RESUMEN
Recent findings in our lab demonstrated that the risk of cocaine relapse is closely linked to the hyperexcitability of cortical pyramidal neurons in the secondary motor cortex (M2), noticeable 45 days after cocaine intravenous self-administration (IVSA). The present study was designed to explore the underlying mechanisms of neuronal alterations in M2. Our hypothesis was that M2 neurons were affected directly by cocaine taking behaviors. This hypothesis was tested by monitoring individual neuronal activity in M2 using MiniScopes for in vivo Ca 2+ imaging in C57BL/6J mice when they had access to cocaine IVSA as a reinforcement (RNF) contingent to active lever press (ALP) but not to inactive lever press (ILP). With support of our established pipeline to processing Ca 2+ imaging data, the current study was designed to monitor M2 neuronal ensembles at the single-neuron level in real time with high temporal resolution and high throughput in each IVSA session and longitudinally among multiple IVSA sessions. Specifically, five consecutive 1-hr daily IVSA sessions were used to model the initial cocaine taking behaviors. Besides detailed analyses of IVSA events (ALP, ILP, and RNF), the data from Ca 2+ imaging recordings in M2 were analyzed by (1) comparing neuronal activation within a daily IVSA session (i.e., the first vs. the last 15 min) and between different daily sessions (i.e., the first vs. the last IVSA day), (2) associating Ca 2+ transients with individual IVSA events, and (3) correlating Ca 2+ transients with the cumulative effects of IVSA events. Our data demonstrated that M2 neurons are exquisitely sensitive to and significantly affected by concurrent operant behaviors and the history of drug exposure, which in turn sculpt the upcoming operant behaviors and the response to drugs. As critical nodes of the reward loop, M2 neurons appear to be the governing center orchestrating the establishment of addiction-like behaviors.
RESUMEN
Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)-as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A's role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2afl/fl (Kdm2a KO), was generated by crossing the Kdm2a floxed mice (Kdm2afl/fl) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (Kdm2afl/fl) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2afl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.
Asunto(s)
Hepatopatías , FN-kappa B , Ratones , Animales , FN-kappa B/genética , FN-kappa B/metabolismo , Hígado/metabolismo , Inflamación/genética , Inflamación/metabolismo , Transducción de Señal , Hepatopatías/metabolismoRESUMEN
BACKGROUND: Most efforts in addiction research have focused on the involvement of the medial prefrontal cortex, including the infralimbic, prelimbic, and anterior cingulate cortical areas, in cocaine-seeking behaviors. However, no effective prevention or treatment for drug relapse is available. METHODS: We focused instead on the motor cortex, including both the primary and supplementary motor areas (M1 and M2, respectively). Addiction risk was evaluated by testing cocaine seeking after intravenous self-administration (IVSA) of cocaine in Sprague Dawley rats. The causal relationship between the excitability of cortical pyramidal neurons (CPNs) in M1/M2 and addiction risk was explored by ex vivo whole-cell patch clamp recordings and in vivo pharmacological or chemogenetic manipulation. RESULTS: Our recordings showed that on withdrawal day 45 (WD45) after IVSA, cocaine, but not saline, increased the excitability of CPNs in the cortical superficial layers (primarily layer 2, denoted L2) but not in layer 5 (L5) in M2. Bilateral microinjection of the GABAA (gamma-aminobutyric acid A) receptor agonist muscimol to the M2 area attenuated cocaine seeking on WD45. More specifically, chemogenetic inhibition of CPN excitability in L2 of M2 (denoted M2-L2) by the DREADD (designer receptor exclusively activated by designer drugs) agonist compound 21 prevented drug seeking on WD45 after cocaine IVSA. This chemogenetic inhibition of M2-L2 CPNs had no effects on sucrose seeking. In addition, neither pharmacological nor chemogenetic inhibition manipulations altered general locomotor activity. CONCLUSIONS: Our results indicate that cocaine IVSA induces hyperexcitability in the motor cortex on WD45. Importantly, the increased excitability in M2, particularly in L2, could be a novel target for preventing drug relapse during withdrawal.
Asunto(s)
Cocaína , Corteza Motora , Ratas , Animales , Ratas Sprague-Dawley , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Comportamiento de Búsqueda de Drogas , Recurrencia , AutoadministraciónRESUMEN
High levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by Fkbp5 is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. Fkbp5 has been previously linked to neurite outgrowth and hippocampal morphology, sex differences in stress response, and epigenetic modification. Presently, primary cultured Fkbp5 KO and WT mouse neurons were examined for neurite outgrowth and mitochondrial signal with and without alcohol. We found neurite specification differences between KO and WT; particularly, mesh-like morphology was observed after alcohol treatment and confirmed higher MitoTracker signal in cultured neurons of Fkbp5 KO compared to WT at both naive and alcohol-treated conditions. Brain regions that express FKBP51 protein were identified, and hippocampus was confirmed to possess a high level of expression. RNA-seq profiling was performed using the hippocampus of naïve or alcohol-injected (2 mg EtOH/Kg) male and female Fkbp5 KO and WT mice. Differentially expressed genes (DEGs) were identified between Fkbp5 KO and WT at baseline and following alcohol treatment, with female comparisons possessing a higher number of DEGs than male comparisons. Pathway analysis suggested that genes affecting calcium signaling, lipid metabolism, and axon guidance were differentially expressed at naïve condition between KO and WT. Alcohol treatment significantly affected pathways and enzymes involved in biosynthesis (Keto, serine, and glycine) and signaling (dopamine and insulin receptor), and neuroprotective role. Functions related to cell morphology, cell-to-cell signaling, lipid metabolism, injury response, and post-translational modification were significantly altered due to alcohol. In summary, Fkbp5 plays a critical role in the response to acute alcohol treatment by altering metabolism and signaling-related genes.
Asunto(s)
Trastornos Relacionados con Alcohol , Etanol , Femenino , Masculino , Animales , Ratones , Etanol/farmacología , Metabolismo de los Lípidos , Inyecciones , Consumo de Bebidas Alcohólicas , GlicinaRESUMEN
FK506-binding protein 51 (encoded by Fkpb51, also known as Fkbp5) has been associated with stress-related mental illness. To investigate its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assisted morphological analysis revealed that male Fkbp51 knock-out (KO) mice possess more elongated dentate gyrus (DG) but shorter hippocampal height in coronal sections when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls and pharmacological manipulation experiments suggest that this may occur through the regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support a role for FKBP51 in the regulation of microtubule-associated protein expression. Furthermore, Fkbp51 KO hippocampi exhibited decreases in ßIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory mechanism of Parkin by FKBP51 and the significance of their interaction on disease onset. KO has more flattened hippocampus using AI-assisted measurement Both pyramidal cell layer (PCL) of CA and granular cell layer (GCL) of DG distinguishable as two layers: deep cell layer and superficial layer. Distinct MAP2 expression between deep and superficial layer between KO and WT, Higher Parkin expression in KO brain Mechanism of FKBP51 inhibition resulting in Parkin, MAP2, Tau, and Tubulin expression differences between KO and WT mice, and resulting neurite outgrowth differences.
Asunto(s)
Hipocampo/metabolismo , Proteínas de Unión a Tacrolimus/genética , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Encéfalo/anatomía & histología , Células Cultivadas , Hipocampo/anatomía & histología , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Neuronas/citología , Neuronas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas de Unión a Tacrolimus/antagonistas & inhibidores , Proteínas de Unión a Tacrolimus/deficiencia , Proteínas de Unión a Tacrolimus/metabolismo , Tubulina (Proteína)/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba , Proteínas tau/metabolismoRESUMEN
It is essential to identify the neuronal mechanisms of Alzheimer's Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aß oligomers (AßOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AßO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AßO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.
Asunto(s)
Enfermedad de Alzheimer , Receptores AMPA , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Calcio/metabolismo , Humanos , Motivación , Núcleo Accumbens/metabolismo , Receptores AMPA/metabolismo , Receptores Sensibles al Calcio , Sinapsis/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiónicoRESUMEN
Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca2+ influx-triggered excitotoxicity through Ca2+-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.
Asunto(s)
Calcio , Enfermedades del Sistema Nervioso , Receptores AMPA , Calcio/metabolismo , Ácido Glutámico , Humanos , Enfermedades del Sistema Nervioso/metabolismo , Receptores AMPA/metabolismo , Receptores Sensibles al CalcioRESUMEN
Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21 days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21 days, relative to 2 days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2 days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21 days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Etanol/toxicidad , Corteza Insular/efectos de los fármacos , Factores de Edad , Animales , Etanol/administración & dosificación , Corteza Insular/crecimiento & desarrollo , Corteza Insular/fisiopatología , Masculino , Técnicas de Placa-Clamp , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Maduración SexualRESUMEN
AIMS: Limited vs extended drug exposure has been proposed as one of the key factors in determining the risk of relapse, which is the primary characteristic of addiction behaviors. The current studies were designed to explore the related behavioral effects and neuronal alterations in the insular cortex (IC), an important brain region involved in addiction. METHODS: Experiments started with rats at the age of 35 days, a typical adolescent stage when initial drug exposure occurs often in humans. The drug-seeking/taking behaviors, and membrane properties and intrinsic excitability of IC pyramidal neurons were measured on withdrawal day (WD) 1 and WD 45-48 after limited vs extended cocaine intravenous self-administration (IVSA). RESULTS: We found higher cocaine-taking behaviors at the late withdrawal period after limited vs extended cocaine IVSA. We also found minor but significant effects of limited but not extended cocaine exposure on the kinetics and amplitude of action potentials on WD 45, in IC pyramidal neurons. CONCLUSION: Our results indicate potential high risks of relapse in young rats with limited but not extended drug exposure, although the adaptations detected in the IC may not be sufficient to explain the neural changes of higher drug-taking behaviors induced by limited cocaine IVSA.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Administración Intravenosa , Cocaína/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Corteza Insular/efectos de los fármacos , Potenciales de Acción/fisiología , Administración Intravenosa/métodos , Animales , Inhibidores de Captación de Dopamina/administración & dosificación , Esquema de Medicación , Comportamiento de Búsqueda de Drogas/fisiología , Corteza Insular/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
BACKGROUND: Adolescence and early-adulthood are vulnerable developmental periods during which binge drinking can have long-lasting effects on brain function. However, little is known about the effects of binge drinking on the pyramidal cells of the prelimbic cortex (PrL) during early and protracted withdrawal periods. METHODS: In the present study, we performed whole-cell patch clamp recordings and dendritic spine staining to examine the intrinsic excitability, spontaneous excitatory post-synaptic currents (sEPSCs), and spine morphology of pyramidal cells in the PrL from rats exposed to chronic intermittent ethanol (CIE) during adolescence or early-adulthood. RESULTS: Compared to chronic intermittent water (CIW)-treated controls, the excitability of PrL-L5 pyramidal neurons was significantly increased 21 days after adolescent CIE but decreased 21 days after early-adult CIE. No changes of excitability in PrL Layer (L) 5 were detected 2 days after either adolescent or early-adulthood CIE. Interestingly, decreases in sEPSC amplitude and increases in thin spines ratio were detected 2 days after adolescent CIE. Furthermore, decreased frequency and amplitude of sEPSCs, accompanied by a decrease in the density of total spines and non-thin spines were observed 21 days after adolescent CIE. In contrast, increased frequency and amplitude of sEPSCs, accompanied by increased densities of total spines and non-thin spines were found 21 days after early adult CIE. CONCLUSION: CIE produced prolonged neuronal and synaptic alterations in PrL-L5, and the developmental stage, i.e., adolescence vs. early-adulthood when subjects receive CIE, is a key factor in determining the direction of these changes.
Asunto(s)
Etanol/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/crecimiento & desarrollo , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Factores de Edad , Animales , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
Prenatal alcohol exposure (PAE)-induced clinical symptoms have been widely reported but effective treatments are not yet available due to our limited knowledge of the neuronal mechanisms underlying behavioral outputs. Operant behaviors, including both goal-directed and habitual actions, are essential for everyday life. The dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) have been identified as mediating each type of instrumental behavior, respectively. The current studies were designed to evaluate the effects of PAE (i.e., 3 g/kg, twice a day on gestational days 17-20) on goal-directed vs. habitual behaviors in both females and males during their adolescent and adult stages. We found that PAE-treated adult, but not adolescent, males display similar habitual oral sucrose self-administration but reduced goal-directed sucrose self-administration, compared to those treated by prenatal control (water) exposure (PCE). There were no differences in either habitual or goal-directed sucrose taking between PCE- vs. PAE-treated adolescent and adult females. These results indicate sex- and age-specific effects of PAE on operant behaviors. Further, whole-cell patch clamp recordings showed that the excitability of medium-sized spiny neurons (MSNs) in the posterior DMS (pDMS), but not the anterior DMS (aDMS), was significantly decreased in PAE-treated adult male rats. Notably, chemogenetic enhancement of MSN excitability in the pDMS by the DREADD agonist, compound 21, rescued the motivation of PAE-treated male adult rats. These data suggest that the pDMS may be a key neuronal substrate mediating the PAE-induced low motivation in male adults.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Etanol/toxicidad , Motivación/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Caracteres Sexuales , Factores de Edad , Animales , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Cuerpo Estriado/metabolismo , Etanol/administración & dosificación , Femenino , Masculino , Motivación/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
BACKGROUND AND PURPOSE: Binge drinking is a serious problem among adolescents and young adults despite its adverse consequences on the brain and behavior. One area that remains poorly understood concerns the impact of chronic intermittent ethanol (CIE) exposure on incentive learning. METHODS: Here, we examined the effects of CIE exposure during different developmental stages on conditioned approach and conditioned reward learning in rats experiencing acute or protracted withdrawal from alcohol. Two or 21 days after adolescent or adult CIE exposure, male rats were exposed to pairings of a light stimulus (CS) and food pellets for 3 consecutive daily sessions (30 CS-food pellet pairings per session). This was followed by conditioned approach testing measuring responses (food trough head entries) to the CS-only presentations and by conditioned reward testing measuring responses on a lever producing the CS and on another producing a tone. We then measured behavioral sensitization to repeated injections of heroin (2 mg/kg/d for 9 days). RESULTS: Adolescent and adult alcohol-treated rats showed significantly impaired conditioned reward learning regardless of withdrawal period (acute or prolonged). We found no evidence of changes to conditioned approach learning after adolescent or adult exposure to CIE. Finally, in addition to producing long-term impairments in incentive learning, CIE exposure enhanced locomotor activity in response to heroin and had no effect on behavioral sensitization to heroin regardless of age and withdrawal period. CONCLUSIONS: Our work sets a framework for identifying CIE-induced alterations in incentive learning and inducing susceptibility to subsequent opioid effects.
Asunto(s)
Conducta Animal/fisiología , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Heroína/farmacología , Aprendizaje/efectos de los fármacos , Locomoción/efectos de los fármacos , Narcóticos/farmacología , Recompensa , Animales , Conducta de Elección/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Motivación , RatasRESUMEN
Alcohol use typically begins in adolescence, increasing the likelihood of adult mental disorders such as anxiety. However, the cellular mechanisms underlying the consequences of adolescent alcohol exposure as well as the behavioral consequences remain poorly understood. We examined the effects of adolescent or adult chronic intermittent ethanol (CIE) exposure on intrinsic excitability of striatal medium-sized spiny neurons (MSNs) and anxiety levels. Rats underwent one of the following procedures: (1) light-dark transition (LDT) and open-field (OF) tests to evaluate anxiety levels and general locomotion; (2) whole-cell patch clamp recordings and biocytin labeling to assess excitability of striatal MSNs, as well as morphological properties; and (3) western blot immunostaining to determine small conductance (SK) calcium-activated potassium channel protein levels. Three weeks, but not 2 days, after CIE treatment, adolescent CIE-treated rats showed shorter crossover latency from the light to dark side in the LDT test and higher MSN excitability in the nucleus accumbens shell (NAcS). Furthermore, the amplitude of the medium afterhyperpolarization (mAHP), mediated by SK channels, and SK3 protein levels in the NAcS decreased concomitantly. Finally, increased anxiety levels, increased excitability, and decreased amplitude of mAHP of NAcS MSNs were reversed by SK channel activator 1-EBIO and mimicked by the SK channel blocker apamin. Thus, adolescent ethanol exposure increases adult anxiety-like behavior by downregulating SK channel function and protein expression, which leads to an increase of intrinsic excitability in NAcS MSNs. SK channels in the NAcS may serve as a target to treat adolescent alcohol binge exposure-induced mental disorders, such as anxiety in adulthood.
Asunto(s)
Ansiedad/metabolismo , Etanol/farmacología , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Masculino , Neuronas/metabolismo , Núcleo Accumbens/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-DawleyRESUMEN
Prenatal alcohol exposure (PAE) is an insidious yet preventable cause of developmental disability. The prenatal stage is a critical period for brain development with the concurrence of high vulnerability to the acute and prolonged effects of PAE. There is substantial evidence from both human observations and laboratory experiments that PAE is a common risk factor that predisposes to an array of postnatal mental disorders, including emotional, cognitive, and motor deficits. Although it is well accepted that PAE causes substantial morbidity, available treatments are limited. One reason is the lack of sufficient understanding about the neuroalterations induced by PAE, and how these changes contribute to PAE-induced mental disorders. Among a number of brain structures that have been explored extensively in PAE, the striatum has attracted great attention in the last 20 years in the field of PAE neurobiology. Interestingly, in animal models, the striatum has been considered as a pivotal switch of brain dysfunction induced by PAE, such as addiction, anxiety, depression, and neurodegeneration. In this review, we focus on recent advances in the understanding of morphological and functional changes in brain regions related to alterations after PAE, in particular the striatum. Because this region is central for behavior, emotion and cognition, there is an urgent need for more studies to uncover the PAE-induced alterations at the circuit, neuronal, synaptic and molecular levels, which will not only improve our understanding of the neuroplasticity induced by PAE, but also provide novel biological targets to treat PAE-related mental disorders with translational significance.
Asunto(s)
Bebidas Alcohólicas/efectos adversos , Cuerpo Estriado/efectos de los fármacos , Trastornos del Espectro Alcohólico Fetal , Efectos Tardíos de la Exposición Prenatal , Consumo de Bebidas Alcohólicas/efectos adversos , Animales , Conducta/efectos de los fármacos , Cognición/efectos de los fármacos , Cuerpo Estriado/patología , Cuerpo Estriado/fisiología , Emociones/efectos de los fármacos , Femenino , Trastornos del Espectro Alcohólico Fetal/patología , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Humanos , Intercambio Materno-Fetal , EmbarazoRESUMEN
Environmental enrichment (EE) has long been postulated as a behavioral treatment for drug addiction based on its preventive effects in animal models: rodents experiencing prior EE exhibit increased resistance to establishing drug taking and seeking. However, the therapeutic effects of EE, namely, the effects of EE when applied after drug exposure, are often marginal and transient. Using incubation of cue-induced cocaine craving, a rat relapse model depicting progressive intensification of cocaine seeking after withdrawal from cocaine self-administration, our present study reveals that after cocaine withdrawal, in vivo circuit-specific long-term depression (LTD) unmasks the therapeutic power of EE to achieve long-lasting anti-relapse effects. Specifically, our previous results show that cocaine self-administration generates AMPA receptor (AMPAR)-silent excitatory synapses within the basolateral amygdala (BLA) to nucleus accumbens (NAc) projection, and maturation of these silent synapses via recruiting calcium-permeable (CP) AMPARs contributes to incubation of cocaine craving. Here, we show that after cocaine withdrawal and maturation of silent synapses, the BLA-to-NAc projection became highly resistant to EE. However, optogenetic LTD applied to this projection in vivo transiently re-silenced these silent synapses by removing CP-AMPARs. During this transient window, application of EE resulted in the insertion of nonCP-AMPARs, thereby remodeling the "incubated" BLA-to-NAc projection. Consequently, incubation of cocaine craving was decreased persistently. These results reveal a mechanistic basis through which the persistent anti-relapse effects of EE can be unleashed after drug withdrawal.
Asunto(s)
Terapia Conductista/métodos , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/terapia , Núcleo Accumbens/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Sinapsis , Amígdala del Cerebelo/fisiopatología , Animales , Cocaína/efectos adversos , Masculino , Inhibición Neural , Vías Nerviosas/fisiopatología , Ratas , Ratas Sprague-Dawley , Recurrencia , Resultado del TratamientoRESUMEN
Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.
Asunto(s)
Trastornos Relacionados con Cocaína/fisiopatología , Ansia/fisiología , Núcleo Accumbens/fisiopatología , Corteza Prefrontal/fisiopatología , Sinapsis/fisiología , Animales , Comportamiento de Búsqueda de Drogas/fisiología , Electrofisiología , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Plasticidad Neuronal/fisiología , Núcleo Accumbens/efectos de los fármacos , Optogenética , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacosRESUMEN
[This corrects the article on p. e122 in vol. 5.].
RESUMEN
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.
Asunto(s)
Amígdala del Cerebelo/citología , Cocaína/efectos adversos , Inhibidores de Captación de Dopamina/efectos adversos , Comportamiento de Búsqueda de Drogas/fisiología , Núcleo Accumbens/citología , Síndrome de Abstinencia a Sustancias , Sinapsis/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Channelrhodopsins , Condicionamiento Operante , Modelos Animales de Enfermedad , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Antagonistas del GABA/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Núcleo Accumbens/efectos de los fármacos , Picrotoxina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Autoadministración , Espermina/farmacología , Síndrome de Abstinencia a Sustancias/patología , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/psicología , Sinapsis/efectos de los fármacosRESUMEN
To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction.