RESUMEN
Incubation of craving is a phenomenon describing the intensification of craving for a reward over extended periods of abstinence from reinforcement. Animal models use instrumental markers of craving to reward cues to examine incubation, while human paradigms rely on subjective self-reports. Here, we characterize an animal-inspired, novel human paradigm that showed strong positive relationships between self-reports and instrumental markers of craving for favored palatable foods. Further, we found consistent nonlinear relationships with time since last consumption and self-reports, and preliminary patterns between time and instrumental responses. These findings provide a novel approach to establishing an animal-inspired human model of incubation.
Asunto(s)
Condicionamiento Operante , Ansia , Autoinforme , Humanos , Ansia/fisiología , Femenino , Masculino , Condicionamiento Operante/fisiología , Adulto Joven , Adulto , Recompensa , Alimentos , Señales (Psicología) , Conducta Alimentaria/fisiología , Adolescente , Factores de TiempoRESUMEN
Experiencing some early life adversity can have an "inoculating" effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.
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Conducta Animal , Núcleo Accumbens/fisiopatología , Trastornos Relacionados con Opioides/prevención & control , Resiliencia Psicológica , Estrés Psicológico , Transcriptoma , Animales , Animales Recién Nacidos , Femenino , Regulación de la Expresión Génica , Masculino , Núcleo Accumbens/efectos de los fármacos , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Opioides/metabolismo , Fenotipo , Ratas , Ratas Long-Evans , Receptores AMPA/genética , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Factores SexualesRESUMEN
Protein interacting with C kinase 1 (PICK1) is an AMPA receptor binding protein that works in conjunction with glutamate receptor interacting protein (GRIP) to balance the number of GluA2-containing AMPARs in the synapse. In male mice, disrupting PICK1 in the medial prefrontal cortex (mPFC) leads to a decrease in cue-induced cocaine seeking and disrupting GRIP in the mPFC has the opposing effect, consistent with other evidence that removal of GluA2-containing AMPARs potentiates reinstatement. However, PICK1 does not seem to play the same role in female mice, as knockdown of either PICK1 or GRIP in the mPFC leads to similar increases in cue-induced cocaine seeking. These previous findings indicate that the role of PICK1 in the prefrontal cortex is sex specific. The goal of the current study was to examine whether ovarian hormones contribute to the effect of prefrontal PICK1 knockdown on reinstatement of cocaine seeking. While we replicated the increased cue-induced cocaine seeking in prefrontal PICK1 knockdown sham mice, we did not see any difference between the GFP control mice and PICK1 knockdowns following ovariectomy. However, this effect was driven primarily by an increase in cocaine seeking in ovariectomized GFP control mice while there was no effect ovariectomy in PICK1 knockdown mice. Taken together, these findings suggest that circulating ovarian hormones interact with the effects of PICK1 on cue-induced reinstatement.
Asunto(s)
Cocaína , Ratones , Animales , Masculino , Femenino , Cocaína/farmacología , Núcleo Accumbens/metabolismo , Sinapsis , Corteza Prefrontal , Hormonas/metabolismo , Autoadministración , Extinción PsicológicaRESUMEN
Exposure to adversity during early childhood and adolescence increases an individual's vulnerability to developing substance use disorder. Despite the knowledge of this vulnerability, the mechanisms underlying it are still poorly understood. Excitatory afferents to the nucleus accumbens (NAc) mediate responses to both stressful and rewarding stimuli. Understanding how adolescent social isolation alters these afferents could inform the development of targeted interventions both before and after drug use. Here, we used social isolation rearing as a model of early life adversity which we have previously demonstrated increases vulnerability to cocaine addiction-like behaviour. The current study examined the effect of social isolation rearing on presynaptic glutamatergic transmission in NAc medium spiny neurons in both male and female mice. We show that social isolation rearing alters presynaptic plasticity in the NAc by decreasing the paired-pulse ratio and the size of the readily releasable pool of glutamate. Optogenetically activating the glutamatergic input from the ventral hippocampus to the NAc is sufficient to recapitulate the decreases in paired-pulse ratio and readily releasable pool size seen following electrical stimulation of all NAc afferents. Further, optogenetically inhibiting the ventral hippocampal afferent during electrical stimulation eliminates the effect of early life adversity on the paired-pulse ratio or readily releasable pool size. In summary, we demonstrate that social isolation rearing leads to alterations in glutamate transmission driven by projections from the ventral hippocampus. These data suggest that targeting the circuit from the ventral hippocampus to the nucleus accumbens could provide a means to reverse stress-induced plasticity.
Asunto(s)
Ácido Glutámico/metabolismo , Núcleo Accumbens/metabolismo , Aislamiento Social , Animales , Femenino , Hipocampo/metabolismo , Masculino , Ratones , Optogenética , Receptores de Dopamina D1 , Transmisión SinápticaRESUMEN
Disruption of prefrontal glutamate receptor interacting protein (GRIP), which anchors GluA2-containing AMPA receptors (AMPARs) into the synaptic membrane, potentiates cue-induced cocaine seeking in both males and females. Protein interacting with C kinase 1 (PICK1) plays an opposing role to that of GRIP, removing AMPARs from the synapse. Consistent with our hypothesis that disruption of PICK1 in the mPFC would lead to a decrease in addiction-like behaviour, we found that conditional deletion of PICK1 in the mPFC attenuates cue-induced cocaine seeking in male mice. However, prefrontal PICK1 deletion had the opposite effect in females, leading to an increase in cue-induced reinstatement of cocaine seeking. We did not see any effects of PICK1 knockdown on sucrose taking or seeking, suggesting the sex-specific effects do not generalise to natural reinforcers. These findings suggest the role of PICK1 in the prefrontal cortex of females may not be consistent with its accepted role in males. To determine whether these sex differences were influenced by gonadal hormones, we gonadectomised a cohort of males and found that removal of circulating androgens eliminated the effect of prefrontal PICK1 knockdown. As there was no effect of gonadectomy on its own on any of the behavioural measures collected, our results suggest that androgens may be involved in compensatory downstream effects of PICK1 knockdown. Taken together, these results highlight the need for consideration of sex as a biological variable when examining mechanisms underlying all behaviours, as convergent sex differences can reveal different mechanisms where behavioural sex differences do not exist.
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Proteínas de Ciclo Celular/metabolismo , Cocaína/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Corteza Prefrontal/metabolismo , Animales , Trastornos Relacionados con Cocaína , Condicionamiento Operante , Femenino , Ácido Glutámico/metabolismo , Masculino , Ratones , Núcleo Accumbens/efectos de los fármacos , Receptores AMPA/metabolismo , Autoadministración , Caracteres Sexuales , Sacarosa/administración & dosificación , Sinapsis/metabolismoRESUMEN
Cocaine-induced plasticity persists during abstinence and is thought to underlie cue-evoked craving. Reversing this plasticity could provide an opportunity for therapeutic intervention. Converging evidence suggest that zeta inhibitory peptide (ZIP) eliminates memories for experience-dependent behaviors, including conditioned drug associations. However, the effect of ZIP on reward seeking and drug-induced plasticity is unknown. The current study examined the effect of ZIP administration in the nucleus accumbens on reinstatement (RI) of cocaine seeking, a rodent model of relapse. We demonstrate that intra-accumbal ZIP administration blocks cocaine-primed RI in rats when administered 24 h or 1 week before testing. These effects of ZIP on drug seeking are specific, as we did not see any effect of ZIP on RI of sucrose seeking. ZIP is a synthetic compound designed to inhibit the atypical PKC, PKMζ, a protein implicated in learning and memory. However, recent evidence from PKMζ-knock-out (KO) mice suggests that ZIP may function through alternative mechanisms. In support of this, we found that ZIP was able to block cue-induced RI in PKMζ-KO mice. One possible mechanism underlying addictive phenotypes is the ability of cocaine to block further plasticity. We hypothesized that ZIP may be working to reverse this anaplasticity. Although ZIP has no effect on accumbal LTD in slices from naive or yoked saline mice, it is able to restore both NMDA-dependent and mGluR5-dependent LTD in animals after cocaine self-administration and withdrawal. These findings demonstrate that intra-accumbal ZIP persistently reverses cocaine-induced behavioral and synaptic plasticity in male and female rodents.SIGNIFICANCE STATEMENT Zeta-inhibitory peptide (ZIP) has been shown to disrupt memory maintenance for experience-dependent behaviors. We examined the effect of ZIP infused into the nucleus accumbens on the reinstatement (RI) of cocaine seeking. We found that intra-accumbal ZIP blocked RI of cocaine seeking 24 h and 1 week later. This effect was specific to RI of cocaine seeking as ZIP did not disrupt RI of food seeking. In conjunction with these behavioral studies we examined the ability of ZIP to reverse cocaine-induced deficits in LTD. We found that ZIP was able to rescue two forms of LTD in cocaine-experienced mice. These studies demonstrate that ZIP is able to reverse cocaine-induced behavioral and synaptic plasticity in a persistent manner.
Asunto(s)
Péptidos de Penetración Celular/farmacología , Cocaína/farmacología , Comportamiento de Búsqueda de Drogas/fisiología , Lipopéptidos/farmacología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Animales , Trastornos Relacionados con Cocaína/fisiopatología , Extinción Psicológica/efectos de los fármacos , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/fisiología , Péptidos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of ß-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced ß-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Inhibidores de la Proteasa del VIH/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Axones/patología , Células Cultivadas , Macaca , Masculino , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Estabilidad Proteica/efectos de los fármacos , Ratas , Ritonavir/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , eIF-2 Quinasa/metabolismoRESUMEN
A single nucleotide polymorphism (SNP) in the human µ-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in drug addiction, pain sensitivity, and, more recently, social behavior. The endogenous opioid system has been shown to regulate social distress and reward in a variety of animal models. However, mechanisms underlying the associations between the OPRM1 A118G SNP and these behaviors have not been clarified. We used a mouse model possessing the human equivalent nucleotide/amino acid substitution to study social affiliation and social defeat behaviors. In mice with the Oprm1 A112G SNP, we demonstrate that the G allele is associated with an increase in home-cage dominance and increased motivation for nonaggressive social interactions, similar to what is reported in human populations. When challenged by a resident aggressor, G-allele carriers expressed less submissive behavior and exhibited resilience to social defeat, demonstrated by a lack of subsequent social avoidance and reductions in anhedonia as measured by intracranial self-stimulation. Protection from social defeat in G-allele carriers was associated with a greater induction of c-fos in a resilience circuit comprising the nucleus accumbens and periaqueductal gray. These findings led us to test the role of endogenous opioids in the A112G mice. We demonstrate that the increase in social affiliation in G carriers is blocked by pretreatment with naloxone. Together, these data suggest a mechanism involving altered hedonic state and neural activation as well as altered endogenous opioid tone in the differential response to aversive and rewarding social stimuli in G-allele carriers.
Asunto(s)
Dominación-Subordinación , Mutación Missense , Polimorfismo de Nucleótido Simple , Receptores Opioides mu/metabolismo , Agresión , Anhedonia , Animales , Femenino , Heterocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/genéticaRESUMEN
The cAMP response element (CRE)-binding protein, CREB, is a transcription factor whose activity in the brain is critical for long-term memory formation. Phosphorylation of Ser133 in the kinase-inducible domain (KID), that in turn leads to the recruitment of the transcriptional coactivator CREB-binding protein (CBP), is thought to mediate the activation of CREB. However, the importance of phosphorylation for CREB binding to DNA and subsequent gene transcription in vivo is controversial. To definitively address the role of CREB phosphorylation in gene transcription and learning and memory, we derived mutant mice lacking the Ser133 phosphorylation site. These mice exhibit normal CREB-mediated gene transcription for a number of genes implicated in learning and memory processes. Furthermore these mice have no deficits in hippocampus- or striatum-dependent learning. Strikingly, our findings show that CREB phosphorylation at Ser133 is not necessary for CREB binding to CRE sites, CREB-mediated transcription, or CREB-mediated behavioral phenotypes associated with learning and memory.
Asunto(s)
Condicionamiento Psicológico/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Miedo/fisiología , Hipocampo/metabolismo , Memoria/fisiología , Transcripción Genética , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Serina/genética , Activación TranscripcionalRESUMEN
The transcription factor cAMP response element-binding protein (CREB) has been implicated in the pathophysiology of depression as well as in the efficacy of antidepressant treatment. However, altering CREB levels appears to have differing effects on anxiety- and depression-related behaviors, depending on which brain region is examined. Furthermore, many manipulations of CREB lead to corresponding changes in other CREB family proteins, and the impact of these changes has been largely ignored. To further investigate the region-specific importance of CREB in depression-related behavior and antidepressant response, we used Creb(loxP/loxP) mice to localize CREB deletion to the hippocampus. In an assay sensitive to chronic antidepressant response, the novelty-induced hypophagia procedure, hippocampal CREB deletion, did not alter the response to chronic antidepressant treatment. In contrast, mice with hippocampal CREB deletion responded to acute antidepressant treatment in this task, and this accelerated response was accompanied by an increase in hippocampal neurogenesis. Upregulation of the CREB-family protein cAMP response-element modulator (CREM) was observed after CREB deletion. Viral overexpression of the activator isoform of CREM, CREMτ, in the hippocampus also resulted in an accelerated response to antidepressants as well as increased hippocampal neurogenesis. This is the first demonstration of CREMτ within the brain playing a role in behavior and specifically in behavioral outcomes following antidepressant treatment. The current results suggest that activation of CREMτ may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment.
Asunto(s)
Antidepresivos/farmacología , Proteína de Unión a CREB/deficiencia , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo , Neurogénesis/efectos de los fármacos , Animales , Bromodesoxiuridina/metabolismo , Proteína de Unión a CREB/genética , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Dependovirus/genética , Dependovirus/metabolismo , Desipramina/uso terapéutico , Proteínas de Dominio Doblecortina , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Miedo/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microinyecciones , Proteínas Asociadas a Microtúbulos/metabolismo , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Neurogénesis/genética , Neuropéptidos/metabolismo , Natación/psicología , Factores de TiempoRESUMEN
Adolescence is a critical period for brain development in humans and stress exposure during this time can have lasting effects on behavior and brain development. Social isolation and loneliness are particularly salient stressors that lead to detrimental mental health outcomes particularly in females, although most of the preclinical work on social isolation has been done in male animals. Our lab has developed a model of post-weaning adolescent social isolation that leads to increased drug reward sensitivity and altered neuronal structure in limbic brain regions. The current study utilized this model to determine the impact of adolescent social isolation on a three-chamber social interaction task both during adolescence and adulthood. We found that while post-weaning isolation does not alter social interaction during adolescence (PND45), it has sex-specific effects on social interaction in adulthood (PND60), potentiating social interaction in male mice and decreasing it in female mice. As early life stress can activate microglia leading to alterations in neuronal pruning, we next examined the impact of inhibiting microglial activation with daily minocycline administration during the first three weeks of social isolation on these changes in social interaction. During adolescence, minocycline dampened social interaction in male mice, while having no effect in females. In contrast, during adulthood, minocycline did not alter the impact of adolescent social isolation in males, with socially isolated males exhibiting higher levels of social interaction compared to their group housed counterparts. In females, adolescent minocycline treatment reversed the effect of social isolation leading to increased social interaction in the social isolation group, mimicking what is seen in naïve males. Taken together, adolescent social isolation leads to sex-specific effects on social interaction in adulthood and adolescent minocycline treatment alters the effects of social isolation in females, but not males.
RESUMEN
Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.
RESUMEN
BACKGROUND: Glutamate signaling within the nucleus accumbens underlies motivated behavior and is involved in psychiatric disease. Although behavioral sex differences in these processes are well-established, the neural mechanisms driving these differences are largely unexplored. In these studies, we examine potential sex differences in synaptic plasticity and excitatory transmission within the nucleus accumbens core. Further understanding of baseline sex differences in reward circuitry will shed light on potential mechanisms driving behavioral differences in motivated behavior and psychiatric disease. METHODS: Behaviorally naïve adult male and female Long-Evans rats, C57Bl/6J mice, and constitutive PKMζ knockout mice were killed and tissue containing the nucleus accumbens core was collected for ex vivo slice electrophysiology experiments. Electrophysiology recordings examined baseline sex differences in synaptic plasticity and transmission within this region and the potential role of PKMζ in long-term depression. RESULTS: Within the nucleus accumbens core, both female mice and rats exhibit higher AMPA/NMDA ratios compared to male animals. Further, female mice have a larger readily releasable pool of glutamate and lower release probability compared to male mice. No significant sex differences were detected in spontaneous excitatory postsynaptic current amplitude or frequency. Finally, the threshold for induction of long-term depression was lower for male animals than females, an effect that appears to be mediated, in part, by PKMζ. CONCLUSIONS: We conclude that there are baseline sex differences in synaptic plasticity and excitatory transmission in the nucleus accumbens core. Our data suggest there are sex differences at multiple levels in this region that should be considered in the development of pharmacotherapies to treat psychiatric illnesses such as depression and substance use disorder.
Understanding normal neural signaling within the nucleus accumbens, a key brain region involved in psychiatric disease including substance use disorder and depression, could provide insight into treatment options for these disorders. Although we know the behaviors regulated by the nucleus accumbens can differ between males and females, we do not understand the underlying differences in brain processing that could contribute to these behavioral differences. Further, even in cases when these behaviors are not different, the underlying brain signaling may exhibit sex-specific mechanisms. The current studies examined excitatory signaling with the nucleus accumbens in both rats and mice at the level of both individual cells and circuits. We found that female rodents (rats and mice) exhibit higher levels of excitatory signaling within the nucleus accumbens than male rodents. Further, procedures that can dampen neural transmission in males are not sufficient to do so in females, suggesting that excitatory signaling in the nucleus accumbens of females is less plastic. Finally, our last set of studies utilized mice missing the protein, PKMζ, and demonstrated that this reversed some of the sex differences seen in normal mice, pointing to a critical role for this protein in maintaining these differences. Our data suggest there are sex differences at multiple levels in this region that should be considered in the development of pharmacotherapies to treat psychiatric illnesses such as depression and substance use disorder.
Asunto(s)
Ácido Glutámico , Núcleo Accumbens , Femenino , Masculino , Ratones , Ratas , Animales , Ratas Long-Evans , Caracteres Sexuales , Potenciales Postsinápticos Excitadores , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena.
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Factor Neurotrófico Derivado del Encéfalo/genética , Trastornos Relacionados con Cocaína/genética , Comportamiento de Búsqueda de Drogas , Extinción Psicológica/fisiología , Animales , Conducta Animal/fisiología , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Polimorfismo de Nucleótido SimpleRESUMEN
Post-weaning social isolation stress has been shown to increase addiction-like behavior in adulthood. These long-term behavioral alterations may be due to long lasting isolation-induced structural changes to neurons in brain regions involved in reward processing. Previous studies have shown that various stressors alter dendritic spine density in the prefrontal cortex (PFC) and the nucleus accumbens, though many of these studies examine the short-term effects of stress, and are primarily conducted in males. There is mounting evidence that males and females exhibit differences in their stress responses, with some studies showing sex differences in stress-induced plasticity. To determine the long-lasting, sex-specific alterations in spine density following post-weaning social isolation, male and female mice were either isolated or group housed at weaning and spine density was measured once they reached adulthood. Post-weaning isolation increased spine density in the PFC of both the males and females, although the effects in the infralimbic cortex were more pronounced in the females. In the nucleus accumbens, adolescent isolation increased spine density in males only in the core and shell. Females also had higher baseline spine density than males in the nucleus accumbens core. Together these data suggest that adolescent social isolation causes long-term, sex-specific alterations to the prefrontal cortex and the nucleus accumbens.
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Espinas Dendríticas/fisiología , Núcleo Accumbens/fisiología , Corteza Prefrontal/fisiología , Aislamiento Social , Estrés Psicológico , Destete , Animales , Animales Recién Nacidos , Encéfalo/fisiología , Corteza Cerebral/fisiología , Femenino , Hipocampo/fisiología , Masculino , Ratones , Neuronas , Recompensa , Caracteres SexualesRESUMEN
BACKGROUND: Dysregulation in the prefrontal cortex underlies a variety of psychiatric illnesses, including substance use disorder, depression, and anxiety. Despite the established sex differences in prevalence and presentation of these illnesses, the neural mechanisms driving these differences are largely unexplored. Here, we investigate potential sex differences in glutamatergic transmission within the medial prefrontal cortex (mPFC). The goal of these experiments was to determine if there are baseline sex differences in transmission within this region that may underlie sex differences in diseases that involve dysregulation in the prefrontal cortex. METHODS: Adult male and female C57Bl/6J mice were used for all experiments. Mice were killed and bilateral tissue samples were taken from the medial prefrontal cortex for western blotting. Both synaptosomal and total GluA1 and GluA2 levels were measured. In a second set of experiments, mice were killed and ex vivo slice electrophysiology was performed on prepared tissue from the medial prefrontal cortex. Spontaneous excitatory postsynaptic currents and rectification indices were measured. RESULTS: Females exhibit higher levels of synaptosomal GluA1 and GluA2 in the mPFC compared to males. Despite similar trends, no statistically significant differences are seen in total levels of GluA1 and GluA2. Females also exhibit both a higher amplitude and higher frequency of spontaneous excitatory postsynaptic currents and greater inward rectification in the mPFC compared to males. CONCLUSIONS: Overall, we conclude that there are sex differences in glutamatergic transmission in the mPFC. Our data suggest that females have higher levels of glutamatergic transmission in this region. This provides evidence that the development of sex-specific pharmacotherapies for various psychiatric diseases is important to create more effective treatments.
Asunto(s)
Ácido Glutámico , Caracteres Sexuales , Femenino , Masculino , Ratones , Animales , Corteza Prefrontal/fisiología , Potenciales Postsinápticos Excitadores , Ratones Endogámicos C57BLRESUMEN
The transcription factor cAMP response element-binding protein (CREB) is required for stress- but not drug-induced reinstatement of cocaine conditioned place preference. To reveal the neural circuitry associated with this CREB dependence, we injected a retrograde tracer into the ventral tegmental area (VTA) and identified afferents that were activated after stress or cocaine exposure in both naive and cocaine-conditioned mice. Neuronal activation, as assessed by Fos expression, was greatly reduced in the dorsal and ventral bed nucleus of the stria terminalis (BNST), lateral septum, and nucleus accumbens shell in mice lacking CREB (CREBαΔ mice) after a 6 min swim stress but not after cocaine exposure (20 mg/kg). Additionally, activation of VTA afferent neurons in the ventral BNST and the infralimbic cortex in CREBαΔ mice was blunted in response to stress. This pattern of neuronal activation persisted in mice that were conditioned to a cocaine place preference procedure before stress exposure. Furthermore, lidocaine inactivation (0.4 µl, 4%) studies demonstrated the necessity of BNST activation for swim-stress-induced reinstatement of cocaine-conditioned reward. Together, the present studies demonstrate that CREB is required for the activation of a unique circuit that converges on the dopamine reward pathway to elicit reinstatement of drug reward and points to the BNST as a key intersection between stress and reward circuits.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Estrés Psicológico , Área Tegmental Ventral/fisiología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Cocaína/administración & dosificación , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/deficiencia , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Estrés Psicológico/genética , Estrés Psicológico/psicología , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Females are more vulnerable than males to many aspects of cocaine use disorder. This vulnerability also translates to opioid use disorder, with females exhibiting stronger behavioral responses than males to drugs such as heroin and morphine. While there is evidence for many overlapping neural mechanisms underlying cocaine and opioid abuse, there is also a breadth of evidence indicating divergent effects of the drugs on synaptic plasticity. This makes it unclear whether the behavioral sex differences seen in substance use disorder across different drugs of abuse rely on the same mechanisms. Ovarian hormones have consistently been implicated as drivers of the behavioral sex differences in cocaine taking and seeking. While there are far fewer studies on the role of ovarian hormones in opioid use disorder, the existing data suggest that ovarian hormones may not drive these behavioral effects in the same manner as in cocaine use disorder. This review highlights evidence that behavioral sex differences in substance use disorder might be driven by different mechanisms depending on drug class.
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Cocaína , Trastornos Relacionados con Opioides , Trastornos Relacionados con Sustancias , Femenino , Hormonas Gonadales , Hormonas , Humanos , Masculino , Caracteres SexualesRESUMEN
Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures. This method leads to sustained neurogenesis and formation of an expanded cortical plate that establishes distinct upper and deep cortical layers for neurons and astrocytes, resembling the third trimester embryonic human neocortex. Using the SNO system, we further identify a critical role of WNT/ß-catenin signaling in regulating human cortical neuron subtype fate specification, which is disrupted by a psychiatric-disorder-associated genetic mutation in patient induced pluripotent stem cell (iPSC)-derived SNOs. These results demonstrate the utility of SNOs for investigating previously inaccessible human-specific, late-stage cortical development and disease-relevant mechanisms.
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Células Madre Pluripotentes Inducidas , Neocórtex , Humanos , Neurogénesis , Neuronas , OrganoidesRESUMEN
Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits. Therefore, evidence on the regulatory and functional interactions between these systems is considered essential for revealing the role of neuromodulators. This postulate extends to contemporary neurobiological hypotheses of major neuropsychiatric disorders. These hypotheses have focused largely on aberrations in the integrity or regulation of individual ascending modulatory systems, with little regard for the likely possibility that dysregulation in multiple ascending neuromodulatory systems and their interactions contribute essentially to the symptoms of these disorders. This review will paradigmatically focus on neuromodulator interactions in the PFC and be further constrained by an additional focus on their role in cognitive functions. Recent evidence indicates that individual neuromodulators, in addition to their general state-setting or gating functions, encode specific cognitive operations, further substantiating the importance of research concerning the parallel recruitment of neuromodulator systems and interactions between these systems.