RESUMO
Major depressive disorder (MDD) is a debilitating and costly human condition. Treatment for MDD relies heavily on the use of antidepressants that are slow to produce mood-related changes and are not effective in all patients, such as selective serotonin reuptake inhibitors (SSRIs). Several novel compounds, including negative allosteric modulators of GABA-A receptors containing the α5-subunit (GABA-NAMs), are under investigation for potential fast acting therapeutic use in MDD. Preclinical evidence that these compounds produce a rapid antidepressant-like response comes primarily from simple tests of escape behavior and preference for rewarding stimuli after chronic stress. To increase the ethological relevance of these compounds, we tested the hypothesis that the GABA-NAM, L-655,708, would produce an antidepressant-like response in more complex stress-sensitive social and sex behaviors, which are of relevance to the symptoms of human depression. In male rats subjected to chronic restraint stress, injection of L-655,708 increased reward in a sexual conditioned place preference task, increased male sexual activity with a receptive female, and re-established male social dominance hierarchies within 24 h. We also report increased sucrose preference in the social defeat stress (SDS) model of depression following GABA-NAM administration, demonstrating that its antidepressant-like actions are independent of the type of chronic stress administered. This work extends the impact of GABA-NAMs beyond traditional tests of anhedonia and further supports the development of alpha5 subunit-selective GABA-NAMs as a potential fast-acting therapeutic approach for treating human MDD.
Assuntos
Transtorno Depressivo Maior , Receptores de GABA , Ratos , Humanos , Masculino , Feminino , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/farmacologia , Receptores de GABA-A/fisiologia , Comportamento Sexual , Ácido gama-AminobutíricoRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. After publication, Scott M. Thompson found significant concerns about the data and duly notified The University of Maryland. The University of Maryland conducted an internal investigation which confirmed that the article was compromised. Namely in Figure 2B, the Investigation Committee determined that the western blots used to create the figure were not the ones used for the quantification and concluded that the figure was falsified to fit the hypothesis. In Figure 2C and D, the Investigation Committee determined that the densitometry data (pCaMKII, pS831, CamKII and GluA1) used to create the histogram were falsified to fit the hypothesis.
RESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. After publication, Scott M. Thompson found significant concerns about the data and duly notified The University of Maryland. The University of Maryland conducted an internal investigation which confirmed that the article was compromised. Namely in Figure 2B, the Investigation Committee determined that the western blots used to create the figure were not the ones used for the quantification and concluded that the figure was falsified to fit the hypothesis. In Figure 2C and 2D, the Investigation Committee determined that the densitometry data (pCaMKII, pS831, CamKII and GluA1) used to create the histogram were falsified to fit the hypothesis.
Assuntos
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
Optogenetics is a technology that is growing rapidly in neuroscience, establishing itself as a fundamental investigative tool. As this tool is increasingly utilized across the neuroscience community and is one of the primary research techniques being presented at neuroscience conferences and in journals, we believe that it is important that this technology is introduced into the undergraduate neuroscience research laboratory. While there has been a significant body of work concentrated to deploy optogenetics in invertebrate model organisms, little to no work has focused on brining this technology to mammalian model organisms in undergraduate neuroscience laboratories. The establishment of in vivo optogenetics could provide for high-impact independent research projects for upper-level undergraduate students. Here we review the considerations for establishing in vivo optogenetics with the use of rodents in an undergraduate laboratory setting and provide some cost-saving guidelines to assist in making optogenetic technologies financially accessible. We discuss opsin selection, cell-specific opsin expression strategies, species selection, experimental design, selection of light delivery systems, and the construction of implantable optical fibers for the application of in vivo optogenetics in rodents.
RESUMO
Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior.
Assuntos
Região CA1 Hipocampal/metabolismo , Corticosterona/metabolismo , Aprendizagem Espacial , Estresse Psicológico/metabolismo , Sinapses/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Corticosterona/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Estresse Psicológico/fisiopatologia , Sinapses/metabolismoRESUMO
Cholinergic innervation of the prefrontal cortex is critical for various forms of cognition, although the efferent modulators contributing to acetylcholine (ACh) release are not well understood. The main source of cortical ACh, the basal forebrain, receives projections from lateral and perifornical hypothalamic neurons releasing the peptides orexin (orexin A; OxA, and orexin B; OxB), of which OxA is hypothesized to play a role in various cognitive functions. We sought to assess one such function known to be susceptible to basal forebrain cholinergic manipulation, olfactory discrimination acquisition, and reversal learning, in rats following intra-basal forebrain infusion of OxA or the orexin 1 receptor (OxR1) antagonist SB-334867. OxA administration facilitated, while OxR1 antagonism impaired performance on both the acquisition and reversal portions of the task. These data suggest that orexin acting in the basal forebrain may be important for cortical-dependant executive functions, possibly through the stimulation of cortical ACh release.
Assuntos
Prosencéfalo Basal/metabolismo , Função Executiva/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Aprendizagem/fisiologia , Neuropeptídeos/metabolismo , Receptores de Orexina/metabolismo , Animais , Masculino , Microdiálise , Percepção Olfatória/fisiologia , Orexinas , Ratos , Ratos Sprague-DawleyRESUMO
Chronic stress promotes depression, but how it disrupts cognition and mood remains unknown. Chronic stress causes atrophy of pyramidal cell dendrites in the hippocampus and cortex in human and animal models, and a depressive-like behavioral state. We now test the hypothesis that excitatory temporoammonic (TA) synapses in the distal dendrites of CA1 pyramidal cells in rats are altered by chronic unpredictable stress (CUS) and restored by chronic antidepressant treatment, in conjunction with the behavioral consequences of CUS. We observed a decrease in AMPAR-mediated excitation at TA-CA1 synapses, but not Schaffer collateral-CA1 synapses, after CUS, with a corresponding layer-specific decrease in GluA1 expression. Both changes were reversed by chronic fluoxetine. CUS also disrupted long-term memory consolidation in the Morris water maze, a function of TA-CA1 synapses. The decreases in TA-CA1 AMPAR-mediated excitation and performance in the consolidation test were correlated positively with decreases in sucrose preference, a measure of anhedonia. We conclude that chronic stress selectively decreases AMPAR number and function at specific synapses and suggest that this underlies various depressive endophenotypes. Our findings provide evidence that glutamatergic dysfunction is an underlying cause of depression and that current first-line antidepressant drugs act by restoring excitatory synaptic strength. Our findings suggest novel therapeutic targets for this debilitating disease.
Assuntos
Região CA1 Hipocampal/fisiopatologia , Células Piramidais/metabolismo , Receptores de AMPA/metabolismo , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Fluoxetina/farmacologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
The causes of major depression remain unknown. Antidepressants elevate concentrations of monoamines, particularly serotonin, but it remains uncertain which downstream events are critical to their therapeutic effects. We found that endogenous serotonin selectively potentiated excitatory synapses formed by the temporoammonic pathway with CA1 pyramidal cells via activation of serotonin receptors (5-HT(1B)Rs), without affecting nearby Schaffer collateral synapses. This potentiation was expressed postsynaptically by AMPA-type glutamate receptors and required calmodulin-dependent protein kinase-mediated phosphorylation of GluA1 subunits. Because they share common expression mechanisms, long-term potentiation and serotonin-induced potentiation occluded each other. Long-term consolidation of spatial learning, a function of temporoammonic-CA1 synapses, was enhanced by 5-HT(1B)R antagonists. Serotonin-induced potentiation was quantitatively and qualitatively altered in a rat model of depression, restored by chronic antidepressants, and required for the ability of chronic antidepressants to reverse stress-induced anhedonia. Changes in serotonin-mediated potentiation, and its recovery by antidepressants, implicate excitatory synapses as a locus of plasticity in depression.
Assuntos
Depressão/metabolismo , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Serotonina/fisiologia , Sinapses/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Serotonina/deficiência , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Sinapses/efeitos dos fármacosRESUMO
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28-49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABA(A) receptors with open Cl(-) channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs.
Assuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Espinhas Dendríticas/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Memória de Curto Prazo/efeitos dos fármacos , Fatores Etários , Animais , Espinhas Dendríticas/patologia , Giro Denteado/efeitos dos fármacos , Dopamina/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Transtornos da Memória/fisiopatologia , Núcleo Accumbens/efeitos dos fármacos , Olanzapina , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , TempoRESUMO
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.
Assuntos
Benzodiazepinas/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Recompensa , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Benzamidas/farmacocinética , Benzazepinas/farmacologia , Peso Corporal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacocinética , Seguimentos , Masculino , Olanzapina , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Long-Evans , Trítio/farmacocinéticaRESUMO
Neurofibromatosis 1 (NF1) is a common genetic disorder known to cause a variety of physiological symptoms such as the formation of both benign and malignant tumors, and is also known to cause visuospatial learning deficits. Mouse models of NF1 show increased GTP activation of ras which may alter K+ channels. One candidate K+ channel that may contribute to deficits in NF1 is the SK (small conductance calcium-activated potassium) channel due to its role in regulation of long term potentiation (LTP), a mechanism of learning which has been shown to be impaired in Nf1(+/-) mice. We found that administration of apamin (SK antagonist) either through i.p. injection or micro-osmotic pump to Nf1(+/-) mice significantly improved performance on the water maze task in comparison to saline treated Nf1(+/-) mice on the third day of training and on the corresponding probe test. In this study we demonstrate a possible mechanism for the learning deficits seen in Nf1(+/-) mice and a possible drug therapy for rescuing these deficits.
Assuntos
Apamina/uso terapêutico , Neurofibromatose 1/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Transgênicos , Neurofibromatose 1/genética , Fatores de TempoRESUMO
Fundamental to creativity is prior knowledge and learning capability. One can be creative only to the extent that one's prior knowledge and learning abilities enable. Many of the mental functions of humans that are affected by neuropathology involve levels of learning ability that supercede those used by most animal researchers. Yet there is literature showing that there are similarities in structure and function in the cerebrum within class Mammalia and that nonhuman animals are capable of higher levels of learning than those typically studied by neuroscientists. Reviews of abstracts from the 2005 meeting of the Society for Neuroscience reveal that most neurobehavioral research with animals has involved relatively low levels of learning ability. Thomas's [R.K. Thomas, Brain, Behav. Evol. 17 (1980) 452-474.] hierarchy of learning abilities has been revised here to better include Learning Set Formation which is fundamental to most forms of higher learning. This paper summarizes both the rationale and the methodologies that might be used to assess the roles of neuroanatomical structures involved in the psychological processes that serve as the bases of creativity.
Assuntos
Cognição , Criatividade , Envelhecimento/patologia , Envelhecimento/psicologia , Animais , Comportamento Animal , Ciência Cognitiva/métodos , Humanos , Inteligência , Aprendizagem , Modelos Animais , Modelos Neurológicos , Modelos Psicológicos , NeuroanatomiaRESUMO
Rats were first trained to acquire an olfactory discrimination learning set (ODLS) on 40 olfactory-unique discrimination problems. Following acquisition of ODLS, animals were lesioned bilaterally in the nucleus basalis magnocellularis (nBM) using either quisqualic acid (QUIS) or 192 IgG-saporin (SAP). QUIS animals performed significantly worse than control animals following surgery and SAP animals performed transiently worse than control animals. Despite lowered performances, both QUIS and SAP animals performed significantly better than expected by chance on trial 2 indicating retention of the ODLS previously acquired. Implications for the role of the nBM in aspects of cognitive flexibility and its role in acquisition versus retention are discussed.
Assuntos
Núcleo Basal de Meynert/fisiopatologia , Lesões Encefálicas/patologia , Aprendizagem por Discriminação/fisiologia , Retenção Psicológica/fisiologia , Análise de Variância , Animais , Anticorpos Monoclonais , Núcleo Basal de Meynert/lesões , Comportamento Animal , Lesões Encefálicas/induzido quimicamente , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Aprendizagem por Discriminação/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , N-Glicosil Hidrolases , Bulbo Olfatório/fisiopatologia , Ácido Quisquálico , Ratos , Ratos Long-Evans , Retenção Psicológica/efeitos dos fármacos , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Fatores de TempoRESUMO
Rats with bilateral 192 IgG-saporin lesions to the nucleus basalis magnocellularis (nBM) were tested on olfactory discrimination learning set (ODLS), olfactory discrimination reversal learning set (DRLS), and open field activity. Control animals demonstrated learning set in both the ODLS and DRLS tasks. The nBM-lesioned animals showed initial acquisition impairment in learning set in the ODLS task but eventually demonstrated learning set in both ODLS and DRLS tasks. There were no group differences in open-field activity. Results suggest that removal of the nBM cholinergic system through 192 IgG-saporin lesions impairs early acquisition of learning set compared to control animals, but does not prevent later use of learning set formation. Implications for the non-cholinergic basal forebrain cells in learning set are discussed.