RESUMO
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.
Assuntos
Fluoxetina , Haloperidol , Camundongos Endogâmicos C57BL , Isolamento Social , Animais , Masculino , Camundongos , Feminino , Fluoxetina/farmacologia , Haloperidol/farmacologia , Isolamento Social/psicologia , Imipramina/farmacologia , Modelos Animais de Doenças , Comportamento Animal/fisiologia , Comportamento Animal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologiaRESUMO
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.
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OBJECTIVE: To describe caregiving work outcomes and related indirect (ie, productivity) and direct (ie, caregiving hours and expenses) costs. METHODS: A national, population-based survey to identify employed caregivers assisting a person with treatment-resistant depression (TRD) and a comparison group of employed caregivers assisting others (No TRD). RESULTS: Screening identified 169 TRD caregivers and 1070 No TRD caregivers providing 23.3 and 14.6 mean weekly caregiving hours, respectively. Adjusted annual indirect cost estimates were $11,121 for caregivers of TRD and $7761 for caregivers in the No TRD group (Pâ≤â0.0001). At-work productivity loss (presenteeism) was the largest component. Adjusted annual direct cost estimates were $29,805 for caregivers of TRD and $20,642 for caregivers in the No TRD group (Pâ≤â0.0001). CONCLUSIONS: TRD exacts a toll on caregivers and their employers exceeding that for other caregivers.
Assuntos
Cuidadores , Depressão/economia , Local de Trabalho , Efeitos Psicossociais da Doença , Custos e Análise de Custo , Eficiência , Humanos , PresenteísmoRESUMO
Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus-pituitary-adrenal (HPA) axis.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Finasterida/farmacologia , Estresse Psicológico , Afeto/efeitos dos fármacos , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Ratos , Ratos Long-Evans , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologiaRESUMO
Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAONeo) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC). MAOANeo ES mouse dopamine neurons exhibited an enhanced post-synaptic responsiveness to excitatory inputs, aberrant plasticity in the PFC, and an AB. Systemic administration of the selective antagonist at dopamine D1 receptors SCH23390 fully restored PFC function and rescued AB. Collectively, these findings reveal that dysfunctional mesocortical dopamine signaling at pre-adolescence ties to AB in the MAOANeo ES mouse, and identify dopamine D1 receptor as a molecular target to be exploited for an age-tailored therapy. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.
Assuntos
Agressão/fisiologia , Neurônios Dopaminérgicos/metabolismo , Monoaminoxidase/metabolismo , Rede Nervosa/metabolismo , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo , Área Tegmentar Ventral/metabolismo , Fatores Etários , Agressão/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Benzazepinas/farmacologia , Dopamina/genética , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Monoaminoxidase/genética , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Distribuição Aleatória , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 - but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB - and a significant and selective up-regulation of serotonin 5-HT2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1-3â¯mgâ¯kg-1, IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1-0.3â¯mgâ¯kg-1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.
Assuntos
Transtorno da Personalidade Antissocial/metabolismo , Interação Gene-Ambiente , Privação Materna , Receptor 5-HT2A de Serotonina/metabolismo , Estresse Psicológico/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Transtorno da Personalidade Antissocial/psicologia , Relação Dose-Resposta a Droga , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Estresse Psicológico/psicologiaRESUMO
The enzyme steroid 5α-reductase 2 (5αR2) catalyzes the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. Here, we profiled the behavioral characteristics of 5αR2 heterozygous (HZ) and knockout (KO) mice, as compared with their wild-type (WT) littermates. While male 5αR2 KO mice displayed no overt alterations in motoric, sensory, information-processing and anxiety-related behaviors, they exhibited deficits in neurobehavioral correlates of dominance (including aggression against intruders, mating, and tube dominance) as well as novelty-seeking and risk-taking responses. Furthermore, male 5αR2 KO mice exhibited reduced D2-like dopamine receptor binding in the shell of the nucleus accumbens - a well-recognized molecular signature of social dominance. Collectively, these results suggest that 5αR2 is involved in the establishment of social dominance and its behavioral manifestations. Further studies are warranted to understand how the metabolic actions of 5αR2 on steroid profile may be implicated in social ranking, impulse control, and the modulation of dopamine receptor expression in the nucleus accumbens.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/fisiologia , Comportamento Animal/fisiologia , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Androgênios/metabolismo , Animais , Di-Hidrotestosterona/metabolismo , Transtorno 46,XY do Desenvolvimento Sexual/psicologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/fisiopatologia , Comportamento Exploratório/efeitos dos fármacos , Hipospadia/psicologia , Masculino , Camundongos , Camundongos Knockout , Predomínio Social , Erros Inatos do Metabolismo de Esteroides/psicologia , Testosterona/metabolismoRESUMO
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial confinement (SC), a moderate environmental stressor, increases tic-like responses and elicits TS-like sensorimotor gating deficits in the D1CT-7 mouse, one of the best-validated models of TS. Here, we hypothesized that these adverse effects may be mediated by neurosteroids, given their well-documented role in stress-response orchestration. Indeed, SC increased the levels of progesterone, as well as its derivatives 5α-dihydroprogesterone and allopregnanolone, in the prefrontal cortex (PFC) of D1CT-7 mice. Among these steroids, however, only allopregnanolone (5-15 mg/kg, IP) dose-dependently exacerbated TS-like manifestations in D1CT-7, but not wild-type littermates; these effects were countered by the benchmark anti-tic therapy haloperidol (0.3 mg/kg, IP). Furthermore, the phenotypic effects of spatial confinement in D1CT-7 mice were suppressed by finasteride (25-50 mg/kg, IP), an inhibitor of the main rate-limiting enzyme in allopregnanolone synthesis. These findings collectively suggest that stress may exacerbate TS symptoms by promoting allopregnanolone synthesis in the PFC, and corroborate previous clinical results pointing to finasteride as a novel therapeutic avenue to curb symptom fluctuations in TS.
Assuntos
Pregnanolona/metabolismo , Estresse Psicológico/metabolismo , Síndrome de Tourette/metabolismo , Animais , Relação Dose-Resposta a Droga , Finasterida/farmacologia , Haloperidol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pregnanolona/farmacologia , Progesterona/metabolismo , Estresse Psicológico/fisiopatologia , Síndrome de Tourette/fisiopatologiaRESUMO
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and phonic tics. While TS patients have been also shown to exhibit subtle abnormalities of sensorimotor integration and gait, animal models of this disorder are seldom tested for these functions. To fill this gap, we assessed gait and sensorimotor integration in the D1CT-7 mouse, one of the best-validated animal models of TS. D1CT-7 mice exhibit spontaneous tic-like manifestations, which, in line with the clinical phenomenology of TS, are markedly exacerbated by environmental stress. Thus, to verify whether stress may affect sensorimotor integration and gait functions in D1CT-7 mice, we subjected these animals to a 20-min session of spatial confinement, an environmental stressor that was recently shown to worsen tic-like manifestations. Immediately following this manipulation (or no confinement, for controls), animals were subjected to either the sticky-tape task, to test for sensorimotor integration; or a 60-min session in an open field (42×42cm) force-plate actometer for gait analysis. Gait analyses included spatial, temporal, and dynamic (force) parameters. D1CT-7 mice displayed a longer latency to remove a sticky tape, indicating marked impairments in sensorimotor integration; furthermore, these mutants exhibited shortened stride length, increased stride rate, nearly equal early-phase velocity, and higher late-phase velocity. D1CT-7 mice also ran with greater force amplitude than wild-type (WT) littermates. None of these phenotypes was worsened by spatial confinement. These results highlight the potential importance of testing sensorimotor integration and gait functions as a phenotypic correlate of cortical connectivity deficits in animal models of TS.
Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Síndrome de Tourette/fisiopatologia , Actigrafia , Análise de Variância , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Marcha , Masculino , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Destreza MotoraRESUMO
Tourette syndrome (TS) is a neurodevelopmental condition characterized by multiple, recurring motor and phonic tics. Rich empirical evidence shows that the severity of tics and associated manifestations is increased by several stressors and contextual triggers; however, the neurobiological mechanisms responsible for symptom exacerbation in TS remain poorly understood. This conceptual gap partially reflects the high phenotypic variability in tics, as well as the existing difficulties in operationalizing and standardizing stress and its effects in a clinical setting. Animal models of TS may be highly informative tools to overcome some of these limitations; these experimental preparations have already provided critical insights on key aspects of TS pathophysiology, and may prove useful to identify the neurochemical alterations induced by different stressful contingencies. In particular, emerging knowledge on the role of contextual triggers in animal models of TS may inform the development of novel pharmacological interventions to reduce tic fluctuations in this disorder.
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Tiques , Síndrome de Tourette , Animais , Humanos , Modelos Animais , Pesquisa Translacional BiomédicaRESUMO
Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.
Assuntos
Benzotiazóis/administração & dosagem , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Dopamina/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/agonistas , Assunção de Riscos , Animais , Núcleo Caudado/metabolismo , Dopamina/metabolismo , Masculino , Norepinefrina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Doença de Parkinson/complicações , Pramipexol , Córtex Pré-Frontal/metabolismo , Probabilidade , Putamen/metabolismo , Ratos , Ratos Long-Evans , Serotonina/metabolismoRESUMO
Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner's discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment.
Assuntos
Agressão/fisiologia , Monoaminoxidase/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Humanos , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Transtornos Mentais/patologia , Monoaminoxidase/genéticaRESUMO
BACKGROUND AND PURPOSE: The D1CT-7 mouse is one of the best known animal models of Tourette syndrome (TS), featuring spontaneous tic-like behaviours sensitive to standard TS therapies; these characteristics ensure a high face and predictive validity of this model, yet its construct validity remains elusive. To address this issue, we studied the responses of D1CT-7 mice to two critical components of TS pathophysiology: the exacerbation of tic-like behaviours in response to stress and the presence of sensorimotor gating deficits, which are thought to reflect the perceptual alterations causing the tics. EXPERIMENTAL APPROACH: D1CT-7 and wild-type (WT) littermates were subjected to a 20 min session of spatial confinement (SC) within an inescapable, 10 cm wide cylindrical enclosure. Changes in plasma corticosterone levels, tic-like behaviours and other spontaneous responses were measured. SC-exposed mice were also tested for the prepulse inhibition (PPI) of the startle response (a sensorimotor gating index) and other TS-related behaviours, including open-field locomotion, novel object exploration and social interaction and compared with non-confined counterparts. KEY RESULTS: SC produced a marked increase in corticosterone concentrations in both D1CT-7 and WT mice. In D1CT-7, but not WT mice, SC exacerbated tic-like and digging behaviours, and triggered PPI deficits and aggressive responses. Conversely, SC did not modify locomotor activity or novel object exploration in D1CT-7 mice. Both tic-like behaviours and PPI impairments in SC-exposed D1CT-7 mice were inhibited by standard TS therapies and D1 dopamine receptor antagonism. CONCLUSIONS AND IMPLICATIONS: These findings collectively support the translational and construct validity of D1CT-7 mice with respect to TS. LINKED ARTICLES: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.
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Comportamento Animal , Espaços Confinados , Modelos Animais de Doenças , Filtro Sensorial , Síndrome de Tourette/fisiopatologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos TransgênicosRESUMO
BACKGROUND: Acute stress triggers transient alterations in the synaptic release and metabolism of brain monoamine neurotransmitters. These rapid changes are essential to activate neuroplastic processes aimed at the appraisal of the stressor and enactment of commensurate defensive behaviors. Threat evaluation has been recently associated with the dendritic morphology of pyramidal cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA); thus, we examined the rapid effects of restraint stress on anxiety-like behavior and dendritic morphology in the BLA and OFC of mice. Furthermore, we tested whether these processes may be affected by deficiency of monoamine oxidase A (MAO-A), the primary enzyme catalyzing monoamine metabolism. METHODS: Following a short-term (1-4h) restraint schedule, MAO-A knockout (KO) and wild-type (WT) mice were sacrificed, and histological analyses of dendrites in pyramidal neurons of the BLA and OFC of the animals were performed. Anxiety-like behaviors were examined in a separate cohort of animals subjected to the same experimental conditions. RESULTS: In WT mice, short-term restraint stress significantly enhanced anxiety-like responses, as well as a time-dependent proliferation of apical (but not basilar) dendrites of the OFC neurons; conversely, a retraction in BLA dendrites was observed. None of these behavioral and morphological changes were observed in MAO-A KO mice. CONCLUSIONS: These findings suggest that acute stress induces anxiety-like responses by affecting rapid dendritic remodeling in the pyramidal cells of OFC and BLA; furthermore, our data show that MAO-A and monoamine metabolism are required for these phenomena.
Assuntos
Ansiedade/enzimologia , Complexo Nuclear Basolateral da Amígdala/patologia , Dendritos/patologia , Monoaminoxidase/metabolismo , Córtex Pré-Frontal/patologia , Células Piramidais/patologia , Estresse Psicológico/enzimologia , Animais , Ansiedade/etiologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos da Linhagem 129 , Monoaminoxidase/deficiência , Estresse Psicológico/complicaçõesRESUMO
Tics are repetitive, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive premonitory urges. The most severe tic disorder, Tourette syndrome (TS), is a childhood-onset condition featuring multiple motor and at least one phonic tic for a duration longer than 1 year. The pharmacological treatment of TS is mainly based on antipsychotic agents; while these drugs are often effective in reducing tic severity and frequency, their therapeutic compliance is limited by serious motor and cognitive side effects. The identification of novel therapeutic targets and development of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove extremely useful to test hypotheses on the etiology and neurobiological bases of TS and related conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater focus on endophenotypes and quantitative indices, rather than qualitative descriptors. Given the complex and multifactorial nature of TS and other tic disorders, the selection of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on genetic mutations, environmental interventions as well as pharmacological manipulations. Furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant progress in the identification of novel therapeutic targets for tic disorders.
Assuntos
Modelos Animais de Doenças , Transtornos de Tique , Animais , Endofenótipos , Transtornos de Tique/tratamento farmacológico , Transtornos de Tique/genética , Transtornos de Tique/fisiopatologiaRESUMO
The termination of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is regulated by its uptake by the 5-HT transporter (5-HTT), as well as its degradation by monoamine oxidase (MAO)-A. MAO-A deficiency results in a wide set of behavioral alterations, including perseverative behaviors and social deficits. These anomalies are likely related to 5-HTergic homeostatic imbalances; however, the role of 5-HTT in these abnormalities remains unclear. To ascertain the role of 5-HTT in the behavioral anomalies associated to MAO-A deficiency, we tested the behavioral effects of its blocker fluoxetine on perseverative, social and aggressive behaviors in transgenic animals with hypomorphic or null-allele MAO-A mutations. Acute treatment with the 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-A(Neo) mice. Furthermore, this treatment also reduced perseverative responses (including marble burying and water mist-induced grooming) in both MAO-A mutant genotypes. Both MAO-A mutant lines displayed significant reductions in 5-HTT expression across the prefrontal cortex, amygdala and striatum, as quantified by immunohistochemical detection; however, the down-regulation of 5-HTT in MAO-A(Neo) mice was more pervasive and widespread than in their KO counterparts, possibly indicating a greater ability of the hypomorphic line to enact compensatory mechanisms with respect to 5-HT homeostasis. Collectively, these findings suggest that the behavioral deficits associated with low MAO-A activity may reflect developmental alterations of 5-HTT within 5-HTergic neurons. Furthermore, the translational implications of our results highlight 5-HT reuptake inhibition as an interesting approach for the control of aggressive outbursts in MAO-A deficient individuals.
Assuntos
Agressão/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Monoaminoxidase/deficiência , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Agressão/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Asseio Animal/efeitos dos fármacos , Asseio Animal/fisiologia , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Camundongos Transgênicos , Monoaminoxidase/genética , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologiaRESUMO
Schizophrenia is a severe mental disorder, with a highly complex and heterogenous clinical presentation. Our current perspectives posit that the pathogenic mechanisms of this illness lie in complex arrays of gene × environment interactions. Furthermore, several findings indicate that males have a higher susceptibility for schizophrenia, with earlier age of onset and overall poorer clinical prognosis. Based on these premises, several authors have recently begun exploring the possibility that the greater schizophrenia vulnerability in males may reflect specific gene × sex (G×S) interactions. Our knowledge on such G×S interactions in schizophrenia is still rudimentary; nevertheless, the bulk of preclinical evidence suggests that the molecular mechanisms for such interactions are likely contributed by the neurobiological effects of sex steroids on dopamine (DA) neurotransmission. Accordingly, several recent studies suggest a gender-specific association of certain DAergic genes with schizophrenia. These G×S interactions have been particularly documented for catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), the main enzymes catalyzing DA metabolism. In the present review, we will outline the current evidence on the interactions of DA-related genes and sex-related factors, and discuss the potential molecular substrates that may mediate their cooperative actions in schizophrenia pathogenesis.
RESUMO
The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and ß-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.
Assuntos
Comportamento Animal , Monoaminas Biogênicas/metabolismo , Transtornos Cognitivos , Hipocampo , Memória , Monoaminoxidase/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurotransmissores/metabolismo , Animais , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Potenciação de Longa Duração/genética , Masculino , Camundongos , Camundongos Knockout , Monoaminoxidase/genética , Proteínas do Tecido Nervoso/genética , Neurotransmissores/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Monoamine oxidase (MAO) A, the major enzyme catalyzing the oxidative degradation of serotonin (5-hydroxytryptamine, 5-HT), plays a key role in emotional regulation. In humans and mice, MAO-A deficiency results in high 5-HT levels, antisocial, aggressive, and perseverative behaviors. We previously showed that the elevation in brain 5-HT levels in MAO-A knockout (KO) mice is particularly marked during the first two weeks of postnatal life. Building on this finding, we hypothesized that the reduction of 5-HT levels during these early stages may lead to enduring attenuations of the aggression and other behavioral aberrances observed in MAO-A KO mice. To test this possibility, MAO-A KO mice were treated with daily injections of a 5-HT synthesis blocker, the tryptophan hydroxylase inhibitor p-chloro-phenylalanine (pCPA, 300 mg/kg/day, IP), from postnatal day 1 through 7. As expected, this regimen significantly reduced 5-HT forebrain levels in MAO-A KO pups. These neurochemical changes persisted throughout adulthood, and resulted in significant reductions in marble-burying behavior, as well as increases in spontaneous alternations within a T-maze. Conversely, pCPA-treated MAO-A KO mice did not exhibit significant changes in anxiety-like behaviors in a novel open-field and elevated plus-maze; furthermore, this regimen did not modify their social deficits, aggressive behaviors and impairments in tactile sensitivity. Treatment with pCPA from postnatal day 8 through 14 elicited similar, yet milder, behavioral effects on marble-burying behavior. These results suggest that early developmental enhancements in 5-HT levels have long-term effects on the modulation of behavioral flexibility associated with MAO-A deficiency.
Assuntos
Agressão/fisiologia , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Monoaminoxidase/deficiência , Serotonina/metabolismo , Estimulação Acústica , Fatores Etários , Animais , Animais Recém-Nascidos , Transtornos de Ansiedade/induzido quimicamente , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Feminino , Fenclonina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Knockout , Monoaminoxidase/genética , Mutação/genética , Desempenho Psicomotor/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m(3)) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.