RESUMEN

Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD.

Asunto(s)

Conducta Compulsiva , Cuerpo Estriado , Espinas Dendríticas , Plasticidad Neuronal , Corteza Prefrontal , Quinpirol , Animales , Masculino , Espinas Dendríticas/patología , Corteza Prefrontal/patología , Corteza Prefrontal/efectos de los fármacos , Conducta Compulsiva/fisiopatología , Conducta Compulsiva/patología , Cuerpo Estriado/patología , Cuerpo Estriado/efectos de los fármacos , Quinpirol/farmacología , Ratas , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de los fármacos , Trastorno Obsesivo Compulsivo/patología , Trastorno Obsesivo Compulsivo/fisiopatología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Ratas Wistar

RESUMEN

Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex, and dysfunctional activity of Purkinje cells has been associated with ataxic movements. However, the synaptic characteristics of Purkinje cells in cases of ataxia are not yet well understood. The nicotinamide antagonist 3-acethylpyridine (3-AP) selectively destroys inferior olivary nucleus neurons so it is widely used to induce cerebellar ataxia. Five days after 3-AP treatment (65mg/kg) in adult male Sprague-Dawley rats, motor incoordination was revealed through BBB and Rotarod testing. In addition, in Purkinje cells from lobules V-VII of the cerebellar vermis studied by the Golgi method, the density of dendritic spines decreased, especially the thin and mushroom types. Western blot analysis showed a decrease in AMPA and PSD-95 content with an increase of the α-catenin protein, while GAD-67 and synaptophysin were unchanged. Findings suggest a limited capacity of Purkinje cells to acquire and consolidate afferent excitatory inputs and an aberrant, rigid profile in the movement-related output patterns of Purkinje neurons that likely contributes to the motor-related impairments characteristic of cerebellar ataxias.

Asunto(s)

Cerebelo , Células de Purkinje , Ratas Sprague-Dawley , Animales , Células de Purkinje/efectos de los fármacos , Células de Purkinje/patología , Masculino , Ratas , Cerebelo/efectos de los fármacos , Ataxia Cerebelosa/inducido químicamente , Piridinas/farmacología , Plasticidad Neuronal/efectos de los fármacos

RESUMEN

The central amygdaloid nucleus (CeA) has an ancient phylogenetic development and functions relevant for animal survival. Local cells receive intrinsic amygdaloidal information that codes emotional stimuli of fear, integrate them, and send cortical and subcortical output projections that prompt rapid visceral and social behavior responses. We aimed to describe the morphology of the neurons that compose the human CeA (N = 8 adult men). Cells within CeA coronal borders were identified using the thionine staining and were further analyzed using the "single-section" Golgi method followed by open-source software procedures for two-dimensional and three-dimensional image reconstructions. Our results evidenced varied neuronal cell body features, number and thickness of primary shafts, dendritic branching patterns, and density and shape of dendritic spines. Based on these criteria, we propose the existence of 12 morphologically different spiny neurons in the human CeA and discuss the variability in the dendritic architecture within cellular types, including likely interneurons. Some dendritic shafts were long and straight, displayed few collaterals, and had planar radiation within the coronal neuropil volume. Most of the sampled neurons showed a few to moderate density of small stubby/wide spines. Long spines (thin and mushroom) were observed occasionally. These novel data address the synaptic processing and plasticity in the human CeA. Our morphological description can be combined with further transcriptomic, immunohistochemical, and electrophysiological/connectional approaches. It serves also to investigate how neurons are altered in neurological and psychiatric disorders with hindered emotional perception, in anxiety, following atrophy in schizophrenia, and along different stages of Alzheimer's disease.

Asunto(s)

Núcleo Amigdalino Central , Masculino , Adulto , Animales , Humanos , Filogenia , Espinas Dendríticas/fisiología , Neuronas/fisiología , Interneuronas

RESUMEN

Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.

Asunto(s)

Trastorno del Espectro Autista , Trastorno Depresivo Mayor , Animales , Humanos , Espinas Dendríticas/patología , Trastorno del Espectro Autista/patología , Trastorno Depresivo Mayor/patología , Encéfalo/patología , Transmisión Sináptica , Plasticidad Neuronal/fisiología , Sinapsis/patología

RESUMEN

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague-Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy.

Asunto(s)

Antipsicóticos , Hipocampo , Animales , Ratas , Masculino , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Ratas Endogámicas WKY , Animales Recién Nacidos , Corteza Prefrontal , Risperidona , Antipsicóticos/farmacología , Modelos Animales de Enfermedad

RESUMEN

Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines' maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines.

RESUMEN

Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS.

Asunto(s)

Lóbulo Frontal , Estimulación Magnética Transcraneal , Hipocampo , Metilación de ADN , Epigénesis Genética

RESUMEN

AIMS: Dynamin-2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2-linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin-2 CNM-causing mutation influences the CNS function. METHODS: Heterozygous mice harbouring the p.R465W mutation in the dynamin-2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. RESULTS: HTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin-2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. CONCLUSION: Our findings suggest that the dynamin-2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.

Asunto(s)

Dinamina II , Miopatías Estructurales Congénitas , Animales , Ratones , Modelos Animales de Enfermedad , Dinamina II/genética , Dinamina II/metabolismo , Músculo Esquelético/metabolismo , Mutación , Miopatías Estructurales Congénitas/genética , Neuronas/metabolismo , Transmisión Sináptica

RESUMEN

Extracellular vesicles (EVs) are released by all cell types and are involved in intercellular communication. We evaluated if neural stem cells-derived EVs (NSC-EVs) regulate NSCs proliferation and differentiation under control and stress conditions. We found that NSC-EVs treatment increases cell proliferation and promotes neuronal differentiation and plasticity. The fact that nervous tissue poorly recovers after cellular damage, prump us to evaluate the effect of EVs supplementation under oxidative stress and inflammation. We demonstrate that NSC-EVs restore the proliferative potential of the NSCs affected by oxidative stress. In addition, we provide evidence that oxidative stress and inflammation induce neuronal differentiation. Interestingly, the aberrant cell phenotype induced by inflammation is restored by NSC-EVs treatment, suggesting that these vesicles ameliorate the damage burden in neurons and modulate neuronal plasticity. These results contribute to understand the role of the NSCs-derived EVs as key players for brain tissue generation and regeneration and open new pathways to the development of therapies.

RESUMEN

Sexual experience improves copulatory performance in male rats. Copulatory performance has been associated with dendritic spines density in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), structures involved in the processing of sexual stimuli and the manifestation of sexual behavior. Dendritic spines modulate excitatory synaptic contacts, and their morphology is associated with the ability to learn from experience. This study was designed to determine the effect of sexual experience on the density of different types or shapes of dendritic spines in the mPFC and NAcc of male rats. A total of 16 male rats were used, half of them were sexually experienced while the other half were sexually inexperienced. After three sessions of sexual interaction to ejaculation, the sexually-experienced males presented shorter mount, intromission, and ejaculation latencies. Those rats presented a higher total dendritic density in the mPFC, and a higher numerical density of thin, mushroom, stubby, and wide spines. Sexual experience also increased the numerical density of mushroom spines in the NAcc. In both the mPFC and NAcc of the sexually experienced rats, there was a lower proportional density of thin spines and a higher proportional density of mushroom spines. Results show that the improvement in copulatory efficiency resulting from prior sexual experience in male rats is associated with changes in the proportional density of thin and mushroom dendritic spines in the mPFC and NAcc. This could represent the consolidation of afferent synaptic information in these brain regions, derived from the stimulus-sexual reward association.

Asunto(s)

Agaricales , Núcleo Accumbens , Ratas , Masculino , Animales , Conducta Sexual Animal , Copulación , Corteza Prefrontal , Espinas Dendríticas

RESUMEN

Facial nerve injury in rats have been widely used to study functional and structural changes that occur in the injured motoneurons and other central nervous system structures related with sensorimotor processing. A decrease in long-term potentiation of hippocampal CA3-to-CA1 commissural synapse has recently been reported related to this peripheral injury. Additionally, it has been found increased corticosterone plasmatic levels, impairment in spatial memory consolidation, and hippocampal microglial activation in animals with facial nerve axotomy. In this work, we analyzed the neuronal morphology of hippocampal CA1 and CA3 pyramidal neurons in animals with either reversible or irreversible facial nerve injury. For this purpose, brain tissues of injured animals sacrificed at different postlesion times, were stained with the Golgi-Cox method and compared with control brains. It was found that both reversible and irreversible facial nerve injury-induced significant decreases in dendritic tree complexity, dendritic length, branch points, and spine density of hippocampal neurons. However, such changes' timing varied according to hippocampal area (CA1 vs. CA3), dendritic area (apical vs. basal), and lesion type (reversible vs. irreversible). In general, the observed changes were transient when animals had the possibility of motor recovery (reversible injury), but perdurable if the recovery from the lesion was impeded (irreversible injury). CA1 apical and CA3 basal dendritic tree morphology were more sensible to irreversible injury. It is concluded that facial nerve injury induced significant changes in hippocampal CA1 and CA3 pyramidal neurons morphology, which could be related to LTP impairments and microglial activation in the hippocampal formation, previously described.

Asunto(s)

Traumatismos del Nervio Facial , Ratas , Animales , Traumatismos del Nervio Facial/patología , Nervio Facial , Axotomía , Células Piramidales/fisiología , Hipocampo/fisiología , Neuronas Motoras , Dendritas/patología

RESUMEN

Research on the memory impairment caused by the Amyloid-ß 25-35 (Aß25-35) peptide in animal models has provided an understanding of the causes that occurs in Alzheimer's disease. However, it is uncertain whether this cognitive impairment occurs due to disruption of information encoding and consolidation or impaired retrieval of stored memory. The aim of this study was to determine the effect of the Aß25-35 peptide on the morphology of dendritic spines and the changes in the expression of NR2B and PSD-95 in the hippocampus associated with learning and memory deficit. Vehicle or Aß25-35 peptide (0.1 µg/µL) was bilaterally administered into the CA1 subfield of the rat hippocampus, then tested for spatial learning and memory in the Morris Water Maze. On Day 39, the morphological changes in the CA1 of the hippocampus and dentate gyrus were examined via Golgi-Cox stain. It was observed that the Aß25-35 peptide administered in the CA1 region of the rat hippocampus induced changes to the morphology of dendritic spines and the expression of the NR2B subunit of the NMDA receptor co-localized with both the spatial memory and PSD-95 protein in the hippocampus of learning rats. We conclude that, in soluble form, the Aß25-35 peptide perturbs synaptic plasticity, specifically in the formation of new synapses, thus promoting the progression of memory impairment.

Asunto(s)

Enfermedad de Alzheimer , Espinas Dendríticas , Animales , Ratas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Espinas Dendríticas/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Hipocampo/metabolismo , Aprendizaje por Laberinto , Trastornos de la Memoria/metabolismo , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/metabolismo , Memoria Espacial

RESUMEN

Our ability to learn and remember depends on the active formation, remodeling, and elimination of synapses. Thus, the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring. The structural reorganization of synaptic complexes, changes in actin cytoskeleton and organelle dynamics, as well as modulation of gene expression, determine synaptic plasticity. It has been proposed that dysregulation of these key synaptic homeostatic processes underlies the synaptic dysfunction observed in many neurodegenerative diseases. Much is known about downstream signaling of activated N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoazolepropionate receptors; however, other signaling pathways can also contribute to synaptic plasticity and long-lasting changes in learning and memory. The non-receptor tyrosine kinase c-Abl (ABL1) is a key signal transducer of intra and extracellular signals, and it shuttles between the cytoplasm and the nucleus. This review focuses on c-Abl and its synaptic and neuronal functions. Here, we discuss the evidence showing that the activation of c-Abl can be detrimental to neurons, promoting the development of neurodegenerative diseases. Nevertheless, c-Abl activity seems to be in a pivotal balance between healthy synaptic plasticity, regulating dendritic spines remodeling and gene expression after cognitive training, and synaptic dysfunction and loss in neurodegenerative diseases. Thus, c-Abl genetic ablation not only improves learning and memory and modulates the brain genetic program of trained mice, but its absence provides dendritic spines resiliency against damage. Therefore, the present review has been designed to elucidate the common links between c-Abl regulation of structural changes that involve the actin cytoskeleton and organelles dynamics, and the transcriptional program activated during synaptic plasticity. By summarizing the recent discoveries on c-Abl functions, we aim to provide an overview of how its inhibition could be a potentially fruitful treatment to improve degenerative outcomes and delay memory loss.

RESUMEN

Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes. During this physiological process, the brain is the most affected organ due to changes in its structural and chemical functions, such as changes in plasticity and decrease in the number, diameter, length, and branching of dendrites and dendritic spines. Likewise, it presents a great reduction in volume resulting from the contraction of the gray matter. Consequently, aging can affect not only cognitive functions, including learning and memory, but also the quality of life of older people. As a result of the phenomena, various molecules with notable neuroprotective capacity have been proposed, which provide a therapeutic alternative for people under conditions of aging or some neurodegenerative diseases. It is important to indicate that in recent years the use of molecules with neurotrophic activity has shown interesting results when evaluated in in vivo models. This review aims to describe the neurotrophic potential of molecules such as resveratrol (3,5,4'-trihydroxystilbene), neurotrophins (brain-derived neurotrophic factor), and neurotrophic-type compounds such as the terminal carboxyl domain of the heavy chain of tetanus toxin, cerebrolysin, neuropeptide-12, and rapamycin. Most of these molecules have been evaluated by our research group. Studies suggest that these molecules exert an important therapeutic potential, restoring brain function in aging conditions or models of neurodegenerative diseases. Hence, our interest is in describing the current scientific evidence that supports the therapeutic potential of these molecules with active neurotrophic.

RESUMEN

Visualizing nerve cells has been fundamental for the systematic description of brain structure and function in humans and other species. Different approaches aimed to unravel the morphological features of neuron types and diversity. The inherent complexity of the human nervous tissue and the need for proper histological processing have made studying human dendrites and spines challenging in postmortem samples. In this study, we used Golgi data and open-source software for 3D image reconstruction of human neurons from the cortical amygdaloid nucleus to show different dendrites and pleomorphic spines at different angles. Procedures required minimal equipment and generated high-quality images for differently shaped cells. We used the "single-section" Golgi method adapted for the human brain to engender 3D reconstructed images of the neuronal cell body and the dendritic ramification by adopting a neuronal tracing procedure. In addition, we elaborated 3D reconstructions to visualize heterogeneous dendritic spines using a supervised machine learning-based algorithm for image segmentation. These tools provided an additional upgrade and enhanced visual display of information related to the spatial orientation of dendritic branches and for dendritic spines of varied sizes and shapes in these human subcortical neurons. This same approach can be adapted for other techniques, areas of the central or peripheral nervous system, and comparative analysis between species.

Asunto(s)

Dendritas , Corteza Olfatoria , Humanos , Dendritas/fisiología , Imagenología Tridimensional , Neuronas , Programas Informáticos , Espinas Dendríticas/fisiología

RESUMEN

Enhanced activity and overexpression of Pannexin 1 (Panx1) channels contribute to neuronal pathologies such as epilepsy and Alzheimer's disease (AD). The Panx1 channel ablation alters the hippocampus's glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, Panx1-knockout (Panx1-KO) mice still retain the ability to learn, suggesting that compensatory mechanisms stabilize their neuronal activity. Here, we show that the absence of Panx1 in the adult brain promotes a series of structural and functional modifications in the Panx1-KO hippocampal synapses, preserving spontaneous activity. Compared to the wild-type (WT) condition, the adult hippocampal neurons of Panx1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and an increased proportion of multiple synaptic contacts. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in the actin polymerization and an imbalance between the Rac1 and the RhoA GTPase activities were observed in Panx1-KO brain tissues. Our findings highlight a novel interaction between Panx1 channels, actin, and Rho GTPases, which appear to be relevant for synapse stability.

Asunto(s)

Actinas , Conexinas , Animales , Ratones , Conexinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo

RESUMEN

Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.

RESUMEN

Second-generation antipsychotics are the drugs of choice for the treatment of neurodevelopmental-related mental diseases such as schizophrenia. Despite the effectiveness of these drugs to ameliorate some of the symptoms of schizophrenia, specifically the positive ones, the mechanisms beyond their antipsychotic effect are still poorly understood. Second-generation antipsychotics are reported to have anti-inflammatory, antioxidant and neuroplastic properties. Using the neonatal ventral hippocampus lesion (nVHL) in the rat, an accepted schizophrenia-related model, we evaluated the effect of the second-generation antipsychotic olanzapine (OLZ) in the behavioral, neuroplastic, and neuroinflammatory alterations exhibited in the nVHL animals. OLZ corrected the hyperlocomotion and impaired working memory of the nVHL rats but failed to enhance social behavior disturbances of these animals. In the prefrontal cortex (PFC), OLZ restored the pyramidal cell structural plasticity in the nVHL rats, enhancing the dendritic arbor length, the spinogenesis and the proportion of mature spines. Moreover, OLZ attenuated astrogliosis as well as some pro-inflammatory, oxidative stress, and apoptosis-related molecules in the PFC. These findings reinforce the evidence of anti-inflammatory, antioxidant, and neurotrophic mechanisms of second-generation antipsychotics in the nVHL schizophrenia-related model, which allows for the possibility of developing more specific drugs for this disorder and thus avoiding the side effects of current schizophrenia treatments.

Asunto(s)

Antipsicóticos , Esquizofrenia , Ratas , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Olanzapina/farmacología , Olanzapina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Antioxidantes/farmacología , Ratas Sprague-Dawley , Corteza Prefrontal , Hipocampo , Plasticidad Neuronal , Modelos Animales de Enfermedad

RESUMEN

Lesions to the corticospinal tract result in several neurological symptoms and several rehabilitation protocols have proven useful in attempts to direct underlying plastic phenomena. However, the effects that such protocols may exert on the dendritic spines of motoneurons to enhance accuracy during rehabilitation are unknown. Thirty three female Sprague-Dawley adult rats were injected stereotaxically at the primary motor cerebral cortex (Fr1) with saline (CTL), or kainic acid (INJ), or kainic acid and further rehabilitation on a treadmill 16 days after lesion (INJ+RB). Motor performance was evaluated with the the Basso, Beatie and Bresnahan (BBB) locomotion scale and in the Rotarod. Spine density was quantified in a primary dendrite of motoneurons in Lamina IX in the ventral horn of the thoracolumbar spinal cord as well as spine morphology. AMPA, BDNF, PSD-95 and synaptophysin expression was evaluated by Western blot. INJ+RB group showed higher scores in motor performance. Animals from the INJ+RB group showed more thin, mushroom, stubby and wide spines than the CTL group, while the content of AMPA, BDNF, PSD-95 and Synaptophysin was not different between the groups INJ+RB and CTL. AMPA and synaptophysin content was greater in INJ group than in CTL and INJ+RB groups. The increase in the proportion of each type of spine observed in INJ+RB group suggest spinogenesis and a greater capability to integrate the afferent information to motoneurons under relatively stable molecular conditions at the synaptic level.

Asunto(s)

Corteza Motora , Animales , Femenino , Ratas , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Espinas Dendríticas/fisiología , Ácido Kaínico , Corteza Motora/metabolismo , Neuronas Motoras/metabolismo , Ratas Sprague-Dawley

RESUMEN

Growth factors, such as insulin-like growth factor 1 (IGF-1), among others are known for their critical involvement in learning and memory processes. IGF-1 regulates cognitive functions, synapse density, neurotransmission, and adult neurogenesis and induces structural and synaptic plasticity-specific changes. Although IGF-1 has been suggested to participate in different memory processes, its role in memories associated with negative emotional experiences still remains to be elucidated. The principal aim of the present study was to test whether IGF-1 overexpression using adenoviral vectors in basolateral amygdala (BLA) influences both the expression and formation of contextual fear memory, as well as the hippocampal structural plasticity associated with such memory trace. We found that IGF-1 overexpression promotes the formation and expression of a specific contextual fear memory trace, and such effect persisted at least 7 days after recall. Moreover, the overexpression of this growth factor in BLA upregulates the activation of the ERK/MAPK pathway in this brain structure. In addition, intra-BLA IGF-1 overexpression causes dorsal hippocampus (DH) structural plasticity modifications promoting changes in the proportion of mature dendritic spines in the CA1 region, after a weak conditioning protocol. The present findings contribute to the knowledge underlying BLA-DH trace memory of fear and reveal important new insights into the neurobiology and neurochemistry of fear acquisition modulated by IGF-1 overexpression. The understanding of how IGF-1 modulates the formation of a fear contextual trace may pave the way for the development of novel therapeutic strategies focused on fear, anxiety, and trauma-related disorders.

Asunto(s)

Complejo Nuclear Basolateral , Complejo Nuclear Basolateral/fisiología , Miedo/fisiología , Hipocampo/fisiología , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Memoria/fisiología