58% and 40%, respectively); maximal cell proliferation occurred in lobules II, III, VIb, VIc, VIII, IXa, and IXb of PTZ-SE group and II, V, VIc, VII, and X of Li-Pilo-SE group. An increased number of BrdU/NeuN+ cells was detected in lobules V (17 ± 1.9), VIc (25.8 ± 2.7), and VII (26.2 ± 3.4) after Li-Pilo-SE compared to their control group (9.8 ± 1.7, 12.8 ± 2.8, and 11 ± 1.7, respectively), while the number of BrdU/NeuN+ cells remained the same after PTZ-induced SE or control conditions. SE induced in the developing rat by different experimental models increases cell proliferation in the granular layer of the cerebellar vermis, but only SE of limbic seizures increases neurogenesis in specific cerebellar lobes.

Long-term effects of status epilepticus during infancy in male rats: Sexual behavior and brain response upon exposure to sexually receptive females.

Previous research in female rats showed that induction of status epilepticus (SE) during infancy impairs proceptive sexual behavior at the long run in adulthood but temporarily, since full proceptivity is recovered after four mating trials. In male rats, such equivalent effects have not been explored yet. Thus, SE was experimentally induced by injecting lithium chloride (3 mEq/kg, i.p.) in thirteen-day-old (P13) male pups and then, on P14, pilocarpine hydrochloride (100 mg/kg, s.c.). Controls received the same volume of saline. For Experiment 1, at P90, we analyzed c-Fos immunoreactivity (c-Fos-IR) as a measure of unconditioned brain activity after exposing them to sexually receptive females, but without physical contact. For Experiment 2, a different group of males was tested for locomotor activity, and their sexual behavior was assessed during five trials. Then, serum testosterone and corticosterone levels were measured. Our results showed that a lower proportion of SE males performed mounts, intromissions, and ejaculations, and repeated training did not improve their behavior. The levels of testosterone in SE males were reduced, but corticosterone, c-Fos-IR, and locomotion were similar to controls. These results suggest that SE during infancy impairs adult sexual behavior by reducing testosterone.

Hippocampal distribution of IL-1ß and IL-1RI following lithium-pilocarpine-induced status epilepticus in the developing rat.

The contribution of Interleukin-1ß (IL-1ß) to neuronal injury induced by status epilepticus (SE) in the immature brain remains unclear. The goal of this study was to determine the hippocampal expression of IL-1ß and its type 1 receptor (IL-1RI) following SE induced by the lithium-pilocarpine model in fourteen-days-old rat pups; control animals were given an equal volume of saline instead of the convulsant. IL-1ß and IL-1RI mRNA hippocampal levels were assessed by qRT-PCR 6 and 24 h after SE or control conditions. IL-1ß and IL-1RI expression was detected in the dorsal hippocampus by immunohistochemical procedures; Fluoro-Jade B staining was carried out in parallel sections in order to detect neuronal cell death. IL-1ß mRNA expression was increased 6 h following SE, but not at 24 h; however IL-1RI mRNA expression was unaffected when comparing with the control group. IL-1ß and IL-1RI immunoreactivity was not detected in control animals. IL-1ß and IL-1RI were expressed in the CA1 pyramidal layer, the dentate gyrus granular layer and the hilus 6 h after SE, whereas injured cells were detected 24 h following seizures. Early expression of IL-1ß and IL-1RI in the hippocampus could be associated with SE-induced neuronal cell death mechanisms in the developing rat.

Serum leptin is associated with metabolic syndrome in obese Mexican subjects.

BACKGROUND: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities including insulin resistance, dyslipidemia, high blood pressure, and abdominal adiposity. Obese patients develop leptin resistance, and an increased waist circumference (WC) due to deposition of abdominal fat. The aim of this study was to evaluate the association between circulating leptin levels and MetS among sample adult Mexican workers. METHOD: A total of 204 workers aged 20-56 were evaluated. Anthropometric index, blood pressure, fasting plasma glucose, and lipid profile were measured by spectrophotometric methods. Fasting insulin and leptin were measured by inmunoenzimatic methods. Furthermore, homeostasis model assessment for insulin resistance (HOMA-IR) was calculated. RESULTS: The prevalence of MetS according to the ATP-III criteria was 33.8% and leptin concentrations were 2.5 times higher in women than men. Subjects with MetS had higher levels of leptin (26.7 ± 13.7) compared with those without MetS (20.1 ± 13.9; P <0.001). Leptin increased significantly while BMI increased as well (normal 14.0 ± 8.9, overweight 22.7 ± 11.7 and obese 31.4 ± 14.6) in addition to other variables such as WC, HDL-C, insulin levels, and HOMA index. Each component of MetS was stratified by sex and submitted by linear regression with a 95% of accuracy. The 50% and 53% of the BMI is explained by the concentration of leptin in men and women, respectively (P < 0.001). CONCLUSION: This study found that leptin was associated with the MetS, especially in obesity and insulin resistance, indicating a high risk for university workers to develop hypertension, DM2, and cardiovascular disease.

[Use of lead-glazed ceramic as a source of exposure in children of marginalized indigenous zones of Oaxaca, Mexico]. / Uso de cerámica vidriada como fuente de exposición a plomo en niños indígenas de zonas marginadas de Oaxaca, México.

OBJECTIVE: To find out whether the use of lead-glazed ceramic (LGC) is associated with blood lead levels in indigenous schoolchildren from Oaxaca, México. MATERIALS AND METHODS: We evaluated LGC use at home as a primary source of lead exposure in 387 indigenous schoolchildren in Oaxaca in May 2001. RESULTS: We found an adjusted difference of 3.9µg/dl (p<0.01) in blood lead levels (BLL) among children reporting to use (82%) LGC at home vs those who didn't. BL levels greater or equal than 10 and 20 µg/dl were observed in 60 and 27% of children, respectively. CONCLUSIONS: Lead poisoning from LGC use could remain a concern for public health in Mexico, where there is a need to provide care and further study to verify its effect on BLL.

Status epilepticus during early development disrupts sexual behavior in adult female rats: recovery with sexual experience.

Female sexual behavior is sensitive to stress and diseases. Some studies have shown that status epilepticus (SE) can affect sexual proceptivity and receptivity in female rats and also increases reject responses towards males. However, epidemiologic studies indicate that SE is more frequent in young individuals. Herein, we assessed the effects of SE in infant females on their sexual behavior during adulthood. Thirteen-day-old (P13) rat pups received intraperitoneal injections of lithium chloride (3 mEq/kg). Twenty hours later, at P14, SE was induced by subcutaneous injection of pilocarpine hydrochloride (100 mg/kg s.c.). Control animals were given an equal volume of saline subcutaneously. The animals were weaned at P21 and, later in adulthood, were ovariectomized and hormone-primed with estradiol+progesterone, and their sexual behavior assessed during 4 separate trials of 30 min each with a stud male. Our results indicate that proceptive behaviors (solicitations and hops and darts) were impaired during the first trial, but no alterations were observed for receptivity and attractivity. By trial 3, all SE females displayed normal proceptivity. These results indicate that SE in infancy readily affects proceptivity in a reversible manner. We discuss the role of sexual experience in recovery.

Effect of lithium-pilocarpine-induced status epilepticus on ultrasonic vocalizations in the infant rat pup.

Evidence shows that febrile convulsions induced in rat pups increase ultrasonic vocalizations (USVs); however, the effect of status epilepticus (SE) induced in developing rats on USVs has not been fully investigated. The goal of this study was to analyze USVs following lithium-pilocarpine-induced SE in fourteen-day-old (P14) rat pups. The rat pups were given 3-mEq/kg lithium chloride i.p. on the day before the induction of SE, which was carried out at P14 by subcutaneous injection of 100-mg/kg pilocarpine hydrochloride; control animals were given an equal volume of lithium chloride and saline on P13 and P14, respectively. Ultrasonic vocalizations were monitored at P15, P16, and P21 with a Mini 3 Bat Detector Ultra Sound Advice (15kHz-160kHz) set at 40±4kHz and digitally recorded in WAV format using the Audacity 1.3 beta software. A clear box (60×40×30cm) split down the middle with a holed wall was used; each pup was placed alone in one compartment, whereas its dam was placed on the other cage side at room temperature. Vocalizations were recorded over a 5-minute period, converted to sonograms and spectrograms, and analyzed using the Raven software. Parameters evaluated were as follows: USV frequency, latency to the first USV, and mean USV duration. There was a significant decrease in the latency (35.5±6.9s) and duration (50.8±8.6s) of USVs after SE compared with the control group (81.9±10.8s and 78.1±9.9s, respectively). Status epilepticus affected male and female rats differentially.

Type 2 diabetes mellitus facilitates status epilepticus in adult rats: Seizure severity, neurodegeneration, and oxidative stress.

OBJECTIVE: The goal of this research was to evaluate the effect of DM type 2 (DM2) on SE severity, neurodegeneration, and brain oxidative stress (OS) secondary to seizures. METHODS: DM2 was induced in postnatal day (P) 3 male rat pups by injecting streptozocin (STZ) 100 mg/kg; control rats were injected with citrate buffer as vehicle. At P90, SE was induced by the lithium-pilocarpine administration and seizure latency, frequency, and severity were evaluated. Neurodegeneration was assessed 24 h after SE by Fluoro-Jade B (F-JB) staining, whereas OS was estimated by measuring lipid peroxidation and reactive oxygen species (ROS). RESULTS: DM2 rats showed an increase in latency to the first generalized seizure and SE onset, had a higher number and a longer duration of seizures, and displayed a larger neurodegeneration in the hippocampus (CA3, CA1, dentate gyrus, and hilus), the piriform cortex, the dorsomedial nucleus of the thalamus and the cortical amygdala. Our results also show that only SE, neither DM2 nor the combination of DM2 with SE, caused the increase in ROS and brain lipid peroxidation. SIGNIFICANCE: DM2 causes higher seizure severity and neurodegeneration but did not exacerbate SE-induced OS under these conditions. PLAIN LANGUAGE SUMMARY: Our research performed in animal models suggests that type 2 diabetes mellitus (DM2) may be a risk factor for causing higher seizure severity and seizure-induced neuron cell death. However, even when long-term seizures promote an imbalance between brain pro-oxidants and antioxidants, DM2 does not exacerbate that disproportion.

Microglia and status epilepticus in the immature brain.

Microglia are the resident immune cells of the Central Nervous System (CNS), which are activated due to brain damage, as part of the neuroinflammatory response. Microglia undergo morphological and biochemical modifications during activation, adopting a pro-inflammatory or an antiinflammatory state. In the developing brain, status epilepticus (SE) promotes microglia activation that is associated with neuronal injury in some areas of the brain, such as the hippocampus, thalamus, and amygdala. However, the timing of this activation, the anatomical pattern, and the morphological and biochemical characteristics of microglia in the immature brain are age-dependent and have not been fully characterized. Therefore, this review focuses on the response of microglia to SE and its relationship to neurodegeneration.

Preterm rat survival is enhanced by gestational environmental enrichment.

Throughout the last decade, the estimated global human preterm birth rate was 10.6 %, with higher rates in Asia, South America, and Africa. Preterm individuals, even in adulthood, are more likely to develop cardiorespiratory, renal, and metabolic disorders. On the other hand, when experimental animals are housed in an enriched environment during gestation, the development of the progeny in utero is accelerated, compared to standard housing conditions. By terminating gestation one and a half days before parturition, we investigated whether environmental enrichment restricted to gestation may have an impact on progeny survival. Our results demonstrate that the gestational enriched environment tripled the rat´s offspring survival, which was associated with decreased expression of anxiety-like behaviors in the pregnant mother. Sex of the offspring was not a factor in determining survival. We discuss the effect of increased secretion of various trophic factors and hormones induced by the enriched environment on progeny survival.

Transgenic rodents as dynamic models for the study of respiratory rhythm generation and modulation: a scoping review and a bibliometric analysis.

The pre-Bötzinger complex, situated in the ventrolateral medulla, serves as the central generator for the inspiratory phase of the respiratory rhythm. Evidence strongly supports its pivotal role in generating, and, in conjunction with the post-inspiratory complex and the lateral parafacial nucleus, in shaping the respiratory rhythm. While there remains an ongoing debate concerning the mechanisms underlying these nuclei's ability to generate and modulate breathing, transgenic rodent models have significantly contributed to our understanding of these processes. However, there is a significant knowledge gap regarding the spectrum of transgenic rodent lines developed for studying respiratory rhythm, and the methodologies employed in these models. In this study, we conducted a scoping review to identify commonly used transgenic rodent lines and techniques for studying respiratory rhythm generation and modulation. Following PRISMA guidelines, we identified relevant papers in PubMed and EBSCO on 29 March 2023, and transgenic lines in Mouse Genome Informatics and the International Mouse Phenotyping Consortium. With strict inclusion and exclusion criteria, we identified 80 publications spanning 1997-2022 using 107 rodent lines. Our findings revealed 30 lines focusing on rhythm generation, 61 on modulation, and 16 on both. The primary in vivo method was whole-body plethysmography. The main in vitro method was hypoglossal/phrenic nerve recordings using the en bloc preparation. Additionally, we identified 119 transgenic lines with the potential for investigating the intricate mechanisms underlying respiratory rhythm. Through this review, we provide insights needed to design more effective experiments with transgenic animals to unravel the mechanisms governing respiratory rhythm. The identified transgenic rodent lines and methodological approaches compile current knowledge and guide future research towards filling knowledge gaps in respiratory rhythm generation and modulation.

Genetic analysis and QTL mapping of domestication-related traits in chili pepper (Capsicum annuum L.).

Chili pepper (Capsicum annuum L.) is one of the oldest and most phenotypically diverse pre-Columbian crops of the Americas. Despite the abundance of genetic resources, the use of wild germplasm and landraces in chili pepper breeding is limited. A better understanding of the evolutionary history in chili peppers, particularly in the context of traits of agronomic interest, can contribute to future improvement and conservation of genetic resources. In this study, an F2:3 mapping population derived from a cross between a C. annuum wild accession (Chiltepin) and a cultivated variety (Puya) was used to identify genomic regions associated with 19 domestication and agronomic traits. A genetic map was constructed consisting of 1023 single nucleotide polymorphism (SNP) markers clustered into 12 linkage groups and spanning a total of 1,263.87 cM. A reciprocal translocation that differentiates the domesticated genome from its wild ancestor and other related species was identified between chromosomes 1 and 8. Quantitative trait locus (QTL) analysis detected 20 marker-trait associations for 13 phenotypes, from which 14 corresponded to previously identified loci, and six were novel genomic regions related to previously unexplored domestication-syndrome traits, including form of unripe fruit, seedlessness, deciduous fruit, and growth habit. Our results revealed that the genetic architecture of Capsicum domestication is similar to other domesticated species with few loci with large effects, the presence of QTLs clusters in different genomic regions, and the predominance of domesticated recessive alleles. Our analysis indicates the domestication process in chili pepper has also had an effect on traits not directly related to the domestication syndrome. The information obtained in this study provides a more complete understanding of the genetic basis of Capsicum domestication that can potentially guide strategies for the exploitation of wild alleles.

Anxiolytic effect of chronic intake of supplemental magnesium chloride in rat.

Evidence suggest that magnesium dietary supplementation has several health benefits including lowering blood pressure, reducing insulin resistance, and improving symptoms of depression, anxiety, and migraine. Here, we aimed to study the effect of chronic magnesium supplementation on anxiety-like behavior in rats by supplementing with magnesium their drinking water for 30 days. Anxiety-like behavior was induced by subcutaneous injection of veratrin 30 min before performing elevated plus maze and open field tests to measure anxiety levels and locomotion, respectively. We quantify the concentration of magnesium in plasma and cerebrospinal fluid. We used diazepam to compare the efficacy of magnesium supplementation as an anxiolytic agent. Our results show that rats supplemented with magnesium had a statistically significant decrease in anxiety levels with not effects on locomotion and a statistically significant increase in concentration of magnesium in plasma and cerebrospinal fluid. However, the anxiolytic effect of magnesium supplementation washes-out in 12 days. We discuss the advantages of using supplemental magnesium as anxiolytic.

Analixity: An open source, low-cost analysis system for the elevated plus maze test, based on computer vision techniques.

Manual analysis of behavioral tests in rodents involves inspection of video recordings by a researcher that assesses rodent movements to quantify parameters related with a behavior of interest. The assessment of the researcher during the quantification of such parameters can introduce variability among experimental conditions or among sessions of analysis. Here, we introduce Analixity, a video processing software for the elevated plus maze test (EPM), in which quantification of behavioral parameters is automatic, reducing the time spent in analysis and solving the variability problem. Analixity is an adaptable multiplatform open-source system. Analixity generates an Excel file with the quantified behavioral variables, such as time spent in open and closed arms and in the center zone, number of entries to each zone and total distance traveled during the test. For validation, we compared results obtained by Analixity with results obtained by manual analysis. We did not find statistically significant differences. In addition, we compared the results obtained by Analixity with results obtained by the commercial software ANY-maze. We did not find statistically significant differences in the quantification of parameters such as time spent in open arms, time spent in closed arms, time spent in center zone, number of closed arms, open arms entries, and anxiety index. We concluded that Analixity is an open-source software as reliable and effective as a commercial software.

Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage.

The mechanism of status epilepticus-induced neuronal death in the immature brain is not fully understood. In the present study, we examined the contribution of caspases in our lithium-pilocarpine model of status epilepticus in 14 days old rat pups. In CA1, upregulation of caspase-8, but not caspase-9, preceded caspase-3 activation in morphologically necrotic cells. Pretreatment with a pan-caspase inhibitor provided neuroprotection, showing that caspase activation was not an epiphenomenon but contributed to neuronal necrosis. By contrast, upregulation of active caspase-9 and caspase-3, but not caspase-8, was detected in apoptotic dentate gyrus neurons, which were immunoreactive for doublecortin and calbindin-negative, two features of immature neurons. These results suggest that, in cells which are aligned in series as parts of the same excitatory hippocampal circuit, the same seizures induce neuronal death through different mechanisms. The regional level of neuronal maturity may be a determining factor in the execution of a specific death program.