RESUMEN
Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed â¼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
Asunto(s)
Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Potenciación a Largo Plazo/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismo , Potenciales de Acción/fisiología , Empalme Alternativo/genética , Empalme Alternativo/fisiología , Animales , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Femenino , Células HEK293 , Homeostasis/fisiología , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/fisiología , Antígeno Ventral Neuro-Oncológico , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Proteínas de Unión al ARN/fisiología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sinapsis/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.
Asunto(s)
Extinción Psicológica , Miedo , Animales , Extinción Psicológica/fisiología , Miedo/fisiología , Masculino , Ratones , Neurregulina-1 , Plasticidad Neuronal/fisiología , Parvalbúminas , Corteza Prefrontal/fisiología , Receptor ErbB-4RESUMEN
Nux vomica has been effectively used in Traditional Chinese Medicine. The processing of Nux vomica is necessary to reduce toxicity before it can be used in clinical practice. However, the mechanism for processing detoxification is unclear. hERG channels have been subjected to a routine test for compound cardiac toxicity in the drug development process. Therefore, we examined the effects and mechanisms of strychnine and brucine, two main ingredients of Nux vomica, and their N-oxides on hERG channels. Strychnine and brucine exhibited concentration-dependent inhibition of hERG channels with IC50 values of 25.9⯵M and 44.18⯵M, respectively. However, their nitrogen oxidative derivatives produced by processing of Nux vomica, strychnine N-oxide and brucine N-oxide, lost their activity on hERG channels. Compared to their parent compounds, only an oxygen atom was introduced in the nitrogen oxidative isoforms to compensate for the N+â¯-â¯charge, suggesting that the protonated nitrogen is the key group for strychnine and brucine binding to hERG channel. Alanine-mutagenesis identified Y652 is the most important residue for strychnine and brucine binding to hERG channel. Y652A mutation increased the IC50 for strychnine and brucine by 21.64-fold and 29.78-fold that of WT IhERG, respectively. Docking simulations suggested that the protonated nitrogen of strychnine and brucine formed a cation-π interaction with the aromatic ring of Y652. This study suggests that introduction of an oxygen to compensate for the N+â¯-â¯charge could be a useful strategy for reducing hERG potency and increasing the safety margin of alkaloid-type compounds in drug development.
Asunto(s)
Oxígeno/metabolismo , Canales de Potasio/metabolismo , Estricnina/análogos & derivados , Estricnina/metabolismo , Alcaloides/metabolismo , Línea Celular , Células HEK293 , Humanos , Medicina Tradicional China/métodos , Nitrógeno/metabolismo , Sodio/metabolismo , Relación Estructura-Actividad , Strychnos nux-vomica/química , Regulador Transcripcional ERG/metabolismoRESUMEN
BACKGROUND: The incidence of adolescent depression has markedly risen in recent years, with a high recurrence rate into adulthood. Diagnosis in adolescents is challenging due to subjective factors, highlighting the crucial need for objective diagnostic markers. METHODS: Our study enrolled 204 participants, including healthy controls (n = 88) and first-episode adolescent depression patients (n = 116). Serum samples underwent gas chromatography-mass spectrometry (GC-MS) analysis to assess non-esterified fatty acids (NEFA) expression. Machine learning and ROC analysis were employed to identify potential biomarkers, followed by bioinformatics analysis to explore underlying mechanisms. RESULTS: Nearly all differentially expressed NEFA exhibited significant downregulation. Notably, nonanoic acid, cis-10-pentadecenoic acid, cis-10-carboenoic acid, and cis-11-eicosenoic acid demonstrated excellent performance in distinguishing adolescent depression patients. Metabolite-gene interaction analysis revealed these NEFAs interacted with multiple genes. KEGG pathway analysis on these genes suggested that differentially expressed NEFA may impact PPAR and cAMP signaling pathways. LIMITATIONS: Inclusion of diverse populations for evaluation is warranted. Biomarkers identified in this study require samples that are more in line with the experimental design for external validation, and further basic research is necessary to validate the potential depressive mechanisms of NEFA. CONCLUSIONS: The overall reduction in NEFA expression in first-episode adolescent depression patients suggests a potential mediation of depression symptoms through cAMP and PPAR signaling pathways. NEFA levels show promise as a diagnostic tool for identifying first-episode adolescent depression patients.
Asunto(s)
Depresión , Ácidos Grasos no Esterificados , Humanos , Adolescente , Ácidos Grasos no Esterificados/metabolismo , Depresión/diagnóstico , Receptores Activados del Proliferador del Peroxisoma , Biomarcadores , Cromatografía de Gases y Espectrometría de MasasRESUMEN
Recognizing the affective states of social counterparts and responding appropriately fosters successful social interactions. However, little is known about how the affective states are expressed and perceived and how they influence social decisions. Here, we show that male and female mice emit distinct olfactory cues after experiencing distress. These cues activate distinct neural circuits in the piriform cortex (PiC) and evoke sexually dimorphic empathic behaviors in observers. Specifically, the PiC â PrL pathway is activated in female observers, inducing a social preference for the distressed counterpart. Conversely, the PiC â MeA pathway is activated in male observers, evoking excessive self-grooming behaviors. These pathways originate from non-overlapping PiC neuron populations with distinct gene expression signatures regulated by transcription factors and sex hormones. Our study unveils how internal states of social counterparts are processed through sexually dimorphic mechanisms at the molecular, cellular, and circuit levels and offers insights into the neural mechanisms underpinning sex differences in higher brain functions.
Asunto(s)
Empatía , Caracteres Sexuales , Animales , Masculino , Femenino , Ratones , Empatía/fisiología , Corteza Piriforme/fisiología , Corteza Piriforme/metabolismo , Señales (Psicología) , Ratones Endogámicos C57BL , Afecto/fisiología , Neuronas/fisiología , Neuronas/metabolismo , Conducta Animal/fisiologíaRESUMEN
Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC â dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC â dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.
Asunto(s)
Corteza Insular , Sensación , Humanos , Sensación/fisiología , Neuronas GABAérgicas/metabolismo , Histamina/efectos adversos , Histamina/metabolismo , Prurito/inducido químicamenteRESUMEN
Ketamine is a new, fast, and effective antidepression treatment method; however, the possible dissociation effects, sensory changes, abuse risk, and the inability to accurately identify whether patients have a significant response to ketamine limit its clinical use. Further exploration of the antidepressant mechanisms of ketamine will contribute to its safe and practical application. Metabolites, the products of upstream gene expression and protein regulatory networks, play an essential role in various physiological and pathophysiological processes. In traditional metabonomics it is difficult to achieve the spatial localization of metabolites, which limits the further analysis of brain metabonomics by researchers. Here, we used a metabolic network mapping method called ambient air flow-assisted desorption electrospray ionization (AFADESI)-mass spectrometry imaging (MSI). We found the main changes in glycerophospholipid metabolism around the brain and sphingolipid metabolism changed mainly in the globus pallidus, which showed the most significant metabolite change after esketamine injection. The spatial distribution of metabolic changes was evaluated in the whole brain, and the potential mechanism of esketamine's antidepressant effect was explored in this research.
RESUMEN
BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.
Asunto(s)
Habénula , Adenosina Trifosfato/metabolismo , Animales , Depresión/etiología , Núcleo Dorsal del Rafe/metabolismo , Habénula/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Corteza Prefrontal/metabolismoRESUMEN
It has been recognized that videos have to be encoded in a rate-distortion optimized manner for high coding performance. Therefore, operational coding methods have been developed for conventional distortion metrics such as Sum of Squared Error (SSE). Nowadays, with the rapid development of machine learning, the state-of-the-art learning based metric Video Multimethod Assessment Fusion (VMAF) has been proven to outperform conventional ones in terms of the correlation with human perception, and thus deserves integration into the coding framework. However, unlike conventional metrics, VMAF has no specific computational formulas and may be frequently updated by new training data, which invalidates the existing coding methods and makes it highly desired to develop a rate-distortion optimized method for VMAF. Moreover, VMAF is designed to operate at the frame level, which leads to further difficulties in its application to today's block based coding. In this paper, we propose a VMAF oriented perceptual coding method based on piecewise metric coupling. Firstly, we explore the correlation between VMAF and SSE in the neighborhood of a benchmark distortion. Then a rate-distortion optimization model is formulated based on the correlation, and an optimized block based coding method is presented for VMAF. Experimental results show that 3.61% and 2.67% bit saving on average can be achieved for VMAF under the low_delay_p and the random_access_main configurations of HEVC coding respectively.
RESUMEN
Jingzhaotoxin-I, -III, -IV, -XIII, and -35 (JZTX-I, -III, -IV, -XIII, and -35), gating modifier toxins isolated from the venom of the Chinese tarantula Chilobrachys Jingzhao, were reported to act on cardiac sodium channels and Kv channels. JZTX-I and JZTX-XIII inhibited the hERG channel with the IC50 value of 626.9 nM and 612.6 nM, respectively. JZTX-III, -IV, and -35 share high sequence similarity with JZTX-I and JZTX-XIII, but they showed much lower affinity on the hERG channel compared with JZTX-I and JZTX-XIII. The inhibitory potency of the above five toxins on the hERG channel was not in accordance with their affinity on the Nav1.5 and Kv2.1 channels, indicating that the bioactive surfaces of the five toxins interacting with hERG, Nav1.5 and Kv2.1 are at least in part different. Structure-function analysis of the gating modifier toxins suggested that the functional bioactive surface binding to the hERG channel consists of a conserved hydrophobic patch, surrounding acidic residues (Glu10 in JZTX-XIII, Glu11 in JZTX-I), and basic residues which may be different from residues binding to the Kv2.1 channel.
Asunto(s)
Canal de Potasio ERG1/efectos de los fármacos , Venenos de Araña/toxicidad , Animales , Activación del Canal Iónico/efectos de los fármacosRESUMEN
Thalamic reticular nucleus (TRN) is a group of inhibitory neurons surrounding the thalamus. Due to its important role in sensory information processing, TRN is considered as the target nucleus for the pathophysiological investigation of schizophrenia and autism spectrum disorder (ASD). Prepulse inhibition (PPI) of acoustic startle response, a phenomenon that strong stimulus-induced startle reflex is reduced by a weaker prestimulus, is always found impaired in schizophrenia and ASD. But the role of TRN in PPI modulation remains unknown. Here, we report that parvalbumin-expressing (PV+) neurons in TRN are activated by sound stimulation of PPI paradigm. Chemogenetic inhibition of PV+ neurons in TRN impairs PPI performance. Further investigations on the mechanism suggest a model of burst-rebound burst firing in TRN-auditory thalamus (medial geniculate nucleus, MG) circuitry. The burst firing is mediated by T-type calcium channel in TRN, and rebound burst firing needs the participation of GABAB receptor in MG. Overall, these findings support the involvement of TRN in PPI modulation.
Asunto(s)
Trastorno del Espectro Autista , Inhibición Prepulso , Acústica , Humanos , Reflejo de Sobresalto , Núcleos TalámicosRESUMEN
Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDRâVTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDRâVTA neurons. Importantly, the bidirectional manipulation of 5-HTDRâVTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDRâVTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.
Asunto(s)
Núcleo Dorsal del Rafe/fisiología , Vías Nerviosas/fisiología , Neuronas Serotoninérgicas/fisiología , Estrés Psicológico/fisiopatología , Transmisión Sináptica/fisiología , Área Tegmental Ventral/fisiología , Animales , Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/metabolismo , Ácido Glutámico/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Neuronas Serotoninérgicas/citología , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Área Tegmental Ventral/citología , Área Tegmental Ventral/metabolismo , Proteína Fluorescente RojaRESUMEN
BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear. RESULTS: Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice. CONCLUSIONS: Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD. Video abstract.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/microbiología , Microbioma Gastrointestinal , Homeostasis , Receptores de la Familia Eph/deficiencia , Vitamina B 6/metabolismo , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/psicología , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/microbiología , Trastorno Autístico/psicología , Dopamina/metabolismo , Microbioma Gastrointestinal/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibición Neural , Corteza Prefrontal/metabolismo , Receptores de la Familia Eph/genética , Conducta SocialRESUMEN
BACKGROUND: Anxiety disorders are the most common psychiatric diseases, affecting 28% of people worldwide within their lifetime. The excitation-inhibition imbalance in the amygdala is thought to be an underlying pathological mechanism; however, the cellular and molecular control of amygdala excitation-inhibition balance is largely unknown. METHODS: By using mice expressing chemogenetic activator or inhibitor channel in amygdala parvalbumin (PV) neurons, Erbin mutant mice, and mice with Erbin specifically knocked down in amygdala PV neurons, we systematically investigated the role of amygdala PV neurons and Erbin expressed therein in the pathogenesis of anxiety disorders using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: In naïve mice, chemogenetic inhibition of PV neurons produced anxiogenic effects, suggesting an essential role in the regulation of anxiety. In stressed mice with anxiety, excitatory postsynaptic responses on amygdala PV neurons were selectively diminished, accompanied by a decreased expression of Erbin specifically in amygdala PV neurons. Remarkably, both Erbin mutant mice and amygdala PV-specific Erbin knockdown mice exhibited impaired excitatory postsynaptic responses on amygdala PV neurons and increased anxiety-like behaviors. Furthermore, chemogenetic activation of amygdala PV neurons normalized anxiety behaviors in amygdala PV-specific Erbin knockdown mice and stressed mice. CONCLUSIONS: Together, these results demonstrate that Erbin in PV neurons is critical for maintaining the excitation-inhibition balance in the amygdala and reveal a novel pathophysiological mechanism for anxiety disorders.
Asunto(s)
Amígdala del Cerebelo , Parvalbúminas , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad , Ratones , Neuronas/metabolismo , Parvalbúminas/metabolismoRESUMEN
4-aminopyridine (4-AP), a voltage-gated potassium channel blocker, was revealed to possess proapoptotic properties in various types of cancer cells. The present study aimed to explore the effect of 4AP on a cisplatin (DDP) resistant lung cancer cell line A549/CDDP and the underlying mechanism by which it had an effect. In the present study, an MTT assay and cell cycle analysis were used to determine that 4AP inhibited cell growth in vitro and a tumorigenesis assay in nude mice determined that 4AP also inhibited cell growth in vivo. 4AP induced cell apoptosis of A549/CDDP cells observed by electron microscopy and Annexin VAPC/7ADD analysis. In addition, 4AP enhanced the sensitivity of A549/CDDP cells to DDP as revealed by an MTT assay. Mechanistically, 4AP upregulated the phosphatase and tensin homolog (PTEN) and modulated the phosphoinositide 3kinase/protein kinase B signaling pathway and its downstream cell cycle factors, including cyclin D1, cyclindependent kinase 4 and p21, as well as apoptosisassociated proteins Bcell lymphoma 2, procaspase 9, procaspase 3, cleaved caspase 9 and cleaved caspase 3. The effects of 4AP on cell growth and apoptosis were reversed by PTEN silencing. In conclusion, the results indicated that 4AP inhibited cell growth, induced apoptosis and sensitized A549/CDDP cells to DDP via the upregulation of PTEN. 4AP may be a potential therapeutic agent for patients with DDP resistance.
Asunto(s)
4-Aminopiridina/farmacología , Monoéster Fosfórico Hidrolasas/genética , Tensinas/genética , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , Tensinas/metabolismoRESUMEN
Social isolation during the vulnerable period of adolescence contributes to the occurrence of psychiatric disorders and profoundly affects brain development and adult behavior. Although the impact of social isolation during adolescence on anxiety behaviors has been well studied, much less is known about the onset and underlying mechanisms of these behaviors. We observed that following 2 weeks, but not 1 week, of social isolation, adolescent mice exhibited anxiety behaviors. Strikingly, the mGluR5 protein levels in the amygdala increased concomitantly with anxiety behaviors, and both intraperitoneal administration and intra-basolateral amygdala (BLA) infusion of MPEP, a metabotropic glutamate receptor 5 antagonist, normalized anxiety behaviors. Furthermore, electrophysiological studies showed that 2 weeks of social isolation during adolescence facilitated pyramidal neuronal excitability in the BLA, which could be normalized by MPEP. Together, these results reveal a critical period in adolescence during which social isolation can induce anxiety behaviors and facilitate BLA pyramidal neuronal excitability, both of which are mediated by mGluR5, thus providing mechanistic insights into the onset of anxiety behaviors after social isolation during adolescence.
Asunto(s)
Potenciales de Acción , Envejecimiento/metabolismo , Ansiedad/metabolismo , Complejo Nuclear Basolateral/metabolismo , Células Piramidales/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Aislamiento Social , Regulación hacia Arriba , Potenciales de Acción/efectos de los fármacos , Animales , Ansiedad/fisiopatología , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/fisiopatología , Conducta Animal , Ratones Endogámicos C57BL , Células Piramidales/efectos de los fármacos , Piridinas/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Social isolation during the vulnerable period of adolescence produces emotional dysregulation that often manifests as abnormal behavior in adulthood. The enduring consequence of isolation might be caused by a weakened ability to forget unpleasant memories. However, it remains unclear whether isolation affects unpleasant memories. To address this, we used a model of associative learning to induce the fear memories and evaluated the influence of isolation mice during adolescence on the subsequent retention of fear memories and its underlying cellular mechanisms. Following adolescent social isolation, we found that mice decreased their social interaction time and had an increase in anxiety-related behavior. Interestingly, when we assessed memory retention, we found that isolated mice were unable to forget aversive memories when tested 4 weeks after the original event. Consistent with this, we observed that a single train of high-frequency stimulation (HFS) enabled a late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of isolated mice, whereas only an early-phase LTP was observed with the same stimulation in the control mice. Social isolation during adolescence also increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and application of a tropomyosin-related kinase B (TrkB) receptor inhibitor ameliorated the facilitated L-LTP seen after isolation. Together, our results suggest that adolescent isolation may result in mental disorders during adulthood and that this may stem from an inability to forget the unpleasant memories via BDNF-mediated synaptic plasticity. These findings may give us a new strategy to prevent mental disorders caused by persistent unpleasant memories.
Asunto(s)
Región CA1 Hipocampal/fisiopatología , Miedo/psicología , Potenciación a Largo Plazo/fisiología , Aislamiento Social/psicología , Adolescente , Animales , Ansiedad/fisiopatología , Ansiedad/psicología , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Región CA1 Hipocampal/efectos de los fármacos , Condicionamiento Clásico , Estimulación Eléctrica , Emetina/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Conducta Exploratoria , Miedo/efectos de los fármacos , Miedo/fisiología , Humanos , Relaciones Interpersonales , Potenciación a Largo Plazo/efectos de los fármacos , Ratones , Modelos Animales , Proteínas del Tejido Nervioso/fisiología , Inhibidores de la Síntesis de la Proteína/farmacología , Psicología del Adolescente , Receptor trkB/antagonistas & inhibidores , Receptor trkB/fisiología , Retención en Psicología/efectos de los fármacos , Retención en Psicología/fisiologíaRESUMEN
OBJECTIVE: To study the diagnostic significance of computed tomography (CT) in atrial isomerism. METHOD: In one of the 2 cases of left atrial isomerism, abdominal CT scan with and without contrast enhancement were both performed, the other had plain thoraco-abdominal CT scan, and another case of right atrial isomerism received thoraco-abdominal contrast enhanced scan and thin-slice scan of the trachea. The diagnoses of all the 3 cases were surgically and pathologically confirmed. RESULT: In the CT images of the 2 cases of left atrial isomerism, some typical features were identified including bilaterally symmetric bronchi, levoversion of the heart, horizontally positioned liver, absence of hepatic segment of the inferior vena cava and dilated azygos, short pancreas and double spleen, and mirror image isomerism of the major arteries and abdominal organs. The case of right atrial isomerism had bilateral upper lobe tracheal bronchus, mirror image isomerism of the heart and abdominal organs, short pancreas, translocation of the inferior vena cava to the left of the abdominal aorta, both of which were on the left of the spine. CONCLUSIONS: CT have distinct diagnostic value in revealing thoraco-abdominal organs and major vessels, which can be crucial in the diagnosis and surgical management of patients with atrial isomerism.
Asunto(s)
Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Niño , Femenino , Atrios Cardíacos/anomalías , Cardiopatías Congénitas/cirugía , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca(2+) release, nucleoplasmic Ca(2+) elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca(2+)-sensitive gene expression and promotes dendritic arborization in a nuclear Ca(2+)-dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca(2+) to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity-dependent neuronal functions.
Asunto(s)
Señalización del Calcio/genética , Regulación de la Expresión Génica , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Canales de Potasio de Gran Conductancia Activados por el Calcio/fisiología , Membrana Nuclear/genética , Membrana Nuclear/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/deficiencia , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/citología , Neuronas/metabolismo , Membrana Nuclear/ultraestructura , Fosforilación/genética , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/genéticaRESUMEN
Inhibitory neurons control the firing of glutamatergic neurons and synchronize brain activity. However, little is known about mechanisms of excitatory synapse formation in inhibitory neurons. Here we demonstrate that Erbin is specifically expressed in cortical inhibitory neurons. It localizes at excitatory synapses and regulates AMPA receptor (AMPAR) surface expression. Erbin mutation reduced mEPSCs and AMPAR currents specifically in parvalbumin (PV)-positive interneurons but not in pyramidal neurons. We found that the AMPAR auxiliary protein TARP γ-2 was specifically expressed in cortical interneurons. Erbin interacts with TARP γ-2 and is crucial for its stability. Deletion of the γ-2-interacting domain in Erbin attenuated surface AMPAR and excitatory transmission in PV-positive interneurons. Furthermore, we observed behavioral deficits in Erbin-null mice and in mice expressing an Erbin truncation mutant that is unable to interact with TARP γ-2. These observations demonstrate a crucial function for Erbin in AMPAR surface expression in cortical PV-positive interneurons and may contribute to a better understanding of psychiatric disorders.