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IntroductionClinical and preclinical research on cocaine use disorder (CUD) has shown that sex differences in drug seeking are influenced by hormonal fluctuations. Estradiol (E2), a sex steroid hormone, has been linked to female drug effects, vulnerability to use/abuse, and psychosocial factors. Preclinical studies show that estradiol in females facilitates the extinction of cocaine-seeking behavior indicating a possible role in regulating extinction learning. Similar to females, males’ brains contain the aromatase enzyme which converts testosterone to estradiol. However, it is unclear whether estradiol plays a role in male extinction learning as it does in females. Furthermore, how endogenously aromatized estradiol affects drug addiction in males is unknown. Therefore, this study investigated whether endogenous estradiol regulates cocaine seeking in male rats. We hypothesized that decreased aromatase enzyme activity, resulting in decreased estradiol synthesis in male brains, will impair extinction learning leading to increased cocaine-seeking behavior.MethodsThis hypothesis was tested using cocaine-conditioned place preference (CPP), and short access self-administration (SA), followed by extinction and reinstatement. Before each extinction session for CPP or SA, male rats received an injection of either 1 (low dose) or 2.5 mg/kg (high dose) of the aromatase inhibitor Fadrozole (FAD), or vehicle.ResultsFAD groups showed dose-dependent effects on cocaine-seeking behavior compared to the vehicle group during CPP extinction. Specifically, low dose FAD facilitated extinction of cocaine CPP, whereas high dose FAD impaired it. In contrast, neither dose of FAD had any effects on the extinction of cocaine SA. Interestingly, only the low dose FAD group had decreased active lever pressing during cue- and cocaine-primed reinstatement compared to the vehicle group. Neither dose of FAD had an effect on sucrose extinction or reinstatement of sucrose seeking.DiscussionThese results from CPP experiments suggest that estradiol may impact extinction learning, as a low dose of FAD may strengthen the formation of cocaine extinction memory. Additionally, in male rats undergoing cocaine SA, the same low dose of aromatase inhibitor effectively reduced reinstatement of cocaine-seeking behavior. Thus, estradiol impacts cocaine seeking and extinction in both males and females, and it may also influence the development of sex-specific treatment strategies for CUD.

Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after status epilepticus (SE) robustly increases spontaneous seizure burden weeks later. This suggests that EZH2 upregulation is a protective. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.

El proyecto propone crear bloques con pines a base de diferentes tipos de caliche (baldosa, cielo raso y pared) los cuales, a través de un sistema de compactación, se puedan apilar unos sobre otros hasta formar estructuras en forma de paredes que se encajen como legos. La finalidad de este proyecto es aprovechar los residuos de obras civiles para crear bloques que funcionen como un sistema constructivo alternativo para viviendas temporales y permanentes de fácil montaje, a su vez reduciendo la granulación y la cantidad de material nuevo en la mezcla al utilizar diferentes porcentajes de caliche.