RESUMEN
In interval reproduction tasks, animals must remember the event starting the interval and anticipate the time of the planned response to terminate the interval. The interval reproduction task thus allows for studying both memory for the past and anticipation of the future. We analyzed previously published recordings from the rodent medial prefrontal cortex [J. Henke et al., eLife10, e71612 (2021)] during an interval reproduction task and identified two cell groups by modeling their temporal receptive fields using hierarchical Bayesian models. The firing in the "past cells" group peaked at the start of the interval and relaxed exponentially back to baseline. The firing in the "future cells" group increased exponentially and peaked right before the planned action at the end of the interval. Contrary to the previous assumption that timing information in the brain has one or two time scales for a given interval, we found strong evidence for a continuous distribution of the exponential rate constants for both past and future cell populations. The real Laplace transformation of time predicts exponential firing with a continuous distribution of rate constants across the population. Therefore, the firing pattern of the past cells can be identified with the Laplace transform of time since the past event while the firing pattern of the future cells can be identified with the Laplace transform of time until the planned future event.
Asunto(s)
Neuronas , Corteza Prefrontal , Corteza Prefrontal/fisiología , Corteza Prefrontal/citología , Animales , Ratas , Neuronas/fisiología , Teorema de Bayes , Masculino , Modelos Neurológicos , Memoria/fisiología , Percepción del Tiempo/fisiología , Potenciales de Acción/fisiologíaRESUMEN
Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of µ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and µ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX's distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.
Asunto(s)
Ansia , Preparaciones de Acción Retardada , Giro del Cíngulo , Imagen por Resonancia Magnética , Naltrexona , Antagonistas de Narcóticos , Plasticidad Neuronal , Trastornos Relacionados con Opioides , Tomografía de Emisión de Positrones , Corteza Prefrontal , Humanos , Naltrexona/farmacología , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Masculino , Adulto , Femenino , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Antagonistas de Narcóticos/farmacología , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/diagnóstico por imagen , Plasticidad Neuronal/efectos de los fármacos , Estudios Longitudinales , Ansia/efectos de los fármacos , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/efectos de los fármacos , Persona de Mediana Edad , Receptores Opioides mu/efectos de los fármacos , Fentanilo/administración & dosificación , Fentanilo/análogos & derivadosRESUMEN
This study investigated whether the electric field magnitude (E-field) delivered to the left dorsolateral prefrontal cortex (L-DLPFC) changes resting-state brain activity and the L-DLPFC resting-state functional connectivity (rsFC), given the variability in tDCS response and lack of understanding of how rsFC changes. Twenty-one healthy participants received either 2 mA anodal or sham tDCS targeting the L-DLPFC for 10 min. Brain imaging was conducted before and after stimulation. The fractional amplitude of low-frequency fluctuation (fALFF), reflecting resting brain activity, and the L-DLPFC rsFC were analyzed to investigate the main effect of tDCS, main effect of time, and interaction effects. The E-field was estimated by modeling tDCS-induced individual electric fields and correlated with fALFF and L-DLPFC rsFC. Anodal tDCS increased fALFF in the left rostral middle frontal area and decreased fALFF in the midline frontal area (FWE p < 0.050), whereas sham induced no changes. Overall rsFC decreased after sham (positive and negative connectivity, p = 0.001 and 0.020, respectively), with modest and nonsignificant changes after anodal tDCS (p = 0.063 and 0.069, respectively). No significant differences in local rsFC were observed among the conditions. Correlations were observed between the E-field and rsFC changes in the L-DLPFC (r = 0.385, p = 0.115), left inferior parietal area (r = 0.495, p = 0.037), and right lateral visual area (r = 0.683, p = 0.002). Single-session tDCS induced resting brain activity changes and may help maintain overall rsFC. The E-field in the L-DLPFC is associated with rsFC changes in both proximal and distally connected brain regions to the L-DLPFC.
Asunto(s)
Estudios Cruzados , Corteza Prefontal Dorsolateral , Imagen por Resonancia Magnética , Estimulación Transcraneal de Corriente Directa , Humanos , Estimulación Transcraneal de Corriente Directa/métodos , Masculino , Femenino , Adulto , Adulto Joven , Corteza Prefontal Dorsolateral/fisiología , Vías Nerviosas/fisiología , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagen , Mapeo EncefálicoRESUMEN
Background: Posttraumatic stress disorder and medically unexplained pain frequently co-occur. While pain is common during traumatic events, the processing of pain during trauma and its relation to audiovisual and pain intrusions is poorly understood.Objective: Here we investigate neural activations during painful analogue trauma, focusing on areas that have been related to threat and pain processing, and how they predict intrusion formation. We also examine the moderating role of cumulative lifetime adversity.Methods: Sixty-five healthy women were assessed using functional magnetic resonance imaging. An analogue trauma was induced by an adaptation of the trauma-film paradigm extended by painful electrical stimulation in a 2 (film: aversive, neutral) x 2 (pain: pain, no-pain) design, followed by 7-day audiovisual and pain intrusion assessment using event-based ecological momentary assessment. Intrusions were fitted with Bayesian multilevel regression and a hurdle lognormal distribution.Results: Conjunction analysis confirmed a wide network including anterior insula (AI) and dorsal anterior cingulate cortex (dACC) being active both, during aversive films and pain. Pain resulted in activation in areas amongst posterior insula and deactivation in a network around ventromedial prefrontal cortex (VMPFC). Higher AI and dACC activity during aversive>neutral film predicted greater audiovisual intrusion probability over time and predicted greater audiovisual intrusion frequency particularly for participants with high lifetime adversity. Lower AI, dACC, hippocampus, and VMPFC activity during pain>no-pain predicted greater pain intrusion probability particularly for participants with high lifetime adversity. Weak regulatory VMPFC activation was associated with both increased audiovisual and pain intrusion frequency.Conclusions: Enhanced AI and dACC processing during aversive films, poor pain vs. no-pain discrimination in AI and dACC, as well as weak regulatory VMPFC processing may be driving factors for intrusion formation, particularly in combination with high lifetime adversity. Results shed light on a potential path for the etiology of PTSD and medically unexplained pain.
AI and dACC play a common role for both trauma- and pain-processing.In combination with high lifetime adversity, higher AI and dACC aversive film processing was associated with higher audiovisual intrusion frequency, whereas weaker AI and dACC pain discrimination enhanced the chance for pain intrusions.Weak regulatory VMPFC activity in aversive situations increased both audiovisual and pain intrusion formation.
Asunto(s)
Imagen por Resonancia Magnética , Dolor , Trastornos por Estrés Postraumático , Humanos , Femenino , Adulto , Dolor/psicología , Dolor/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/psicología , Giro del Cíngulo/fisiopatología , Giro del Cíngulo/diagnóstico por imagen , Adulto Joven , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Teorema de BayesRESUMEN
The dorsolateral prefrontal cortex (dlPFC) is reliably engaged in working memory (WM) and comprises different cytoarchitectonic layers, yet their functional role in human WM is unclear. Here, participants completed a delayed-match-to-sample task while undergoing functional magnetic resonance imaging (fMRI) at ultra-high resolution. We examine layer-specific activity to manipulations in WM load and motor response. Superficial layers exhibit a preferential response to WM load during the delay and retrieval periods of a WM task, indicating a lamina-specific activation of the frontoparietal network. Multivariate patterns encoding WM load in the superficial layer dynamically change across the three periods of the task. Last, superficial and deep layers are non-differentially involved in the motor response, challenging earlier findings of a preferential deep layer activation. Taken together, our results provide new insights into the functional laminar circuitry of the dlPFC during WM and support a dynamic account of dlPFC coding.
Asunto(s)
Imagen por Resonancia Magnética , Memoria a Corto Plazo , Corteza Prefrontal , Humanos , Memoria a Corto Plazo/fisiología , Masculino , Femenino , Adulto , Adulto Joven , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefontal Dorsolateral/fisiología , Corteza Prefontal Dorsolateral/diagnóstico por imagen , Mapeo Encefálico/métodosRESUMEN
Kruppel-like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)-induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ-induced seizure in mice. HP-specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down-stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4-KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c-Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ-induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ-induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs.
Asunto(s)
Hipocampo , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel , Ratones Noqueados , Pentilenotetrazol , Convulsiones , Animales , Factor 4 Similar a Kruppel/metabolismo , Convulsiones/metabolismo , Convulsiones/inducido químicamente , Convulsiones/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Millions of people suffer from opioid use disorder, because of the ongoing opioid epidemic. The aversive symptoms of withdrawal are a leading factor for drug relapses, yet there are limited therapeutic options to minimize or prevent withdrawal symptoms. The mechanism behind opioid withdrawal is still not fully understood, thus preventing the development of new therapeutics. This study is an extension of our previously proposed mechanism of a toll-like receptor 2 (TLR2) mediated withdrawal response as a result of morphine induced microbial change that occurs during morphine withdrawal. Transcriptome analysis of the pre-frontal cortex indicated that there was increased expression of genes related to TLR2 signaling in morphine withdrawal treated animals compared to placebo controls. Antibiotic treatment further altered TLR2 related genes, recovering some of the morphine induced effect and leading to additional suppression of some genes related to the TLR2 pathway. Morphine withdrawal induced gene expression was attenuated in a whole body TLR2 knockout model. These results provide more support that TLR2 plays an integral role in morphine withdrawal mechanisms and could be a potential therapeutic target to minimize opioid withdrawal associated co-morbidities.
Asunto(s)
Morfina , Corteza Prefrontal , Transducción de Señal , Síndrome de Abstinencia a Sustancias , Receptor Toll-Like 2 , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/metabolismo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Animales , Transducción de Señal/efectos de los fármacos , Ratones , Masculino , Ratones Noqueados , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Dependencia de Morfina/genética , Dependencia de Morfina/metabolismoRESUMEN
OBJECTIVE: To investigate the effect of Kaixinsan (KXS, a traditional Chinese medicine formula) for alleviating adriamycin-induced depression-like behaviors in mice bearing breast cancer xenografts and explore the pharmacological mechanism. METHODS: Forty female BALB/c mice were randomized equally into control group, model group, and low- and high-dose KXS treatment groups, and in the latter 3 groups, mouse models bearing orthotopic breast cancer 4T1 cell xenografts were established and treated with adriamycin along with saline or KXS via gavage. Depression-like behaviors of the mice were assessed using open field test and elevated plus-maze test, and the changes in serum levels of depression-related factors were examined. RNA-seq analysis and transmission electron microscopy were used and ferroptosis-related factors were detected to explore the mechanisms of adriamycin-induced depression and the therapeutic mechanism of KXS. The results were verified in SH-SY5Y cells using ferroptosis inhibitor Fer-1 as the positive control. RESULTS: KXS significantly alleviated depression-like behaviors and depression-related serological changes induced by adriamycin in the mouse models. RNA-seq results suggested that KXS alleviated chemotherapy-induced depression by regulating oxidative stress, lipid metabolism and iron ion binding in the prefrontal cortex. Pathological analysis and detection of ferroptosis-related factors showed that KXS significantly reduced ferroptosis in the prefrontal cortex of adriamycin-treated mice. In SH-SY5Y cells, both KXS-medicated serum and the ferroptosis inhibitor were capable of attenuating adriamycin-induced cell ferroptosis. CONCLUSION: KXS alleviates adriamycininduced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex of breast cancer-bearing mice.
Asunto(s)
Depresión , Doxorrubicina , Ferroptosis , Ratones Endogámicos BALB C , Corteza Prefrontal , Animales , Ferroptosis/efectos de los fármacos , Ratones , Depresión/tratamiento farmacológico , Depresión/inducido químicamente , Doxorrubicina/efectos adversos , Femenino , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Línea Celular Tumoral , Conducta Animal/efectos de los fármacos , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismoRESUMEN
The reinforcing nature of social interactions is necessary for the maintenance of appropriate social behavior. However, the neural substrates underlying social reward processing and how they might differ based on the sex and internal state of the animal remains unknown. It is also unclear whether these neural substrates are shared with those involved in nonsocial rewarding processing. We developed a fully automated, two choice (social-sucrose) operant assay in which mice choose between social and nonsocial rewards to directly compare the reward-related behaviors associated with two competing stimuli. We performed cellular resolution calcium imaging of medial prefrontal cortex (mPFC) neurons in male and female mice across varying states of water restriction and social isolation. We found that mPFC neurons maintain largely non-overlapping, flexible representations of social and nonsocial reward that vary with internal state in a sex-dependent manner. Additionally, optogenetic manipulation of mPFC activity during the reward period of the assay disrupted reward-seeking behavior across male and female mice. Thus, using a two choice operant assay, we have identified sex-dependent, non-overlapping neural representations of social and nonsocial reward in the mPFC that vary with internal state and that are essential for appropriate reward-seeking behavior.
Asunto(s)
Neuronas , Optogenética , Corteza Prefrontal , Recompensa , Conducta Social , Animales , Corteza Prefrontal/fisiología , Femenino , Masculino , Neuronas/fisiología , Ratones , Ratones Endogámicos C57BL , Caracteres Sexuales , Conducta Animal/fisiología , Condicionamiento Operante/fisiología , Conducta de Elección/fisiología , Aislamiento Social/psicologíaRESUMEN
BACKGROUND: Multiple Sclerosis (MS) is an autoimmune disease associated with physical disability, psychological impairment, and cognitive dysfunctions. Consequently, the disease burden is substantial, and treatment choices are limited. In this randomized, double-blind study, we conducted repeated prefrontal electrical stimulation in 40 patients with MS to evaluate mental health variables (quality of life, sleep difficulties, psychological distress) and cognitive dysfunctions (psychomotor speed, working memory, attention/vigilance), marking it as the third largest sample size tDCS research conducted in MS to date. METHODS: The patients were randomly assigned (block randomization method) to two groups of sham (n = 20), or 1.5-mA (n = 20) transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (F3) and right frontopolar cortex (Fp2) with anodal and cathodal stimulation respectively (electrode size: 25 cm2). The treatment included 10 sessions of 20 min of stimulation delivered every other day. Outcome measures were MS quality of life, sleep quality, psychological distress, and performance on a neuropsychological test battery dedicated to cognitive dysfunctions in MS (psychomotor speed, working memory, and attention). All outcome measures were evaluated at the pre-intervention and post-intervention assessments. Both patients and technicians delivering the stimulation were unaware of the type of stimulation being used. RESULTS: Repeated prefrontal real tDCS significantly improved quality of life and reduced sleep difficulties and psychological distress compared to the sham group. It, furthermore, improved psychomotor speed, attention, and vigilance compared to the sham protocol. Improvement in mental health outcome variables and cognitive outperformance were interrelated and could predict each other. CONCLUSIONS: Repeated prefrontal and frontopolar tDCS ameliorates secondary clinical symptoms related to mental health and results in beneficial cognitive effects in patients with MS. These results support applying prefrontal tDCS in larger trials for improving mental health and cognitive dysfunctions in MS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06401928.
Asunto(s)
Salud Mental , Esclerosis Múltiple , Corteza Prefrontal , Estimulación Transcraneal de Corriente Directa , Humanos , Estimulación Transcraneal de Corriente Directa/métodos , Método Doble Ciego , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/terapia , Esclerosis Múltiple/psicología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Calidad de Vida , Pruebas Neuropsicológicas , Trastornos del Conocimiento/terapiaRESUMEN
Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.
Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Hipocampo , MicroARNs , Neuroglía , Neuronas , Animales , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Neuronas/metabolismo , Neuroglía/metabolismo , Hipocampo/metabolismo , Ratones Transgénicos , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Regulación de la Expresión Génica , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Corteza Prefrontal/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , MasculinoRESUMEN
Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-ß, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte-microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression.
Asunto(s)
Ácido 2-Aminoadípico , Antidepresivos , Astrocitos , Ginsenósidos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ginsenósidos/farmacología , Masculino , Ácido 2-Aminoadípico/farmacología , Depresión/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Apoptosis/efectos de los fármacosRESUMEN
BACKGROUND: Current models of major depressive disorder (MDD) primarily focus on the structural and functional changes in key prefrontal areas responsible for emotional regulation. Among these regions some sections such as the dorsal prefrontal area, has received limited attention regarding its structural abnormalities in MDD. This study aims to evaluate volumetric abnormalities in brain regions associated with markers of depression severity and episode frequency. METHODS: The study included 33 MDD patients and 33 healthy subjects. Using an atlas-based method, we measured the volumes of several key brain regions based on MRI data. The regions of interest included prefrontal and posterior sections of the middle frontal gyrus (MFG) and superior frontal gyrus (SFG). Additionally, we evaluated the volumes of the dorsal anterior cingulate cortex (dACC), perigenual (rostral) anterior cingulate cortex (pgACC), subgenual cingulate cortex (sgACC), posterior cingulate cortex (PCC), hippocampus (HPC), and parahippocampus (paraHPC). Hamilton Depression Scale (HAM-D) scores and count of the depressive episodes of patients were also obtained. A regression analysis with sex as the confounding factor has been made. RESULTS: Analysis of covariances, controlling for sex, showed significant atrophy in the sgACC in the depression group: F(1, 63) = 4.013, p = 0.049 (left) and F(1, 63) = 8.786, p < 0.004 (right). Poisson regression, also controlling for sex, found that each additional depressive episode was associated with a significant reduction in left posterior MFG volume (0.952 times, 95 % CI, 0.906 to 1.000; p = 0.049). CONCLUSIONS: Findings in this study highlight the structural abnormalities in MDD patients in correlation to either current depression severity or chronicity of the disease.
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Atrofia , Trastorno Depresivo Mayor , Imagen por Resonancia Magnética , Corteza Prefrontal , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/psicología , Masculino , Femenino , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Adulto , Atrofia/patología , Persona de Mediana Edad , Atlas como Asunto , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Privación Materna , Plasticidad Neuronal , Corteza Prefrontal , Resiliencia Psicológica , Animales , Plasticidad Neuronal/fisiología , Masculino , Ratas , Anhedonia/fisiología , Interacción Social , Derrota Social , Hipocampo , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Ratas Wistar , Conducta Animal/fisiología , Conducta Social , Ansiedad/fisiopatologíaRESUMEN
The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.
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Inflamación , Neuronas , Ratas Sprague-Dawley , Corteza Somatosensorial , Animales , Neuronas/metabolismo , Neuronas/fisiología , Masculino , Ratas , Corteza Somatosensorial/fisiopatología , Dolor/fisiopatología , Conducta Animal , Modelos Animales de Enfermedad , Dolor Crónico/fisiopatología , Corteza Prefrontal/fisiopatologíaRESUMEN
Task-related studies have consistently reported that listening to speech sounds activate the temporal and prefrontal regions of the brain. However, it is not well understood how functional organization of auditory and language networks differ when processing speech sounds from its resting state form. The knowledge of language network organization in typically developing infants could serve as an important biomarker to understand network-level disruptions expected in infants with hearing impairment. We hypothesized that topological differences of language networks can be characterized using functional connectivity measures in two experimental conditions (1) complete silence (resting) and (2) in response to repetitive continuous speech sounds (steady). Thirty normal-hearing infants (14 males and 16 females, age: 7.8 ± 4.8 months) were recruited in this study. Brain activity was recorded from bilateral temporal and prefrontal regions associated with speech and language processing for two experimental conditions: resting and steady states. Topological differences of functional language networks were characterized using graph theoretical analysis. The normalized global efficiency and clustering coefficient were used as measures of functional integration and segregation, respectively. We found that overall, language networks of infants demonstrate the economic small-world organization in both resting and steady states. Moreover, language networks exhibited significantly higher functional integration and significantly lower functional segregation in resting state compared to steady state. A secondary analysis that investigated developmental effects of infants aged 6-months or below and above 6-months revealed that such topological differences in functional integration and segregation across resting and steady states can be reliably detected after the first 6-months of life. The higher functional integration observed in resting state suggests that language networks of infants facilitate more efficient parallel information processing across distributed language regions in the absence of speech stimuli. Moreover, higher functional segregation in steady state indicates that the speech information processing occurs within densely interconnected specialized regions in the language network.
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Conectoma , Red Nerviosa , Espectroscopía Infrarroja Corta , Percepción del Habla , Humanos , Femenino , Masculino , Lactante , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Percepción del Habla/fisiología , Conectoma/métodos , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagen , LenguajeRESUMEN
The regulation of emotions is a crucial facet of well-being and social adaptability, with explicit strategies receiving primary attention in prior research. Recent studies, however, emphasize the role of implicit emotion regulation, particularly implicating the ventromedial prefrontal cortex (VMPFC) in association with its implementation. This study delves into the nuanced role of the VMPFC through focality-optimized multichannel transcranial direct current stimulation (tDCS), shedding light on its causal involvement in implicit reappraisal. The primary goal was to evaluate the effectiveness of VMFPC-targeted tDCS and elucidate its role in individuals with high trait anxiety. Participants engaged in implicit and explicit emotion regulation tasks during multichannel tDCS targeting the VMPFC. The outcome measures encompassed negative emotion ratings, pupillary diameter, and saccade count, providing a comprehensive evaluation of emotion regulation efficiency. The intervention exhibited a notable impact, resulting in significant reductions in negative emotion ratings and pupillary reactions during implicit reappraisal, highlighting the indispensable role of the VMPFC in modulating emotional responses. Notably, these effects demonstrated sustained efficacy up to 1 day postintervention. This study underscores the potency of VMPFC-targeted multichannel tDCS in augmenting implicit emotion regulation. This not only contributes insights into the neural mechanisms of emotion regulation but also suggests innovative therapeutic avenues for anxiety disorders. The findings present a promising trajectory for future mood disorder interventions, bridging the gap between implicit emotion regulation and neural stimulation techniques.
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Regulación Emocional , Corteza Prefrontal , Estimulación Transcraneal de Corriente Directa , Humanos , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagen , Regulación Emocional/fisiología , Masculino , Femenino , Adulto , Adulto Joven , Ansiedad/fisiopatología , Ansiedad/terapia , Movimientos Sacádicos/fisiología , Emociones/fisiologíaRESUMEN
While it is widely acknowledged that exercise has positive effects on cognitive function, the specific impacts of different types of exercises, particularly open and closed skill exercises, on cognitive impairment continue to be a debated topic. In this study, we used fNIRS and cognitive psychology tasks to investigate the effects of different types of exercises on cognitive function and brain activity in young adults. We conducted an observational study to assess the cognitive function of participants who had engaged in these exercises for a long period. Additionally, we examined the effects of open skill exercise (badminton) and closed skill exercise (calisthenics) on localized blood flow in the prefrontal lobe of the brain using an experimental research method. Specifically, during the Stroop task, the badminton group exhibited significantly higher â³HbO2 in channel 18, corresponding to the dorsolateral prefrontal cortex, compared to the calisthenics group (F = 4.485, P < 0.05, η2 = 0.074). In the 2-back task, the calisthenics group showed significantly higher â³HbO2 in channel 17, corresponding to the frontopolar area, dorsolateral prefrontal cortex and inferior prefrontal gyrus, than the badminton group (F = 8.842, P < 0.01, η2 = 0.136). Our findings reveal that open skill exercises are more effective in enhancing cognitive inhibition, thereby increasing attention capacity, self-regulation, and flexibility in response to environmental changes. Conversely, closed skill exercises demonstrate greater efficacy in improving working memory within cognitive functions, showcasing an enhanced capacity for information processing and storage. These data indicate that while both open and closed skill exercises are beneficial for cognitive function, they exhibit significant distinctions in some aspects.
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Cognición , Ejercicio Físico , Espectroscopía Infrarroja Corta , Humanos , Cognición/fisiología , Masculino , Adulto Joven , Espectroscopía Infrarroja Corta/métodos , Femenino , Ejercicio Físico/fisiología , Adulto , Corteza Prefrontal/fisiologíaRESUMEN
The ability to switch between rules associating stimuli and responses depend on a circuit including the dorsomedial prefrontal cortex (dmPFC) and the subthalamic nucleus (STN). However, the precise neural implementations of switching remain unclear. To address this issue, we recorded local field potentials from the STN and from the dmPFC of neuropsychiatric patients during behavioral switching. Drift-diffusion modeling revealed that switching is associated with a shift in the starting point of evidence accumulation. Theta activity increases in dmPFC and STN during successful switch trials, while temporally delayed and excessive levels of theta lead to premature switch errors. This seemingly opposing impact of increased theta in successful and unsuccessful switching is explained by a negative correlation between theta activity and the starting point. Together, these results shed a new light on the neural mechanisms underlying the rapid reconfiguration of stimulus-response associations, revealing a Goldilocks' effect of theta activity on switching behavior.
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Corteza Prefrontal , Núcleo Subtalámico , Ritmo Teta , Humanos , Corteza Prefrontal/fisiología , Ritmo Teta/fisiología , Masculino , Femenino , Adulto , Núcleo Subtalámico/fisiología , Persona de Mediana Edad , Estimulación Encefálica ProfundaRESUMEN
Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in early life stress-induced neurobehavioral abnormalities remains unclear. Using the maternally separated (MS) mice, our research has unveiled a novel aspect of this complex relationship. We discovered that the reduced levels of amino acid transporters in the intestine of MS mice led to low glutamine (Gln) levels in the blood and synaptic dysfunction in the medial prefrontal cortex (mPFC). Abnormally low blood Gln levels limit the brain's availability of Gln, which is required for presynaptic glutamate (Glu) and γ-aminobutyric acid (GABA) replenishment. Furthermore, MS resulted in gut microbiota dysbiosis characterized by a reduction in the relative abundance of Lactobacillus reuteri (L. reuteri). Notably, supplementation with L. reuteri ameliorates neurobehavioral abnormalities in MS mice by increasing intestinal amino acid transport and restoring synaptic transmission in the mPFC. In conclusion, our findings on the role of L. reuteri in regulating intestinal amino acid transport and buffering early life stress-induced behavioral abnormalities provide a novel insight into the microbiota-gut-brain signaling basis for emotional behaviors.