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Analysis of hevin function on ethanol-induced plasticity in dopamine hub synapses in the amygdala.

Grant number: 23/17928-8
Support Opportunities:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): March 01, 2024
Effective date (End): August 31, 2024
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Fabio Cardoso Cruz
Grantee:Ben Tagami Rodolpho
Supervisor: Etienne Herzog
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: Université de Bordeaux, Carreire/Victoire, France  
Associated to the scholarship:22/09953-0 - Transcriptome analysis of the bed nucleus of the stria terminalis (BNST) of mice subjected to the rat exposition stress-induced reinstatement of ethanol seeking, BP.MS


Alcohol use disorder (AUD) is a chronic disorder characterized by the compulsion of drug seeking and consumption, loss of control of the amount of drug consumed, and development of negative emotional states after drug interruption. Ethanol can act on different neurotransmission systems, in particular inhibiting the glutamatergic excitatory neurotransmission and increasing the GABAergic inhibitory transmission, which results in disinhibition of dopaminergic neurons of VTA and results in increased release of DA in the mesocortical limbic circuit. Ultimately, chronic ethanol alters glutamatergic synaptic plasticity in the nucleus accumbens, prefrontal cortex, and amygdala leading to the development of ethanol dependence. Recently, a synaptomic analysis of the mouse striatum revealed the existence of physical connections between dopaminergic terminals and glutamatergic synapses. These dopamine hub synapses (DHS) represent 40% of all glutamatergic synapses, suggesting a differential involvement of DHS in the context of ethanol dependence compared to non-DHS glutamatergic synapses. The major goal of this proposal is to determine if chronic ethanol intake affects the composition of these hubs and whether DHSs are present in other regions implicated in the neurobiology of AUD. The amygdala is a complex and multi-nuclei structure capable of processing rewarding and aversive components of AUD. This region also receives dopaminergic projections from the ventral tegmental area (VTA). We will measure the percentage of DHS in the amygdala and study the impact of ethanol injections in the formation of DHSs. Importantly, glial cells, such as astrocytes, can influence the maturation and maintenance of synapses through the release of synaptogenic proteins such as hevin, which is involved in the rewarding process of cocaine and is modified in a region-specific way after alcohol consumption. Thus, we hypothesize that hevin could participate in the reinforcement of DHSs after cocaine or ethanol injections. Finally, since there is a relevant amount of data showing sex differences in the neurobiology of AUD in many species, all the analysis of this experiment will address possible sex-dependent outcomes. In this study, using male and female transgenic VGLUT1-VENUS mice we will first characterize the expression of hevin in VTA-amygdala synapses at basal state and after alcohol or cocaine using FASS to filter amygdala glutamatergic synapses followed by immunoblot and immunofluorescence analysis (Experiment 1). Then, we will inject VGLUT1-VENUS mice with an interference miRNA to generate hevin knockdown animals in amygdala astrocytes in vivo and evaluate the consequences of hevin downregulation in shaping the VTA-amygdala DHS at basal state and after ethanol or cocaine (Experiment 2).

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