RESUMEN
Altered functioning of the bed nucleus of the stria terminalis (BNST) may play a critical role in the etiology of posttraumatic stress disorder (PTSD). Chronic stressors such as racial discrimination and lifetime trauma are associated with an increased risk for PTSD, but it is unknown whether they influence the relationship between BNST functioning and PTSD. We investigated acute post-trauma BNST resting-state functional connectivity (rsFC) as a predictor of future PTSD symptoms in Black trauma survivors. We also examined whether racial discrimination and lifetime trauma moderated the relationship between BNST rsFC and PTSD symptoms. Black adults (N = 95; 54.7% female; mean age = 34.04) were recruited from an emergency department after experiencing a traumatic injury (72.6% were motor vehicle accidents). Two-weeks post-injury, participants underwent a resting-state fMRI scan and completed questionnaires evaluating their PTSD symptoms as well as lifetime exposure to racial discrimination and trauma. Six-months post-injury, PTSD symptoms were reassessed. Whole brain seed-to-voxel analyses were conducted to examine BNST rsFC patterns. Greater rsFC between the BNST and the posterior cingulate cortex, precuneus, left angular gyrus, and hippocampus prospectively predicted six-month PTSD symptoms after adjusting for sex, age, education, and baseline PTSD symptoms. Acute BNST rsFC was a stronger predictor of PTSD symptoms in individuals who experienced more racial discrimination and lifetime trauma. Thus, in the acute aftermath of a traumatic event, the BNST could be a key biomarker of risk for PTSD in Black Americans, particularly for individuals with a greater history of racial discrimination or previous trauma exposure.
Asunto(s)
Negro o Afroamericano , Imagen por Resonancia Magnética , Racismo , Núcleos Septales , Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/etnología , Trastornos por Estrés Postraumático/diagnóstico por imagen , Masculino , Femenino , Núcleos Septales/diagnóstico por imagen , Núcleos Septales/fisiopatología , Adulto , Racismo/psicología , Racismo/etnología , Persona de Mediana Edad , Adulto JovenRESUMEN
Mesial temporal lobe epilepsy (MTLE) is characterized by recurring focal seizures that arise from limbic areas and are often refractory to pharmacological interventions. We have reported that optogenetic stimulation of PV-positive cells in the medial septum at 0.5 Hz exerts seizure-suppressive effects. Therefore, we compared here these results with those obtained by optogenetic stimulation of medial septum PV-positive neurons at 8 Hz in male PV-ChR2 mice (P60-P100) undergoing an initial, pilocarpine-induced status epilepticus (SE). Optogenetic stimulation (5 min ON, 10 min OFF) was performed from day 8 to day 12 after SE at a frequency of 8 Hz (n = 6 animals) or 0.5 Hz (n = 8 animals). Surprisingly, in both groups, no effects were observed on the occurrence of interictal spikes and interictal high frequency oscillations (HFOs). However, 0.5 Hz stimulation induced a significant decrease of seizure occurrence (p < 0.05). Such anti-ictogenic effect was not observed in the 8 Hz protocol that instead triggered seizures (p < 0.05); these seizures were significantly longer under optogenetic stimulation compared to when optogenetic stimulation was not implemented (p < 0.05). Analysis of ictal HFOs revealed that in the 0.5 Hz group, but not in the 8 Hz group, seizures occurring under optogenetic stimulation were associated with significantly lower rates of fast ripples compared to when optogenetic stimulation was not performed (p < 0.05). Our results indicate that activation of GABAergic PV-positive neurons in the medial septum exerts seizure-suppressing effects that are frequency-dependent and associated with low rates of fast ripples. Optogenetic activation of medial septum PV-positive neurons at 0.5 Hz is efficient in blocking seizures in the pilocarpine model of MTLE, an effect that did not occur with 8 Hz stimulation.
Asunto(s)
Epilepsia del Lóbulo Temporal , Optogenética , Convulsiones , Animales , Optogenética/métodos , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/terapia , Masculino , Convulsiones/fisiopatología , Ratones , Pilocarpina/toxicidad , Ratones Transgénicos , Modelos Animales de Enfermedad , Tabique del Cerebro , Núcleos Septales/fisiopatología , Ratones Endogámicos C57BLRESUMEN
In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.
Asunto(s)
Vías Nerviosas , Trauma Psicológico , Recompensa , Núcleos Septales , Conducta Social , Estrés Psicológico , Animales , Femenino , Masculino , Ratones , Encéfalo/patología , Encéfalo/fisiopatología , Calcio/análisis , Calcio/metabolismo , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neurotensina/metabolismo , Optogenética , Trauma Psicológico/patología , Trauma Psicológico/fisiopatología , Núcleos Septales/patología , Núcleos Septales/fisiopatología , Estrés Psicológico/patología , Estrés Psicológico/fisiopatologíaRESUMEN
We earlier reported female-biased, sex-specific involvement of the dorsolateral bed nucleus of the stria terminalis (dl BST) in the formalin-induced pain response in rats. The present study investigated pain effects on mice behaviors. Because the dl BST is densely populated with corticotropin-releasing hormone (CRH) neurons, we examined sex differences in these parameters for the dl BST CRH neurons in male and female mice of a mouse line for which the CRH gene promoter (corticotropin-releasing factor [CRF]-Venus ΔNeo) controls the expression of the modified yellow fluorescent protein (Venus). Approximately 92% of Venus-positive cells in the dl BST were also CRH mRNA-positive, irrespective of sex. Therefore, the cells identified using Venus fluorescence were regarded as CRH neurons. A female-biased sex difference was observed in pain-induced behaviors during the interphase (5-15 min after formalin injection) but not during the later phase (phase 2, 15-60 min) in wild-type mice. In CRF-Venus ΔNeo mice, a female-biased difference was observed in either the earlier phase (phase 1, 0-5 min) or the interphase, but not in phase 2. Patch-clamp recordings taken using an acute BST slice obtained from a CRF-Venus ΔNeo mouse after formalin injection showed miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). Remarkably, the mEPSCs frequency was higher in the Venus-expressing cells of formalin-injected female mice than in vehicle-treated female mice. Male mice showed no increase in mEPSC frequency by formalin injection. Formalin injection had no effect on mEPSC or mIPSC amplitudes in either sex. Pain-induced changes in mEPSC frequency in putative CRH neurons were phase-dependent. Results show that excitatory synaptic inputs to BST CRH neurons are temporally enhanced along with behavioral sex differences in pain response, suggesting that pain signals alter the BST CRH neurons excitability in a sex-dependent manner.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Potenciales Postsinápticos Excitadores/fisiología , Neuronas/fisiología , Dolor/fisiopatología , Núcleos Septales/fisiopatología , Animales , Femenino , Masculino , Ratones , Neuronas/metabolismo , Dolor/metabolismo , Umbral del Dolor/fisiología , Núcleos Septales/metabolismo , Factores SexualesRESUMEN
Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.
Asunto(s)
Consumo de Bebidas Alcohólicas/patología , Reacción de Prevención , Hormona Liberadora de Corticotropina/metabolismo , Sistema Límbico/patología , Neuronas/patología , Sinapsis/patología , Tálamo/patología , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Ansiedad/fisiopatología , Conducta Animal , Potenciales Postsinápticos Excitadores , Femenino , Ácido Glutámico/metabolismo , Potenciales Postsinápticos Inhibidores , Integrasas/metabolismo , Sistema Límbico/fisiopatología , Masculino , Ratones Endogámicos C57BL , Fenotipo , Núcleos Septales/patología , Núcleos Septales/fisiopatología , Caracteres Sexuales , Tálamo/fisiopatologíaRESUMEN
BACKGROUND: Connectivity between the anterior insula (AI) and the bed nucleus of the stria terminalis (BNST) may play a role in negative emotions that drive compulsive drinking in patients with alcohol use disorder (AUD). We hypothesized that reductions in drinking during cognitive behavioral therapy (CBT), an effective treatment that teaches regulation (coping) skills for managing negative emotions during abstinence, would be associated with reductions in resting-state functional connectivity (RSFC) between the AI and the BNST. METHODS: We included 18 patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of AUD who were (1) seeking treatment and (2) drinking heavily at baseline. We measured RSFC as Pearson's correlation between the BNST and multiple regions of interest in the insula at baseline and after completion of 12 weeks of a single-arm clinical trial of outpatient CBT. We also assessed the number of heavy drinking days over the previous 28 days (NHDD) at both time points. We used 1-sample t-tests to evaluate AI-BNST RSFC at baseline, paired t-tests to evaluate changes in AI-BNST RSFC from pre-CBT to post-CBT, and linear regression to evaluate the relationship between changes in AI-BNST RSFC and NHDD. RESULTS: We found a significant positive RSFC between the AI and the BNST at baseline (p = 0.0015). While there were no significant changes in AI-BNST RSFC from pre- to post-CBT at the group level (p = 0.42), we found that individual differences in reductions in AI-BNST RSFC from pre- to post-CBT were directly related to reductions in NHDD from pre- to post-CBT (r = 0.73, p = 0.0008). CONCLUSIONS: These findings provide preliminary evidence that reduced AI-BNST RSFC may be a mechanism of drinking reduction in AUD and that AI-BNST RSFC may be a target for CBT and possibly other treatments.
Asunto(s)
Alcoholismo/fisiopatología , Terapia Cognitivo-Conductual , Corteza Insular/fisiopatología , Núcleos Septales/fisiopatología , Adulto , Alcoholismo/diagnóstico por imagen , Alcoholismo/terapia , Femenino , Humanos , Corteza Insular/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Núcleos Septales/diagnóstico por imagenRESUMEN
The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer's disease, anxiety/fear, schizophrenia, and depression, as well as pain.
Asunto(s)
Encefalopatías/fisiopatología , Ondas Encefálicas/fisiología , Encéfalo/fisiopatología , Estimulación Encefálica Profunda/métodos , Núcleos Septales/fisiopatología , Animales , Encefalopatías/terapia , Epilepsia/fisiopatología , Epilepsia/terapia , Humanos , Trastornos Mentales/fisiopatología , Trastornos Mentales/terapia , Resultado del TratamientoRESUMEN
Modifications in brain regions that govern reward-seeking are thought to contribute to persistent behaviors that are heavily associated with alcohol-use disorder (AUD) including binge ethanol drinking. The bed nucleus of the stria terminalis (BNST) is a critical node linked to both alcohol consumption and the onset, maintenance and progression of adaptive anxiety and stress-related disorders. Differences in anatomy, connectivity and receptor subpopulations, make the BNST a sexually dimorphic region. Previous work indicates that the ventral BNST (vBNST) receives input from the insular cortex (IC), a brain region involved in processing the body's internal state. This IC-vBNST projection has also been implicated in emotional and reward-seeking processes. Therefore, we examined the functional properties of vBNST-projecting, IC neurons in male and female mice that have undergone short-term ethanol exposure and abstinence using a voluntary Drinking in the Dark paradigm (DID) paired with whole-cell slice electrophysiology. First we show that IC neurons projected predominantly to the vBNST. Next, our data show that short-term ethanol exposure and abstinence enhanced excitatory synaptic strength onto vBNST-projecting, IC neurons in both sexes. However, we observed diametrically opposing modifications in excitability across sexes. In particular, short-term ethanol exposure resulted in increased intrinsic excitability of vBNST-projecting, IC neurons in females but not in males. Furthermore, in females, abstinence decreased the excitability of these same neurons. Taken together these findings show that short-term ethanol exposure, as well as the abstinence cause sex-related adaptations in BNST-projecting, IC neurons.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Corteza Insular/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Núcleos Septales/metabolismo , Abstinencia de Alcohol , Animales , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Depresores del Sistema Nervioso Central/administración & dosificación , Depresores del Sistema Nervioso Central/farmacología , Etanol/administración & dosificación , Etanol/farmacología , Femenino , Corteza Insular/fisiopatología , Masculino , Ratones , Vías Nerviosas , Neuronas/fisiología , Técnicas de Placa-Clamp , Núcleos Septales/fisiopatología , Caracteres Sexuales , Factores SexualesRESUMEN
In schizophrenia, impairments in affect are prominent and anxiety disorders are prevalent. Neuroimaging studies of fear and anxiety in schizophrenia have focused on the amygdala and show alterations in connectivity. Emerging evidence suggests that the bed nucleus of the stria terminalis (BNST) also plays a critical role in anxiety, especially during anticipation of an unpredictable threat; however, previous studies have not examined the BNST in schizophrenia. In the present study, we examined BNST function and connectivity in people with schizophrenia (n = 31; n = 15 with comorbid anxiety) and controls (n = 15) during anticipation of unpredictable and predictable threat. A secondary analysis tested for differences in activation and connectivity of the central nucleus of the amygdala (CeA), which has also been implicated in threat anticipation. Analyses tested for group differences in both activation and connectivity during anticipation of unpredictable threat and predictable threat (p < .05). Relative to controls, individuals with schizophrenia showed stronger BNST-middle temporal gyrus (MTG) connectivity during unpredictable threat anticipation and stronger BNST-MTG and BNST-dorsolateral prefrontal connectivity during predictable threat anticipation. Comparing subgroups of individuals with schizophrenia and a comorbid anxiety disorder (SZ+ANX) to those without an anxiety disorder (SZ-ANX) revealed broader patterns of altered connectivity. During unpredictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions of the salience network (insula, dorsal anterior cingulate cortex). During predictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions associated with fear processing (insula, extended amygdala, prefrontal cortex). A secondary CeA analysis revealed a different pattern; the SZ+ANX group had weaker CeA connectivity across multiple brain regions during threat anticipation compared to the SZ-ANX group. These findings provide novel evidence for altered functional connectivity during threat anticipation in schizophrenia, especially in individuals with comorbid anxiety.
Asunto(s)
Amígdala del Cerebelo/fisiopatología , Miedo/fisiología , Esquizofrenia/fisiopatología , Núcleos Septales/fisiopatología , Adulto , Síntomas Afectivos/fisiopatología , Anticipación Psicológica/fisiología , Ansiedad/fisiopatología , Trastornos de Ansiedad/fisiopatología , Mapeo Encefálico , Comorbilidad , Conectoma/métodos , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Red Nerviosa/fisiopatología , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: For individuals with Alcohol Use Disorder (AUD), long-term recovery is difficult in part due to symptoms of anxiety that occur during early abstinence and can trigger relapse. Research in rodent models of AUD has identified the bed nucleus of the stria terminalis (BNST), a small, sexually dimorphic, subcortical region, as critical for regulating anxiety-like behaviors during abstinence, particularly in female mice. Furthermore, prolonged alcohol use and subsequent abstinence alter BNST afferent and efferent connections to other brain regions. To our knowledge, however, no studies of early abstinence have investigated BNST structural connectivity in humans during abstinence; this study addresses that gap. METHODS: Nineteen participants with AUD currently in early abstinence and 20 healthy controls completed a diffusion tensor imaging (DTI) scan. BNST structural connectivity was evaluated using probabilistic tractography. A linear mixed model was used to test between-groups differences in BNST network connectivity. Exploratory analyses were conducted to test for correlations between BNST connectivity and alcohol use severity and anxiety within the abstinence group. Sex was included as a factor for all analyses. RESULTS: The BNST showed stronger structural connectivity with the BNST network in early abstinence women than in control women, which was not seen in men. Women also showed region-specific differences, with stronger BNST-hypothalamus structural connectivity but weaker vmPFC-BNST structural connectivity than men. Exploratory analyses also demonstrated a relationship between alcohol use severity and vmPFC-BNST structural connectivity that was moderated by sex. CONCLUSIONS: This study is the first to demonstrate BNST structural connectivity differences in early abstinence and revealed key sex differences. The sex-specific differences in BNST structural connectivity during early abstinence could underlie known sex differences in abstinence symptoms and relapse risk and help to inform potential sex-specific treatments.
Asunto(s)
Abstinencia de Alcohol , Alcoholismo/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Núcleos Septales/diagnóstico por imagen , Adulto , Alcoholismo/fisiopatología , Alcoholismo/psicología , Ansiedad/psicología , Estudios de Casos y Controles , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Corteza Prefrontal/fisiopatología , Núcleos Septales/fisiopatología , Factores Sexuales , Adulto JovenRESUMEN
Seizures can emerge from multiple or large foci in temporal lobe epilepsy, complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons, which provide extensive projections throughout the hippocampus, is used to control seizures. We utilized the chronic intrahippocampal kainate mouse model of temporal lobe epilepsy, which results in spontaneous seizures and as is often the case in human patients, presents with hippocampal sclerosis. Medial septal GABAergic neuron populations were immunohistochemically labelled and were not reduced in epileptic conditions. Genetic labelling with mRuby of medial septal GABAergic neuron synaptic puncta and imaging across the rostral to caudal extent of the hippocampus, also indicated an unchanged number of putative synapses in epilepsy. Furthermore, optogenetic stimulation of medial septal GABAergic neurons consistently modulated oscillations across multiple hippocampal locations in control and epileptic conditions. Finally, wireless optogenetic stimulation of medial septal GABAergic neurons, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose medial septal GABAergic neurons as a novel target for optogenetic control of seizures in temporal lobe epilepsy.
Asunto(s)
Neuronas GABAérgicas/fisiología , Hipocampo/fisiopatología , Optogenética , Convulsiones/fisiopatología , Núcleos Septales/fisiopatología , Animales , Epilepsia del Lóbulo Temporal/fisiopatología , Femenino , Masculino , RatonesRESUMEN
Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this 'proxy intervention' concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Neuronas GABAérgicas/fisiología , Convulsiones/fisiopatología , Núcleos Septales/fisiopatología , Animales , Excitación Neurológica/fisiología , Ratas , Ratas Long-EvansRESUMEN
Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.
Asunto(s)
Antígenos de Neoplasias/genética , Trastorno Autístico , Conducta Animal , Proteínas/genética , Núcleos Septales , Conducta Social , Vasopresinas , Animales , Antígenos de Neoplasias/metabolismo , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/fisiopatología , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Noqueados , Neuronas/metabolismo , Neuronas/patología , Proteínas/metabolismo , Núcleos Septales/metabolismo , Núcleos Septales/fisiopatología , Vasopresinas/deficiencia , Vasopresinas/farmacologíaRESUMEN
Focal limbic seizures can cause loss of consciousness. Previous work suggests that hippocampal seizures can increase activity in the lateral septum (LS) and decrease cholinergic output from the basal forebrain (BF), leading to deficits in conscious arousal. The mechanism by which LS and BF interact is unclear. In this study, we used anterograde and retrograde tracing to investigate anatomical pathways connecting LS and BF. We found that LS projects directly to BF and indirectly to BF via the thalamic paratenial nucleus (PT). Acute electrophysiology experiments during electrically induced focal limbic seizures showed that multiunit activity decreased in PT during the ictal period and was associated with increased cortical slow wave activity. These results suggest that LS could functionally inhibit BF during a seizure directly, or could indirectly decrease excitatory output to BF through PT. Further work investigating such parallel inhibitory and excitatory pathways to subcortical arousal may ultimately lead to new treatment targets for consciousness-impairing limbic seizures.
Asunto(s)
Prosencéfalo Basal/fisiopatología , Vías Nerviosas/fisiopatología , Convulsiones/fisiopatología , Núcleos Septales/fisiopatología , Animales , Nivel de Alerta/fisiología , Hipocampo/fisiopatología , Núcleos Talámicos de la Línea Media/fisiopatología , Ratas , Ratas Long-Evans , Ratas Sprague-DawleyRESUMEN
The comorbidities of depression and chronic pain have long been recognized in the clinic, and several preclinical studies have demonstrated depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for depression and chronic pain. Recently, we reported that the mesolimbic dopaminergic system was tonically suppressed during chronic pain by enhanced inhibitory synaptic inputs to neurons projecting from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA), suggesting that tonic suppression of the mesolimbic dopaminergic system by this neuroplastic change may be involved in chronic pain-induced depression-like behaviors. In this study, we hypothesized that inhibitory synaptic inputs to VTA-projecting dlBNST neurons are also enhanced in animal models of depression, thereby suppressing the mesolimbic dopaminergic system. To test this hypothesis, we performed whole-cell patch-clamp electrophysiology using brain slices prepared from rats exposed to chronic mild stress (CMS), a widely used animal model of depression. The results showed a significant enhancement in the frequency of spontaneous inhibitory postsynaptic currents in VTA-projecting dlBNST neurons in the CMS group compared with the no stress group. The findings revealed enhanced inhibitory synaptic inputs to VTA-projecting dlBNST neurons in this rat model of depression, suggesting that this neuroplastic change is a neuronal mechanism common to depression and chronic pain that causes dysfunction of the mesolimbic dopaminergic system, thereby inducing depression-like behaviors.
Asunto(s)
Inhibición Neural/fisiología , Neuronas/fisiología , Núcleos Septales/fisiopatología , Estrés Psicológico/fisiopatología , Transmisión Sináptica/fisiología , Área Tegmental Ventral/fisiopatología , Animales , Enfermedad Crónica , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Ratas Sprague-DawleyRESUMEN
When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.
Asunto(s)
Anticipación Psicológica , Trastornos de Ansiedad/psicología , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Trastornos de Ansiedad/diagnóstico por imagen , Trastornos de Ansiedad/fisiopatología , Mapeo Encefálico , Estimulación Eléctrica , Miedo , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/fisiopatología , Respuesta Galvánica de la Piel , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Sustancia Gris Periacueductal/diagnóstico por imagen , Sustancia Gris Periacueductal/fisiopatología , Estimulación Luminosa , Estudios Prospectivos , Núcleos Septales/diagnóstico por imagen , Núcleos Septales/fisiopatología , Incertidumbre , Adulto JovenRESUMEN
Ample evidence suggests that early life stress (ELS) is a high-risk factor for the development of visceral pain disorders, whereas the mechanism underlying neuronal circuit remains elusive. Herein, we employed neonatal colorectal distension (CRD) to induce visceral hypersensitivity in rats. A combination of electrophysiology, pharmacology, behavioral test, molecular biology, chemogenetics and optogenetics confirmed that CRD in neonatal rats could predispose the elevated firing frequency of the parvocellular corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of hypothalamus (PVN) in adulthood, with the CRH neurons activated and the frequency of spontaneous inhibitory postsynaptic currents (sIPSC) diminished, both contributing to chronic visceral hypersensitivity. Moreover, following administration of exogenous GABA (300â¯mM/0.5⯵L) and GABAA receptor agonist muscimol (3â¯mM/0.5⯵L) in PVN, visceral hyperalgesia was abrogated. In addition, the PVN-projecting GABAergic neurons were mainly distributed in the anterior ventral (AV) region in the bed nucleus of stria terminalis (BNST), and the excitability of these GABAergic neurons was weakened in visceral hypersensitivity. Specific depletion of the GABAergic neurons in AV region precipitated visceral hyperalgesia. Moreover, chemogenetic activation of the PVN-projecting neurons alleviated the visceral hypersensitivity. Photoactivation of PVN-projecting GABAergic neurons abated the visceral hypersensitivity in neonatal-CRD rats, whereas photoinhibition evoked visceral hyperalgesia in naïve rats. Our findings demonstrated that disinhibition of the PVN-projecting GABAergic neurons in AV region contributed to the excitation of CRH neurons, thereby mediating visceral hypersensitivity. Our study might provide a novel insight into the neuronal circuits involved in the ELS-induced visceral hypersensitivity.
Asunto(s)
Neuronas GABAérgicas/fisiología , Hiperalgesia/fisiopatología , Inhibición Neural/fisiología , Núcleo Hipotalámico Paraventricular/fisiopatología , Núcleos Septales/fisiopatología , Dolor Visceral/fisiopatología , Animales , Animales Recién Nacidos , Conducta Animal/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratas , Estrés Psicológico/fisiopatologíaRESUMEN
Seizures originating from limbic structures, especially when prolonged for several minutes/hours up to status epilepticus (SE), can cause specific neurodegenerative phenomena in limbic and subcortical structures. The cholinergic nuclei belonging to the basal forebrain (BF) (namely, medial septal nucleus (MSN), diagonal band of Broca (DBB), and nucleus basalis of Meynert (NBM)) belong to the limbic system, while playing a pivotal role in cognition and sleep-waking cycle. Given the strong interconnections linking these limbic nuclei with limbic cortical structures, a persistent effect of SE originating from limbic structures on cBF morphology is plausible. Nonetheless, only a few experimental studies have addressed this issue. In this review, we describe available data and discuss their significance in the scenario of seizure-induced brain damage. In detail, the manuscript moves from a recent study in a model of focally induced limbic SE, in which the pure effects of seizure spreading through the natural anatomical pathways towards the cholinergic nuclei of BF were tracked by neuronal degeneration. In this experimental setting, a loss of cholinergic neurons was measured in all BF nuclei, to various extents depending on the specific nucleus. These findings are discussed in the light of the effects on the very same nuclei following SE induced by systemic injections of kainate or pilocarpine. The various effects including discrepancies among different studies are discussed. Potential implications for human diseases are included.
Asunto(s)
Prosencéfalo Basal/fisiopatología , Núcleo Basal de Meynert/fisiopatología , Neuronas Colinérgicas/patología , Banda Diagonal de Broca/fisiopatología , Núcleos Septales/fisiopatología , Estado Epiléptico/fisiopatología , Amígdala del Cerebelo/fisiopatología , Animales , Prosencéfalo Basal/patología , Núcleo Basal de Meynert/patología , Corteza Cerebral/fisiopatología , Banda Diagonal de Broca/patología , Hipocampo/fisiopatología , Humanos , Vías Nerviosas/fisiopatología , Núcleos Septales/patología , Estado Epiléptico/patologíaRESUMEN
The lateral septum (LS) is a brain region implicated in motivation, addiction, anxiety, and affect. We recently found that LS is necessary for cocaine-seeking behaviors including conditioned place preference and reinstatement of extinguished drug seeking, which involve LS input to limbic regions including ventral tegmental area (VTA) and orexin neurons in hypothalamus. Here, we microinjected baclofen-muscimol (B-M) in LS prior to testing in a behavioral economics (BE) paradigm. We found that intra-LS B-M decreased motivation (increased demand elasticity; α) for cocaine, but did not change consumption at low effort (Q0 ). We also compared the effects of LS inhibition with the effects of treatment with the benzodiazepine diazepam, which has been shown to facilitate reward pathways and disinhibit VTA dopamine neurons. Pretreatment with diazepam blocked the effects of LS inhibition and restored cocaine demand to that following vehicle treatment. These changes in cocaine demand after LS inhibition or diazepam were not due to effects on anxiety, as both manipulations produced similar effects on anxiety measures but opposing effects on drug taking. Collectively, these studies point to LS as a critical region driving motivation for cocaine, likely through its interactions with the mesolimbic dopamine system.
Asunto(s)
Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/farmacología , Diazepam/farmacología , Motivación/efectos de los fármacos , Núcleos Septales/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/farmacología , Moduladores del GABA/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Núcleos Septales/fisiopatologíaRESUMEN
The United States is experiencing an opioid crisis imposing enormous fiscal and societal costs and driving the staggering overdose death rate. While prescription opioid analgesics are essential for treating acute pain, cessation of use in individuals with a physical dependence induces an aversive withdrawal syndrome that promotes continued drug use to alleviate/avoid these symptoms. Additionally, repeated bouts of withdrawal often lead to an increased propensity for relapse. Understanding the neurobiology underlying withdrawal is essential for providing novel treatment options to alleviate physiological and affective components accompanying the cessation of opiate use. Here, we administered morphine and precipitated withdrawal with naloxone to investigate behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice demonstrated sensitized withdrawal symptoms. Since the bed nucleus of the stria terminalis (BNST) plays a role in mediating withdrawal-associated behaviors, we examined plastic changes in inhibitory synaptic transmission within this structure 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared with controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling in female mice. Intriguingly, these opposing GABAergic effects were contingent upon activity-dependent dynamics within the ex vivo slice. Our findings suggest that male and female mice exhibit some divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may contribute to the expression of behaviors following opioid withdrawal.