RESUMEN
Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC's cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3 mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.
Asunto(s)
Corteza Insular , Animales , Femenino , Embarazo , Ratones , Masculino , Corteza Insular/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Ratones Endogámicos C57BL , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiologíaRESUMEN
The brain and immune system communicate through complex bidirectional pathways, but the specificity by which the brain perceives or even remembers alterations in immune homeostasis is still poorly understood. Recent data revealed that immune-related information under peripheral inflammatory conditions, termed as "immunengram", were represented in specific neuronal ensembles in the insular cortex (IC). Chemogenetic reactivation of these neuronal ensembles was sufficient to retrieve the inflammatory stages, indicating that the brain can store and retrieve specific immune responses. Against this background, the current approach was designed to investigate the ability of the IC to process states of immunosuppression pharmacologically induced by the mechanistic target of rapamycin (mTOR) inhibitor rapamycin. We here show that the IC perceives the initial state of immunosuppression, reflected by increased deep-brain electroencephalography (EEG) activity during acute immunosuppressive drug treatment. Following an experienced period of immunosuppression, though, diminished splenic cytokine production as formerly induced by rapamycin could not be reinstated by nonspecific chemogenetic activation or inhibition of the IC. These findings suggest that the information of a past, or experienced status of pharmacologically induced immunosuppression is not represented in the IC. Together, the present work extends the view of immune-to-brain communication during the states of peripheral immunosuppression and foster the prominent role of the IC for interoception.
Asunto(s)
Inmunosupresores , Corteza Insular , Sirolimus , Animales , Sirolimus/farmacología , Corteza Insular/efectos de los fármacos , Masculino , Inmunosupresores/farmacología , Electroencefalografía , Terapia de Inmunosupresión/métodos , Citocinas/metabolismo , Citocinas/inmunología , Ratones , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismoRESUMEN
Ordinary sensations from inside the body are important causes and consequences of our affective states and behaviour, yet the roles of neurotransmitters in interoceptive processing have been unclear. With a within-subjects design, this experiment tested the impacts of acute increases of endogenous extracellular serotonin on the neural processing of attended internal sensations and the links of these effects to anxiety using a selective serotonin reuptake inhibitor (SSRI) (20 mg CITALOPRAM) and a PLACEBO. Twenty-one healthy volunteers (fourteen female, mean age 23.9) completed the Visceral Interoceptive Attention (VIA) task while undergoing functional magnetic resonance imaging (fMRI) with each treatment. The VIA task required focused attention on the heart, stomach, or visual sensation. The relative neural interoceptive responses to heart sensation [heart minus visual attention] (heart-IR) and stomach sensation [stomach minus visual attention] (stomach-IR) were compared between treatments. Visual attention subtraction controlled for the general effects of CITALOPRAM on sensory processing. CITALOPRAM was associated with lower interoceptive processing in viscerosensory (the stomach-IR of bilateral posterior insular cortex) and integrative/affective (the stomach-IR and heart-IR of bilateral amygdala) components of interoceptive neural pathways. In anterior insular cortex, CITALOPRAM reductions of heart-IR depended on anxiety levels, removing a previously known association between anxiety and the region's response to attended heart sensation observed with PLACEBO. Preliminary post hoc analysis indicated that CITALOPRAM effects on the stomach-IR of the amygdalae corresponded to acute anxiety changes. This direct evidence of general and anxiety-linked serotonergic influence on neural interoceptive processes advances our understanding of interoception, its regulation, and anxiety.
Asunto(s)
Ansiedad , Citalopram , Interocepción , Imagen por Resonancia Magnética , Inhibidores Selectivos de la Recaptación de Serotonina , Humanos , Femenino , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Masculino , Citalopram/farmacología , Adulto Joven , Adulto , Interocepción/fisiología , Interocepción/efectos de los fármacos , Ansiedad/fisiopatología , Atención/efectos de los fármacos , Atención/fisiología , Corteza Insular/diagnóstico por imagen , Corteza Insular/efectos de los fármacos , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Corazón/efectos de los fármacosRESUMEN
AIMS: Continued alcohol consumption despite negative consequences is a core symptom of alcohol use disorder. This is modeled in mice by pairing negative stimuli with alcohol, such as adulterating alcohol solution with quinine. Mice consuming alcohol under these conditions are considered to be engaging in aversion-resistant intake. Previously, we have observed sex differences in this behavior, with females more readily expressing aversion-resistant consumption. We also identified three brain regions that exhibited sex differences in neuronal activation during quinine-alcohol drinking: ventromedial prefrontal cortex (vmPFC), posterior insular cortex (PIC), and ventral tegmental area (VTA). Specifically, male mice showed increased activation in vmPFC and PIC, while females exhibited increased activation in VTA. In this study, we aimed to identify what specific type of neurons are activated in these regions during quinine-alcohol drinking. METHOD: We assessed quinine-adulterated alcohol intake using the two-bottle choice procedure. We also utilized RNAscope in situ hybridization in the three brain regions that previously exhibited a sex difference to examine colocalization of Fos, glutamate, GABA, and dopamine. RESULT: Females showed increased aversion-resistant alcohol consumption compared to males. We also found that males had higher colocalization of glutamate and Fos in vmPFC and PIC, while females had greater dopamine and Fos colocalization in the VTA. CONCLUSIONS: Collectively, these experiments suggest that glutamatergic output from the vmPFC and PIC may have a role in suppressing, and dopaminergic activity in the VTA may promote, aversion-resistant alcohol consumption. Future experiments will examine neuronal circuits that contribute to sex differences in aversion resistant consumption.
Asunto(s)
Consumo de Bebidas Alcohólicas , Neuronas , Quinina , Caracteres Sexuales , Animales , Quinina/farmacología , Femenino , Masculino , Ratones , Neuronas/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Mesencéfalo/metabolismo , Mesencéfalo/efectos de los fármacos , Corteza Insular/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Etanol/farmacología , Ácido Glutámico/metabolismoRESUMEN
Evidence indicates that the anterior (aIC), but not posterior (pIC), insular cortex promotes cued reinstatement of cocaine seeking after extinction in rats. It is unknown whether these subregions also regulate heroin seeking and whether such involvement depends on prior extinction learning. To address these questions, we used baclofen and muscimol (BM) to inactivate the aIC or pIC bilaterally during a seeking test after extinction or prolonged withdrawal from heroin. Male Sprague-Dawley rats in the extinction groups underwent 10+ days of heroin self-administration, followed by 6+ days of extinction sessions, and subsequent cued or heroin-primed reinstatement. Results indicate that aIC inactivation increased cued reinstatement of heroin seeking after extinction, whereas pIC inactivation prevented cued reinstatement. To determine whether these effects were extinction-dependent, we conducted a subsequent study using both sexes with prolonged withdrawal. Male and female rats in the withdrawal groups underwent 10+ days of heroin self-administration, followed by cued seeking tests after 1 and 14 days of homecage withdrawal to measure incubation of heroin craving. In this case, the findings indicate that aIC inactivation had no effect on incubation of heroin craving after withdrawal in either sex, whereas pIC inactivation decreased heroin craving only in males. These findings suggest that the aIC and pIC have opposing roles in suppressing vs promoting cued heroin seeking after extinction and that these roles are distinct from those in cocaine seeking. Moreover, the incubation of craving results suggest that new contingency learning is necessary to recruit the aIC in cued heroin seeking.
Asunto(s)
Baclofeno , Señales (Psicología) , Comportamiento de Búsqueda de Drogas , Extinción Psicológica , Heroína , Corteza Insular , Muscimol , Ratas Sprague-Dawley , Autoadministración , Síndrome de Abstinencia a Sustancias , Animales , Masculino , Extinción Psicológica/efectos de los fármacos , Heroína/administración & dosificación , Heroína/farmacología , Ratas , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Baclofeno/farmacología , Baclofeno/administración & dosificación , Femenino , Corteza Insular/efectos de los fármacos , Muscimol/farmacología , Muscimol/administración & dosificación , Narcóticos/farmacología , Narcóticos/administración & dosificaciónRESUMEN
Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.
Asunto(s)
Disfunción Cognitiva , Corteza Insular , Ketamina , Aislamiento Social , Animales , Ketamina/farmacología , Ratones , Masculino , Corteza Insular/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Ratones Endogámicos C57BL , Memoria/efectos de los fármacos , Cognición/efectos de los fármacos , Conducta Social , Corteza Cerebral/efectos de los fármacos , Neuronas/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológicoRESUMEN
Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.
Asunto(s)
Complejo Nuclear Basolateral , Emociones , Corteza Insular , Inhibición Neural , Reconocimiento en Psicología , Percepción Visual , Animales , Nivel de Alerta , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Emociones/efectos de los fármacos , Emociones/fisiología , Agonistas del GABA/farmacología , Corteza Insular/efectos de los fármacos , Corteza Insular/fisiología , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Norepinefrina/administración & dosificación , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Percepción Visual/fisiologíaRESUMEN
A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu3) to produce stress adaptations. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu3-NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu3-NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu3-NAM group. Similar to the insular cortex, mGlu3-NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu3-NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu3 receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects.
Asunto(s)
Adaptación Fisiológica/fisiología , Conducta Animal/fisiología , Corteza Insular/metabolismo , Neurotransmisores/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septales/metabolismo , Tiazoles/farmacología , Adaptación Fisiológica/efectos de los fármacos , Regulación Alostérica , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Clásico , Cadena Alimentaria , Corteza Insular/efectos de los fármacos , Masculino , Odorantes , Ratas , Ratas Long-Evans , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Núcleos Septales/efectos de los fármacosRESUMEN
An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.
Asunto(s)
Aprendizaje por Asociación , Conectoma , Corteza Insular , Red Nerviosa , Plasticidad Neuronal , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Citalopram/farmacología , Femenino , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiología , Humanos , Corteza Insular/diagnóstico por imagen , Corteza Insular/efectos de los fármacos , Corteza Insular/fisiología , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/efectos de los fármacos , Lóbulo Parietal/fisiología , Descanso , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Adulto JovenRESUMEN
Chronic inflammation in the central nervous system is one mechanism through which human immunodeficiency virus (HIV) may lead to progressive cognitive decline. Given cannabis's (CB's) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and evidence implicating the insula in both, we examined independent and interactive effects of HIV and CB on insular circuitry, cognition, and immune function. We assessed resting-state functional connectivity (rsFC) of three insula subregions among 106 participants across four groups (co-occurring: HIV+/CB+; HIV-only: HIV+/CB-; CB-only: HIV-/CB+; controls: HIV-/CB-). Participants completed a neurocognitive battery assessing functioning across multiple domains and self-reported somatic complaints. Blood samples quantified immune function (T-cell counts) and inflammation (tumor necrosis factor alpha [TNF-α]). We observed interactive HIV × CB effects on rsFC strength between two anterior insula (aI) subregions and sensorimotor cortices such that, CB appeared to normalize altered rsFC among non-using PLWH. Specifically, compared to controls, HIV-only and CB-only groups displayed decreased dorsal anterior insula (DI) - postcentral gyrus rsFC and increased ventral anterior insula (VI) - supplementary motor area rsFC, whereas the co-occurring group displayed DI and VI rsFC more akin to that of controls. Altered DI - postcentral rsFC correlated with decreased processing speed and somatic complaints, but did not significantly correlate with inflammation (TNF-α). These outcomes implicate insula - sensorimotor neurocircuitries in HIV and CB and are consistent with prior work suggesting that CB use may normalize insula functioning among PLWH.
Asunto(s)
Cannabis , Infecciones por VIH , Corteza Insular , Marihuana Medicinal , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico por imagen , Factor de Necrosis Tumoral alfa , Corteza Insular/efectos de los fármacos , Recuento de Linfocitos , Marihuana Medicinal/uso terapéuticoRESUMEN
Avoidance of sick individuals is vital to the preservation of one's health and preventing transmission of communicable diseases. To do this successfully, one must identify social cues for sickness, which include sickness behaviors and chemosignals, and use this information to orchestrate social interactions. While many social species are highly capable with this process, the neural mechanisms that provide for social responses to sick individuals are only partially understood. To this end, we used a task in which experimental rats were allowed to investigate two conspecifics, one healthy and one sick. To imitate sickness, one conspecific received the viral mimic Polyinosinic:polycytidylic acid (Poly I:C) and the other saline. In a 5-minute social preference test, experimental male and female adult rats avoided Poly I:C treated adult conspecifics but did not adjust social interaction in response to Poly I:C treated juvenile conspecifics. Seeking a neural locus of this behavior, we inhibited the insular cortex, a region necessary for social behaviors directed toward conspecifics in distress. Insular cortex inactivation via administration of the GABAA agonist muscimol to experimental rats prior to social preference tests eliminated the preference to avoid sick adult conspecifics. These results suggest that some aspect of conspecific illness may be encoded in the insular cortex which is anatomically positioned to coordinate a situationally appropriate social response.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Conducta Animal/fisiología , Agonistas de Receptores de GABA-A/farmacología , Conducta de Enfermedad/efectos de los fármacos , Corteza Insular/efectos de los fármacos , Muscimol/farmacología , Interacción Social , Animales , Antivirales/administración & dosificación , Femenino , Masculino , Odorantes , Poli I-C/administración & dosificación , RatasRESUMEN
Insular cortex is a critical brain region that participates in the interoceptive sensations. Here, we combined the iDISCO + method and Fos immunostaining to confirm that the middle part of the right-side, but not the left-side, insular cortex in adult male mice is activated by intraperitoneal injection of lithium chloride. Lateralized activation of the insular cortex is also observed in adult female mice, but not in young or aged male mice. Furthermore, asymmetrical activation of the insular cortex was completely blocked when both sides of the vagal nerve are transected, whereas intravenous injection of lithium chloride has no effect on the insular activation. Combined together, these results indicate that the insular cortex unilaterally responds to aversive visceral stimuli in an age-dependent way and this process depends on the vagal afferent pathways.
Asunto(s)
Envejecimiento/fisiología , Corteza Insular/fisiología , Cloruro de Litio/administración & dosificación , Cloruro de Litio/farmacología , Envejecimiento/efectos de los fármacos , Animales , Mapeo Encefálico , Femenino , Imagenología Tridimensional , Inyecciones Intraperitoneales , Corteza Insular/diagnóstico por imagen , Corteza Insular/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Estimulación Física , Proteínas Proto-Oncogénicas c-fos/metabolismo , Coloración y Etiquetado , VagotomíaRESUMEN
Associative learning allows animals to adapt their behavior in response to environmental cues. For example, sensory cues associated with food availability can trigger overconsumption even in sated animals. However, the neural mechanisms mediating cue-driven non-homeostatic feeding are poorly understood. To study this, we recently developed a behavioral task in which contextual cues increase feeding even in sated mice. Here, we show that an insular cortex to central amygdala circuit is necessary for conditioned overconsumption, but not for homeostatic feeding. This projection is marked by a population of glutamatergic nitric oxide synthase-1 (Nos1)-expressing neurons, which are specifically active during feeding bouts. Finally, we show that activation of insular cortex Nos1 neurons suppresses satiety signals in the central amygdala. The data, thus, indicate that the insular cortex provides top-down control of homeostatic circuits to promote overconsumption in response to learned cues.
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Conducta Alimentaria/fisiología , Corteza Insular/fisiología , Neuronas/fisiología , Óxido Nítrico Sintasa de Tipo I/genética , Hipernutrición/etiología , Animales , Clozapina/análogos & derivados , Clozapina/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Señales (Psicología) , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/efectos de los fármacos , Femenino , Corteza Insular/efectos de los fármacos , Corteza Insular/metabolismo , Corteza Insular/patología , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Hipernutrición/genética , Hipernutrición/metabolismo , Hipernutrición/patologíaRESUMEN
There is increasing evidence showing that HDACs regulates BDNF (brain-derived neurotrophic factor) expression through its interaction with the Bdnf gene promoter, a key regulator to consolidate memory. Although the nuclear mechanisms regulated by HDACs that control BDNF expression have been partially described recently, the temporal events for memory consolidation remain unknown. Hence, in this work, we studied the temporal pattern for the activation of the BDNF/TrkB pathway through class I HDAC inhibition to enhance object recognition memory (ORM) consolidation. To this end, we inhibited class I HDAC into the insular cortex (IC) and a weak ORM protocol was used to assess temporal expression and function of the BDNF/TrkB pathway in the IC. We found that cortical class I HDAC inhibition enhanced long-term ORM, coincident with a clear peak of BDNF expression at 4 h after acquisition. Furthermore, the tyrosine kinase B (TrkB) receptor blockade at 4 h, but not at 8 h, impaired the consolidation of ORM. These results suggest that histone acetylation regulates the temporal expression of BDNF in cortical circuits potentiating the long-term recognition memory.
Asunto(s)
Benzamidas/farmacología , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Corteza Insular/efectos de los fármacos , Glicoproteínas de Membrana/efectos de los fármacos , Consolidación de la Memoria/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Proteínas Tirosina Quinasas/efectos de los fármacos , Piridinas/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Regulación de la Expresión Génica , Código de Histonas , Corteza Insular/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Consolidación de la Memoria/fisiología , Memoria a Largo Plazo/fisiología , Ratones , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Receptor trkB/antagonistas & inhibidores , Reconocimiento en Psicología/fisiologíaRESUMEN
It is well-known that antibiotics affect commensal gut bacteria; however, only recently evidence accumulated that gut microbiota (GM) can influence the central nervous system functions. Preclinical animal studies have repeatedly highlighted the effects of antibiotics on brain activity; however, translational studies in humans are still missing. Here, we present a randomized, double-blind, placebo-controlled study investigating the effects of 7 days intake of Rifaximin (non-absorbable antibiotic) on functional brain connectivity (fc) using magnetoencephalography. Sixteen healthy volunteers were tested before and after the treatment, during resting state (rs), and during a social stressor paradigm (Cyberball game-CBG), designed to elicit feelings of exclusion. Results confirm the hypothesis of an involvement of the insular cortex as a common node of different functional networks, thus suggesting its potential role as a central mediator of cortical fc alterations, following modifications of GM. Also, the Rifaximin group displayed lower connectivity in slow and fast beta bands (15 and 25 Hz) during rest, and higher connectivity in theta (7 Hz) during the inclusion condition of the CBG, compared with controls. Altogether these results indicate a modulation of Rifaximin on frequency-specific functional connectivity that could involve cognitive flexibility and memory processing.
Asunto(s)
Antibacterianos/uso terapéutico , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Corteza Insular/efectos de los fármacos , Rifaximina/uso terapéutico , Adulto , Mapeo Encefálico/métodos , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Magnetoencefalografía/métodos , Masculino , Persona de Mediana Edad , Descanso/fisiología , Adulto JovenRESUMEN
Although delta opioid receptors (DOP) are now known to play a major role in modulating chronic pain and controlling emotional processes, unfortunately, some DOP agonists, such as SNC80, reportedly produced convulsive-like behaviors manifesting as tremor-like behaviors in a preclinical study. Therefore, these induced convulsions limit the progress of the clinical development of DOP agonists. However, mechanisms underlying DOP-induced convulsant activity remain unclarified. Thus, the study aimed to elucidate mechanisms that could cause tremor-like behaviors of SNC80. These drugs were microinjected into the ventral hippocampus CA3 (vCA3), amygdala (AMY), and insular cortex (IC) of mice. In addition, we examined the extracellular glutamate levels after DOP agonist local treatment. Microinjection of SNC80 into the vCA3 increased the number of tremor-like behaviors and extracellular glutamate levels but did not cause tremor-like behaviors in mice when microinjected into IC and AMY. Pretreatment with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainite receptor antagonist CNQX into vCA3 totally inhibited the SNC80-induced increases in tremor-like behaviors. In contrast, another DOP agonist, KNT-127, did not cause tremor-like behaviors in any of the tested brain areas. Further, the extracellular glutamate levels in the hippocampus were significantly lower in the KNT-127-treated mice than in the SNC80-treated mice. Our results showed that the administration of SNC80, but not KNT-127, into vCA3 induced tremor-like behaviors by activating glutamatergic neurons in mice. We propose that KNT-127 should be further studied clinically as a DOP agonist that is expected to have a low risk for convulsions than those resulting in antinociceptive and antidepressant effects.
Asunto(s)
Analgésicos Opioides/farmacología , Conducta Animal/efectos de los fármacos , Benzamidas/farmacocinética , Hipocampo/efectos de los fármacos , Morfinanos/farmacología , Piperazinas/farmacocinética , Animales , Ansiolíticos/farmacología , Antidepresivos/farmacología , Ansiedad/tratamiento farmacológico , Corteza Insular/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Naltrexona/farmacología , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides delta/metabolismoRESUMEN
AIMS: Limited vs extended drug exposure has been proposed as one of the key factors in determining the risk of relapse, which is the primary characteristic of addiction behaviors. The current studies were designed to explore the related behavioral effects and neuronal alterations in the insular cortex (IC), an important brain region involved in addiction. METHODS: Experiments started with rats at the age of 35 days, a typical adolescent stage when initial drug exposure occurs often in humans. The drug-seeking/taking behaviors, and membrane properties and intrinsic excitability of IC pyramidal neurons were measured on withdrawal day (WD) 1 and WD 45-48 after limited vs extended cocaine intravenous self-administration (IVSA). RESULTS: We found higher cocaine-taking behaviors at the late withdrawal period after limited vs extended cocaine IVSA. We also found minor but significant effects of limited but not extended cocaine exposure on the kinetics and amplitude of action potentials on WD 45, in IC pyramidal neurons. CONCLUSION: Our results indicate potential high risks of relapse in young rats with limited but not extended drug exposure, although the adaptations detected in the IC may not be sufficient to explain the neural changes of higher drug-taking behaviors induced by limited cocaine IVSA.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Administración Intravenosa , Cocaína/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Corteza Insular/efectos de los fármacos , Potenciales de Acción/fisiología , Administración Intravenosa/métodos , Animales , Inhibidores de Captación de Dopamina/administración & dosificación , Esquema de Medicación , Comportamiento de Búsqueda de Drogas/fisiología , Corteza Insular/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21 days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21 days, relative to 2 days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2 days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21 days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Etanol/toxicidad , Corteza Insular/efectos de los fármacos , Factores de Edad , Animales , Etanol/administración & dosificación , Corteza Insular/crecimiento & desarrollo , Corteza Insular/fisiopatología , Masculino , Técnicas de Placa-Clamp , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Maduración SexualRESUMEN
The concept of self and self-referential processing has a growing explanatory value in psychiatry and neuroscience, referring to the cognitive organization and perceptual differentiation of self-stimuli in health and disease. Conditions in which selfhood loses its natural coherence offer a unique opportunity for elucidating the mechanisms underlying self-disturbances. We assessed the psychoactive effects of psilocybin (230 µg/kg p.o.), a preferential 5-HT1A/2A agonist known to induce shifts in self-perception. Our placebo-controlled, double-blind, within-subject crossover experiment (n = 17) implemented a verbal self-monitoring task involving vocalizations and participant identification of real-time auditory source- (self/other) and pitch-modulating feedback. Subjective experience and task performance were analyzed, with time-point-by-time-point assumption-free multivariate randomization statistics applied to the spatiotemporal dynamics of event-related potentials. Psilocybin-modulated self-experience, interacted with source to affect task accuracy, and altered the late phase of self-stimuli encoding by abolishing the distinctiveness of self- and other-related electric field configurations during the P300 timeframe. This last effect was driven by current source density changes within the supragenual anterior cingulate and right insular cortex. The extent of the P300 effect was associated with the intensity of psilocybin-induced feelings of unity and changed meaning of percepts. Modulations of late encoding and their underlying neural generators in self-referential processing networks via 5-HT signaling may be key for understanding self-disorders. This mechanism may reflect a neural instantiation of altered self-other and relational meaning processing in a stimulus-locked time domain. The study elucidates the neuropharmacological foundation of subjectivity, with implications for therapy, underscoring the concept of connectedness.