RESUMEN
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
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.
Asunto(s)
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 with low social status are at heightened risk of major depressive disorder (MDD), and MDD also influences social status. While the interrelationship between MDD and social status is well-defined, the behavioral causality between these two phenotypes remains unexplored. Here, we investigated the behavioral relationships between depressive and dominance behaviors in male mice exposed to chronic restraint stress and the role of medial prefrontal cortex (mPFC) astrocytes in these behaviors. Chronic restraint stress induced both depressive and submissive behaviors. Chemogenetic mPFC astrocyte activation significantly enhanced dominance in chronic stress-induced submissive mice by increasing the persistence of defensive behavior, although it did not affect depressive behaviors. Notably, repetitive winning experiences following mPFC astrocyte stimulation exerted anti-depressive effects in chronic restraint stress-induced depressive mice. These data indicate that mPFC astrocyte-derived winning experience renders anti-depressive effects, and may offer a new strategy for treating depression caused by low status in social hierarchies by targeting mPFC astrocytes.
Asunto(s)
Astrocitos , Conducta Animal , Depresión , Ratones Endogámicos C57BL , Corteza Prefrontal , Estrés Psicológico , Animales , Astrocitos/metabolismo , Masculino , Estrés Psicológico/complicaciones , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/patología , Depresión/fisiopatología , Predominio Social , Enfermedad Crónica , Restricción Física , RatonesRESUMEN
Post-traumatic stress disorder (PTSD) has been linked to altered communication within the limbic system, including reduced structural connectivity in the uncinate fasciculus (UNC; i.e., decreased fractional anisotropy; FA) and reduced resting-state functional connectivity (RSFC) between the hippocampus and ventromedial prefrontal cortex (vmPFC). Previous research has demonstrated attenuation of PTSD symptoms and alterations in RSFC following exposure-based psychotherapy. However, the relationship between changes in structural and functional connectivity patterns and PTSD symptoms following treatment remains unclear. To investigate this, we conducted a secondary analysis of data from a randomized clinical trial of intensive exposure therapy, evaluating alterations in UNC FA, hippocampus-vmPFC RSFC, and PTSD symptoms before (pre-treatment), 7 days after (post-treatment), and 30 days after (follow-up) the completion of therapy. Our results showed that post-treatment changes in RSFC were positively correlated with post-treatment and follow-up changes in UNC FA and that post-treatment changes in UNC FA were positively correlated with post-treatment and follow-up changes in PTSD symptoms. These findings suggest that early changes in functional connectivity are associated with sustained changes in anatomical connectivity, which in turn are linked to reduced PTSD symptom severity.
Asunto(s)
Corteza Prefrontal , Trastornos por Estrés Postraumático , Sustancia Blanca , Humanos , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/terapia , Trastornos por Estrés Postraumático/patología , Trastornos por Estrés Postraumático/psicología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología , Masculino , Adulto , Femenino , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/patología , Terapia Implosiva/métodos , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/fisiopatología , Imagen de Difusión Tensora/métodos , Persona de Mediana Edad , Imagen por Resonancia Magnética , Vías Nerviosas/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Resultado del TratamientoRESUMEN
Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.
Asunto(s)
Mesocricetus , Microglía , Corteza Prefrontal , Predominio Social , Estrés Psicológico , Animales , Microglía/metabolismo , Microglía/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Masculino , Estrés Psicológico/metabolismo , Cricetinae , Plasticidad Neuronal/fisiología , Derrota Social , Minociclina/farmacologíaRESUMEN
Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD.
Asunto(s)
Conducta Compulsiva , Cuerpo Estriado , Espinas Dendríticas , Plasticidad Neuronal , Corteza Prefrontal , Quinpirol , Animales , Masculino , Espinas Dendríticas/patología , Corteza Prefrontal/patología , Corteza Prefrontal/efectos de los fármacos , Conducta Compulsiva/fisiopatología , Conducta Compulsiva/patología , Cuerpo Estriado/patología , Cuerpo Estriado/efectos de los fármacos , Quinpirol/farmacología , Ratas , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de los fármacos , Trastorno Obsesivo Compulsivo/patología , Trastorno Obsesivo Compulsivo/fisiopatología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Ratas WistarRESUMEN
Based on recent genome-wide association studies, it is theorized that altered regulation of autophagy contributes to the pathophysiology of schizophrenia and bipolar disorder. As activity of autophagy-regulatory pathways is controlled by discrete phosphorylation sites on the relevant proteins, phospho-protein profiling is one of the few approaches available for enabling a quantitative assessment of autophagic activity in the brain. Despite this, a comprehensive phospho-protein assessment in the brains of schizophrenia and bipolar disorder subjects is currently lacking. Using this direction, our broad screening identifies an increase in AMP-activated protein kinase (AMPK)-mediated phospho-activation of the pro-autophagy protein beclin-1 solely in the prefrontal cortex of female, but not male, schizophrenia subjects. Using a reverse translational approach, we surprisingly find that this increase in beclin-1 activity facilitates synapse formation and enhances cognition. These findings are interpreted in the context of human studies demonstrating that female schizophrenia subjects have a lower susceptibility to cognitive dysfunction than males.
Asunto(s)
Autofagia , Beclina-1 , Esquizofrenia , Caracteres Sexuales , Esquizofrenia/patología , Esquizofrenia/metabolismo , Esquizofrenia/genética , Humanos , Femenino , Masculino , Beclina-1/metabolismo , Beclina-1/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Fosforilación , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Sinapsis/metabolismo , Sinapsis/patología , Transducción de Señal , Ratones , Cognición/fisiología , AdultoRESUMEN
It is well established that hearing loss can lead to widespread plasticity within the central auditory pathway, which is thought to contribute to the pathophysiology of audiological conditions such as tinnitus and hyperacusis. Emerging evidence suggests that hearing loss can also result in plasticity within brain regions involved in higher-level cognitive functioning like the prefrontal cortex; findings which may underlie the association between hearing loss and cognitive impairment documented in epidemiological studies. Using the 40-Hz auditory steady state response to assess sound-evoked gamma oscillations, we previously showed that noise-induced hearing loss results in impaired gamma phase coherence within the prefrontal but not the auditory cortex. To determine whether region-specific structural or molecular changes accompany this differential plasticity following hearing loss, in the present study we utilized Golgi-Cox staining to assess dendritic organization and synaptic density, as well as Western blotting to measure changes in synaptic signaling proteins in these cortical regions. We show that following noise exposure, impaired gamma phase coherence within the prefrontal cortex is accompanied by alterations in pyramidal cell dendritic morphology and decreased expression of proteins involved in GABAergic (GAD65) and glutamatergic (NR2B) neurotransmission; findings that were not observed in the auditory cortex, where gamma phase coherence remained unchanged post-noise exposure. In contrast to the noise-induced effects we observed in the prefrontal cortex, plasticity in the auditory cortex was characterized by an increase in NR2B suggesting increased excitability, as well as increases in the synaptic proteins PSD95 and synaptophysin within the auditory cortex. Overall, our results highlight the disparate effect of noise-induced hearing loss on auditory and higher-level brain regions as well as potential structural and molecular mechanisms by which hearing loss may contribute to impaired cognitive and sensory functions mediated by the prefrontal and auditory cortices.
Asunto(s)
Corteza Auditiva , Pérdida Auditiva Provocada por Ruido , Corteza Prefrontal , Pérdida Auditiva Provocada por Ruido/fisiopatología , Pérdida Auditiva Provocada por Ruido/patología , Pérdida Auditiva Provocada por Ruido/metabolismo , Corteza Auditiva/metabolismo , Corteza Auditiva/fisiopatología , Corteza Auditiva/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Animales , Masculino , Plasticidad Neuronal/fisiología , Glutamato Descarboxilasa/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Dendritas/patología , Dendritas/metabolismo , Ritmo Gamma/fisiología , Células Piramidales/metabolismo , Células Piramidales/patología , RatasRESUMEN
BACKGROUND: Anxious depression (AD) is a common subtype of major depressive disorder (MDD). Neuroimaging studies of AD have revealed inconsistent and heterogeneous brain alterations with the use of single-model methods. Therefore, it is necessary to explore the pathogenesis of AD using multi-model imaging analyses to obtain more homogeneous and robust results. METHODS: One hundred and eighty-two patients with MDD and 64 matched healthy controls (HCs) were recruited. Voxel-based morphometry (VBM) was used to estimate the gray matter volume (GMV) of all subjects. The GMV differences between the AD and non-anxious depression (NAD) participants were used as regions of interest (ROIs) for subsequent resting state functional connectivity (rs-FC) analyses. Correlation analysis was used to evaluate the associations between clinical symptoms and abnormal function in specific brain areas. RESULTS: Decreased GMV in the medial frontal gyrus (MFG) and the superior frontal gyrus (SFG) was observed in the AD group compared to the NAD group. Taking the MFG and SFG as ROIs, the rs-FC analysis revealed decreased FC between the left SFG and left temporal pole and between the left SFG and right MFG in the AD group compared to the NAD group. Finally, the FC between the left SFG and left temporal pole was negatively correlated with HAMD-17 scores in the AD group. CONCLUSION: By combining the GMV and rs-FC models, this study revealed that structural and functional disruption of the affective network may be an important pathophysiology underlying AD. The structural impairment may serve as the foundation of the functional impairment.
Asunto(s)
Trastorno Depresivo Mayor , Sustancia Gris , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Adulto , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/patología , Persona de Mediana Edad , Estudios de Casos y Controles , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/patología , Conectoma , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patologíaRESUMEN
Studies of the impact of brain injury on memory processes often focus on the quantity and episodic richness of those recollections. Here, we argue that the organization of one's recollections offers critical insights into the impact of brain injury on functional memory. It is well-established in studies of word list memory that free recall of unrelated words exhibits a clear temporal organization. This temporal contiguity effect refers to the fact that the order in which word lists are recalled reflects the original presentation order. Little is known, however, about the organization of recall for semantically rich materials, nor how recall organization is impacted by hippocampal damage and memory impairment. The present research is the first study, to our knowledge, of temporal organization in semantically rich narratives in three groups: (1) Adults with bilateral hippocampal damage and severe declarative memory impairment, (2) adults with bilateral ventromedial prefrontal cortex (vmPFC) damage and no memory impairment, and (3) demographically matched non-brain-injured comparison participants. We find that although the narrative recall of adults with bilateral hippocampal damage reflected the temporal order in which those narratives were experienced above chance levels, their temporal contiguity effect was significantly attenuated relative to comparison groups. In contrast, individuals with vmPFC damage did not differ from non-brain-injured comparison participants in temporal contiguity. This pattern of group differences yields insights into the cognitive and neural systems that support the use of temporal organization in recall. These data provide evidence that the retrieval of temporal context in narrative recall is hippocampal-dependent, whereas damage to the vmPFC does not impair the temporal organization of narrative recall. This evidence of limited but demonstrable organization of memory in participants with hippocampal damage and amnesia speaks to the power of narrative structures in supporting meaningfully organized recall despite memory impairment.
Asunto(s)
Amnesia , Hipocampo , Recuerdo Mental , Humanos , Hipocampo/patología , Hipocampo/diagnóstico por imagen , Hipocampo/fisiopatología , Recuerdo Mental/fisiología , Masculino , Femenino , Persona de Mediana Edad , Amnesia/fisiopatología , Amnesia/patología , Amnesia/psicología , Adulto , Narración , Anciano , Pruebas Neuropsicológicas , Factores de Tiempo , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/lesionesRESUMEN
Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T1) and iron concentration (proxied by transverse relaxation time T2*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T1 values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.
Asunto(s)
Trastorno Depresivo Mayor , Giro del Cíngulo , Imagen por Resonancia Magnética , Vaina de Mielina , Corteza Prefrontal , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Femenino , Masculino , Adulto , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/patología , Vaina de Mielina/patología , Persona de Mediana Edad , Hierro/metabolismo , Estudios de Casos y ControlesRESUMEN
Malfunctioning in executive functioning has been proposed as a risk factor for intimate partner violence (IPV). This is not only due to its effects on behavioral regulation but also because of its association with other variables such as sexism. Executive dysfunctions have been associated with frontal and prefrontal cortical thickness. Therefore, our first aim was to assess differences in cortical thickness in frontal and prefrontal regions, as well as levels of sexism, between two groups of IPV perpetrators (with and without executive dysfunctions) and a control group of non-violent men. Second, we analyzed whether the cortical thickness in the frontal and prefrontal regions would explain sexism scores. Our results indicate that IPV perpetrators classified as dysexecutive exhibited a lower cortical thickness in the right rostral anterior cingulate superior frontal bilaterally, caudal middle frontal bilaterally, right medial orbitofrontal, right paracentral, and precentral bilaterally when compared with controls. Furthermore, they exhibited higher levels of sexism than the rest of the groups. Most importantly, in the brain structures that distinguished between groups, lower thickness was associated with higher sexism scores. This research emphasizes the need to incorporate neuroimaging techniques to develop accurate IPV profiles or subtypes based on neuropsychological functioning.
Asunto(s)
Función Ejecutiva , Violencia de Pareja , Imagen por Resonancia Magnética , Sexismo , Humanos , Masculino , Función Ejecutiva/fisiología , Adulto , Violencia de Pareja/psicología , Imagen por Resonancia Magnética/métodos , Pruebas Neuropsicológicas , Adulto Joven , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Femenino , Persona de Mediana Edad , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patologíaRESUMEN
Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.
Asunto(s)
Corteza Prefrontal , Animales , Corteza Prefrontal/patología , Masculino , Trastornos Paranoides , Macaca mulatta , Humanos , Tálamo/patología , Recompensa , Femenino , CulturaRESUMEN
BACKGROUND: Disordered eating behaviors are prevalent among youngsters and highly associated with dysfunction in neurocognitive systems. We aimed to identify the potential changes in individuals with bulimia symptoms (sub-BN) to generate insights to understand developmental pathophysiology of bulimia nervosa. METHODS: We investigated group differences in terms of degree centrality (DC) and gray matter volume (GMV) among 145 undergraduates with bulimia symptoms and 140 matched control undergraduates, with the secondary analysis of the whole brain connectivity in these regions of interest showing differences in static functional connectivity (FC). RESULTS: The sub-BN group exhibited abnormalities of the right dorsolateral prefrontal cortex and right orbitofrontal cortex in both GMV and DC, and displayed decreased FC between these regions and the precuneus. We also observed that sub-BN presented with reduced FC between the calcarine and superior temporal gyrus, middle temporal gyrus and inferior parietal gyrus. Additionally, brain-behavioral associations suggest a distinct relationship between these FCs and psychopathological symptoms in sub-BN group. CONCLUSIONS: Our study demonstrated that individuals with bulimia symptoms present with aberrant neural patterns that mainly involved in cognitive control and reward processing, as well as attentional and self-referential processing, which could provide important insights into the pathology of BN.
Asunto(s)
Bulimia Nerviosa , Corteza Prefontal Dorsolateral , Imagen por Resonancia Magnética , Humanos , Bulimia Nerviosa/diagnóstico por imagen , Bulimia Nerviosa/fisiopatología , Bulimia Nerviosa/patología , Bulimia Nerviosa/psicología , Femenino , Adulto Joven , Corteza Prefontal Dorsolateral/diagnóstico por imagen , Corteza Prefontal Dorsolateral/fisiopatología , Corteza Prefontal Dorsolateral/patología , Adulto , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/patología , Masculino , AdolescenteRESUMEN
Experiencing peer abuse in childhood can damage mental health, but some people exhibit resilience against these negative outcomes. However, it remains uncertain which specific changes in brain structures are associated with this type of resilience. We categorized 217 participants into three groups: resilience group, susceptibility group, and healthy control group, based on their experiences of peer abuse and mental health problems. They underwent MRI scans to measure cortical thickness in various brain regions of the prefrontal cortex. We employed covariance analysis to compare cortical thickness among these groups. Individuals who resilient to anxiety exhibited smaller cortical thickness in the bilateral inferior frontal gyrus (IFG), and with larger thickness in the right medial orbitofrontal cortex (mOFC), while those resilient to stress was associated with smaller thickness in both the bilateral IFG and bilateral middle frontal gyrus (MFG). These findings deepen our understanding of the neural mechanisms underlying resilience and offer insight into improving individual resilience.
Asunto(s)
Regulación Emocional , Imagen por Resonancia Magnética , Grupo Paritario , Resiliencia Psicológica , Humanos , Masculino , Femenino , Regulación Emocional/fisiología , Adulto , Adulto Joven , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Ansiedad/psicología , Ansiedad/diagnóstico por imagen , Grosor de la Corteza Cerebral , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Adolescente , Maltrato a los Niños/psicología , Susceptibilidad a EnfermedadesRESUMEN
Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.
Asunto(s)
Disfunción Cognitiva , Estrés del Retículo Endoplásmico , Ferroptosis , Hipoxia , Neuronas , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Hipoxia/metabolismo , Hipoxia/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Ciclohexilaminas/farmacología , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/metabolismo , Humanos , Quinoxalinas , Compuestos de Espiro , Sistema de Transporte de Aminoácidos y+RESUMEN
Loss-of-function mutations in the progranulin (GRN) gene are an autosomal dominant cause of Frontotemporal Dementia (FTD). These mutations typically result in haploinsufficiency of the progranulin protein. Grn+/- mice provide a model for progranulin haploinsufficiency and develop FTD-like behavioral abnormalities by 9-10 months of age. In previous work, we demonstrated that Grn+/- mice develop a low dominance phenotype in the tube test that is associated with reduced dendritic arborization of layer II/III pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), a region key for social dominance behavior in the tube test assay. In this study, we investigated whether progranulin haploinsufficiency induced changes in dendritic spine density and morphology. Individual layer II/III pyramidal neurons in the prelimbic mPFC of 9-10 month old wild-type or Grn+/- mice were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D reconstruction for morphometry analysis. Dendritic spine density in Grn+/- mice was comparable to wild-type littermates, but the apical dendrites in Grn+/- mice had a shift in the proportion of spine types, with fewer stubby spines and more thin spines. Additionally, apical dendrites of Grn+/- mice had longer spines and smaller thin spine head diameter in comparison to wild-type littermates. These changes in spine morphology may contribute to altered circuit-level activity and social dominance deficits in Grn+/- mice.
Asunto(s)
Espinas Dendríticas , Haploinsuficiencia , Corteza Prefrontal , Progranulinas , Animales , Espinas Dendríticas/metabolismo , Corteza Prefrontal/patología , Corteza Prefrontal/metabolismo , Progranulinas/deficiencia , Progranulinas/genética , Ratones , Células Piramidales/metabolismo , Células Piramidales/patología , Masculino , Ratones Endogámicos C57BLRESUMEN
Early life adversity (ELA) increases the likelihood of later-life neuropsychiatric disorders and cognitive dysfunction. Importantly, ELA, neuropsychiatric disorders, and cognitive deficits all involve aberrant immune signaling. Microglia are the primary neuroimmune cells and regulate brain development. Microglia are particularly sensitive to early life insults, which can program their responses to future challenges. ELA in the form of maternal separation (MS) in rats alters later-life microglial morphology and the inflammatory profile of the prefrontal cortex, a region important for cognition. However, the role of microglial responses during MS in the development of later cognition is not known. Therefore, here we aimed to determine whether the presence of microglia during MS mediates long-term impacts on adult working memory. Clodronate liposomes were used to transiently deplete microglia from the brain, while empty liposomes were used as a control. We hypothesized that if microglia mediate the long-term impacts of ELA on working memory in adulthood, then depleting microglia during MS would prevent these deficits. Importantly, microglial function shifts throughout the neonatal period, so an exploratory investigation assessed whether depletion during the early versus late neonatal period had different effects on adult working memory. Surprisingly, empty liposome treatment during the early, but not late, postnatal period induced microglial activity changes that compounded with MS to impair working memory in females. In contrast, microglial depletion later in infancy impaired later life working memory in females, suggesting that microglial function during late infancy plays an important role in the development of cognitive function. Together, these findings suggest that microglia shift their sensitivity to early life insults across development. Our findings also highlight the potential for MS to impact some developmental processes only when compounded with additional neuroimmune challenges in a sex-dependent manner.
Asunto(s)
Cognición , Privación Materna , Memoria a Corto Plazo , Microglía , Animales , Microglía/metabolismo , Microglía/patología , Femenino , Ratas , Masculino , Animales Recién Nacidos , Corteza Prefrontal/patología , Ratas Sprague-Dawley , Factores de EdadRESUMEN
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder. Oxidative stress and inflammatory responses have a vital role in the pathophysiology of IBD as well as seizure. IBD is associated with extraintestinal manifestations. This study aimed to explore the relationship between colitis and susceptibility to seizures, with a focus on the roles of neuroinflammation and oxidative stress in acetic acid-induced colitis in mice. Forty male Naval Medical Research Institute mice were divided into four groups: control, colitis, pentylenetetrazole (PTZ), and colitis + PTZ. Colitis was induced by intrarectal administration of acetic acid, and seizures were induced by intravenous injection of PTZ 7 days postcolitis induction. Following the measurement of latency to seizure, the mice were killed, and their colons and prefrontal cortex (PFC) were dissected. Gene expression of inflammatory markers including interleukin-1ß, tumor necrosis factor-alpha, NOD-like receptor protein 3, and toll-like receptor 4, as well as total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels were measured in the colon and PFC. Histopathological evaluations were performed on the colon samples. Data were analyzed by t-test or one-way variance analysis. Colitis decreased latency to seizure, increased gene expression of inflammatory markers, and altered levels of MDA, nitrite, and TAC in both the colon and PFC. Simultaneous induction of colitis and seizure exacerbated the neuroimmune response and oxidative stress in the PFC and colon. Results concluded that neuroinflammation and oxidative stress in the PFC at least partially mediate the comorbid decrease in seizure latency in mice with colitis.