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Neurobiology study of relapse to alcohol and cocaine seeking: identification of plasticity in neuronal ensembles that encodes addiction-related memories

Grant number: 18/15505-4
Support type:Research Grants - Young Investigators Grants- Phase 2
Duration: May 01, 2019 - April 30, 2024
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Fabio Cardoso Cruz
Grantee:Fabio Cardoso Cruz
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Assoc. researchers:Cleopatra da Silva Planeta ; Gustavo José da Silva Pereira ; Paola Palombo ; Paula Cristina Bianchi ; Rodrigo Molini Leão ; Sheila Antonagi Engi
Associated research grant:13/24986-2 - The role of neuronal ensembles in context-induced reinstatement of ethanol seeking: pharmacogenetic, optogenetic and molecular investigation, AP.JP
Associated grant(s):19/23454-3 - The role of matricellular protein hevin in cocaine reward effects in mice, AV.EXT
Associated scholarship(s):20/01331-4 - Effect of epigenetic changes in the nociceptin system caused by maternal separation stress on the consumption of ethanol in mice, BP.IC
19/24073-3 - Role of cannabinoid CB1 receptors in modulating neural circuits involved in the interaction between maternal separation stress and ethanol intake in mice, BP.PD
19/26246-2 - The role of differents subtypes of GABAergics interneurons on impulsive behavior and ethanol-seeking, BP.DR
+ associated scholarships 20/01343-2 - Involvement of medial prefrontal cortex neuronal ensembles and its perineuronal NETs on incubation of cocaine craving, BP.IC
19/17065-4 - Neurobiology study of relapse to alcohol seeking: role of neuronal ensembles in the basolateral amygdala that encodes addiction-related memories, BP.PD
19/17799-8 - Neurobiology study of neuronal ensembles in the basolateral amygdala that encodes addiction-related memories, BP.MS - associated scholarships

Abstract

Correlational data suggests that learned associations are encoded within sparsely distributed patterns of neurons called neuronal ensembles that are selectively activated during learned behaviors. Until recently it has been difficult to prove that neuronal ensembles mediate learned behaviors because both traditional pharmacological and lesion methods, and newer optogenetic and chemo genetic methods alter activity of neurons regardless of whether they were selectively activated or not activated during learned behaviors. Additionally, previous studies on synaptic and molecular alterations induced by learning did not distinguish between behaviorally activated and non-activated neurons. Based on these considerations, we propose to combine some methodologies, considered as state-of-art (overlap, optogenetic regulation, FACS, causal role experiments, c-Fos::teop-Cre and LacZ rats) to assess different aspects of ensemble-specific neuroadaptations in different brain areas in context-induced reinstatement of alcohol seeking and incubation of cocaine seeking. Understanding the role of these neuronal ensembles in behavior and the ways that repeated drug administration alters them will help us to understand how drugs of abuse produce the learned behaviors associated with addiction. Aim 1: Identification and characterization of neuronal ensembles activated during incubation of cocaine craving behavior. We will use the cfos-tetO-Cre transgenic rats, FACS followed by spectrophotometry, optogenetic and virus vectors to identify and show causal role to neuronal ensembles in nucleus accumbens that are repeatedly activated during tests for incubation of cocaine craving.Aim 2: Demonstrated context-specific selection of neuronal ensembles that were distinct when exposed to alcohol self-administration training context or extinction context. We intend to demonstrate context-specific induction of the pharmacogenetic (beta-galactosidase) and optogenetic protein (channel rhodopsin) in these neuronal ensembles that will be used to show selective inhibition of memories associated with alcohol taking or extinction of alcohol seeking. (AU)