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RATIONALE: Despite the existing anatomical and physiological evidence pointing to the involvement of orexinergic projections from the lateral hypothalamus (LH) in regulating fear-related responses, little is known regarding the contribution of the orexin system in the prelimbic cortex (PL) on contextual fear. OBJECTIVES: We investigated the role of orexin-A (OrxA) and orexin type 1 receptors (Orx1R) in the PL during the expression of contextual conditioned fear in mice. METHODS: Neural tract tracing of the LH-PL pathway and Orx1R immunoreactivity in the PL of C57BL/6 male mice were performed. In a pharmacological approach, the animals were treated with either the Orx1R selective antagonist SB 334,867 (3, 30, and 300 nM/0.1 µL) or OrxA (28, 70, and 140 pmol/0.1 µL) in the PL before the test session of contextual fear conditioning. RESULTS: Neural tract tracing deposits in the LH showed some perikarya, mainly axons and terminal buttons in the PL, suggesting LH-PL reciprocate pathways. Furthermore, we showed a profuse network comprised of Orx1R-labeled thin varicose fibers widely distributed in the same field of LH-PL pathways projection. The selective blockade of Orx1R with SB 334,867 at 30 and 300 nM in the PL caused a decrease in freezing response, whereas the treatment with OrxA at 140 pmol promoted an increase in freezing response. CONCLUSION: In summary, these data confirmed an anatomical link between LH and PL, established the presence of Orx1R in the PL, and a modulatory role of the orexin system in such structure, possibly mainly via Orx1R, during contextual fear conditioning.
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Individuals considered resilient can overcome adversity, achieving normal physical and psychological development, while those deemed vulnerable may not. Adversity promotes structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, activity-dependent synaptic plasticity is intricately linked to neuronal shaping resulting from experiences. We hypothesize that this plasticity plays a crucial role in resilience processes. However, there is a notable absence of studies investigating this plasticity and behavioral changes following social adversity at different life stages. Consequently, we evaluated the impact of social adversity during early postnatal development (maternal separation [MS]), adulthood (social defeat [SD]), and a combined exposure (MS + SD) on behavioral outcomes (anxiety, motivation, anhedonia, and social interaction). We also examined cFos expression induced by social interaction in mPFC and hippocampus of adult male rats. Behavioral analyses revealed that SD-induced anhedonia, whereas MS + SD increased social interaction and mitigated SD-induced anhedonia. cFos evaluation showed that social interaction heightened plasticity in the prelimbic (PrL) and infralimbic (IL) cortices, dentate gyrus (DG), CA3, and CA1. Social interaction-associated plasticity was compromised in IL and PrL cortices of the MS and SD groups. Interestingly, social interaction-induced plasticity was restored in the MS + SD group. Furthermore, plasticity was impaired in DG by all social stressors, and in CA3 was impaired by SD. Our findings suggest in male rats (i) two adverse social experiences during development foster resilience; (ii) activity-dependent plasticity in the mPFC is a foundation for resilience to social adversity; (iii) plasticity in DG is highly susceptible to social adversity.
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Privação Materna , Plasticidade Neuronal , Córtex Pré-Frontal , Resiliência Psicológica , Animais , Plasticidade Neuronal/fisiologia , Masculino , Ratos , Anedonia/fisiologia , Interação Social , Derrota Social , Hipocampo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ratos Wistar , Comportamento Animal/fisiologia , Comportamento Social , Ansiedade/fisiopatologiaRESUMO
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.
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Comportamento Compulsivo , Corpo Estriado , Espinhas Dendríticas , Plasticidade Neuronal , Córtex Pré-Frontal , Quimpirol , Animais , Masculino , Espinhas Dendríticas/patologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Comportamento Compulsivo/fisiopatologia , Comportamento Compulsivo/patologia , Corpo Estriado/patologia , Corpo Estriado/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Plasticidade Neuronal/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/patologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Ratos WistarRESUMO
INTRODUCTION: Craving is a multifactorial behavior caused by central circuit imbalance. The proposed treatments involve exercise and reduced food intake. However, the treatments frequently fail. This study aimed to investigate the effect of 10 consecutive sessions of anodal transcranial direct current stimulation over the right dorsolateral prefrontal cortex on food craving and eating consumption of women affected by overweight and obesity. METHODS: A randomized double-blind controlled trial with 50 volunteers was divided into two groups (active-tDCS: n = 25 and sham-tDCS: n = 25). There were a total of 10 consecutive tDCS sessions (2 mA, for 20 min) with an F4 anodal-F3 cathodal montage. We evaluated the effects on eating behavior (food craving, uncontrolled eating, emotional eating, and cognitive restriction), food consumption (calories and macronutrients), and anthropometric and body composition variables (weight, body mass index, waist circumference, and body fat percentage). RESULTS: There were no statistically significant results between groups at the baseline regarding sociodemographic and clinical characteristics. Also, there was no significant interaction between time versus group for any of the variables studied. Treatment with tDCS was well tolerated and there were no serious adverse effects. CONCLUSIONS: In women affected by overweight and obesity with food cravings, 10 sessions of F4 (anodal) and F3 (cathodal) tDCS did not produce changes in eating behavior, food consumption, and anthropometric and body composition.
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Fissura , Obesidade , Sobrepeso , Estimulação Transcraniana por Corrente Contínua , Humanos , Feminino , Estimulação Transcraniana por Corrente Contínua/métodos , Obesidade/terapia , Obesidade/psicologia , Sobrepeso/terapia , Sobrepeso/psicologia , Adulto , Método Duplo-Cego , Pessoa de Meia-Idade , Comportamento Alimentar/psicologia , Córtex Pré-Frontal Dorsolateral , Ingestão de Alimentos/psicologiaRESUMO
BACKGROUND: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRß in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. RESULTS: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. CONCLUSIONS: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.
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Transtorno Autístico , Neurônios , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Animais , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Camundongos , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Modelos Animais de Doenças , Masculino , Córtex Cerebral/metabolismo , Camundongos Knockout , Transmissão Sináptica/fisiologia , Camundongos Endogâmicos C57BL , FemininoRESUMO
Resumen Introducción: El trastorno obsesivo-compulsivo (TOC) se caracteriza por obsesiones y compulsiones. Las obsesiones corresponden a ideas o imágenes intrusivas y la compulsión es el acto motor o cognitivo para aplacar la obsesión. Su prevalência mundial es del 3 % y existen diferentes factores que influyen en su aparición, que pueden ser biológicos, psicológicos o ambientales. Por otra parte, las funciones ejecutivas son un conjunto de habilidades que regulan la cognición y el comportamiento, donde este estudio busca describir la relación y afectación de las funciones ejecutivas en personas que padecen TOC. Materiales y métodos: Artículo de revisión narrativa a partir del estado del arte sobre el TOC y las funciones ejecutivas. Resultados: Diversos estudios han reportado la relación clínico-anatómica entre signos y síntomas característicos del TOC y la alteración evidenciada en funciones ejecutivas. Las funciones ejecutivas impactan el funcionamiento en la vida diaria y se encuentran fuertemente relacionadas al TOC, generando limitaciones funcionales en estos pacientes. Para esta afección hay tratamientos como las terapias farmacológica, psicológica y quirúrgica. Discusión: Se encuentra la necesidad de implementar, dentro de su tratamiento, la rehabilitación neuropsicológica para rehabilitar y fortalecer las funciones ejecutivas, buscando que se desarrolle de manera integral y que le permita a la persona desenvolverse de manera óptima en su día a día. Conclusión: Las funciones ejecutivas son un componente fundamental para nuestro funcionamiento y autonomía, es por esto que al estar el TOC directamente relacionado con fallas en estas funciones, se considera un punto importante para tener en cuenta al acompañar y tratar a personas que presentan este trastorno.
Abstract Introduction: Obsessive-compulsive disorder (OCD) is characterized by obsessions and compulsions. Obsessions correspond to intrusive ideas or images and compulsion is the motor or cognitive act to appease the obsession. Its worldwide prevalence is 3%. There are different factors that influence its appearance, which can be biological, psychological and environmental. Executive functions are a set of skills that regulate cognition and behavior. The objective is to describe the relationship and impact of executive functions in people who suffer from OCD. Materials and methods: Narrative review article based on the state of the art on obsessive-compulsive disorder and executive functions. Results: Various studies report a clinical-anatomical relationship between characteristic signs and symptoms of OCD and alterations evident in executive functions. Executive functions impact functioning in daily life. These functions are strongly related to OCD, generating functional limitations in these patients. For this condition there are treatments such as pharmacological, psychological and surgical therapy. Discussion: There is a need to implement neuropsychological rehabilitation within its treatment to rehabilitate and strengthen such processes, seeking to develop it comprehensively and allow the person to function optimally in their daily lives. Conclusion: Executive functions are a fundamental component for our functioning and autonomy, which is why, since OCD is directly related to failures in these functions, they are considered an important point to take into account when accompanying and treating people who present this condition. disorder.
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Maladaptive avoidance behaviour is often observed in patients suffering from anxiety and trauma- and stressor-related disorders. The prefrontal-amygdala-hippocampus network is implicated in learning and memory consolidation. Neuroinflammation in this circuitry alters network dynamics, resulting in maladaptive avoidance behaviour. The two-way active avoidance test is a well-established translational model for assessing avoidance responses to stressful situations. While some animals learn the task and show adaptive avoidance (AA), others show strong fear responses to the test environment and maladaptive avoidance (MA). Here, we investigated if a distinct neuroinflammation pattern in the prefrontal-amygdala-hippocampus network underlies the behavioural difference observed in these animals. Wistar rats were tested 8 times and categorized as AA or MA based on behaviour. Brain recovery followed for the analysis of neuroinflammatory markers in this network. AA and MA presented distinct patterns of neuroinflammation, with MA showing increased astrocyte, EAAT-2, IL-1ß, IL-17 and TNF-É in the amygdala. This neuroinflammatory pattern may underlie these animals' fear response and maladaptive avoidance. Further studies are warranted to determine the specific contributions of each inflammatory factor, as well as the possibility of treating maladaptive avoidance behaviour in patients with psychiatric disorders with anti-inflammatory drugs targeting the amygdala.
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5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.
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Hipocampo , Córtex Pré-Frontal , Sono , Vigília , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , Masculino , Sono/efeitos dos fármacos , Sono/fisiologia , Eletroencefalografia , Ritmo Teta/efeitos dos fármacos , Alucinógenos/farmacologiaRESUMO
Cognitive control of behavior is crucial for well-being, as allows subject to adapt to changing environments in a goal-directed way. Changes in cognitive control of behavior is observed during cognitive decline in elderly and in pathological mental conditions. Therefore, the recovery of cognitive control may provide a reliable preventive and therapeutic strategy. However, its neural basis is not completely understood. Cognitive control is supported by the prefrontal cortex, structure that integrates relevant information for the appropriate organization of behavior. At neurophysiological level, it is suggested that cognitive control is supported by local and large-scale synchronization of oscillatory activity patterns and neural spiking activity between the prefrontal cortex and distributed neural networks. In this review, we focus mainly on rodent models approaching the neuronal origin of these prefrontal patterns, and the cognitive and behavioral relevance of its coordination with distributed brain systems. We also examine the relationship between cognitive control and neural activity patterns in the prefrontal cortex, and its role in normal cognitive decline and pathological mental conditions. Finally, based on these body of evidence, we propose a common mechanism that may underlie the impaired cognitive control of behavior.
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Encéfalo , Roedores , Animais , Humanos , Idoso , Córtex Pré-Frontal/fisiologia , Neurônios/fisiologia , Cognição/fisiologiaRESUMO
Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.
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Hipocampo , Convulsões , Ratos , Animais , Masculino , Hipocampo/patologia , Encéfalo , Córtex Pré-Frontal/fisiologia , Memória de Curto Prazo/fisiologiaRESUMO
The second part of this review is an attempt to explain why only Homo sapiens developed language. It should be remarked that this review is based on the opinion of a clinical neurologist and does not intend to go beyond an overview of this complex topic. The progressive development of language was probably due to the expansion of the prefrontal cortex (PFC) and its networks. PFC is the largest area of the human cerebral cortex and is much more expanded in humans than in other primates. To achieve language, several other functions should have been attained, including abstraction, reasoning, expanded working memory, and executive functions. All these functions are strongly related to PFC and language had a profound retroactive impact on them all. Language and culture produce anatomic and physiological modifications in the brain. Learning to read is presented as an example of how culture modifies the brain.
A segunda parte desta revisão é uma tentativa de explicar por que apenas o Homo sapiens desenvolveu a linguagem. Ressalta-se que esta revisão é baseada na opinião de um neurologista clínico e não pretende ir além de uma visão geral deste tema complexo. O desenvolvimento progressivo da linguagem provavelmente se deveu à expansão do córtex pré-frontal (PFC) e de suas conexões. O PFC é a maior área do córtex cerebral humano e é muito maior em seres humanos do que em outros primatas. Para adquirir a linguagem, diversas outras funções precisavam ter sido alcançadas, incluindo abstração, raciocínio, expansão da memória de trabalho e funções executivas. Todas essas funções estão fortemente relacionadas com o PFC e a linguagem teve um profundo impacto retroativo em todas elas. A linguagem e a cultura produzem modificações anatômicas e fisiológicas no cérebro. Aprender a ler é apresentado como um exemplo de como a cultura modifica o cérebro.
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Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.
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Ansiedade , Comportamento Animal , Canabidiol , Hipocampo , Obesidade Materna , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Animais , Feminino , Canabidiol/farmacologia , Gravidez , Ratos , Masculino , Obesidade Materna/metabolismo , Ansiedade/metabolismo , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Comportamento Social , Obesidade/metabolismo , Endocanabinoides/metabolismoRESUMO
The present study utilized the spared nerve injury (SNI) to create a mouse model of depression to investigate the impact of esketamine on depressive-like behaviors, on the expression of PSD-95 and CRMP2 proteins, and on changes in neuronal dendritic spine plasticity in the prefrontal cortex (PFC). Depressive-like behavioral tests were performed 1 h after esketamine treatment, and the PFC tissues were obtained on the fourth day after completing the behavioral tests. Then, dendritic spine density and morphology in the PFC were measured using Golgi staining, and CRMP2 and PSD-95 proteins were obtained from PFC tissue by western blotting. The results of this study showed that esketamine significantly increased the immobility time in the forced swimming test and tail suspension test. In the open field test, esketamine increased the time spent in the open arms, the time spent in the central area, and the total distance covered. It also increased the protein expression levels of CRMP2 and PSD-95 in addition to the total and mature dendritic spine density of the PFC in SNI-depressed mice. Esketamine can significantly improve depression-like behaviors in SNI-depressed mice and promote an increase in dendritic spine density and maturation in the PFC. These effects may be associated with changes in CRMP2 and PSD-95 expression.
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Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food. We compared between conditions and found that the social condition exerts significant influence on individual displacement patterns, even when efficient navigation rules leading to reward had been previously learned. Thus, movement patterns and consequent task performance were strongly dependent on contingent social interactions arising during collective displacement, yet their influence on individual behavior was determined by dominance hierarchy. Dominant animals did not behave as leaders during collective displacement; conversely, they were most sensitive to the social environment adjusting their performance accordingly. Social ranking in turn was associated with specific spontaneous neural activity patterns in the prefrontal cortex and hippocampus, with dominant mice showing higher firing rates, larger ripple oscillations, and stronger neuronal entrainment by ripples than subordinate animals. Moreover, dominant animals selectively increased their cortical spiking activity during collective movement, while subordinate mice did not modify their firing rates, consistent with dominant animals being more sensitive to the social context. These results suggest that dominance hierarchy influences behavioral performance during contingent social interactions, likely supported by the coordinated activity in the hippocampal-prefrontal circuit.
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BACKGROUND AND PURPOSE: Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in AYA-treated rats. EXPERIMENTAL APPROACH: We focused on the 5-HT1A and 5-HT2A receptors, as DMT exhibits a high affinity for both of them, along with the infralimbic cortex in which activity and plasticity play crucial roles in regulating the mnemonic process under analysis. KEY RESULTS: A single oral treatment with AYA containing 0.3 mg·kg-1 of DMT increased the within-session extinction of contextual freezing behaviour without affecting its recall. This protocol, when repeated twice on consecutive days, enhanced extinction recall. These effects were consistent for both 1- and 21-day-old memories in males and females. AYA effects on fear extinction were independent of changes in anxiety and general exploratory activity: AYA- and vehicle-treated animals showed no differences when tested in the elevated plus-maze. The 5-HT2A receptor antagonist MDL-11,939 and the 5-HT1A receptor antagonist WAY-100635 infused into the infralimbic cortex respectively blocked within- and between-session fear extinction effects resulting from repeated oral administration of AYA. CONCLUSION AND IMPLICATIONS: Our findings highlight complementary mechanisms by which AYA facilitates the behavioural suppression of aversive memories in the rat infralimbic cortex. These results suggest potential beneficial effects of AYA or DMT in stress-related disorders.
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Banisteriopsis , Extinção Psicológica , Medo , Receptor 5-HT1A de Serotonina , Receptor 5-HT2A de Serotonina , Animais , Medo/efeitos dos fármacos , Medo/fisiologia , Masculino , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Ratos , Banisteriopsis/química , Alucinógenos/farmacologia , Alucinógenos/administração & dosagem , Ratos Sprague-Dawley , Comportamento Animal/efeitos dos fármacos , Piridinas/farmacologiaRESUMO
RATIONALE: Chronic stress exposure disrupts the medial prefrontal cortex's (mPFC) ability to regulate impulses, leading to the loss of control over alcohol drinking in rodents, emphasizing the critical role of this forebrain area in regulating alcohol consumption. Moreover, chronic stress exposure causes lateralization of mPFC functions with volumetric and functional changes, resulting in hyperactivity in the right hemisphere and functional decrease in the left. OBJECTIVES: This study investigated the inhibitory role of the left prelimbic cortex (LPrL) on ethanol consumption induced by chronic social defeat stress (SDS) in male mice and to examine if inactivation of the LPrL causes disinhibition of the right mPFC, leading to an increase in ethanol consumption. We also investigated the role of lateralization and neurochemical alterations in the mPFC related to ethanol consumption induced by chronic SDS. To this end, we examined the activation patterns of ΔFosB, VGLUT2, and GAD67 in the left and right mPFC. RESULTS: Temporarily blocking the LPrL or right PrL (RPrL) cortices during acute SDS did not affect male mice's voluntary ethanol consumption in male mice. When each cortex was blocked in mice previously exposed to chronic SDS, ethanol consumption also remained unaffected. However, male mice with LPrL lesions during chronic SDS showed an increase in voluntary ethanol consumption, which was associated with enhanced ΔFosB/VGLUT2-positive neurons within the RPrL cortex. CONCLUSIONS: The results suggest that the LPrL may play a role in inhibiting ethanol consumption induced by chronic SDS, while the RPrL may be involved in the disinhibition of ethanol consumption.
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Consumo de Bebidas Alcoólicas , Córtex Pré-Frontal , Derrota Social , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Camundongos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Etanol/administração & dosagem , Etanol/farmacologia , Lateralidade Funcional/efeitos dos fármacos , Doença CrônicaRESUMO
Two inbred strains, Lewis (LEW) and Spontaneously Hypertensive Rats (SHR), are well-known for their contrasting behavior related to anxiety/emotionality. Studies with these two strains led to the discovery of the Quantitative Trait Loci (QTL) on chromosome 4 (Anxrr16). To better understand the influences of this genomic region, the congenic rat strain SLA16 (SHR.LEW-Anxrr16) was developed. SLA16 rats present higher hyperactivity/impulsivity, deficits in learning and memory, and lower basal blood pressure than the SHR strain, even though genetic differences between them are only in chromosome 4. Thus, the present study proposed the alpha-synuclein and the dopaminergic system as candidates to explain the differential behavior of SHR and SLA16 strains. To accomplish this, beyond the behavioral analysis, we performed (I) the Snca gene expression and (II) quantification of the alpha-synuclein protein in the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) of SHR and SLA16 strains; (III) sequencing of the 3'UTR of the Snca gene; and (IV) evaluation of miRNA binding in the 3'UTR site. A Single Nucleotide Polymorphism (SNP) was identified in the 3'UTR of the Snca gene, which exhibited upregulation in the HPC of SHR compared to SLA16 females. Alpha-synuclein protein was higher in the HPC of SHR males compared to SLA16 males. The results of this work suggested that differences in alpha-synuclein HPC content could be influenced by miRNA regulation and associated with behavioral differences between SHR and SLA16 animals.
Assuntos
MicroRNAs , alfa-Sinucleína , Animais , Feminino , Masculino , Ratos , Regiões 3' não Traduzidas , alfa-Sinucleína/genética , Hipocampo , Ratos Endogâmicos Lew , Ratos Endogâmicos SHRRESUMO
AIMS: The present study was developed to investigate how litter reduction-induced obesity promotes early depressive-related behaviors in rodent offspring. MAIN METHODS: We employed a standardized litter size reduction protocol, dividing litters into groups: normal litters (NL), consisting of six males and six females pups and small litters (SL), comprising two males and two females pups. Maternal behavior was monitored during the initial week of lactation. Subsequently, we assessed the pups for weight gain, locomotor activity, social play behavior, and performance in forced swimming test. We further evaluated the weights of retroperitoneal and perigonadal fat tissues, along with the expression of glial fibrillary acidic pprotein (GFAP) in the hippocampus and prefrontal cortex of the offspring. KEY FINDINGS: Our results indicated that litter size reduction led to an increased the maternal behavior. In contrast, offspring from the SL group displayed greater weight gain and increased, retroperitoneal and perigonadal fat. Both male and female rodents in the SL group exhibited decreased social play behavior, and male offspring spent more time immobile during the forced swimming test, suggesting a depressive-like phenotype. Notably, we observed an increase in the GFAP expression in the prefrontal cortex of male rodents, with a trend toward increased expression in the hippocampus. SIGNIFICANCE: Obesity may facilitate the development of early depressive-like behaviors, potentially associated with elevated GFAP expression in the prefrontal cortex.