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 Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: May 01, 2019
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fabio Cardoso Cruz
• Grantee: Fabio Cardoso Cruz
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated 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 research grant(s): 19/23454-3 - The role of matricellular protein hevin in cocaine reward effects in mice, AV.EXT
• Associated scholarship(s): 24/15513-8 - Effects of Acute Sleep Deprivation in the Reinstatement of Fentanyl Self-Administration in Male and Female Rats: Evaluation of the Opioidergic Pathway Modulation, BP.MS; 24/15870-5 - Evaluation of the Potentialization of the Reinforcing Effect of Cocaine by MDMB-4en-PINACA and Impacts on the Dopaminergic System of Mice, BP.IC; 24/04202-1 - Investigation of the Molecular Mechanisms Involved in the Interaction between Ethanol and Cocaine in a Simultaneous Self-Administration Model in Rats: A Metabolomic Study of the Accumbens Nucleus, BP.MS; + associated scholarships 24/07203-9 - Neurobiology study of relapse to alcohol seeking: role of neuronal ensembles in the basolateral amygdala that encodes addiction-related memories, BP.PD; 23/14542-1 - Prenatal Exposure to Cocaine: Impacts on Neuronal Plasticity and Behavioral Sensitivity in Adolescent Rats, BP.IC; 23/11187-6 - UNRAVELING THE MOLECULAR ENIGMA OF ETHANOL RELAPSE: EXPLORING PLASTICITY IN PARVALBUMIN-POSITIVE INTERNEURONS OF THE AMYGDALA., BP.DR; 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; 22/02379-6 - Involvement of endocannabinoid system on locomotor cross-sensitization between social isolament stress and cocaine in adolescent mice, BP.IC; 20/04389-3 - Maternal separation stress and behaviors related to alcohol dependence in mice: assessment of CRFergic neurotransmission, BP.DR; 21/00838-0 - Investigation of the participation of hippocampal projections to infralimbic cortex and nucleus acumbens in the context-induced reinstatement of ethanol seeking, BP.DR; 21/05094-0 - Mechanisms of behavioral inhibition: the neurophysiology of neuronal ensembles related to ethanol addiction, BP.PD; 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; 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; 19/26246-2 - The role of differents subtypes of GABAergics interneurons on impulsive behavior and ethanol-seeking, BP.DR; 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; 16/18701-3 - Cannabidiol treatment in behaviours related to ethanol addiction: in vitro and in vivo studies, BP.PD - 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)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BERTAGNA, NATALIA B.; HOLMGREN, ELEANOR B.; ENGI, SHEILA A.; HA, LINH; CRUZ, FABIO C.; ALBRECHET-SOUZA, LUCAS; WILLS, TIFFANY A.. BNST CRF receptor type 1 modulates mechanical hypersensitivity induced by adolescent alcohol exposure in adult female mice. Psychopharmacology, v. 241, n. 12, p. 11-pg., 2024-09-30. (21/13317-9, 18/15505-4)

BIANCHI, PAULA CRISTINA; PALOMBO, PAOLA; ENGI, SHEILA ANTONAGI; DE OLIVEIRA, PAULO EDUARDO CARNEIRO; TAVARES, GABRIELLE EMILY BOAVENTURA; ANJOS-SANTOS, ALEXIA; YOKOYAMA, THAIS SUEMI; PLANETA, CLEOPATRA DA SILVA; CRUZ, FABIO CARDOSO; LEAO, RODRIGO MOLINI. Involvement of Pre-limbic Cortex-Nucleus accumbens projections in Context-Induced alcohol seeking. Brain Research, v. 1841, p. 16-pg., 2024-06-15. (14/02296-7, 13/24986-2, 18/15505-4)

FAVORETTO, C. A.; BERTAGNA, N. B.; ANJOS-SANTOS, A.; LOSS, C. M.; RODOLPHO, B. T.; RIGHI, T.; BEZERRA, F. R.; BIANCHI, P. C.; CRUZ, F. C.. Impacts of maternal separation stress on ethanol intake and endocannabinoid system in adolescent mice. Neuroscience, v. 565, p. 14-pg., 2024-12-06. (18/15505-4, 19/24073-3)

FERREIRA, SARA EMI M. M.; SOARES, LEONARDO M.; LIRA, CLARICE R.; YOKOYAMA, THAIS S.; ENGI, SHEILA A.; CRUZ, FABIO C.; LEA, RODRIGO M.. Ethanol-induced locomotor sensitization: Neuronal activation in the nucleus accumbens and medial prefrontal cortex. Neuroscience Letters, v. 749, APR 1 2021. (18/15505-4)

FAVORETTO, C. A.; BERTAGNA, N. B.; RIGHI, T.; RODOLPHO, B. T.; ANJOS-SANTOS, A.; SILVA, F. B. R.; BIANCHI, P. C.; CRUZ, F. C.. Impacts of maternal separation stress on ethanol-related responses, anxiety-and depressive-like behaviors in adolescent mice. Neuroscience Letters, v. 809, p. 12-pg., 2023-05-23. (19/24073-3, 18/15505-4)

FELIPE, JAQUELINE MOREIRA; PALOMBO, PAOLA; BIANCHI, PAULA CRISTINA; ZANIBONI, CAROLINE RIBERTI; ANESIO, AUGUSTO; YOKOYAMA, THAIS SUEMI; ENGI, SHEILA ANTONAGI; CARNEIRO-DE-OLIVEIRA, PAULO EDUARDO; PLANETA, CLEOPATRA DA SILVA; LEAO, RODRIGO MOLINI; et al. Dorsal hippocampus plays a causal role in context-induced reinstatement of alcohol-seeking in rats. Behavioural Brain Research, v. 398, FEB 1 2021. (18/15505-4)