RESUMEN
Working memory is a cognitive function serving goal-oriented behavior. In the last decade, working memory training has been shown to improve performance and its efficacy for the treatment of several neuropsychiatric disorders has begun to be examined. Neuroimaging studies have contributed to elucidate the brain areas involved but little is known about the underlying cellular events. A growing body of evidence has provided a link between working memory and relatively long-lasting epigenetic changes. However, the effects elicited by working memory training at the epigenetic level remain unknown. In this study we establish an animal model of working memory training and explore the changes in histone H3 acetylation (H3K9,14Ac) and histone H3 dimethylation on lysine 27 (H3K27Me2) triggered by the procedure in the brain regions of the corticostriatothalamic circuit (prelimbic/infralimbic cortex (PrL/IL), dorsomedial striatum (DMSt) and dorsomedial thalamus (DMTh)). Mice trained on a spontaneous alternation task showed improved alternation scores when tested with a retention interval that disrupts the performance of untrained animals. We then determined the involvement of the brain areas of the corticostriatothalamic circuit in working memory training by measuring the marker of neuronal activation c-fos. We observed increased c-fos levels in PrL/IL and DMSt in trained mice 90min after training. These animals also presented lower immunoreactivity for H3K9,14Ac in DMSt 24h but not 90min after the procedure. Increases in H3K27Me2, a repressive chromatin mark, were found in the DMSt and DMTh 24h after the task. Altogether, we present a mouse model to study the cellular underpinnings of working memory training and provide evidence indicating delayed chromatin remodeling towards repression triggered by the procedure.
Asunto(s)
Encéfalo/fisiología , Ensamble y Desensamble de Cromatina/fisiología , Aprendizaje , Memoria a Corto Plazo/fisiología , Animales , Encéfalo/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Retención en Psicología , Estadísticas no ParamétricasRESUMEN
RATIONALE: Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. OBJECTIVE: Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. METHODS: Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. RESULTS: In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. CONCLUSION: In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.
Asunto(s)
Hormona Liberadora de Corticotropina/biosíntesis , Fluoxetina/farmacología , Desamparo Adquirido , Receptores de Hormona Liberadora de Corticotropina/biosíntesis , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/psicología , Técnica del Anticuerpo Fluorescente , Fluoxetina/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hibridación in Situ , Masculino , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Dysfunction of hippocampal plasticity has been proposed to play a critical role in the pathophysiology of depression. However, antidepressant drug effects on synaptic plasticity and cytoskeletal remodeling remain controversial. The aim of the present study was to evaluate in animals exposed to the learned helplessness (LH) paradigm, an accepted experimental model of depression, the effect of chronic treatment with fluoxetine (FLX) on synaptic and cytoskeletal proteins known to undergo plastic changes. Synaptophysin (SYN), postsynaptic density 95 (PSD-95), axon growth-associated protein 43 (GAP-43), and cytoskeletal proteins (intermediate neurofilaments and MAP-2) were studied in the hippocampus by immunohistochemistry. Whereas LH animals treated 21 days with saline (LH-S group) displayed diminished SYN and PSD-95 immunostainings in the CA3 but not in the DG, chronic treatment with FLX not only reversed the despaired behavior induced by exposure to LH paradigm, but also fully recovered SYN and PSD-95 labeling to control values. Similar results were obtained for the axonal remodeling marker GAP-43. FLX treatment did not modify either the decreased light neurofilament subunit (NFL) observed in the hippocampus of LH animals or any other cytoskeletal protein studied. When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by decreased SYN, PSD-95, and NFL labelings. Results indicate that the synapse remodeling induced by FLX in the CA3 region could underlie its behavioral efficacy despite the absence of cytoskeletal remodeling and that the stability of synaptic changes would depend on the continuous administration of the drug.
Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Conducta Animal/efectos de los fármacos , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/psicología , Fluoxetina/uso terapéutico , Desamparo Adquirido , Sinapsis/metabolismo , Animales , Antidepresivos de Segunda Generación/administración & dosificación , Axones/fisiología , Biomarcadores , Citoesqueleto/efectos de los fármacos , Citoesqueleto/patología , Interpretación Estadística de Datos , Trastorno Depresivo/metabolismo , Fluoxetina/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Masculino , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Wistar , Recurrencia , Sinapsis/efectos de los fármacos , Fijación del TejidoRESUMEN
BACKGROUND: Atrophy of pyramidal hippocampal neurons and of the entire hippocampus has been reported in experimental models of depression and in depressive patients respectively. We investigated the efficacy of valproic acid (VPA) for reversing a depressive-like behaviour and a cytoskeletal alteration in the hippocampus, the loss of the light neurofilament subunit (NF-L). METHODS: Depressive-like behaviour was induced by inescapable stress. Animals were divided into four groups: two to assess the response to 21 days of treatment with 200 mg/kg (I.P.) of valproic acid, and two in which the treatment was interrupted and the effects of VPA were evaluated 90 days later. Depressive-like behaviour was evaluated by the quantification of escape movements in a swimming test. NF-L was quantified by immunohistochemistry in dentate gyrus and CA3 of hippocampus. RESULTS: VPA corrected the depressive-like behaviour and reversed the diminution of NF-L in the hippocampus. Ninety days after the end of the treatment, and in contrast to the results previously obtained with fluoxetine, no recurrence of the depressive-like behaviour was observed. CONCLUSIONS: Despite interruption of the treatment, a long-lasting effect of VPA was observed. A possible relationship between the effect on NF-L and the prevention of depressive-like behaviour recurrence could be suggested.
Asunto(s)
Antidepresivos , Citoesqueleto/efectos de los fármacos , Depresión/tratamiento farmacológico , Hipocampo/citología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Atrofia , Conducta Animal/efectos de los fármacos , Depresión/psicología , Inmunohistoquímica , Masculino , Proteínas de Neurofilamentos/metabolismo , Ratas , Ratas Wistar , Estrés Psicológico/complicaciones , Estrés Psicológico/psicología , Natación/psicología , Fijación del TejidoRESUMEN
It has been demonstrated that the neuronal plasticity and resilience could participate in the pathophysiology of neurodegenerative diseases such as Alzheimer and others like depression and schizophrenia. Recently, it has been proposed a new intracellular pathway, known as Wnt pathway, which could be related to the induction of the plastic changes mentioned above. The glycogen synthase kinase-3beta (GSK-3beta), one of the main enzymes of the Wnt signaling, has been associated to Alzheimer;s and schizophrenia diseases etiology. Furthermore, the mood stabilizing agents;s action mechanism, like lithium and valproic acid, implies the inhibition of this protein. The issue of this work is to describe the proteins that are recruited when this pathway is activated and the GSK-3beta role in the pathologies mentioned.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Depresión/fisiopatología , Esquizofrenia/fisiopatología , Transducción de Señal/fisiología , Proteínas Wnt/fisiología , Enfermedad de Alzheimer/enzimología , Depresión/enzimología , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Plasticidad Neuronal/fisiología , Esquizofrenia/enzimología , Factores de Transcripción , beta Catenina/fisiologíaRESUMEN
Hypercortisolism is a common trait of Cushing's disease and depression. These two disorders also share hippocampal volume decrease and cognitive deficits. However, experimentally induced hypercortisolism induces neuronal atrophy, which has been proposed to be the phenomenon underlying the hippocampal shrinkage. We hypothesized that the above-mentioned atrophy is due to a deleterious effect of high concentrations of glucocorticoids on cytoskeletal proteins. One or two pellets (100 mg each) of corticosterone were subcutaneously implanted in adult rats. Twenty-one days later, light, medium and heavy subunits of intermediate neurofilaments (NFL, NFM and NFH) and the microtubule-associated protein 2 (MAP2) were quantified by immunohistochemistry in Ammon's horn and dentate gyrus. We also evaluated the in vitro glutamate release in hippocampal slices. Both doses of corticosterone induced a decrement of NFL, NFM and NFH in both hippocampal areas but only 200 mg decreased MAP2. This dose also diminished the potassium-stimulated glutamate release. All of these changes seemed not to be due to neuron loss, as no decrement in neuron-specific nuclear protein-positive cells was found. With the exception of NFL, the above-mentioned diminution was not observed in the globus pallidus, one of the brain regions with the lowest glucocorticoid receptor density. These results provide a subcellular insight into the trophic changes found in experimental models of hypercortisolism. The coincidence between decrements in MAP2 and glutamate release suggests possible links between high glucocorticoid levels, dendritic atrophy and the cognitive impairment reported in patients suffering from Cushing's disease and depression.
Asunto(s)
Antiinflamatorios/administración & dosificación , Corticosterona/administración & dosificación , Proteínas del Citoesqueleto/metabolismo , Regulación de la Expresión Génica/genética , Hipocampo/efectos de los fármacos , Animales , Antiinflamatorios/sangre , Recuento de Células/métodos , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Ácido Glutámico/metabolismo , Hipocampo/anatomía & histología , Inmunohistoquímica/métodos , Técnicas In Vitro , Masculino , Fosfopiruvato Hidratasa/metabolismo , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
The proconvulsive effect of the new generation of antidepressants remains controversial. The authors investigated in naïve rats the effect of chronic treatment with fluoxetine (FLX) on the convulsive threshold and on two parameters of the hippocampal glutamatergic neurotransmission: the in vitro glutamate release and the binding of [3H] MK801 to NMDA receptors. While the acute treatment with FLX provoked no change either in seizure susceptibility or in the glutamate release, the chronic treatment decreased the convulsive threshold in coincidence with an increment in the in vitro glutamate release. No significant effects on the binding of [3H] MK801 to NMDA receptors were found to be attributable to the FLX treatment. We also assessed the effect of the chronic treatment with FLX on the seizure threshold in rats exposed to an experimental model of depression, the learned helplessness paradigm (LH). While a decrease in the K+-stimulated glutamate release was observed in non treated LH animals, when they were chronically injected with FLX, no changes in the epileptic susceptibility and no increments in the glutamate release were found. Our results indicate that chronic treatment with FLX decreases the epileptic threshold in naïve but not in LH rats and that this effect correlates with the levels of the hippocampal glutamate release.