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1.
BMC Womens Health ; 23(1): 162, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-37024841

RESUMO

Rising rates of chronic conditions were cited as one of the key public health concerns in the Fiscal Year (FY) 2021 U.S. Senate and House of Representatives appropriations bills, where a review of current National Institutes of Health (NIH) portfolios relevant to research on women's health was requested. Chronic conditions were last defined by the US Department of Health and Human Services (HHS) in 2010. However, existing definitions of chronic conditions do not incorporate sex or gender considerations. Sex and gender influence health, yet significant knowledge gaps exist in the evidence-base for prevention, diagnosis, and treatment of chronic diseases amongst women. The presentation, prevalence, and long-term effects of chronic conditions and multimorbidity differs in women from men. A clinical framework was developed to adequately assess the NIH investment in research related to chronic conditions in women. The public health needs and NIH investment related to conditions included in the framework were measured. By available measures, research within the NIH has not mapped to the burden of chronic conditions among women. Clinical research questions and endpoints centered around women can be developed and implemented; clinical trials networks with expanded or extended eligibility criteria can be created; and data science could be used to extrapolate the effects of overlapping or multiple morbidities on the health of women. Aligning NIH research priorities to address the specific needs of women with chronic diseases is critical to addressing women's health needs from a life course perspective.


Assuntos
National Institutes of Health (U.S.) , Saúde da Mulher , Masculino , Estados Unidos , Feminino , Humanos , Saúde Pública , Doença Crônica
2.
Mol Psychiatry ; 25(12): 3304-3321, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-30120415

RESUMO

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find that 5-HT2C receptor antagonism potentiates the antidepressant and anxiolytic effects of SSRIs. Together our findings demonstrate opposing roles for 5-HT2C receptors in the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists for both reduction of motor side effects of SSRIs and augmentation of therapeutic antidepressant and anxiolytic effects.


Assuntos
Receptor 5-HT2C de Serotonina , Inibidores Seletivos de Recaptação de Serotonina , Animais , Gânglios da Base , Dopamina , Camundongos , Serotonina , Substância Negra
3.
Mol Psychiatry ; 25(9): 2070-2085, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626912

RESUMO

Although long-studied in the central nervous system, there is increasing evidence that dopamine (DA) has important roles in the periphery including in metabolic regulation. Insulin-secreting pancreatic ß-cells express the machinery for DA synthesis and catabolism, as well as all five DA receptors. In these cells, DA functions as a negative regulator of glucose-stimulated insulin secretion (GSIS), which is mediated by DA D2-like receptors including D2 (D2R) and D3 (D3R) receptors. However, the fundamental mechanisms of DA synthesis, storage, release, and signaling in pancreatic ß-cells and their functional relevance in vivo remain poorly understood. Here, we assessed the roles of the DA precursor L-DOPA in ß-cell DA synthesis and release in conjunction with the signaling mechanisms underlying DA's inhibition of GSIS. Our results show that the uptake of L-DOPA is essential for establishing intracellular DA stores in ß-cells. Glucose stimulation significantly enhances L-DOPA uptake, leading to increased DA release and GSIS reduction in an autocrine/paracrine manner. Furthermore, D2R and D3R act in combination to mediate dopaminergic inhibition of GSIS. Transgenic knockout mice in which ß-cell D2R or D3R expression is eliminated exhibit diminished DA secretion during glucose stimulation, suggesting a new mechanism where D2-like receptors modify DA release to modulate GSIS. Lastly, ß-cell-selective D2R knockout mice exhibit marked postprandial hyperinsulinemia in vivo. These results reveal that peripheral D2R and D3R receptors play important roles in metabolism through their inhibitory effects on GSIS. This opens the possibility that blockade of peripheral D2-like receptors by drugs including antipsychotic medications may significantly contribute to the metabolic disturbances observed clinically.


Assuntos
Dopamina , Células Secretoras de Insulina , Animais , Dopamina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo
4.
Proc Natl Acad Sci U S A ; 114(22): 5719-5724, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28507136

RESUMO

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.


Assuntos
Gânglios da Base/fisiologia , Transportador 3 de Aminoácido Excitatório/genética , Atividade Motora/genética , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Anfetaminas/farmacologia , Animais , Linhagem Celular , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Asseio Animal/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Receptores de Dopamina D1/metabolismo , Reflexo de Sobressalto/fisiologia
5.
Pediatr Res ; 83(2): 506-513, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29053702

RESUMO

BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH) is the only available intervention, but neuroprotection is incomplete and variable. Seizures are common in infants with HIE undergoing TH and may worsen outcome. Phenobarbital (PB) is sometimes added, although use of prophylactic PB is controversial in the neonate. We hypothesize that prophylactic PB will not reduce, and may enhance, the neuroprotective effects of TH on brain injury and motor outcomes in the postnatal day 10 (P10) hypoxic-ischemic (HI) rat.MethodsP10 rat pups were subjected to unilateral HI and 4 h recovery with: normothermia (N); hypothermia (TH); and hypothermia with phenobarbital (TH+PB). Brain damage was assessed longitudinally at 24 h and 2 weeks using brain magnetic resonance imaging and 12 weeks using histochemical analysis. Motor function was assessed with the beam walk and cylinder tests.ResultsTH and TH+PB induced neuroprotection, as measured by global brain damage score and improved motor function. Exploratory analyses suggest that TH+PB may confer enhanced protection, especially to the extent of damage.ConclusionProphylactic PB with TH is not deleterious and may provide additional long-term neuroprotection, including improvement of motor outcomes following HI in the term-equivalent, neonatal rat.


Assuntos
Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/patologia , Fenobarbital/uso terapêutico , Animais , Animais Recém-Nascidos , Anticonvulsivantes/uso terapêutico , Comportamento Animal , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Feminino , Hipotermia , Imageamento por Ressonância Magnética , Masculino , Destreza Motora , Neuroproteção , Ratos , Ratos Wistar , Convulsões/terapia , Temperatura , Fatores de Tempo
6.
J Neurosci ; 36(15): 4377-88, 2016 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-27076432

RESUMO

Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [(11)C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. Moreover, load-dependent changes in connectivity between left and right frontoparietal networks (Δ connectivity lFPN-rFPN) predicted interindividual differences in task performance more accurately than other fMRI and PET imaging measures. Δ Connectivity lFPN-rFPN was not related to cortical dopamine release capacity. A second study in unmedicated patients with schizophrenia showed no abnormalities in load-dependent connectivity but showed a weaker relationship between Δ connectivity lFPN-rFPN and working memory performance in patients compared with matched healthy individuals. Poor working memory performance in patients was, in contrast, related to deficient cortical dopamine release. Our findings indicate that interactions between brain networks dynamically adapt to fluctuating environmental demands. These dynamic adaptations underlie successful working memory performance in healthy individuals and are not well predicted by amphetamine-induced dopamine release capacity. SIGNIFICANCE STATEMENT: It is unclear how communication between brain networks responds to changing environmental demands during complex cognitive processes. Also, unknown in regard to these network dynamics is the role of neuromodulators, such as dopamine, and whether their dysregulation could underlie cognitive deficits in neuropsychiatric illness. We found that connectivity between brain networks changes with working-memory load and greater increases predict better working memory performance; however, it was not related to capacity for dopamine release in the cortex. Patients with schizophrenia did show dynamic internetwork connectivity; however, this was more weakly associated with successful performance in patients compared with healthy individuals. Our findings indicate that dynamic interactions between brain networks may support the type of flexible adaptations essential to goal-directed behavior.


Assuntos
Dopamina/metabolismo , Memória de Curto Prazo , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adulto , Feminino , Lobo Frontal/fisiopatologia , Humanos , Individualidade , Imageamento por Ressonância Magnética , Masculino , Lobo Parietal/fisiopatologia , Tomografia por Emissão de Pósitrons , Desempenho Psicomotor , Pirrolidinas , Compostos Radiofarmacêuticos , Salicilamidas
7.
Hum Brain Mapp ; 38(2): 678-687, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27659299

RESUMO

Deficits in attention have been implicated in Obsessive-Compulsive Disorder (OCD), yet their neurobiological bases are poorly understood. In unmedicated adults with OCD (n = 30) and healthy controls (n = 32), they used resting state functional connectivity MRI (rs-fcMRI) to examine functional connectivity between two neural networks associated with attentional processes: the default mode network (DMN) and the salience network (SN). They then used path analyses to examine putative relationships across three variables of interest: DMN-SN connectivity, attention, and OCD symptoms. In the OCD compared with healthy control participants, there was significantly reduced inverse connectivity between the anterior medial prefrontal cortex (amPFC) and the anterior insular cortex, regions within the DMN and SN, respectively. In OCD, reduced inverse DMN-SN connectivity was associated with both increased OCD symptom severity and decreased sustained attention. Path analyses were consistent with a potential mechanistic explanation: OCD symptoms are associated with an imbalance in DMN-SN networks that subserve attentional processes and this effect of OCD on DMN-SN connectivity is associated with decreased sustained attention. This work builds upon a growing literature suggesting that reduced inverse DMN-SN connectivity may represent a trans-diagnostic marker of attentional processes and suggests a potential mechanistic account of the relationship between OCD and attention. Reduced inverse DMN-SN connectivity may be an important target for treatment development to improve attention in individuals with OCD. Hum Brain Mapp 38:678-687, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Córtex Cerebral/fisiopatologia , Modelos Neurológicos , Vias Neurais/fisiopatologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Adolescente , Adulto , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 111(20): 7450-5, 2014 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-24794528

RESUMO

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.


Assuntos
Hipocampo/embriologia , Interneurônios/citologia , Inibição Neural , Transplante de Células-Tronco , Animais , Transtornos Cognitivos/fisiopatologia , Ciclina D2/genética , Modelos Animais de Doenças , Dopamina/metabolismo , Medo , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Parvalbuminas/metabolismo , Transtornos Psicóticos/fisiopatologia , Células-Tronco/citologia
9.
Pediatr Res ; 78(3): 264-71, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25996893

RESUMO

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity in survivors. Therapeutic hypothermia (TH) is the only available intervention, but the protection is incomplete. Preclinical studies of HIE/TH in the rodent have relied on the postnatal day (P) 7 rat whose brain approximates a 32-36 wk gestation infant, less relevant for these studies. We propose that HIE and TH in the term-equivalent P10 rat will be more translational. METHODS: P10-11 rat pups were subjected to unilateral hypoxia-ischemia (HI) and 4 h recovery in normothermic (N) or hypothermic (TH) conditions. Brain damage was assessed longitudinally at 24 h, 2 wk, and 12 wk. Motor function was assessed with the beam walk; recognition memory was measured by novel object recognition. RESULTS: Neuroprotection with TH was apparent at 2 and 12 wk in both moderately and severely damaged animals. TH improved motor function in moderate, but not severe, damage. Impaired object recognition occurred with severe damage with no evidence of protection of TH. CONCLUSION: This adaptation of the immature rat model of HI provides a reproducible platform to further study HIE/TH in which individual animals are followed up longitudinally to provide a useful translational preclinical model.


Assuntos
Encéfalo/patologia , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/fisiopatologia , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/fisiopatologia , Feminino , Aprendizagem , Imageamento por Ressonância Magnética , Masculino , Modelos Animais , Destreza Motora , Gravidez , Ratos , Ratos Wistar , Temperatura , Nascimento a Termo , Fatores de Tempo , Pesquisa Translacional Biomédica
10.
Viruses ; 16(4)2024 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-38675969

RESUMO

The prevalence of hepatitis B and delta viruses (HBV/HDV) among people who use drugs (PWUD) remains largely unknown. In the context of one Philadelphia-based harm reduction organization (HRO), this study aimed to assess HBV/HDV prevalence and facilitate linkage to care. Participants completed a demographic HBV/HDV risk factor survey and were screened for HBV and reflexively for HDV if positive for HBV surface antigen or isolated core antibody. Fisher's exact tests and regression were used to understand relationships between risks and HBV blood markers. Of the 498 participants, 126 (25.3%) did not have hepatitis B immunity, 52.6% had been vaccinated against HBV, and 17.9% had recovered from a past infection. Eleven (2.2%) participants tested positive for isolated HBV core antibody, 10 (2.0%) for HBV surface antigen, and one (0.2%) for HDV antibody. History of incarceration was associated with current HBV infection, while transactional sex and experience of homelessness were predictive of previous exposure. This study found high rates of current and past HBV infection, and a 10% HBV/HDV co-infection rate. Despite availability of vaccine, one quarter of participants remained vulnerable to infection. Findings demonstrate the need to improve low-threshold HBV/HDV screening, vaccination, and linkage to care among PWUD. The study also identified gaps in the HBV/HDV care cascade, including lack of point-of-care diagnostics and lack of support for HROs to provide HBV services.


Assuntos
Hepatite B , Hepatite D , Programas de Rastreamento , Humanos , Feminino , Masculino , Philadelphia/epidemiologia , Hepatite B/prevenção & controle , Hepatite B/epidemiologia , Hepatite B/imunologia , Adulto , Pessoa de Meia-Idade , Hepatite D/epidemiologia , Hepatite D/diagnóstico , Hepatite D/imunologia , Prevalência , Usuários de Drogas/estatística & dados numéricos , Fatores de Risco , Adulto Jovem , Vírus Delta da Hepatite/imunologia , Vírus Delta da Hepatite/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/genética , Antígenos de Superfície da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue
11.
Birth Defects Res C Embryo Today ; 99(4): 247-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24339036

RESUMO

Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably ß-N-methylamino-l-alanine l-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction.


Assuntos
Cycas/química , Cycas/toxicidade , Mutagênicos/toxicidade , Diamino Aminoácidos/toxicidade , Esclerose Lateral Amiotrófica/induzido quimicamente , Esclerose Lateral Amiotrófica/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Toxinas de Cianobactérias , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Mutagênicos/química , Neurotoxinas/química , Neurotoxinas/toxicidade
12.
Affect Sci ; 4(3): 600-607, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37744987

RESUMO

Affective science is a broad and burgeoning field, and the National Institutes of Health (NIH) support research on a similarly broad range of topics. Across NIH, funding is available for basic, translational, and intervention research, including research in non-human animals, healthy populations, and those with or at risk for disease. Multiple NIH Institutes and Centers have specific programs devoted to topics within the affective science umbrella. Here, we introduce the funding priorities of these six: the National Cancer Institute (NCI), National Center for Complementary and Integrative Health (NCCIH), National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Institute on Drug Abuse (NIDA), and National Institute on Minority Health and Health Disparities (NIMHD). We then discuss overlapping themes and offer a perspective on promising research directions.

13.
J Neurosci ; 31(44): 15742-50, 2011 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-22049417

RESUMO

Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits through L-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRI-based therapy.


Assuntos
Gânglios da Base/efeitos dos fármacos , Dopamina/metabolismo , Fluoxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Gânglios da Base/patologia , Gânglios da Base/fisiopatologia , Contagem de Células , Cromatografia Líquida de Alta Pressão/métodos , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Fluoxetina/uso terapêutico , Ácido Homovanílico/metabolismo , Levodopa/farmacologia , Levodopa/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Desempenho Psicomotor/efeitos dos fármacos , Distribuição Aleatória , Teste de Desempenho do Rota-Rod , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Transdução de Sinais/fisiologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos
14.
Proc Natl Acad Sci U S A ; 105(19): 7076-81, 2008 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-18458327

RESUMO

DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.


Assuntos
Alelos , Cognição , Mutação/genética , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Esquizofrenia/genética , Animais , Diferenciação Celular , Transtornos Cognitivos/patologia , Giro Denteado/patologia , Modelos Animais de Doenças , Memória , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Córtex Pré-Frontal/patologia , Fatores de Risco , Transmissão Sináptica
15.
Biol Psychiatry ; 90(12): 829-842, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950210

RESUMO

BACKGROUND: Increased physical activity is a common feature of anorexia nervosa (AN). Although high activity levels are associated with greater risk of developing AN, particularly when combined with dieting, most individuals who diet and exercise maintain a healthy body weight. It is unclear why some individuals develop AN while most do not. A rodent model of resilience and vulnerability to AN would be valuable to research. Dopamine, which is believed to play a crucial role in AN, regulates both reward and activity and may modulate vulnerability. METHODS: Adolescent and young adult female C57BL/6N mice were tested in the activity-based anorexia (ABA) model, with an extended period of food restriction in adult mice. ABA was also tested in dopamine transporter knockdown mice and wild-type littermates. Mice that adapted to conditions and maintained a stable body weight were characterized as resilient. RESULTS: In adults, vulnerable and resilient phenotypes emerged in both the ABA and food-restricted mice without wheels. Vulnerable mice exhibited a pronounced increase in running throughout the light cycle, which dramatically peaked prior to requiring removal from the experiment. Resilient mice exhibited an adaptive decrease in total running, appropriate food anticipatory activity, and increased consumption, thereby achieving stable body weight. Hyperdopaminergia accelerated progression of the vulnerable phenotype. CONCLUSIONS: Our demonstration of distinct resilient and vulnerable phenotypes in mouse ABA significantly advances the utility of the model for identifying genes and neural substrates mediating AN risk and resilience. Modulation of dopamine may play a central role in the underlying circuit.


Assuntos
Anorexia Nervosa , Animais , Anorexia , Anorexia Nervosa/genética , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
16.
Neuron ; 49(4): 603-15, 2006 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-16476668

RESUMO

Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.


Assuntos
Transtornos Cognitivos/genética , Corpo Estriado/metabolismo , Expressão Gênica/fisiologia , Córtex Pré-Frontal/anormalidades , Receptores de Dopamina D2/metabolismo , Adenilil Ciclases/metabolismo , Análise de Variância , Animais , Comportamento Animal/fisiologia , Isótopos de Carbono/farmacocinética , Transtornos Cognitivos/fisiopatologia , Desoxiglucose/farmacocinética , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Doxiciclina/farmacologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Masculino , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , N-Metilaspartato/toxicidade , Córtex Pré-Frontal/lesões , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ensaio Radioligante/métodos , Tempo de Reação/genética , Receptores de Dopamina D2/genética , Espiperona/farmacocinética , Fatores de Tempo , Trítio/farmacocinética
17.
Brain Behav Immun ; 24(5): 839-49, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19944751

RESUMO

Recurrent hypoglycemia is a common problem among infants and children that is associated with several metabolic disorders and insulin-dependent diabetes mellitus. Although studies have reported a relationship between a history of juvenile hypoglycemia and psychological health problems, the direct effects of recurrent moderate hypoglycemia have not been fully determined. Thus, in this study, we used an animal model to examine the effects of recurrent hypoglycemia during the juvenile period on affective, social, and motor function (assessed under euglycemic conditions) across development. To model recurrent hypoglycemia, rats were administered 5 U/kg of insulin or saline twice per day from postnatal day (P)10 to P19. Body weight gain was retarded in insulin-treated rats during the treatment period, but recovered by the end of treatment. However, insulin-treated rats displayed increases in affective reactivity that emerged early during treatment and persisted after treatment into early adulthood. Specifically, insulin-treated pups showed increased maternal separation-induced vocalizations as infants, and an exaggerated acoustic startle reflex as juveniles and young adults. Moreover, young adult rats with a history of recurrent juvenile hypoglycemia exhibited increased fear-potentiated startle and increases in behavioral and hormonal responses to restraint stress. Some of these effects were sex-dependent. The changes in affective behavior in insulin-exposed pups were accompanied by decreases in adolescent social play behavior. These results provide evidence that recurrent, transient hypoglycemia during juvenile development can lead to increases in fear-related behavior and stress reactivity. Importantly, these phenotypes are not reversed with normalization of blood glucose and may persist into adulthood.


Assuntos
Comportamento Animal/fisiologia , Hipoglicemia/fisiopatologia , Atividade Motora/fisiologia , Comportamento Social , Análise de Variância , Animais , Glicemia/metabolismo , Feminino , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Insulina , Masculino , Privação Materna , Distribuição Aleatória , Ratos , Recidiva , Restrição Física , Filtro Sensorial/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia
18.
Dev Psychobiol ; 52(2): 121-32, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20091810

RESUMO

Severe psychological stress in the first trimester of pregnancy increases the risk of schizophrenia in the offspring. To begin to investigate the role of glucocorticoid receptors in this association, we determined the effects of the glucocorticoid dexamethasone (2 mg/kg), administered to pregnant rats on gestation days 6-8, on maternal behaviors and schizophrenia-relevant behaviors in the offspring. Dams receiving dexamethasone exhibited increased milk ejection bouts during nursing. Offspring of dexamethasone-treated dams (DEX) showed decreased juvenile social play and a blunted acoustic startle reflex in adolescence and adulthood, effects that were predicted by frequency of milk ejections in the dams. DEX offspring also showed increased prepulse inhibition of startle and reduced amphetamine-induced motor activity, effects not correlated with maternal behavior. It is postulated that over-stimulation of receptors targeted by glucocorticoids in the placenta or other maternal tissues during early gestation can lead to psychomotor and social behavioral deficits in the offspring. Moreover, some of these deficits may be mediated by alterations in postnatal maternal behavior and physiology produced by early gestational exposure to excess glucocorticoids.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dexametasona/farmacologia , Comportamento Materno/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de Glucocorticoides/fisiologia , Comportamento Social , Anfetamina/farmacologia , Análise de Variância , Animais , Feminino , Glucocorticoides/farmacologia , Masculino , Troca Materno-Fetal , Jogos e Brinquedos , Gravidez , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos
19.
Nat Neurosci ; 9(6): 729-31, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16648847

RESUMO

Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.


Assuntos
Proliferação de Células/efeitos da radiação , Giro Denteado/fisiologia , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento Animal/efeitos da radiação , Bromodesoxiuridina , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Divisão Celular/efeitos da radiação , Giro Denteado/efeitos dos fármacos , Giro Denteado/efeitos da radiação , Ambiente Controlado , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Comportamento Alimentar/efeitos da radiação , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Habituação Psicofisiológica/efeitos da radiação , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos da radiação , Transtornos da Memória/fisiopatologia , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Células-Tronco/efeitos da radiação , Raios X
20.
J Neurosci ; 28(27): 6872-83, 2008 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-18596162

RESUMO

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1(tm1.1Lwr+/-)) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.


Assuntos
Corpo Estriado/anormalidades , Hipocampo/anormalidades , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/anormalidades , Transtornos de Sensação/genética , Animais , Atrofia/genética , Atrofia/metabolismo , Atrofia/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Heterozigoto , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ventrículos Laterais/anormalidades , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Inibição Neural/genética , Vias Neurais/anormalidades , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Neuregulina-1 , Agonistas Nicotínicos/farmacologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Regiões Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transtornos de Sensação/metabolismo , Transtornos de Sensação/fisiopatologia
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