Post-ischemia depression (PID) is a condition that affects approximately 30% of survivors from stroke or cardiac arrest and has an important impact on patients’ quality of life. Previous studies support important roles of the endocannabinoid (eCB) system in depression and brain ischemia. This study attempts to link all three variables together by investigating the role and mechanism of eCB signaling in the development of PID. A global ischemia + hypotension model was used to induce a PID phenotype in CD1 mice. Three ischemic time frames were tested, and even though all three could induce significant cell death in the CA1 region of the hippocampus, only the 15-minute time point led to an increased immobility time on the forced swimming test (FST). The main goal of this study was to investigate the effect of a cannabinoid type-I receptor (CB1R) antagonist/inverse agonist, AM281, on the development of two depressive symptoms: anhedonia, measured with the sucrose preference test (SPT), and behavioral despair, measured with the FST. AM281 administration was able to significantly reduce the symptoms of anhedonia and behavioural despair. Subsequently, the mechanism behind this antidepressant-like effect was investigated. Administration of bicuculine with AM281 did not significantly affect the antidepressant effect on the FST, therefore suggesting that AM281 does not act on GABAergic synapses. A similar protocol was adopted with NVP-AM077, where its administration combined with AM281 was able to block the effect of AM281, thus confirming the importance of glutamatergic synapses for the antidepressant effect of AM281. Furthermore, the administration of a TAT-GLUR2 peptide did not significantly affect the effect of AM281, implying that the astroglial cell-mediated LTD (long-term depression) at glutamatergic synapses is not involved in the antidepressant effects of AM281. Finally, a bilateral intra-BLA (basolateral nucleus of the amygdala) administration of AM281 was able to reduce the immobility time on the FST. In conclusion, these results highlight the important contribution of BLA glutamatergic synapses to the antidepressant-like effect conferred by AM281.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-01-10T15:53:45Z No. of bitstreams: 1 AronDeMirandaHenriquesAlves_TESE.pdf: 2139619 bytes, checksum: 54285e7e9d5391a21bf97d42a9b9afaa (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-01-12T10:50:00Z (GMT) No. of bitstreams: 1 AronDeMirandaHenriquesAlves_TESE.pdf: 2139619 bytes, checksum: 54285e7e9d5391a21bf97d42a9b9afaa (MD5) / Made available in DSpace on 2017-01-12T10:50:01Z (GMT). No. of bitstreams: 1 AronDeMirandaHenriquesAlves_TESE.pdf: 2139619 bytes, checksum: 54285e7e9d5391a21bf97d42a9b9afaa (MD5) Previous issue date: 2015-12-16 / Os objetivos desta tese foram os de investigar padr?es comportamentais e eletrofisiol?gicos associados ? resili?ncia e suscetibilidade ao estresse social induzido em camundongos. Para isso, utilizamos um protocolo de indu??o de estresse cr?nico cont?nuo a partir de derrotas sociais baseado no paradigma residente-intruso. Os resultados da tese s?o apresentados em dois estudos. No primeiro estudo, camundongos C57BL/6J submetidos a epis?dios repetidos de derrota social apresentaram motiva??o tardia para interagir com um camundongo desconhecido em sess?es prolongadas (10 min) do teste de intera??o social. Utilizando uma abordagem etol?gica associada ? an?lise computacional de v?deos foi poss?vel rastrear precisamente a posi??o dos camundongos durante a realiza??o de comportamentos de investiga??o social. Analisamos ainda a express?o detalhada de comportamentos defensivos, tais como investiga??o em postura estendida e fugas, ambos associados ao comportamento de investiga??o social. A partir dessas an?lises demonstramos que a realiza??o do comportamento de investiga??o social em postura estendida era significativamente maior para o grupo derrotado comparado ao grupo controle. Ainda, um subgrupo de camundongos derrotados apresentou investiga??o social em postura estendida de forma persistente e sem habitua??o. Utilizando uma medida da dist?ncia de investiga??o durante as investiga??es sociais calculamos um ?ndice de aproxima??o (IA) para cada animal e separamos um subgrupo apresentando fen?tipo relacionado ? ansiedade. A incid?ncia de fugas tamb?m foi maior no grupo derrotado em compara??o com os controles. A persist?ncia na ocorr?ncia desse comportamento foi observada em um subgrupo de camundongos submetidos ?s derrotas sociais. Calculamos ent?o um ?ndice de fugas (IF) que se correlacionou inversamente com a prefer?ncia por sacarose, sendo ?til para identificar animais aned?nicos. No segundo estudo, foram combinados an?lise etol?gica e registros eletrofisiol?gicos com tetrodos na ?rea tegmentar ventral de camundongos submetidos ? derrotas sociais. Utilizando crit?rios eletrofisiol?gicos e farmacol?gicos classificamos unidades na ?rea tegmentar ventral como supostos neur?nios dopamin?rgicos e n?o-dopamin?rgicos. Durante o comportamento de investiga??o social foi observado que a modula??o da taxa de disparo dessas subpopula??es neuronais distintas ocorreu de maneira oposta em animais suscet?veis e resilientes ao estresse social. Em suma, propomos que sess?es prolongadas associadas ? an?lise etol?gica detalhada durante os testes de intera??o social podem prover informa??o para classifica??o de camundongos em resilientes e suscept?veis ap?s repetidas derrotas sociais. Ainda, a express?o do fen?tipo suscet?vel parece estar associada ao comprometimento do sistema dopamin?rgico mesol?mbico na atribui??o de valor de incentivo ?s intera??es sociais normalmente associadas ao aumento da atividade neuronal mesol?mbica. / The aims of this thesis were to investigate behavioral and electrophysiological patterns associated to resilience and susceptibility to social stress in mice. For this, we used a chronic social defeat stress protocol based on the resident-intruder paradigm. The results are presented here in two studies. In the first study, C57BL/6J mice submitted to repeated social defeat episodes showed delayed motivation to interact with an unfamiliar conspecific in long duration (10 min) sessions of the social interaction test. By using an ethological approach combined with computational video analysis, it was possible to track precisely the mouse position during social investigation behavior performance. With that approach, it was analyzed the detailed expression of defensive behaviors, such as stretched attended postures and flights, both associated to social investigation behaviors. From these analyzes, it was demonstrated that social investigation behaviors based on stretched attend postures were significantly higher in defeated mice in comparison to controls. Still, a subpopulation of defeated mice showed persistently and non-habituating stretched attend postures during social investigation. By using a measure based on the investigation distance during social investigations, it was possible to compute an approach index (AI) to each animal and separate a subpopulation showing an anxiety-related phenotype. The flight incidence was also increased in defeated group as compared with controls. The persistent occurrence of this behavior was observed in a subpopulation of defeated mice. We calculated a flight index (FI) that inversely correlated with sucrose preference, showing to be useful to identify anhedonic animals. In the second study, we combined ethological approach and electrophysiological recordings in the ventral tegmental area of mice submitted to chronic social defeat stress. By using electrophysiological and pharmacological criteria, single-units recorded from the ventral tegmental area were classified as putative dopaminergic and non-dopaminergic neurons. During the social investigation behavior it was observed that firing rate modulations of distinct neuronal subpopulations occurred in opposite manner in social defeat susceptible and resilient mice. In summary, this work proposes that longer sessions of the social interaction test associated to ethological approach can provide information for the behavioral classifications of resilient and susceptible mice after social defeat stress. Furthermore, the expression of susceptible phenotype could be related to the midbrain dopaminergic system impairment in the incentive value assignment to social interactions normally associated with increased mesolimbic neuronal activity.

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