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Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with â¼3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.
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Red Nerviosa/fisiología , Conducta Sexual Animal/fisiología , Animales , Estrógenos/metabolismo , Ciclo Estral/efectos de los fármacos , Femenino , Hormonas Esteroides Gonadales/farmacología , Hipotálamo Anterior/fisiología , Masculino , Ratones Endogámicos C57BL , Red Nerviosa/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ovario/metabolismo , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Receptores de Progesterona/metabolismo , Conducta Sexual Animal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
Sexually naive animals have to distinguish between the sexes because they show species-typical interactions with males and females without meaningful prior experience. However, central neural pathways in naive mammals that recognize sex of other individuals remain poorly characterized. We examined the role of the principal component of the bed nucleus of stria terminalis (BNSTpr), a limbic center, in social interactions in mice. We find that activity of aromatase-expressing BNSTpr (AB) neurons appears to encode sex of other animals and subsequent displays of mating in sexually naive males. Silencing these neurons in males eliminates preference for female pheromones and abrogates mating success, whereas activating them even transiently promotes male-male mating. Surprisingly, female AB neurons do not appear to control sex recognition, mating, or maternal aggression. In summary, AB neurons represent sex of other animals and govern ensuing social behaviors in sexually naive males.
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Sistema Límbico/metabolismo , Núcleos Septales/fisiología , Conducta Sexual Animal/fisiología , Amígdala del Cerebelo/fisiología , Animales , Aromatasa/metabolismo , Encéfalo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Feromonas/metabolismo , Caracteres Sexuales , Conducta SocialRESUMEN
We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (Grin2d) and metabotropic receptor 4 (Grm4) and downregulation of the GABA-A receptor associated protein (Gabarap) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.
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Agua Potable , Ácido Glutámico , Humanos , Femenino , Masculino , Animales , Ratones , Ratones Endogámicos C57BL , Aspartame , Receptores de GABA-A , Ansiedad/inducido químicamente , Ansiedad/genética , Amígdala del Cerebelo , Diazepam , ARN Mensajero , Expresión Génica , Ácido gamma-AminobutíricoRESUMEN
Respiration-rhythmic oscillations in the local field potential emerge in the mPFC, a cortical region with a key role in the regulation of cognitive and emotional behavior. Respiration-driven rhythms coordinate local activity by entraining fast γ oscillations as well as single-unit discharges. To what extent respiration entrainment differently engages the mPFC network in a behavioral state-dependent manner, however, is not known. Here, we compared the respiration entrainment of mouse PFC local field potential and spiking activity (23 male and 2 female mice) across distinct behavioral states: during awake immobility in the home cage (HC), during passive coping in response to inescapable stress under tail suspension (TS), and during reward consumption (Rew). Respiration-driven rhythms emerged during all three states. However, prefrontal γ oscillations were more strongly entrained by respiration during HC than TS or Rew. Moreover, neuronal spikes of putative pyramidal cells and putative interneurons showed significant respiration phase-coupling throughout behaviors with characteristic phase preferences depending on the behavioral state. Finally, while phase-coupling dominated in deep layers in HC and Rew conditions, TS resulted in the recruitment of superficial layer neurons to respiration. These results jointly suggest that respiration dynamically entrains prefrontal neuronal activity depending on the behavioral state.SIGNIFICANCE STATEMENT The mPFC, through its extensive connections (e.g., to the amygdala, the striatum, serotoninergic and dopaminergic nuclei), flexibly regulates cognitive behaviors. Impairment of prefrontal functions can lead to disease states, such as depression, addiction, or anxiety disorders. Deciphering the complex regulation of PFC activity during defined behavioral states is thus an essential challenge. Here, we investigated the role of a prefrontal slow oscillation that has recently attracted rising interest, the respiration rhythm, in modulating prefrontal neurons during distinct behavioral states. We show that prefrontal neuronal activity is differently entrained by the respiration rhythm in a cell type- and behavior-dependent manner. These results provide first insight into the complex modulation of prefrontal activity patterns by rhythmic breathing.
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Corteza Prefrontal , Respiración , Ratones , Masculino , Femenino , Animales , Corteza Prefrontal/fisiología , Amígdala del Cerebelo , Células Piramidales , Neuronas/fisiologíaRESUMEN
BACKGROUND: Virtual reality (VR) and stress balls can be used during phlebotomy in school-age children. OBJECTIVES: This randomized controlled study was conducted to evaluate the effect of distraction methods using VR and stress balls on the emotional behavior, pain, fear, and anxiety associated with phlebotomy in children aged 7-12. METHODS: A parallel trial with a three-arm design approach was adopted for this randomized controlled trial, guided by the CONSORT checklist. The study sample (n = 150) was divided into VR, stress ball, and control group using stratified randomization. The mean scores obtained from the Children's Emotional Manifestation Scale, Wong-Baker FACES Pain Rating Scale, Child Anxiety Scale-State, and Child Fear Scale were compared between the groups. Linear regression analysis and correlation analysis were performed. RESULTS: Significant differences were found in phlebotomy-related pain, fear, and anxiety. While there was no difference in emotional behavior before the phlebotomy, a significant difference was found after the phlebotomy. Being in the virtual reality group explained 30.8 % of the difference between the before and after phlebotomy-related-emotional behavior scores. A strong, positive, and significant relationship was found between emotional behavior scores after phlebotomy and phlebotomy-related fear, pain, and anxiety scores (p < .01). CONCLUSION: Virtual reality and stress ball distraction were found to be effective in reducing pain, fear, and anxiety during phlebotomy. Virtual reality distraction is effective in reducing negative emotional behaviors. APPLICATION TO PRACTICE: The VR distraction can be used in the pediatric population in pain, fear, anxiety, and emotional behavior management during phlebotomy. CLINICALTRIALS: gov Identifier: NCT05818761.
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Screeners are used in early intervention and early childhood education and care programs to identify children's potential need for further evaluation and diagnostics. The Strengths and Difficulties Questionnaire (SDQ) is a brief behavioral screening instrument that can be completed by both parents and educators to assess the social and emotional traits of children. However, multiple informants' reports vary. In this study, the extent to which parents' (n = 241) and educators' (n = 157) differ and agree in their assessments of children aged 3.5 years on average, was examined. T-tests were used to examine differences between informants and correlations within a multitrait-multimethod matrix (MTMM) in their agreement. Results showed moderate to high levels of rater agreement ranging from r = .35 and r = .53 on the five subscales of the SDQ. We found that hyperactivity, peer relationship problems, and prosocial behavior vary due to meaningful reasons, e.g., the home vs. pre-school setting, and the informant's relationship towards the child. Hyperactivity seems to be relatively consistent across settings. Methodological variations might explain differences in emotional symptoms and conduct problems. Considering ratings from multiple informants outlines a more comprehensive view of children's behavior and should be preferred over single-informant research designs.
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BACKGROUND: The "missing" link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. METHODS: Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. RESULTS: Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS-IFI16-STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. CONCLUSIONS: Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.
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Retrovirus Endógenos , Ratones , Masculino , Animales , Microglía/metabolismo , Ratones Endogámicos C57BL , Depresión/tratamiento farmacológico , Transducción de Señal , Inflamación/metabolismo , Estrés Psicológico/psicologíaRESUMEN
OBJECTIVE: This study was undertaken to determine the short-term and longer term impact of sociodemographic disadvantage on the emotional-behavioral status of youths with new onset epilepsy and their unaffected siblings at the time of diagnosis and the subsequent 3 years. METHODS: Three hundred twelve youths with newly diagnosed epilepsies and 223 unaffected siblings, aged 6-16 years, were independently assessed regarding their emotional and behavioral status by their parents and teachers at baseline, and at 18 at 36 months later; youths with seizures also completed self-report measures of depression, anxiety, and hostility at those three time points. A sociodemographic disadvantage score was computed for each family (children with newly diagnosed seizures and their siblings), and families were separated into four categories from most disadvantaged to least disadvantaged. RESULTS: In both children and siblings, the least disadvantaged group exhibited the lowest level of neurobehavioral problems, whereas the most disadvantaged group showed a higher level of neurobehavioral problems across all the same behavior metrics. Findings remained stable and significant across all informants (parent, teacher, child) and across all time periods (throughout the 3-year period). Furthermore, both corrected and uncorrected linear regression analyses indicated that disadvantage was a more constant and stable predictor of behavioral and emotional problems over time compared to clinical seizure characteristics and abnormalities in magnetic resonance imaging and electroencephalographic testing. SIGNIFICANCE: Sociodemographic disadvantage bears a strong relationship to youths with emotional and behavioral problems both at the time of diagnosis as well as prospectively. The relationship is robust and reflected in reports from multiple informants (parent, teacher, child self-report), evident in siblings as well, and possibly more explanatory than traditional clinical seizure variables. Future studies will be needed to determine whether this disadvantage factor is modifiable with early intervention.
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Epilepsia , Hermanos , Adolescente , Humanos , Niño , Convulsiones/diagnóstico , Convulsiones/psicología , Epilepsia/psicología , Padres , EmocionesRESUMEN
Anxiety and pain hypersensitivity are neurobehavioral comorbidities commonly reported by patients with epilepsies, and preclinical models are suitable to investigate the neurobiology of behavioral and neuropathological alterations associated with these epilepsy-related comorbidities. This work aimed to characterize endogenous alterations in nociceptive threshold and anxiety-like behaviors in the Wistar Audiogenic Rat (WAR) model of genetic epilepsy. We also assessed the effects of acute and chronic seizures on anxiety and nociception. WARs from acute and chronic seizure protocols were divided into two groups to assess short- and long-term changes in anxiety (1 day or 15 days after seizures, respectively). To assess anxiety-like behaviors, the laboratory animals were submitted to the open field, light-dark box, and elevated plus maze tests. The von Frey, acetone, and hot plate tests were used to measure the endogenous nociception in seizure-free WARs, and postictal antinociception was recorded at 10, 30, 60, 120, 180 min, and 24 h after seizures. Seizure-free WARs presented increased anxiety-like behaviors and pain hypersensitivity, displaying mechanical and thermal allodynia (to heat and cold stimuli) in comparison to nonepileptic Wistar rats. Potent postictal antinociception that persisted for 120 to 180 min was detected after acute and chronic seizures. Additionally, acute and chronic seizures have magnified the expression of anxiety-like behaviors when assessed at 1 day and 15 days after seizures. Behavioral analysis indicated more severe and persistent anxiogenic-like alterations in WARs submitted to acute seizures. Therefore, WARs presented pain hypersensitivity and increased anxiety-like behaviors endogenously associated with genetic epilepsy. Acute and chronic seizures induced postictal antinociception in response to mechanical and thermal stimuli and increased anxiety-like behaviors when assessed 1 day and 15 days later. These findings support the presence of neurobehavioral alterations in subjects with epilepsy and shed light on the use of genetic models to characterize neuropathological and behavioral alterations associated with epilepsy.
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Epilepsia , Nocicepción , Ratas , Animales , Ratas Wistar , Convulsiones/complicaciones , Convulsiones/genética , Convulsiones/patología , Ansiedad/etiología , Dolor , Modelos Animales de EnfermedadRESUMEN
Infections during pregnancy are associated with an increased risk of neuropsychiatric disorders with developmental etiologies, such as schizophrenia and autism spectrum disorders (ASD). Studies have shown that the animal model of maternal immune activation (MIA) reproduces a wide range of phenotypes relevant to the study of neurodevelopmental disorders. Emerging evidence shows that (R)-ketamine attenuates behavioral, cellular, and molecular changes observed in animal models of neuropsychiatric disorders. Here, we investigate whether (R)-ketamine administration during adolescence attenuates some of the phenotypes related to neurodevelopmental disorders in an animal model of MIA. For MIA, pregnant Swiss mice received intraperitoneally (i.p.) lipopolysaccharide (LPS; 100 µg/kg/day) or saline on gestational days 15 and 16. The two MIA-based groups of male offspring received (R)-ketamine (20 mg/kg/day; i.p.) or saline from postnatal day (PND) 36 to 50. At PND 62, the animals were examined for anxiety-like behavior and locomotor activity in the open-field test (OFT), as well as in the social interaction test (SIT). At PND 63, the prefrontal cortex (PFC) was collected for analysis of oxidative balance and gene expression of the cytokines IL-1ß, IL-6, and TGF-ß1. We show that (R)-ketamine abolishes anxiety-related behavior and social interaction deficits induced by MIA. Additionally, (R)-ketamine attenuated the increase in lipid peroxidation and the cytokines in the PFC of the offspring exposed to MIA. The present work suggests that (R)-ketamine administration may have a long-lasting attenuation in deficits in emotional behavior induced by MIA, and that these effects may be attributed to its antioxidant and anti-inflammatory activity in the PFC.
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Ketamina , Trastornos del Neurodesarrollo , Efectos Tardíos de la Exposición Prenatal , Ratones , Embarazo , Animales , Humanos , Femenino , Masculino , Ketamina/efectos adversos , Conducta Animal , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Modelos Animales de Enfermedad , Citocinas , Trastornos del Neurodesarrollo/metabolismo , FenotipoRESUMEN
Cortisol is a potent human steroid hormone that plays key roles in the central nervous system, influencing processes such as brain neuronal synaptic plasticity and regulating the expression of emotional and behavioral responses. The relevance of cortisol stands out in the disease, as its dysregulation is associated with debilitating conditions such as Alzheimer's Disease, chronic stress, anxiety and depression. Among other brain regions, cortisol importantly influences the function of the hippocampus, a structure central for memory and emotional information processing. The mechanisms fine-tuning the different synaptic responses of the hippocampus to steroid hormone signaling remain, however, poorly understood. Using ex vivo electrophysiology and wild type (WT) and miR-132/miR-212 microRNAs knockout (miRNA-132/212-/-) mice, we examined the effects of corticosterone (the rodent's equivalent to cortisol in humans) on the synaptic properties of the dorsal and ventral hippocampus. In WT mice, corticosterone predominantly inhibited metaplasticity in the dorsal WT hippocampi, whereas it significantly dysregulated both synaptic transmission and metaplasticity at dorsal and ventral regions of miR-132/212-/- hippocampi. Western blotting further revealed significantly augmented levels of endogenous CREB and a significant CREB reduction in response to corticosterone only in miR-132/212-/- hippocampi. Sirt1 levels were also endogenously enhanced in the miR-132/212-/- hippocampi but unaltered by corticosterone, whereas the levels of phospo-MSK1 were only reduced by corticosterone in WT, not in miR-132/212-/- hippocampi. In behavioral studies using the elevated plus maze, miRNA-132/212-/- mice further showed reduced anxiety-like behavior. These observations propose miRNA-132/212 as potential region-selective regulators of the effects of steroid hormones on hippocampal functions, thus likely fine-tuning hippocampus-dependent memory and emotional processing.
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Corticosterona , MicroARNs , Ratones , Humanos , Animales , Corticosterona/farmacología , Corticosterona/metabolismo , Hidrocortisona/metabolismo , Hipocampo/metabolismo , MicroARNs/metabolismo , Plasticidad NeuronalRESUMEN
BACKGROUND: Survivors of invasive group B Streptococcus (iGBS) disease, notably meningitis, are at increased risk of neurodevelopmental impairment. However, the limited studies to date have a median follow-up to 18 months and have mainly focused on moderate or severe neurodevelopmental impairment, with no previous studies on emotional-behavioral problems among iGBS survivors. METHODS: In this multicountry, matched cohort study, we included children aged 18 months to 17 years with infant iGBS sepsis and meningitis from health demographic surveillance systems, or hospital records in Argentina, India, Kenya, Mozambique, and South Africa. Children without an iGBS history were matched to iGBS survivors for sex and age. Our primary outcomes were emotional-behavioral problems and psychopathological conditions as measured with the Child Behavior Checklist (CBCL). The CBCL was completed by the child's primary caregiver. RESULTS: Between October 2019 and April 2021, 573 children (mean age, 7.18 years) were assessed, including 156 iGBS survivors and 417 non-iGBS comparison children. On average, we observed more total problems and more anxiety, attention, and conduct problems for school-aged iGBS survivors compared with the non-iGBS group. No differences were found in the proportion of clinically significant psychopathological conditions defined by the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). CONCLUSIONS: Our findings suggested that school-aged iGBS survivors experienced increased mild emotional behavioral problems that may affect children and families. At-risk neonates including iGBS survivors need long-term follow-up with integrated emotional-behavioral assessments and appropriate care. Scale-up will require simplified assessments that are free and culturally adapted.
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Países en Desarrollo , Streptococcus agalactiae , Niño , Estudios de Cohortes , Humanos , Renta , Lactante , Recién Nacido , SobrevivientesRESUMEN
Performance-based measures of children's executive functions (EFs) do not capture children's application of these skills during everyday emotionally-laden and socially-mediated interactions. The current study demonstrates the value of using assessor report of self-regulation behaviors (inhibitory control and positive affect/engagement) in addition to EF tasks when studying early childhood experiences and development in a rural lower-middle-income country setting. In a sample of 1302 disadvantaged 4-year-olds living in rural Pakistan, we found that directly assessed EFs were significantly related to assessor observations of children's inhibitory control and positive affect/engagement during a structured assessment protocol. However, EFs and two types of self-regulation behaviors demonstrated unique associations with children's (1) contextual experiences, as indexed by family socio-economic resources, participation in parenting interventions, and children's physical growth; and (2) age-salient developmental outcomes, as indexed by direct assessment of pre-academic skills and maternal report of prosocial behaviors and behavior problems. First, family wealth uniquely predicted only observed positive affect/engagement, whereas maternal education uniquely predicted only EFs. Second, children's antecedent linear growth was a significant predictor of both EFs and positive affect/engagement, but exposure to an enhanced nutrition intervention during the first 2 years of life and preschoolers' hair cortisol concentration were associated only with observed self-regulation behaviors. Finally, both EFs and observed positive affect/engagement uniquely predicted children's pre-academic skills. In contrast, only assessors' ratings of positive affect/engagement uniquely predicted maternal report of prosocial behaviors and only assessors' ratings of inhibitory control uniquely predicted maternal report of behavioral problems.
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Función Ejecutiva , Autocontrol , Niño , Preescolar , Humanos , Función Ejecutiva/fisiología , Pakistán , Responsabilidad Parental , Relaciones Padres-HijoRESUMEN
Long-chain (LC) n-3 polyunsaturated fatty acids (PUFAs) have drawn attention in the field of neuropsychiatric disorders, in particular depression. However, whether dietary supplementation with LC n-3 PUFA protects from the development of mood disorders is still a matter of debate. In the present study, we studied the effect of a two-month exposure to isocaloric diets containing n-3 PUFAs in the form of relatively short-chain (SC) (6% of rapeseed oil, enriched in α-linolenic acid (ALA)) or LC (6% of tuna oil, enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) PUFAs on behavior and synaptic plasticity of mice submitted or not to a chronic social defeat stress (CSDS), previously reported to alter emotional and social behavior, as well as synaptic plasticity in the nucleus accumbens (NAc). First, fatty acid content and lipid metabolism gene expression were measured in the NAc of mice fed a SC (control) or LC n-3 (supplemented) PUFA diet. Our results indicate that LC n-3 supplementation significantly increased some n-3 PUFAs, while decreasing some n-6 PUFAs. Then, in another cohort, control and n-3 PUFA-supplemented mice were subjected to CSDS, and social and emotional behaviors were assessed, together with long-term depression plasticity in accumbal medium spiny neurons. Overall, mice fed with n-3 PUFA supplementation displayed an emotional behavior profile and electrophysiological properties of medium spiny neurons which was distinct from the ones displayed by mice fed with the control diet, and this, independently of CSDS. Using the social interaction index to discriminate resilient and susceptible mice in the CSDS groups, n-3 supplementation promoted resiliency. Altogether, our results pinpoint that exposure to a diet rich in LC n-3 PUFA, as compared to a diet rich in SC n-3 PUFA, influences the NAc fatty acid profile. In addition, electrophysiological properties and emotional behavior were altered in LC n-3 PUFA mice, independently of CSDS. Our results bring new insights about the effect of LC n-3 PUFA on emotional behavior and synaptic plasticity.
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Ácidos Grasos Omega-3 , Núcleo Accumbens , Animales , Dieta , Suplementos Dietéticos , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Insaturados/metabolismo , Humanos , Ratones , Núcleo Accumbens/metabolismoRESUMEN
Epilepsy is often associated with emotional disturbances and the endocannabinoid (eCB) system tunes synaptic transmission in brain regions regulating emotional behavior. Thus, persistent alteration of eCB signaling after repeated seizures may contribute to the development of epilepsy-related emotional disorders. Here we report that repeatedly eliciting seizures (kindling) in the amygdala caused a long-term increase in anxiety and impaired fear memory retention, which was paralleled by an imbalance in GABA/glutamate presynaptic activity and alteration of synaptic plasticity in the basolateral amygdala (BLA), in male rats. Anandamide (AEA) content was downregulated after repeated seizures, and pharmacological enhancement of AEA signaling rescued seizure-induced anxiety by restoring the tonic control of the eCB signaling over glutamatergic transmission. Moreover, AEA signaling augmentation also rescued the seizure-induced alterations of fear memory by restoring the phasic control of eCB signaling over GABAergic activity and plasticity in the BLA. These results indicate that modulation of AEA signaling represents a potential and promising target for the treatment of comorbid emotional dysfunction associated with epilepsy.SIGNIFICANCE STATEMENT Epilepsy is a heterogeneous neurologic disorder commonly associated with comorbid emotional alterations. However, the management of epilepsy is usually restricted to the control of seizures. The endocannabinoid (eCB) system, particularly anandamide (AEA) signaling, controls neuronal excitability and seizure expression and regulates emotional behavior. We found that repeated seizures cause an allostatic maladaptation of AEA signaling in the amygdala that drives emotional alterations. Boosting AEA signaling through inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH), restored both synaptic and behavioral alterations. FAAH inhibitors dampen seizure activity in animal models and are used in clinical studies to treat the negative consequences associated with stress. Thereby, they are accessible and can be clinically evaluated to treat both seizures and comorbid conditions associated with epilepsy.
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Síntomas Afectivos/fisiopatología , Amígdala del Cerebelo/fisiopatología , Ácidos Araquidónicos , Endocannabinoides , Epilepsia/fisiopatología , Alcamidas Poliinsaturadas , Transducción de Señal , Sinapsis , Síntomas Afectivos/etiología , Síntomas Afectivos/psicología , Amidohidrolasas/fisiología , Animales , Ansiedad/psicología , Epilepsia/complicaciones , Epilepsia/psicología , Miedo/psicología , Ácido Glutámico/fisiología , Excitación Neurológica , Masculino , Ratas , Ratas Long-Evans , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Brain monoaminergic neurotransmitters, such as dopamine (DA), serotonin (5-HT), and noradrenaline (NA), play crucial roles in neuronal and physiological functions, including social behaviors. Isolation housing may induce behavioral and neurochemical abnormalities in rats, although its influence on neurotransmitter levels remains obscure. This study investigated the influence of isolation- or group-housing on core body temperature (Tcore ), locomotor activity (ACT), emotional behavior, and neurotransmitter levels in male Wistar rats. Behavioral changes were monitored using the open field test (OFT) and social interaction test (SIT). After 4 weeks, brain tissues were collected to quantify 5-HT, DA, and NA concentrations. Body weight and basal Tcore during both the light and dark phase were higher in isolation-housed than in group-housed rats, although no significant difference was seen in ACT. No significant differences were observed during the OFT. Isolation-housed rats showed increased line crossing and decreased social behavior during the SIT. Isolation-housed rats exhibited decreased levels of 5-HT in the caudate putamen and amygdala, and elevated and decreased NA levels in the paraventricular hypothalamic nucleus and hippocampus, respectively. However, DA levels were unaffected. Thus, housing environments may affect brain areas that regulate various neuronal and physiological functions, such as memory, stress responses, and emotional behavior.
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Neurotransmisores , Serotonina , Animales , Dopamina , Masculino , Norepinefrina , Ratas , Ratas WistarRESUMEN
Heat exposure affects several physiological, neuronal, and emotional functions. Notably, monoaminergic neurotransmitters in the brain such as noradrenaline, dopamine, and serotonin, which regulate several basic physiological functions, such as thermoregulation, food intake, and energy balance, are affected by heat exposure and heat acclimation. Furthermore, cognition and emotional states are also affected by heat exposure and changes in brain monoamine levels. Short-term heat exposure has been reported to increase anxiety in some behavioral tests. In contrast, there is a possibility that long-term heat exposure decreases anxiety due to heat acclimation. These changes might be due to adaptation of the core body temperature and/or brain monoamine levels by heat exposure. In this review, we first outline the changes in brain monoamine levels and thereafter focus on changes in emotional behavior due to heat exposure and heat acclimation. Finally, we describe the relationships between emotional behavior and brain monoamine levels during heat acclimation.
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Ansiedad , Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de la radiación , Cognición/efectos de la radiación , Termotolerancia , Animales , Conducta Animal/efectos de la radiación , Encéfalo/metabolismo , Ratones , RatasRESUMEN
Neuropeptide Y (NPY), an abundant peptide in the central nervous system, is expressed in neurons of various regions throughout the brain. The physiological and behavioral effects of NPY are mainly mediated through Y1, Y2, and Y5 receptor subtypes, which are expressed in regions regulating food intake, fear and anxiety, learning and memory, depression, and posttraumatic stress. In particular, the nucleus accumbens (NAc) has one of the highest NPY concentrations in the brain. In this review, we summarize the role of NPY in the NAc. NPY is expressed principally in medium-sized aspiny neurons, and numerous NPY immunoreactive fibers are observed in the NAc. Alterations in NPY expression under certain conditions through intra-NAc injections of NPY or receptor agonists/antagonists revealed NPY to be involved in the characteristic functions of the NAc, such as alcohol intake and drug addiction. In addition, control of mesolimbic dopaminergic release via NPY receptors may take part in these functions. NPY in the NAc also participates in fat intake and emotional behavior. Accumbal NPY neurons and fibers may exert physiological and pathophysiological actions partly through neuroendocrine mechanisms and the autonomic nervous system.
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Neuropéptido Y/metabolismo , Núcleo Accumbens/metabolismo , Animales , Sistema Nervioso Autónomo/metabolismo , Humanos , Neuronas/metabolismo , Receptores de Neuropéptido Y/metabolismoRESUMEN
Maternal breastfeeding has an impact on motor and emotional development in children of the next generation. Elucidating how breastfeeding during infancy affects brain regional structural development in early adolescence will be helpful for promoting healthy development. However, previous studies that have shown relationships between breastfeeding during infancy and cortical brain regions in adolescence are usually based on maternal retrospective recall of breastfeeding, and the accuracy of the data is unclear. In this study, we investigated the association between breastfeeding duration and brain regional volume in a population-neuroimaging study of early adolescents in Japan (N â= â207; 10.5-13.4 years) using voxel-based morphometry, which enabled us to analyze the whole brain. We evaluated breastfeeding duration as indexed by maternal and child health handbook records during infancy. The results showed a significant positive correlation between the duration of breastfeeding and gray matter volume in the dorsal and ventral striatum and the medial orbital gyrus. Post hoc exploratory analyses revealed that the duration of breastfeeding was significantly correlated with emotional behavior. Additionally, the volume in the medial orbital gyrus mediated an association between breastfeeding duration and emotional behavior. This is the first study to evaluate the effect of breastfeeding during infancy on regional brain volumes in early adolescence based on maternal and child health handbook records. Our findings shed light upon the importance of maternal breastfeeding for brain development related to emotional and motivational processing in early adolescence.
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Lactancia Materna , Cuerpo Estriado/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Adolescente , Niño , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos/fisiología , Estudios Retrospectivos , Factores de TiempoRESUMEN
Dual-process models with a default-interventionist architecture explain early emotional action tendencies by a stimulus-driven process, and they allow goal-directed processes to intervene only in a later stage. An alternative dual-process model with a parallel-competitive architecture developed by Moors, Boddez, and De Houwer (Emotion Review, 9(4), 310-318, 2017), in contrast, explains early emotional action tendencies by a goal-directed process. This model proposes that stimulus-driven and goal-directed processes often operate in parallel and compete with each other, and that if they do compete, the goal-directed process often wins the competition. To examine these predictions, we set up a goal-directed process in an experimental group by rewarding participants for avoiding positive stimuli and for approaching negative stimuli and punishing them for the opposite behavior. We expected this process to compete with a potentially preexisting stimulus-driven process in which positive stimuli are associated with approach and negative stimuli with avoidance. We compared the elicited action tendencies of participants in this group with a control group in which only the stimulus-driven process could operate. Early approach and avoidance tendencies were assessed via motor evoked potentials (MEP) measured in the finger muscles previously trained to approach or to avoid stimuli after single-pulse transcranial magnetic stimulation (TMS) delivered at 400 ms. Results confirmed that positive/negative stimuli led to stronger avoidance/approach tendencies in the experimental group but not to approach/avoidance tendencies in the control group. This suggests that goal-directed processes are indeed able to determine relatively early emotional action tendencies, but it does not show that goal-directed process can defeat stimulus-driven processes.