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1.
Sci Rep ; 12(1): 10182, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715502

RESUMO

Deficits in social interaction or social cognition are key phenotypes in a variety of chronic mental diseases, yet, their modeling and molecular dissection are only in their infancy. The Disrupted-in-Schizophrenia 1 (DISC1) signaling pathway is considered to play a role in different psychiatric disorders such as schizophrenia, depression, and biopolar disorders. DISC1 is involved in regulating the dopaminergic neurotransmission in, among others, the mesolimbic reward system. A transgenic rat line tgDISC1 has been introduced as a model system to study behavioral phenotypes associated with abnormal DISC1 signaling pathways. Here, we evaluated the impact of impaired DISC1 signaling on social (social interaction) and non-social (sucrose) reward preferences in the tgDISC1 animal model. In a plus-maze setting, rats chose between the opportunity for social interaction with an unfamiliar juvenile conspecific (social reward) or drinking sweet solutions with variable sucrose concentrations (non-social reward). tgDISC1 rats differed from wild-type rats in their social, but not in their non-social reward preferences. Specifically, DISC1 rats showed a lower interest in interaction with the juvenile conspecific, but did not differ from wild-type rats in their preference for higher sucrose concentrations. These results suggest that disruptions of the DISC1 signaling pathway that is associated with altered dopamine transmission in the brain result in selective deficits in social motivation reminiscent of phenotypes seen in neuropsychiatric illness.


Assuntos
Anedonia , Esquizofrenia , Anedonia/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Ratos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Sacarose
2.
BMC Psychiatry ; 22(1): 320, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513818

RESUMO

BACKGROUND: Gender differences have been found to be associated with individuals' pleasure. Cognitive flexibility and emotional expressivity might play an important role between gender differences and pleasure. This current study is to explore the mediating role of cognitive flexibility and emotional expressivity in the relationship between gender differences and pleasure. METHOD: In this cross-sectional study, a sample of 1107 full-time university students from five colleges in Tianjin, Chinese mainland was investigated by questionnaire. All participants completed the Temporal Experience of Pleasure Scale (TEPs), the Cognitive Flexibility Inventory (CFI), and the Berkeley Expressivity Questionnaire (BEQ). RESULTS: The results of independent T-test suggested that females reported better emotional expressivity, anticipatory pleasure and consummatory pleasure than males, whereas males had better cognitive flexibility than females. Using bootstrapping approach revealed that the partially mediation effects of cognitive flexibility on gender differences in anticipatory and consummatory pleasure, and that of emotional expressivity on gender differences in anticipatory and consummatory pleasure. Results of this present study stated that cognitive flexibility and emotional expressivity play a partial mediating role in explaining gender differences in anticipatory and consummatory pleasure. CONCLUSION: Females had higher anticipatory and consummatory pleasure because they tend to use emotional regulation strategy to express their emotion.


Assuntos
Cognição , Prazer , Anedonia/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Prazer/fisiologia , Fatores Sexuais , Inquéritos e Questionários
3.
Neuroimage Clin ; 34: 102990, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35305499

RESUMO

BACKGROUND: A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD. METHODS: 35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons. RESULTS: The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation. CONCLUSIONS: This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression.


Assuntos
Transtorno Depressivo Maior/terapia , Transtorno Depressivo Resistente a Tratamento/patologia , Habenula/fisiopatologia , Anedonia/fisiologia , Estudos de Casos e Controles , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/terapia , Habenula/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Ideação Suicida
4.
Int J Mol Sci ; 23(4)2022 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-35216176

RESUMO

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.


Assuntos
Anedonia/fisiologia , Ciclo-Oxigenase 2/metabolismo , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Celecoxib/farmacologia , Citalopram/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Elevação dos Membros Posteriores/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Inibidores de Captação de Serotonina/farmacologia , Estresse Psicológico/tratamento farmacológico , Natação/fisiologia
5.
Eur J Psychotraumatol ; 13(1): 2015949, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35070161

RESUMO

Background: Anhedonia, the reduction of pleasure and reward-seeking behaviour, is a transdiagnostic symptom with well-described neural circuit mediators. Although typically observed during disease state, extant hypotheses suggest that anhedonia may also be an early risk factor for development of psychopathology. Understanding the contribution of anhedonia to the trauma-response trajectory may bolster inferences about biological mechanisms contributing to pre-trauma risk versus trauma-related symptom expression, knowledge of which could aid in targeted interventions. Objective: Using a prospective, longitudinal design in a population at risk for trauma disorders, we tested the hypothesis that anhedonia may be a pre-trauma risk factor for post-traumatic stress disorder (PTSD) symptoms. Methods: Adult male participants from the Marine Resilience Study (N = 2,593) were assessed across three time-points (pre-deployment, 3-month and 6-month post-deployment). An anhedonia factor was extracted from self-report instruments pre-trauma and tested for its relationship with development of PTSD re-experiencing symptoms after deployment. Results: Higher pre-deployment anhedonia predicted increased PTSD intrusive re-experiencing symptoms at 3- and 6-months post-deployment when controlling for pre-trauma PTSD and depression symptoms. Depression symptoms were not significant predictors of subsequent PTSD intrusive re-experiencing symptoms. Anhedonia at 3 mo also robustly predicted maintenance of PTSD intrusive re-experiencing symptoms at the 6 mo time point. Conclusions: Pre-deployment anhedonia may be a pre-trauma risk factor for PTSD, not simply a state-dependent effect of trauma exposure and PTSD symptom expression. Anhedonia may contribute to persistence and/or chronicity of re-experiencing symptoms after the emergence of PTSD symptoms.


Antecedentes: La anhedonia, reducción del placer y del comportamiento de búsqueda de recompensa, es un síntoma transdiagnóstico con circuitos neurales mediadores bien descritos. Aunque es observada típicamente durante estados patológicos, hipótesis existentes sugieren que la anhedonia puede ser también un factor de riesgo temprano para el desarrollo de psicopatología. La comprensión de la contribución de la anhedonia a la trayectoria de la respuesta al trauma puede reforzar las inferencias sobre los mecanismos biológicos que contribuyen al riesgo pre-trauma versus la expresión sintomática relacionada al trauma, conocimiento que puede ayudar en intervenciones dirigidas.Objetivo: Utilizando un diseño longitudinal prospectivo en una población de riesgo para trastornos traumáticos, probamos la hipótesis de que la anhedonia puede ser un factor de riesgo pre-trauma para síntomas de trastorno de estrés postraumático (TEPT).Métodos: Participantes masculinos adultos del Estudio de Resiliencia de la Marina (N = 2,593) fueron evaluados a lo largo de 3 puntos temporales (antes del despliegue, a los 3 meses, y a los 6 meses post-despliegue). Se extrajo un factor para anhedonia a partir de instrumentos auto-aplicados pre-trauma y fue evaluado por su relación con el desarrollo de síntomas de re-experimentación del TEPT después del despliegue.Resultados: Una anhedonia más alta pre-despliegue predijo un aumento de síntomas de TEPT a los 3 y 6 meses post-despliegue, al controlar con síntomas de TEPT y de depresión pre-trauma. Los síntomas depresivos no fueron predictores significativos de síntomas de TEPT posteriores. La anhedonia a los 3 meses predijo también de forma robusta la mantención de síntomas de TEPT a los 6 meses.Conclusiones: La anhedonia pre-despliegue puede ser un factor de riesgo pre-trauma para TEPT, no sólo como un efecto dependiente del estado de la exposición al trauma y la expresión de síntomas de TEPT. La anhedonia puede contribuir a la persistencia y/o cronicidad de síntomas de re-experimentación tras el inicio de los síntomas de TEPT.


Assuntos
Anedonia/fisiologia , Militares/psicologia , Psicopatologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Campanha Afegã de 2001- , Humanos , Guerra do Iraque 2003-2011 , Estudos Longitudinais , Masculino , Estudos Prospectivos , Recompensa , Fatores de Risco , Adulto Jovem
6.
Schizophr Bull ; 48(2): 335-346, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34891171

RESUMO

Anhedonia, the reduced capacity to experience pleasure, has long been considered a prominent feature of schizophrenia spectrum disorders. Many domain-specific conceptualizations of anhedonia and pleasure capacity have been developed, and there currently exist a variety of self-report assessment tools that purport to assess these various domains. The current systematic review and meta-analysis (PROSPERO: CRD42020156169) aimed to quantify overall and domain-specific self-reported anhedonia in people with schizophrenia compared to nonpsychiatric controls. We performed a literature search of PsycINFO, MEDLINE, and Embase databases for dissertations and peer-reviewed articles published in English prior to June 2021. Studies employing a psychometrically validated self-report measure of anhedonia, pleasure experience or affect in people with schizophrenia, schizoaffective, or schizophreniform disorders; studies utilizing at least one clearly defined healthy or community control group for comparison; and studies providing sufficient data to calculate effect sizes were included in this review. Random and mixed effects meta-analyses, meta-regressions, and subgroup comparisons were run across domains of anhedonia to explore weighted mean effect sizes and their associated moderators. In total, 146 studies met inclusion criteria, yielding 390 Hedges' g effect sizes from the included comparisons. People with schizophrenia reported moderate-to-large elevations in overall and domain-specific anhedonia. A sensitivity analysis accounting for high risk of bias studies did not significantly impact results. Lastly, patient sex, education, negative symptom severity, antipsychotic class, and trait negative affect differentially moderated effect sizes across domains of anhedonia. Despite the heterogeneity inherent in schizophrenia spectrum disorders, self-reported anhedonia is ubiquitously reported across self-report measures in this population.


Assuntos
Anedonia/fisiologia , Esquizofrenia/complicações , Adulto , Feminino , Humanos , Masculino , Psicometria/instrumentação , Psicometria/métodos , Esquizofrenia/fisiopatologia , Autorrelato
7.
Behav Brain Res ; 421: 113725, 2022 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-34929235

RESUMO

Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the neurobiology underpinning sex differences in the long-term consequences of childhood stress remains unknown. Thus, the aim of this study was to determine whether stress applied during the prepubertal juvenile period (postnatal day 27-29) in rats induces sex-specific changes in anxiety-like behaviour, anhedonia, and antidepressant-like behaviour in adulthood in males and females. The impact of juvenile stress on two systems in the brain associated with these behaviours and that develop during the juvenile period, the mesocorticolimbic dopaminergic system and hippocampal neurogenesis, were also investigated. Juvenile stress altered escape-oriented behaviours in the forced swim test in both sexes, decreased latency to drink a palatable substance in a novel environment in the novelty-induced hypophagia test in both sexes, and decreased open field supported rearing behavior in females. These behavioural changes were accompanied by stress-induced increases in tyrosine hydroxylase immunoreactivity in the prefrontal cortex of both sexes, but not other regions of the mesocorticolimbic dopaminergic system. Juvenile stress did not impact anhedonia in adulthood as measured by the saccharin preference test and had no effect hippocampal neurogenesis across the longitudinal axis of the hippocampus. These results suggest that juvenile stress has long-lasting impacts on antidepressant-like and reward-seeking behaviour in adulthood and these changes may be due to alterations to catecholaminergic innervation of the medial prefrontal cortex.


Assuntos
Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Depressão/fisiopatologia , Hipocampo/fisiologia , Neurogênese/fisiologia , Córtex Pré-Frontal/metabolismo , Recompensa , Estresse Psicológico/fisiopatologia , Fatores Etários , Anedonia/fisiologia , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
8.
Int J Mol Sci ; 22(20)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34681636

RESUMO

Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified.


Assuntos
Anedonia/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Estresse Psicológico/fisiopatologia , Anedonia/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Calbindina 2/metabolismo , Proliferação de Células , Meio Ambiente , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Estresse Fisiológico
9.
Nat Neurosci ; 24(11): 1601-1613, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663957

RESUMO

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression-major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.


Assuntos
Adaptação Fisiológica/fisiologia , Anedonia/fisiologia , Neurônios Dopaminérgicos/metabolismo , Dor/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Condicionamento Operante/fisiologia , Neurônios Dopaminérgicos/química , Feminino , Masculino , Optogenética/métodos , Dor/genética , Ratos , Ratos Long-Evans , Ratos Transgênicos , Área Tegmentar Ventral/química
10.
Mol Neurobiol ; 58(11): 5971-5985, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34432265

RESUMO

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Anedonia/efeitos dos fármacos , Anedonia/fisiologia , Animais , Axônios/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Corpo Estriado/metabolismo , Depressão/etiologia , Depressão/prevenção & controle , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/psicologia , Feminino , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , /metabolismo , Estresse Oxidativo , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Pramipexol/farmacologia , Pramipexol/uso terapêutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Método Simples-Cego , Medula Espinal/metabolismo , Medula Espinal/patologia
11.
Schizophr Bull ; 47(6): 1524-1533, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34420057

RESUMO

Amotivation is related to value representation. A comprehensive account of amotivation requires a mechanistic understanding of how the brain exploits external information to represent value. To achieve maximal value discriminability, brain valuation system will dynamically adapt its coding sensitivity to the range of values available in any given condition, so-called range adaptive coding. We administered an experimental task to 30 patients with chronic schizophrenia (C-SCZ), 30 first-episode schizophrenia (FE-SCZ), 34 individuals with high social anhedonia (HSoA), and their paired controls to assess range adaptation ability. C-SCZ patients exhibited over-adaptation and their performances were negatively correlated with avolition symptoms and positive symptoms and positively correlated with blunted-affect symptoms and self-reported consummatory interpersonal pleasure scores, though the results were non-significant. FE-SCZ patients exhibited reduced adaptation, which was significantly and negatively correlated with avolition symptoms and positively correlated with the overall proportion of choosing to exert more effort. Although HSoA participants exhibited comparable range adaptation to controls, their performances were significantly and negatively correlated with the proportion of choosing to exert more effort under the lowest value condition. Our results suggest that different stages of schizophrenia spectrum showed distinct range adaptation patterns. Range adaptation impairments may index a possible underlying mechanism for amotivation symptoms in FE-SCZ and more complicated and pervasive effects on clinical symptoms in C-SCZ.


Assuntos
Adaptação Psicológica/fisiologia , Anedonia/fisiologia , Apatia/fisiologia , Motivação/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Comportamento Social , Adulto , Doença Crônica , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito
12.
Cell Rep ; 36(6): 109508, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380036

RESUMO

Astrocytic contributions to neuroinflammation are widely implicated in disease, but they remain incompletely explored. We assess medial prefrontal cortex (PFC) and visual cortex (VCX) astrocyte and whole-tissue gene expression changes in mice following peripherally induced neuroinflammation triggered by a systemic bacterial endotoxin, lipopolysaccharide, which produces sickness-related behaviors, including anhedonia. Neuroinflammation-mediated behavioral changes and astrocyte-specific gene expression alterations peak when anhedonia is greatest and then reverse to normal. Notably, region-specific molecular identities of PFC and VCX astrocytes are largely maintained during reactivity changes. Gene pathway analyses reveal alterations of diverse cell signaling pathways, including changes in cell-cell interactions of multiple cell types that may underlie the central effects of neuroinflammation. Certain astrocyte molecular signatures accompanying neuroinflammation are shared with changes reported in Alzheimer's disease and mouse models. However, we find no evidence of altered neuronal survival or function in the PFC even when neuroinflammation-induced astrocyte reactivity and behavioral changes are significant.


Assuntos
Astrócitos/metabolismo , Córtex Cerebral/patologia , Inflamação/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Anedonia/fisiologia , Animais , Comunicação Celular , Inflamação/genética , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Fenótipo , Células Piramidais/patologia , Transcrição Genética
13.
Behav Brain Res ; 412: 113445, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34224764

RESUMO

A decreased H1 receptor activity is observed in the anterior cingulate cortex (aCgCx) of depressed patients. The role of this abnormality in the development of depression-related processes is unstudied. We examined the influence of a decreased brain H1 receptor activity on rat behavior in the sucrose preference test. The H1 receptor deficit was simulated by injection of an H1 antagonist into the aCgCx; also, two aCgCx projection areas, lateral and medial entorhinal cortices were examined. A blockade of H1-receptors in the aCgCx and lateral entorhinal cortex (LEntCx) significantly reduced sucrose preference. These findings suggest the existence of H1 receptor-mediated aCgCx-LEntCx circuitry mechanism regulating anhedonic-like behavior in rats. The presented data suggest that H1 receptor-mediated processes might be a therapeutic target in depressive disorders.


Assuntos
Anedonia/fisiologia , Receptores Histamínicos H1/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiologia , Histamina/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Córtex Olfatório/metabolismo , Córtex Olfatório/fisiologia , Ratos , Ratos Wistar , Receptores Histamínicos H1/fisiologia
14.
J Child Adolesc Psychopharmacol ; 31(8): 531-537, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34283918

RESUMO

Objectives: Irritability and anhedonia are cardinal symptoms of depression for children and adolescents. However, anhedonia may be more strongly associated with illness severity compared with irritability. The present study evaluated the impact of irritability and anhedonia on symptom severity and functional impairment among depressed children and adolescents. Methods: Participants were 383 children and adolescents presenting for outpatient treatment at a community mental health center or academic medical center. Children and adolescents were diagnosed with unipolar depression or bipolar disorder. Regression models predicted depression severity and functional impairment from irritability and anhedonia after covarying age, gender, depressive and hypomanic symptoms, and diagnosis. Results: Greater irritability and anhedonia were associated with more severe depression symptoms. Greater irritability, but not anhedonia, was associated with lower global functioning and family quality of life (QoL), and more externalizing problems. Greater anhedonia was associated with lower overall, emotional, self-esteem, and social QoL. Neither irritability nor anhedonia was associated with school or physical QoL, nonsuicidal self-injury, suicidal ideation, number of comorbid diagnoses, or internalizing problems. Conclusions: Irritability was associated with more markers of depression severity, whereas anhedonia was associated with indicators of functional impairment. This study used a cross-sectional observational design and therefore cannot provide information about cause and effect relationships between variables. Irritability and anhedonia were derived from their respective subscales of the General Behavior Inventory and included only caregiver-reported symptoms but not child- or adolescent-reported symptoms. Identifying the impact of specific symptoms of depression may assist clinicians in delivering more individualized interventions to target symptoms that result in greater impairment.


Assuntos
Anedonia/fisiologia , Transtorno Bipolar/diagnóstico , Depressão/complicações , Humor Irritável/fisiologia , Desempenho Físico Funcional , Índice de Gravidade de Doença , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Qualidade de Vida
15.
Behav Brain Res ; 414: 113470, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34280463

RESUMO

Obesity is a costly, global epidemic that is perpetuated by an unhealthy diet. A significant factor in the initial consumption and maintenance of an unhealthy diet is the abundance of highly palatable, calorically dense foods. The aim of the present study is to better understand the effects of high fat diet (HFD) consumption on food valuation and preference, and to elucidate the neurobiological mechanisms mediating these effects. By using a novel food preference assay, we found that prolonged consumption of a HFD diminishes preference for and consumption of the more calorically dense food choice when two lab diets are presented. Additionally, we demonstrated that prolonged HFD consumption dampens ventral tegmental c-fos induction during hedonic feeding, implicating the mesolimbic dopamine signaling pathway as a target of HFD. Notably, both the changes in food preference and this reduced c-fos induction were reversed during withdrawal from HFD. Further, HFD-induced alterations in food preference were attenuated by exercise. Our findings suggest that prolonged HFD consumption leads to anhedonia and altered feeding choices, and this is associated with changes in mesolimbic dopamine signaling.


Assuntos
Anedonia/fisiologia , Dieta Hiperlipídica , Dopamina/metabolismo , Comportamento Alimentar/fisiologia , Preferências Alimentares/fisiologia , Condicionamento Físico Animal/fisiologia , Estriado Ventral/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Comportamento Animal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia
16.
Behav Brain Res ; 413: 113453, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252503

RESUMO

Light exposure at night disrupts circadian-regulated biological functions, including mood. However, the consequence of fragmenting the night period and distributing it across the 24-hr period is less understood. Here we show that fragmenting an 8 -h and 6 -h night into equally distributed 2 -h periods throughout the 24-hr day results in period lengthening of the circadian rhythm in mice. Furthermore, mice exhibited less anxiety, which indicates increased risk-taking behavior, and a lack of pleasure-seeking, known as anhedonia. The successive alley and open field tests were used to assess anxiety, while the sucrose preference test was used to assess anhedonia. Analysis of depressive-like behaviors with the forced swim and tail suspension tests were not observed. After two weeks in 12 h light - 12 h dark, mice exposed to the fragmented night recovered and exhibited normal behaviors for both anxiety and anhedonia. Our results are congruent with published studies that describe the detrimental effects of constant light conditions on circadian rhythms and mood. These findings unveil the negative impact that fragmenting the day-night cycle has on circadian rhythms and mood.


Assuntos
Anedonia/fisiologia , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Ritmo Circadiano/fisiologia , Fotoperíodo , Assunção de Riscos , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Schizophr Bull ; 47(6): 1534-1543, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34240217

RESUMO

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αß = .22, 95% CI = 0.02, 0.48) and social functioning (αß = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL.


Assuntos
Anedonia/fisiologia , Funcionamento Psicossocial , Transtornos Psicóticos/fisiopatologia , Reforço Psicológico , Adolescente , Depressão , Feminino , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde , Risco
18.
Hum Brain Mapp ; 42(15): 5063-5074, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34302413

RESUMO

Aberrant brain structural connectivity in major depressive disorder (MDD) has been repeatedly reported, yet many previous studies lack integration of different features of MDD with structural connectivity in multivariate modeling approaches. In n = 595 MDD patients, we used structural equation modeling (SEM) to test the intercorrelations between anhedonia, anxiety, neuroticism, and cognitive control in one comprehensive model. We then separately analyzed diffusion tensor imaging (DTI) connectivity measures in association with those clinical variables, and finally integrated brain connectivity associations, clinical/cognitive variables into a multivariate SEM. We first confirmed our clinical/cognitive SEM. DTI analyses (FWE-corrected) showed a positive correlation of anhedonia with fractional anisotropy (FA) in the right anterior thalamic radiation (ATR) and forceps minor/corpus callosum, while neuroticism was negatively correlated with axial diffusivity (AD) in the left uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF). An extended SEM confirmed the associations of ATR FA with anhedonia and UF/IFOF AD with neuroticism impacting on cognitive control. Our findings provide evidence for a differential impact of state and trait variables of MDD on brain connectivity and cognition. The multivariate approach shows feasibility of explaining heterogeneity within MDD and tracks this to specific brain circuits, thus adding to better understanding of heterogeneity on the biological level.


Assuntos
Anedonia , Transtorno Depressivo Maior , Imagem de Tensor de Difusão , Função Executiva , Neuroticismo , Substância Branca/patologia , Adulto , Anedonia/fisiologia , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/fisiopatologia , Função Executiva/fisiologia , Feminino , Humanos , Análise de Classes Latentes , Masculino , Pessoa de Meia-Idade , Neuroticismo/fisiologia , Fenótipo , Substância Branca/diagnóstico por imagem
19.
Artigo em Inglês | MEDLINE | ID: mdl-34000290

RESUMO

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease with symptoms that go beyond the domain of glucose metabolism. In fact, research has shown that T2DM is accompanied by neurodegeneration and neuroinflammation. Interestingly, Major Depressive Disorder (MDD), a mood disorder characterized mainly by depressed mood and anhedonia is a key feature of T2DM. A body of evidence demonstrates that there are many shared neuroimmune mechanisms underlying the pathophysiology of T2DM and MDD. Therefore, here we review the state-of-art regarding the underlying factors common to both T2DM and MDD. Furthermore, we briefly discuss how depressive symptoms in diabetic patients could be tackled by using novel therapeutic approaches uncovered by these shared mechanisms. Understanding the comorbidity of depression in diabetic patients is essential to fully address T2DM pathophysiology and treatment.


Assuntos
Comorbidade , Transtorno Depressivo Maior , Diabetes Mellitus Tipo 2 , Inflamação/imunologia , Neuroimunomodulação , Anedonia/fisiologia , Barreira Hematoencefálica/fisiopatologia , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/fisiopatologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endocanabinoides/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Doenças Metabólicas/fisiopatologia
20.
Neuroreport ; 32(10): 869-874, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029288

RESUMO

OBJECTIVE: Recent studies have suggested that ninjin'yoeito (NYT), a traditional Japanese Kampo medicine, improves diminished motivation in humans and animals, rendering it a novel therapeutic option for impaired motivation. To better characterize the effect of NYT on motivation, we examined its effect on motivated behaviors in mice. METHODS: Mouse models of neurodegeneration-related apathy, in which striatal dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) were progressively damaged by diphtheria toxin expression, were chosen. RESULTS: The decrease in effort-based operant responding for rewards (sucrose pellets), indicative of the mouse's motivated behavior, in the affected mice was not suppressed by chronic treatment with NYT suspended in drinking water at 1% (w/v). Mice were then subjected to a sucrose preference test, wherein they freely chose to ingest tap water and a sucrose solution without being required to exert effort. The affected mice showed a decline in preference for sucrose over tap water, relative to nonaffected controls, indicating anhedonia-like traits. In contrast to the diminished operant behavior, the anhedonic behavior in the affected mice was prevented by the NYT administration. Furthermore, NYT did not affect the size of Drd2 mRNA disappearance in the striatum of affected mice, suggesting that the NYT effect was unrelated to DTA-mediated neurodegeneration. CONCLUSION: These results demonstrate that the beneficial effect of NYT on motivation is mediated, at least in part, through the potentiation of hedonic capacity by certain neuromodulatory pathways.


Assuntos
Anedonia/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicina Kampo/métodos , Motivação/efeitos dos fármacos , Receptores de Dopamina D2/biossíntese , Anedonia/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Corpo Estriado/metabolismo , Expressão Gênica , Japão , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Motivação/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Dopamina D2/genética
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