RESUMEN
Although sensitizing processes occur earlier, schizophrenia is diagnosed in young adulthood, which suggests that it might involve a pathological transition during late brain development in predisposed individuals. Parvalbumin (PV) interneuron alterations have been noticed, but their role in the disease is unclear. Here we demonstrate that adult LgDel+/- mice, a genetic model of schizophrenia, exhibit PV neuron hypo-recruitment and associated chronic PV neuron plasticity together with network and cognitive deficits. All these deficits can be permanently rescued by chemogenetic activation of PV neurons or D2R antagonist treatments, specifically in the ventral hippocampus (vH) or medial-prefrontal cortex during a late-adolescence-sensitive time window. PV neuron alterations were initially restricted to the hippocampal CA1/subiculum, where they became responsive to treatment in late adolescence. Therefore, progression to disease in schizophrenia-model mice can be prevented by treatments supporting vH-mPFC PV network function during a sensitive time window late in adolescence, suggesting therapeutic strategies to prevent the outbreak of schizophrenia.
Asunto(s)
Disfunción Cognitiva/terapia , Antagonistas de los Receptores de Dopamina D2/farmacología , Hipocampo/efectos de los fármacos , Interneuronas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Esquizofrenia/terapia , Adolescente , Animales , Modelos Animales de Enfermedad , Hipocampo/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Parvalbúminas/metabolismo , Corteza Prefrontal/patologíaRESUMEN
The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement in rodent models of cocaine use disorder. The output from the mPFC is potently modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets. We previously showed that treatment with chondroitinase ABC (ABC) reduced the consolidation and reconsolidation of a cocaine conditioned place preference memory. However, self-administration memories are more difficult to disrupt. Here we report in male rats that ABC treatment in the mPFC attenuated the consolidation and blocked the reconsolidation of a cocaine self-administration memory. However, reconsolidation was blocked when rats were given a novel, but not familiar, type of retrieval session. Furthermore, ABC treatment prior to, but not after, memory retrieval blocked reconsolidation. This same treatment did not alter a sucrose memory, indicating specificity for cocaine-induced memory. In naive rats, ABC treatment in the mPFC altered levels of PV intensity and cell firing properties. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during the novel retrieval session revealed that ABC prevented reward-associated increases in high-frequency oscillations and synchrony of these oscillations between the dHIP and mPFC. Together, this is the first study to show that ABC treatment disrupts reconsolidation of the original memory when combined with a novel retrieval session that elicits coupling between the dHIP and mPFC. This coupling after ABC treatment may serve as a fundamental signature for how to disrupt reconsolidation of cocaine memories and reduce relapse.
Asunto(s)
Condroitina ABC Liasa , Cocaína , Hipocampo , Memoria , Corteza Prefrontal , Autoadministración , Animales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Masculino , Ratas , Cocaína/administración & dosificación , Cocaína/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Condroitina ABC Liasa/farmacología , Memoria/efectos de los fármacos , Memoria/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Ratas Sprague-Dawley , Parvalbúminas/metabolismo , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Trastornos Relacionados con Cocaína/fisiopatologíaRESUMEN
Current anesthetic theory is mostly based on neurons and/or neuronal circuits. A role for astrocytes also has been shown in promoting recovery from volatile anesthesia, while the exact modulatory mechanism and/or the molecular target in astrocytes is still unknown. In this study by animal models in male mice and electrophysiological recordings in vivo and in vitro, we found that activating astrocytes of the paraventricular thalamus (PVT) and/or knocking down PVT astrocytic Kir4.1 promoted the consciousness recovery from sevoflurane anesthesia. Single-cell RNA sequencing of the PVT reveals two distinct cellular subtypes of glutamatergic neurons: PVT GRM and PVT ChAT neurons. Patch-clamp recording results proved astrocytic Kir4.1-mediated modulation of sevoflurane on the PVT mainly worked on PVT ChAT neurons, which projected mainly to the mPFC. In summary, our findings support the novel conception that there is a specific PVTâprefrontal cortex projection involved in consciousness recovery from sevoflurane anesthesia, which is mediated by the inhibition of sevoflurane on PVT astrocytic Kir4.1 conductance.
Asunto(s)
Astrocitos , Estado de Conciencia , Núcleos Talámicos de la Línea Media , Canales de Potasio de Rectificación Interna , Sevoflurano , Animales , Astrocitos/fisiología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Masculino , Ratones , Sevoflurano/farmacología , Estado de Conciencia/fisiología , Estado de Conciencia/efectos de los fármacos , Núcleos Talámicos de la Línea Media/fisiología , Núcleos Talámicos de la Línea Media/efectos de los fármacos , Núcleos Talámicos de la Línea Media/citología , Canales de Potasio de Rectificación Interna/metabolismo , Ratones Endogámicos C57BL , Anestésicos por Inhalación/farmacología , Vías Nerviosas/fisiología , Vías Nerviosas/efectos de los fármacos , Neuronas/fisiología , Neuronas/efectos de los fármacos , Corteza Prefrontal/fisiología , Corteza Prefrontal/efectos de los fármacos , Lóbulo Frontal/fisiología , Lóbulo Frontal/efectos de los fármacos , Periodo de Recuperación de la AnestesiaRESUMEN
Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10â d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.
Asunto(s)
Comportamiento de Búsqueda de Drogas , Extinción Psicológica , Plasticidad Neuronal , Corteza Prefrontal , Ratas Sprague-Dawley , Receptor trkB , Estimulación del Nervio Vago , Animales , Masculino , Ratas , Estimulación del Nervio Vago/métodos , Comportamiento de Búsqueda de Drogas/fisiología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Receptor trkB/metabolismo , Receptor trkB/antagonistas & inhibidores , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de los fármacos , Extinción Psicológica/fisiología , Extinción Psicológica/efectos de los fármacos , Corteza Prefrontal/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Autoadministración , Cocaína/farmacología , Cocaína/administración & dosificaciónRESUMEN
Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which modulate neurovascular coupling-a process that regulates cerebral hemodynamics in response to neuronal activation. However, separating neuronal and astrocytic effects from cocaine's direct vasoactive effects has been challenging, partially due to limitations of neuroimaging techniques able to differentiate vascular from neuronal and glial effects at high temporal and spatial resolutions. Here, we used a newly-developed multi-channel fluorescence and optical coherence Doppler microscope (fl-ODM) that allows for simultaneous measurements of neuronal and astrocytic activities (reflected by the intracellular calcium changes in neurons Ca2+N and astrocytes Ca2+A, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca2+ indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca2+ fluorescence and 3D cerebral blood flow velocity (CBFv) in vascular networks in the mouse cortex. We assessed cocaine's effects in the prefrontal cortex (PFC) and found that the CBFv changes triggered by cocaine were temporally correlated with astrocytic Ca2+A activity. Chemogenetic inhibition of astrocytes during the baseline state resulted in blood vessel dilation and CBFv increases but did not affect neuronal activity, suggesting modulation of spontaneous blood vessel's vascular tone by astrocytes. Chemogenetic inhibition of astrocytes during a cocaine challenge prevented its vasoconstricting effects alongside the CBFv decreases, but it also attenuated the neuronal Ca2+N increases triggered by cocaine. These results document a role of astrocytes both in regulating vascular tone and consequently blood flow, at baseline and for modulating the vasoconstricting and neuronal activation responses to cocaine in the PFC. Strategies to inhibit astrocytic activity could offer promise for ameliorating vascular and neuronal toxicity from cocaine misuse.
Asunto(s)
Astrocitos , Calcio , Circulación Cerebrovascular , Cocaína , Neuronas , Corteza Prefrontal , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Animales , Cocaína/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Masculino , Calcio/metabolismo , Ratones Endogámicos C57BL , Acoplamiento Neurovascular/efectos de los fármacos , Acoplamiento Neurovascular/fisiologíaRESUMEN
Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.
Asunto(s)
Complejo Nuclear Basolateral , Cocaína , Consolidación de la Memoria , Neuronas , Corteza Prefrontal , Animales , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Cocaína/farmacología , Masculino , Ratas , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Señales (Psicología) , Ratas Sprague-Dawley , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Autoadministración , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Espinas Dendríticas/fisiología , Trastornos Relacionados con Cocaína/metabolismo , Trastornos Relacionados con Cocaína/fisiopatología , Memoria/efectos de los fármacos , Memoria/fisiologíaRESUMEN
Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.
Asunto(s)
Extinción Psicológica/fisiología , Miedo/fisiología , Metabolómica , Microbiota/fisiología , Neuronas/fisiología , Animales , Antibacterianos/farmacología , Trastorno Autístico/metabolismo , Sangre/metabolismo , Calcio/metabolismo , Líquido Cefalorraquídeo/química , Líquido Cefalorraquídeo/metabolismo , Señales (Psicología) , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Espinas Dendríticas/fisiología , Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Heces/química , Vida Libre de Gérmenes , Indicán/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Microbiota/inmunología , Inhibición Neural , Neuroglía/patología , Neuroglía/fisiología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Fenilpropionatos/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/inmunología , Corteza Prefrontal/fisiología , Esquizofrenia/metabolismo , Transcriptoma , Nervio Vago/fisiologíaRESUMEN
Drug addiction is a chronic and relapse brain disorder. Psychostimulants such as cocaine and amphetamine are highly addictive drugs. Abuse drugs target various brain areas in the nervous system. Recent studies have shown that the prefrontal cortex (PFC) plays a key role in regulating addictive behaviors. The PFC is made up of excitatory glutamatergic cells and gamma-aminobutyric acid (GABAergic) interneurons. Recently, studies showed that GABA level was related with psychostimulant addiction. In this review, we will introduce the role and mechanism of GABA and γ-aminobutyric acid receptors (GABARs) of the PFC in regulating drug addiction, especially in psychostimulant addiction.
Asunto(s)
Estimulantes del Sistema Nervioso Central , Corteza Prefrontal , Trastornos Relacionados con Sustancias , Ácido gamma-Aminobutírico , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Humanos , Ácido gamma-Aminobutírico/metabolismo , Animales , Trastornos Relacionados con Sustancias/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Receptores de GABA/metabolismoRESUMEN
Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.
Asunto(s)
Amígdala del Cerebelo , Ansiedad , Traumatismos Cerrados de la Cabeza , Corteza Prefrontal , Animales , Corteza Prefrontal/efectos de los fármacos , Masculino , Traumatismos Cerrados de la Cabeza/complicaciones , Ansiedad/tratamiento farmacológico , Amígdala del Cerebelo/efectos de los fármacos , Ratones , Vías Nerviosas/efectos de los fármacos , Ratones Endogámicos C57BL , Homólogo 4 de la Proteína Discs Large/metabolismoRESUMEN
Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8 weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2 h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SIRS males. Compared to group-housed counterparts, SIRS males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SIRS males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SIRS male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SIRS). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SIRS males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.
Asunto(s)
Agresión , Inhibidores de Histona Desacetilasas , Ratones Endogámicos C57BL , Corteza Prefrontal , Aislamiento Social , Estrés Psicológico , Animales , Masculino , Inhibidores de Histona Desacetilasas/farmacología , Aislamiento Social/psicología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Agresión/efectos de los fármacos , Ratones , Depsipéptidos/farmacología , Piridinas/farmacología , Benzamidas/farmacología , Restricción Física , Transmisión Sináptica/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Células Piramidales/metabolismoRESUMEN
Maternal stress and glucocorticoid exposure during pregnancy have multigenerational effects on neuroendocrine function and behaviours in offspring. Importantly, effects are transmitted through the paternal lineage. Altered phenotypes are associated with profound differences in transcription and DNA methylation in the brain. In the present study, we hypothesized that maternal prenatal synthetic glucocorticoid (sGC) exposure in the F0 pregnancy will result in differences in miRNA levels in testes germ cells and sperm across multiple generations, and that these changes will associate with modified microRNA (miRNA) profiles and gene expression in the prefrontal cortex (PFC) of subsequent generations. Pregnant guinea-pigs (F0) were treated with multiple courses of the sGC betamethasone (Beta) (1 mg kg-1; gestational days 40, 41, 50, 51, 60 and 61) in late gestation. miRNA levels were assessed in testes germ cells and in F2 PFC using the GeneChip miRNA 4.0 Array and candidate miRNA measured in epididymal sperm by quantitative real-time PCR. Maternal Beta exposure did not alter miRNA levels in germ cells derived from the testes of adult male offspring. However, there were significant differences in the levels of four candidate miRNAs in the sperm of F1 and F2 adult males. There were no changes in miRNA levels in the PFC of juvenile F2 female offspring. The present study has identified that maternal Beta exposure leads to altered miRNA levels in sperm that are apparent for at least two generations. The fact that differences were confined to epididymal sperm suggests that the intergenerational effects of Beta may target the epididymis. KEY POINTS: Paternal glucocorticoid exposure prior to conception leads to profound epigenetic changes in the brain and somatic tissues in offspring, and microRNAs (miRNAs) in sperm may mediate these changes. We show that there were significant differences in the miRNA profile of epididymal sperm in two generations following prenatal glucocorticoid exposure that were not observed in germ cells derived from the testes. The epididymis is a probable target for intergenerational programming. The effects of prenatal glucocorticoid treatment may span multiple generations.
Asunto(s)
Glucocorticoides , MicroARNs , Efectos Tardíos de la Exposición Prenatal , Espermatozoides , Animales , Femenino , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Cobayas , Glucocorticoides/farmacología , Testículo/efectos de los fármacos , Testículo/metabolismo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Betametasona/farmacología , Exposición Materna/efectos adversosRESUMEN
Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTDs). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole cell patch-clamp recording. Acute MeHg exposure (20 µM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) charges were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPA receptor- nor NMDA receptor-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired-pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.NEW & NOTEWORTHY Prefrontal cortical neurons are highly susceptible to glutamatergic excitotoxicity associated with neuronal degeneration in frontal dementia and to environmental toxicant exposure, one potential contributor to FTD. However, this has not been systematically studied. Our results demonstrate that methylmercury exposure leads to hyperexcitability of prefrontal cortical neurons by shifting excitatory to inhibitory (E-I) balance and raising sensitivity for spiking. Our results provide a mechanism by which environmental neurotoxicants may contribute to pathogenesis of diseases such as FTD.
Asunto(s)
Potenciales Postsinápticos Excitadores , Compuestos de Metilmercurio , Corteza Prefrontal , Células Piramidales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Animales , Compuestos de Metilmercurio/toxicidad , Masculino , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Ratas , Ratas Sprague-Dawley , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiopatologíaRESUMEN
Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
Asunto(s)
Anestésicos por Inhalación , Corteza Prefrontal , Sevoflurano , Animales , Sevoflurano/toxicidad , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratones , Anestésicos por Inhalación/toxicidad , Masculino , Animales Recién Nacidos , Femenino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Estudio de Asociación del Genoma CompletoRESUMEN
Clinical and preclinical evidence has demonstrated an increased risk for neuropsychiatric disorders following prenatal cannabinoid exposure. However, given the phytochemical complexity of cannabis, there is a need to understand how specific components of cannabis may contribute to these neurodevelopmental risks later in life. To investigate this, a rat model of prenatal cannabinoid exposure was utilized to examine the impacts of specific cannabis constituents (Δ9-tetrahydrocannabinol [THC]; cannabidiol [CBD]) alone and in combination on future neuropsychiatric liability in male and female offspring. Prenatal THC and CBD exposure were associated with low birth weight. At adolescence, offspring displayed sex-specific behavioural changes in anxiety, temporal order and social cognition, and sensorimotor gating. These phenotypes were associated with sex and treatment-specific neuronal and gene transcriptional alterations in the prefrontal cortex, and ventral hippocampus, regions where the endocannabinoid system is implicated in affective and cognitive development. Electrophysiology and RT-qPCR analysis in these regions implicated dysregulation of the endocannabinoid system and balance of excitatory and inhibitory signalling in the developmental consequences of prenatal cannabinoids. These findings reveal critical insights into how specific cannabinoids can differentially impact the developing fetal brains of males and females to enhance subsequent neuropsychiatric risk.
Asunto(s)
Conducta Animal , Cannabidiol , Dronabinol , Hipocampo , Corteza Prefrontal , Efectos Tardíos de la Exposición Prenatal , Modelos Animales , Animales , Ratas , Dronabinol/toxicidad , Cannabidiol/toxicidad , Factores Sexuales , Corteza Prefrontal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Masculino , Femenino , Embarazo , Conducta Animal/efectos de los fármacos , Ratas Wistar , Memoria/efectos de los fármacos , Ansiedad/inducido químicamente , Cognición/efectos de los fármacos , Conducta Impulsiva/efectos de los fármacos , Psicotrópicos/toxicidadRESUMEN
Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-ß1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-ß1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-ß1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.
Asunto(s)
Antidepresivos , Ketamina , Ratones Endogámicos C57BL , Fosforilación Oxidativa , Bazo , Esplenectomía , Nervio Vago , Animales , Ketamina/farmacología , Antidepresivos/farmacología , Bazo/efectos de los fármacos , Bazo/metabolismo , Ratones , Masculino , Nervio Vago/efectos de los fármacos , Nervio Vago/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Derrota SocialRESUMEN
The infralimbic cortex (IL) is part of the medial prefrontal cortex (mPFC), exerting top-down control over structures that are critically involved in the development of alcohol use disorder (AUD). Activity of the IL is tightly controlled by γ-aminobutyric acid (GABA) transmission, which is susceptible to chronic alcohol exposure and withdrawal. This inhibitory control is regulated by various neuromodulators, including 5-hydroxytryptamine (5-HT; serotonin). We used chronic intermittent ethanol vapor inhalation exposure, a model of AUD, in male Sprague-Dawley rats to induce alcohol dependence (Dep) followed by protracted withdrawal (WD; 2 weeks) and performed ex vivo electrophysiology using whole-cell patch clamp to study GABAergic transmission in layer V of IL pyramidal neurons. We found that WD increased frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs), whereas miniature IPSCs (mIPSCs; recorded in the presence of tetrodotoxin) were unaffected by either Dep or WD. The application of 5-HT (50 µM) increased sIPSC frequencies and amplitudes in naive and Dep rats but reduced sIPSC frequencies in WD rats. Additionally, 5-HT2A receptor antagonist M100907 and 5-HT2C receptor antagonist SB242084 reduced basal GABA release in all groups to a similar extent. The blockage of either 5-HT2A or 5-HT2C receptors in WD rats restored the impaired response to 5-HT, which then resembled responses in naive rats. Our findings expand our understanding of synaptic inhibition in the IL in AUD, indicating that antagonism of 5-HT2A and 5-HT2C receptors may restore GABAergic control over IL pyramidal neurons. SIGNIFICANCE STATEMENT: Impairment in the serotonergic modulation of GABAergic inhibition in the medial prefrontal cortex contributes to alcohol use disorder (AUD). We used a well-established rat model of AUD and ex vivo whole-cell patch-clamp electrophysiology to characterize the serotonin modulation of GABAergic transmission in layer V infralimbic (IL) pyramidal neurons in ethanol-naive, ethanol-dependent (Dep), and ethanol-withdrawn (WD) male rats. We found increased basal inhibition following WD from chronic alcohol and altered serotonin modulation. Exogenous serotonin enhanced GABAergic transmission in naive and Dep rats but reduced it in WD rats. 5-HT2A and 5-HT2C receptor blockage in WD rats restored the typical serotonin-mediated enhancement of GABAergic inhibition. Our findings expand our understanding of synaptic inhibition in the infralimbic neurons in AUD.
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Alcoholismo , Etanol , Potenciales Postsinápticos Inhibidores , Corteza Prefrontal , Ratas Sprague-Dawley , Serotonina , Síndrome de Abstinencia a Sustancias , Transmisión Sináptica , Ácido gamma-Aminobutírico , Animales , Masculino , Serotonina/metabolismo , Ratas , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Alcoholismo/metabolismo , Alcoholismo/fisiopatología , Etanol/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Ácido gamma-Aminobutírico/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismoRESUMEN
Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.
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Neuronas GABAérgicas , Interneuronas , Ketamina , Parvalbúminas , Corteza Prefrontal , Sinapsis , Animales , Ketamina/farmacología , Ketamina/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Parvalbúminas/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Masculino , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Ratones , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Ratones Endogámicos C57BL , Antagonistas de Aminoácidos Excitadores/farmacologíaRESUMEN
BACKGROUND: The principle of gain control determines the efficiency of neuronal processing and can be enhanced with pharmacological or brain stimulation methods. It is a key factor for cognitive control, but the degree of how much gain control may be enhanced underlies a physical limit. METHODS: To investigate whether methylphenidate (MPH) and transcranial direct current stimulation (tDCS) share common underlying mechanisms and cognitive effects, we administered MPH and anodal tDCS (atDCS) over the right inferior frontal gyrus both separately and combined, while healthy adult participants (n = 104) performed a response selection and inhibition task. The recorded EEG data were analyzed with a focus on theta band activity, and source estimation analyses were conducted. RESULTS: The behavioral data show that MPH and atDCS revealed interactive effects on the ability to inhibit responses. Both MPH and atDCS modulated task-related theta oscillations in the supplementary motor area when applied separately, making a common underlying mechanism likely. When both stimulation methods were combined, there was no doubling of effects in the supplementary motor area but a shift to inferior frontal areas in the cortical network responsible for theta-driven processing. CONCLUSIONS: The results indicate that both MPH and atDCS likely share a common underlying neuronal mechanism, and interestingly, they demonstrate interactive effects when combined, which are most likely due to the physical limitations of gain control increases. The current study provides critical groundwork for future combined applications of MPH and non-invasive brain stimulation.
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Inhibición Psicológica , Metilfenidato , Ritmo Teta , Estimulación Transcraneal de Corriente Directa , Humanos , Masculino , Femenino , Adulto , Adulto Joven , Metilfenidato/farmacología , Ritmo Teta/fisiología , Ritmo Teta/efectos de los fármacos , Electroencefalografía , Estimulantes del Sistema Nervioso Central/farmacología , Corteza Prefrontal/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Motora/fisiología , Corteza Motora/efectos de los fármacosRESUMEN
BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.
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Dopamina , Núcleo Accumbens , Corteza Prefrontal , Serotonina , Animales , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Locomoción/efectos de los fármacos , Microdiálisis , Factores de Edad , Conducta Animal/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Vocalización Animal/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Ratas Wistar , Alucinógenos/farmacologíaRESUMEN
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.