Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 136
Filtrar
1.
Front Neuroendocrinol ; 75: 101156, 2024 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-39353534

RESUMEN

Parkinson's disease (PD) is characterized by motor symptoms due to loss of brain dopamine and non-motor symptoms, including gastrointestinal disorders. Although there is no cure for PD, symptomatic treatments are available. L-Dopa is the gold standard PD therapy, but most patients develop dyskinesias (LID), which are challenging to manage. Amantadine is recognized as the most effective drug for LID, but its adverse effects limit the use in patients. Here we review how 5α-reductase inhibitors (5ARIs), drugs used to treat benign prostatic hyperplasia and alopecia, exhibit beneficial effects in PD animal models. 5ARIs show neuroprotective properties in brain and gut dopaminergic systems, and reduce dyskinesias in rodent model of PD. Additionally, the 5ARI finasteride dampened dopaminergic-induced drug gambling in PD patients. Neuroprotection and antidyskinetic activities of 5ARIs in animal models of PD suggest their potential repurposing in men with PD to address gut dysfunction, protect brain DA and inhibit dyskinesias.

2.
Artículo en Inglés | MEDLINE | ID: mdl-38828012

RESUMEN

Recent shifts in societal attitudes towards cannabis have led to a dramatic increase in consumption rates in many Western countries, particularly among young people. This trend has shed light on a significant link between cannabis use disorder (CUD) and pathological reactive aggression, a condition involving disproportionate aggressive and violent reactions to minor provocations. The discourse on the connection between cannabis use and aggression is frequently enmeshed in political and legal discussions, leading to a polarized understanding of the causative relationship between cannabis use and aggression. However, integrative analyses from both human and animal research indicate a complex, bidirectional interplay between cannabis misuse and pathological aggression. On the one hand, emerging research reveals a shared genetic and environmental predisposition for both cannabis use and aggression, suggesting a common underlying biological mechanism. On the other hand, there is evidence that cannabis consumption can lead to violent behaviors while also being used as a self-medication strategy to mitigate the negative emotions associated with pathological reactive aggression. This suggests that the coexistence of pathological aggression and CUD may result from overlapping vulnerabilities, potentially creating a self-perpetuating cycle where each condition exacerbates the other, escalating into externalizing and violent behaviors. This article aims to synthesize existing research on the intricate connections between these issues and propose a theoretical model to explain the neurobiological mechanisms underpinning this complex relationship.

3.
Br J Pharmacol ; 181(17): 3064-3081, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38689378

RESUMEN

BACKGROUND AND PURPOSE: Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS. EXPERIMENTAL APPROACH: Studies were conducted using CIN-d and D1CT-7 mice, two TS models characterized by early-life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos. KEY RESULTS: Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals. CONCLUSION AND IMPLICATIONS: Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.


Asunto(s)
Cuerpo Estriado , Modelos Animales de Enfermedad , Agonistas Muscarínicos , Receptor Muscarínico M4 , Síndrome de Tourette , Animales , Síndrome de Tourette/metabolismo , Síndrome de Tourette/tratamiento farmacológico , Receptor Muscarínico M4/metabolismo , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/antagonistas & inhibidores , Ratones , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Masculino , Agonistas Muscarínicos/farmacología , Conducta Animal/efectos de los fármacos , Piridinas/farmacología , Tics/tratamiento farmacológico , Tics/metabolismo , Tiofenos/farmacología , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M1/agonistas , Dioxoles/farmacología , Ratones Endogámicos C57BL , Tiadiazoles
4.
Nat Commun ; 15(1): 2769, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38553486

RESUMEN

Multiple neurological disorders are associated with gastrointestinal (GI) symptoms, including autism spectrum disorder (ASD). However, it is unclear whether GI distress itself can modify aspects of behavior. Here, we show that mice that experience repeated colitis have impaired active social engagement, as measured by interactions with a foreign mouse, even though signs of colitis were no longer present. We then tested the hypothesis that individuals with ASD harbor a microbiota that might differentially influence GI health by performing microbiota transplantation studies into male germfree animals, followed by induction of colitis. Animals that harbor a microbiota from ASD individuals have worsened gut phenotypes when compared to animals colonized with microbiotas from familial neurotypical (NT) controls. We identify the enrichment of Blautia species in all familial NT controls and observe an association between elevated abundance of Bacteroides uniformis and reductions in intestinal injury. Oral treatment with either of these microbes reduces colon injury in mice. Finally, provision of a Blautia isolate from a NT control ameliorates gut injury-associated active social engagement in mice. Collectively, our data demonstrate that past intestinal distress is associated with changes in active social behavior in mice that can be ameliorated by supplementation of members of the human microbiota.


Asunto(s)
Trastorno del Espectro Autista , Colitis , Enfermedades Gastrointestinales , Microbiota , Humanos , Masculino , Ratones , Animales , Trastorno del Espectro Autista/terapia , Participación Social , Colitis/terapia , Suplementos Dietéticos
5.
Neurosci Biobehav Rev ; 160: 105637, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38519023

RESUMEN

Tics are sudden, repetitive movements or vocalizations. Tic disorders, such as Tourette syndrome (TS), are contributed by the interplay of genetic risk factors and environmental variables, leading to abnormalities in the functioning of the cortico-striatal-thalamo-cortical (CSTC) circuitry. Various neurotransmitter systems, such as gamma-aminobutyric acid (GABA) and dopamine, are implicated in the pathophysiology of these disorders. Building on the evidence that tic disorders are predominant in males and exacerbated by stress, emerging research is focusing on the involvement of neuroactive steroids, including dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone, in the ontogeny of tics and other phenotypes associated with TS. Emerging evidence indicates that DHEAS levels are significantly elevated in the plasma of TS-affected boys, and the clinical onset of this disorder coincides with the period of adrenarche, the developmental stage characterized by a surge in DHEAS synthesis. On the other hand, allopregnanolone has garnered particular attention for its potential to mediate the adverse effects of acute stress on the exacerbation of tic severity and frequency. Notably, both neurosteroids act as key modulators of GABA-A receptors, suggesting a pivotal role of these targets in the pathophysiology of various clinical manifestations of tic disorders. This review explores the potential mechanisms by which these and other neuroactive steroids may influence tic disorders and discusses the emerging therapeutic strategies that target neuroactive steroids for the management of tic disorders.


Asunto(s)
Neuroesteroides , Trastornos de Tic , Tics , Síndrome de Tourette , Masculino , Humanos , Pregnanolona/farmacología
6.
Neuropsychopharmacology ; 49(9): 1373-1382, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38396257

RESUMEN

Persistence is the propensity to maintain goal-directed actions despite adversities. While this temperamental trait is crucial to mitigate depression risk, its neurobiological foundations remain elusive. Developing behavioral tasks to capture persistence in animal models is crucial for understanding its molecular underpinnings. Here, we introduce the Sinking Platform Test (SPT), a novel high-throughput paradigm to measure persistence. Mice were trained to exit a water-filled tank by ascending onto a platform above water level. Throughout the training, mice were also occasionally exposed to "failure trials," during which an operator would submerge a platform right after the mouse climbed onto it, requiring the mouse to reach and ascend a newly introduced platform. Following training, mice were subjected to a 5-min test exclusively consisting of failure trials. Male and female mice exhibited comparable persistence, measured by the number of climbed platforms during the test. Furthermore, this index was increased by chronic administration of fluoxetine or imipramine; conversely, it was reduced by acute and chronic haloperidol. Notably, six weeks of social isolation reduced SPT performance, and this effect was rescued by imipramine treatment over the last two weeks. A 4-week regimen of voluntary wheel running also improved persistence in socially isolated mice. Finally, comparing transcriptomic profiles of the prefrontal cortex of mice with high and low SPT performance revealed significant enrichment of immediate-early genes known to shape susceptibility for chronic stress. These findings highlight the potential of SPT as a promising method to uncover the biological mechanisms of persistence and evaluate novel interventions to enhance this response.


Asunto(s)
Fluoxetina , Haloperidol , Ratones Endogámicos C57BL , Aislamiento Social , Animales , Masculino , Ratones , Femenino , Fluoxetina/farmacología , Haloperidol/farmacología , Aislamiento Social/psicología , Imipramina/farmacología , Modelos Animales de Enfermedad , Conducta Animal/fisiología , Conducta Animal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología
7.
J Neurosci Methods ; 403: 110026, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38029972

RESUMEN

BACKGROUND: Self-grooming behavior in rodents serves as a valuable behavioral index for investigating stereotyped and perseverative responses. Most current grooming analyses rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. NEW METHOD: Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are input into a naïve Bayes classifier, trained with manual video observations. The effectiveness of this method was tested using CIN-d mice, an animal model developed through early-life depletion of striatal cholinergic interneurons (CIN-d) and featuring prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. RESULTS: The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations than controls. However, this elevation was not correlated with increases in grooming force. Notably, the dopaminergic antagonist haloperidol reduced grooming force and duration. COMPARISON WITH EXISTING METHODS: In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. CONCLUSIONS: Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of neuropsychiatric disorders.


Asunto(s)
Conducta Animal , Movimiento , Ratones , Masculino , Animales , Conducta Animal/fisiología , Aseo Animal/fisiología , Teorema de Bayes , Haloperidol/farmacología , Roedores
8.
bioRxiv ; 2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37503098

RESUMEN

Background: Self-grooming behavior in rodents serves as a valuable model for investigating stereotyped and perseverative responses. Most current grooming analyses primarily rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. New Method: Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are then input into a naïve Bayes classifier, trained with manual video observations. To validate the effectiveness of this method, we applied it to the behavioral analysis of the early-life striatal cholinergic interneuron depletion (CIN-d) mouse, a model of tic pathophysiology recently developed in our laboratory, which exhibits prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. Results: The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations compared to controls. However, this elevation was not correlated with increases in grooming force. Notably, haloperidol, a benchmark therapy for tic disorders, reduced both grooming force and duration. Comparison with Existing Methods: In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. Conclusions: Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of tic disorders and other psychiatric conditions.

9.
10.
CNS Neurosci Ther ; 29(11): 3173-3182, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37269073

RESUMEN

AIMS: Antisocial personality disorder (ASPD) and conduct disorder (CD) are characterized by a persistent pattern of violations of societal norms and others' rights. Ample evidence shows that the pathophysiology of these disorders is contributed by orbitofrontal cortex (OFC) alterations, yet the underlying molecular mechanisms remain elusive. To address this knowledge gap, we performed the first-ever RNA sequencing study of postmortem OFC samples from subjects with a lifetime diagnosis of ASPD and/or CD. METHODS: The transcriptomic profiles of OFC samples from subjects with ASPD and/or CD were compared to those of unaffected age-matched controls (n = 9/group). RESULTS: The OFC of ASPD/CD-affected subjects displayed significant differences in the expression of 328 genes. Further gene-ontology analyses revealed an extensive downregulation of excitatory neuron transcripts and upregulation of astrocyte transcripts. These alterations were paralleled by significant modifications in synaptic regulation and glutamatergic neurotransmission pathways. CONCLUSION: These preliminary findings suggest that ASPD and CD feature a complex array of functional deficits in the pyramidal neurons and astrocytes of the OFC. In turn, these aberrances may contribute to the reduced OFC connectivity observed in antisocial subjects. Future analyses on larger cohorts are needed to validate these results.


Asunto(s)
Trastorno de la Conducta , Transcriptoma , Humanos , Trastorno de Personalidad Antisocial/genética , Trastorno de Personalidad Antisocial/diagnóstico , Corteza Prefrontal
11.
Psychopharmacology (Berl) ; 240(6): 1359-1372, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37129616

RESUMEN

RATIONALE: The prepulse inhibition (PPI) of the startle reflex is the best-established index of sensorimotor gating. We documented that the neurosteroid allopregnanolone (AP) is necessary to reduce PPI in response to D1 dopamine receptor agonists. Since Sprague-Dawley (SD) rats are poorly sensitive to the PPI-disrupting effects of these drugs, we hypothesized that AP might increase this susceptibility. OBJECTIVES: We tested whether AP is sufficient to increase the vulnerability of SD rats to PPI deficits in response to the D1 receptor full agonist SKF82958. METHODS: SD rats were tested for PPI after treatment with SKF82958 (0.05-0.3 mg/kg, SC) in combination with either intraperitoneal (1-10 mg/kg) or intracerebral (0.5 µg/µl/side) AP administration into the medial prefrontal cortex (mPFC) or nucleus accumbens shell. To rule out potential confounds, we measured whether SKF82958 affected the endogenous mPFC levels of AP. RESULTS: SD rats exhibited marked PPI deficits in response to the combination of systemic and intra-mPFC AP with SKF82958 but not with the D2 receptor agonist quinpirole (0.3-0.6 mg/kg, SC). SKF82958 did not elevate mPFC levels of AP but enhanced the content of its precursor progesterone. The PPI deficits caused by SKF82958 in combination with AP were opposed by the AP antagonist isoallopregnanolone (10 mg/kg, IP) and the glutamate NMDA receptor positive modulator CIQ (5 mg/kg, IP). CONCLUSION: These results suggest that AP enables the detrimental effects of D1 receptor activation on sensorimotor gating. AP antagonism or glutamatergic modulation counters these effects and may have therapeutic potential for neuropsychiatric disorders characterized by gating deficits.


Asunto(s)
Pregnanolona , Receptores de Dopamina D1 , Ratas , Animales , Masculino , Ratas Sprague-Dawley , Pregnanolona/farmacología , Benzazepinas/farmacología , Reflejo de Sobresalto , Filtrado Sensorial , Estimulación Acústica/métodos
12.
Neuropsychopharmacology ; 48(9): 1288-1299, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37198434

RESUMEN

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortem studies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, partially CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement - a mild acute stressor that increases AP levels in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in partially CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS-related manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.


Asunto(s)
Tics , Síndrome de Tourette , Femenino , Masculino , Ratones , Animales , Pregnanolona/farmacología , Modelos Animales de Enfermedad , Conducta Estereotipada
13.
Neuropharmacology ; 233: 109548, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37080337

RESUMEN

Vulnerability to cocaine use disorder depends upon a combination of genetic and environmental risk factors. While early life adversity is a critical environmental vulnerability factor for drug misuse, allelic variants of the monoamine oxidase A (MAOA) gene have been shown to moderate its influence on the risk of drug-related problems. However, data on the interactions between MAOA variants and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model capturing the interaction of genetic (low-activity alleles of the Maoa gene; MAOANeo) and environmental (i.e., ES) vulnerability factors displays an increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from male MAOANeo ES mice repeatedly treated with cocaine. The activation of either dopamine D2 or CB1 receptors contributes to cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene-environment interaction in VTA dopamine neurons of male pre-adolescent mice and contributes to our understanding of neural mechanisms of vulnerability for early onset cocaine use.


Asunto(s)
Trastornos Relacionados con Cocaína , Cocaína , Estrés Fisiológico , Animales , Masculino , Ratones , Fármacos del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Trastornos Relacionados con Cocaína/metabolismo , Neuronas Dopaminérgicas , Endocannabinoides/metabolismo , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Área Tegmental Ventral
14.
Eur Arch Psychiatry Clin Neurosci ; 273(2): 411-425, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36094569

RESUMEN

Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9). We focused on this brain region, given its well-recognized role in social response and ASB pathophysiology. Given that all individuals also had a substance use disorder (SUD) diagnosis, two age-matched control groups were used: SUD only and unaffected controls. Tissues were processed for immunoblotting analyses on eight key serotonergic targets: tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of brain serotonin synthesis; serotonin transporter (SERT), the primary carrier for serotonin uptake; monoamine oxidase A (MAOA), the primary enzyme for serotonin catabolism; and five serotonin receptors previously shown to influence social behavior: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4. Our analyses documented a significant increase in 5-HT2A receptor levels in the ASB + SUD group compared to SUD-only controls. Furthermore, TPH2 levels were significantly reduced in the SUD group (including SUD only and ASB + SUD) compared to unaffected controls. No difference was detected in the expression of any other serotonergic target. These results are in keeping with previous evidence showing high 5-HT2A receptor binding in the OFC of pathologically aggressive individuals and point to this molecule as a potential target for ASB treatment.


Asunto(s)
Trastorno de Personalidad Antisocial , Corteza Prefrontal , Receptor de Serotonina 5-HT2A , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Trastorno de Personalidad Antisocial/complicaciones , Trastorno de Personalidad Antisocial/enzimología , Trastorno de Personalidad Antisocial/metabolismo , Autopsia , Monoaminooxidasa/metabolismo , Corteza Prefrontal/enzimología , Corteza Prefrontal/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/enzimología , Trastornos Relacionados con Sustancias/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Agresión , Estudios de Casos y Controles
15.
Neurobiol Stress ; 21: 100489, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36532377

RESUMEN

Ample evidence indicates that environmental stress impairs information processing, yet the underlying mechanisms remain partially elusive. We showed that, in several rodent models of psychopathology, the neurosteroid allopregnanolone (AP) reduces the prepulse inhibition (PPI) of the startle, a well-validated index of sensorimotor gating. Since this GABAA receptor activator is synthesized in response to acute stress, we hypothesized its participation in stress-induced PPI deficits. Systemic AP administration reduced PPI in C57BL/6J mice and Long-Evans, but not Sprague-Dawley rats. These effects were reversed by isoallopregnanolone (isoAP), an endogenous AP antagonist, and the GABAA receptor antagonist bicuculline and mimicked by AP infusions in the medial prefrontal cortex (mPFC). Building on these findings, we tested AP's implication in the PPI deficits produced by several complementary regimens of acute and short-term stress (footshock, restraint, predator exposure, and sleep deprivation). PPI was reduced by acute footshock, sleep deprivation as well as the combination of restraint and predator exposure in a time- and intensity-dependent fashion. Acute stress increased AP concentrations in the mPFC, and its detrimental effects on PPI were countered by systemic and intra-mPFC administration of isoAP. These results collectively indicate that acute stress impairs PPI by increasing AP content in the mPFC. The confirmation of these mechanisms across distinct animal models and several acute stressors strongly supports the translational value of these findings and warrants future research on the role of AP in information processing.

16.
Sci Adv ; 8(47): eabm7069, 2022 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-36417527

RESUMEN

Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused defects in social interaction and communication, which are behaviors that relate to core symptoms of autism. Mutation of Top2a in zebrafish caused down-regulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets have binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation (H3K27me3). Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of the PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.

17.
J Psychiatr Res ; 155: 252-259, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36113395

RESUMEN

Childhood adversity is associated with the development or expression of many neuropsychiatric disorders, including those with strong genetic underpinnings. Despite reported associations between perceived stress and tic severity, the relationship between potentially traumatic events in childhood and Tourette Syndrome (TS), a highly heritable neuropsychiatric disorder, is unknown. This study aimed to assess whether exposure to eight categories of adverse childhood experiences (ACEs) is associated with TS severity and impairment, and whether TS genetic risk modifies this association. Online survey data were collected from 351 adult males with TS who previously participated in genetic studies. Participants completed the ACE questionnaire and a lifetime version of the Yale Global Tic Severity Scale (YGTSS). Demographic and relevant health data were assessed; polygenic risk scores (PRS) measuring aggregated TS genetic risk were derived using genome-wide association data. Univariable and multivariable linear regressions examined the relationships between childhood adversity and retrospectively recalled worst-ever tic severity and impairment, adjusting for covariates. Potential gene-by-environment (GxE) interactions between ACE and PRS were estimated. After covariate adjustment, there was a significant graded dose-response relationship between ACE Scores and increases in lifetime worst-ever tic severity and impairment. There was some evidence that TS genetic risk moderated the relationship between ACE Score and tic impairment, but not tic severity, particularly for individuals with higher TS polygenic risk. We provide evidence that childhood adversity is associated with higher lifetime TS severity and impairment, although future longitudinal studies with genetically-sensitive designs are needed to determine whether these relationships are causal and/or directional.


Asunto(s)
Experiencias Adversas de la Infancia , Tics , Síndrome de Tourette , Adulto , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Síndrome de Tourette/diagnóstico
19.
Child Abuse Negl ; 128: 105591, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35306342

RESUMEN

BACKGROUND: Child maltreatment has emerged as an important risk factor for substance use. However, despite evidence consistently demonstrating that substance use peaks during emerging adulthood, less is known about the specificity of maltreatment effects on substance use during this critical developmental period. Further, the factors that might play a role in these associations are not well understood. OBJECTIVE: The current study examined the associations between child maltreatment types (i.e., physical abuse, physical neglect, sexual abuse, emotional abuse, and emotional neglect) and past month marijuana, alcohol, and tobacco use among emerging adults, and tested whether impulsivity accounted for these associations. METHODS: Participants were 500 emerging adults ranging in age between 18 and 25 years old (M = 18.96, SD = 1.22, 49.6% male) recruited from a large, public university in the Midwest United States. RESULTS: Tests of indirect effects suggested that impulsivity accounted for associations between emotional abuse and past month marijuana, alcohol, and tobacco use. CONCLUSIONS: Current findings provide support for impulsivity as a mechanism linking childhood emotional abuse to substance use among emerging adults, highlighting the need for targeted screening and intervention.


Asunto(s)
Adultos Sobrevivientes del Maltrato a los Niños , Maltrato a los Niños , Trastornos Relacionados con Sustancias , Adolescente , Adulto , Adultos Sobrevivientes del Maltrato a los Niños/psicología , Niño , Maltrato a los Niños/psicología , Femenino , Humanos , Conducta Impulsiva , Masculino , Abuso Físico , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/psicología , Adulto Joven
20.
Artículo en Inglés | MEDLINE | ID: mdl-35257831

RESUMEN

In childhood and adolescence, overt antisocial and aggressive manifestations are typically diagnosed as conduct disorder (CD). Given that the emerging research has pointed to the influence of 5-HT2A receptors in the ontogeny of aggression, we aimed to analyze the association of its genetic polymorphisms with CD. The study included 228 male adolescent subjects (120 with and 108 without CD). CD was diagnosed according to Structured Clinical Interview for DSM-IV criteria, while evaluations of aggressive/dissociative behaviors were performed using psychometric questionnaires including the PCL-YV, OAS-M, KADS, and CBCL. Platelet 5-HT concentration was determined by spectrophotofluorometry. Genotyping of 5-HT2A receptor polymorphisms rs2070040, rs9534511, rs4142900, rs9534512 was performed using TaqMan SNP Genotyping Assays. Subjective irritability, physical aggression toward others, and antisocial behavior were strongly associated with the G allele of rs2070040 and rs4142900, and the C allele of rs9534511 and rs9534512. A significantly increased platelet 5-HT concentration in CD subjects, compared to controls, was lost after the correction according to the smoking status. Our results indicate an association of the studied HTR2A polymorphisms and their haplotypes with irritability and impulsivity traits, which may contribute to the aggressive and antisocial behavior in male adolescents with CD.


Asunto(s)
Trastorno de la Conducta , Receptor de Serotonina 5-HT2A , Adolescente , Agresión , Plaquetas/metabolismo , Trastorno de la Conducta/sangre , Trastorno de la Conducta/genética , Humanos , Masculino , Polimorfismo Genético , Receptor de Serotonina 5-HT2A/sangre , Receptor de Serotonina 5-HT2A/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...