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Previous issue date: 2015-02-24 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq / A administra??o de nicotina em seres humanos e roedores ? pensada como
um melhorador de mem?ria e aten??o, tamb?m pelo seu efeito positivo na Doen?a
de Alzheimer. O complexo do Septo Medial / Banda Diagonal de Broca (MS/DBB) ?
um dos principais sistemas colin?rgicos ? massivamente projetado para o
hipocampo atrav?s da F?mbria-F?rnix, via esta chamada de via septo-hipocampal.
Foi demonstrado que o MS/DBB afeta diretamente o potencial de campo local (LFP)
e a organiza??o r?tmica do hipocampo, especialmente na gera??o do ritmo teta - um
LFP r?tmico intrinsecamente relacionado com a fun??o mnem?nica do hipocampo.
Experimentos in vitro deram evid?ncias de que a nicotina aplicada no MS/DBB pode
gerar um ritmo teta na rede local do MS/DBB. Assim, o presente estudo se prop?e a
elucidar a fun??o da nicotina no MS/DBB sobre a via septo-hipocampal.
Experimentos in vivo, comparando o efeito de microinfus?es no MS/DBB de solu??o
salina (n = 5) ou nicotina (n = 8) em camundongos anestesiados por
ketamina/xilazina mostraram um aumento na densidade de pot?ncia no espectro
banda de gama (35 a 55 Hz) em ambas as estruturas (teste de Wilcoxon Rank-Sum,
p = 0,038), mas sem alterar a coer?ncia entre as estruturas na mesma banda (teste
de Wilcoxon Rank-Sum, p = 0,60). Houve tamb?m uma diminui??o na densidade
pot?ncia na banda delta (1-3 Hz) ? oscila??o induzida pela ketamina. Realizamos
tamb?m experimentos in vitro sobre o efeito da nicotina na voltagem de membrana e
no potencial de a??o de neur?nios do MS/DBB. Registramos neur?nios (n=22) em
current-clamp antes e depois da presen?a de nicotina no meio extracellular; 12
neur?nios responderam ? nicotina, metade aumentou a taxa de potenciais de a??o;
outros seis diminu?ram, diferindo significativamente no limiar do potencial de a??o (-
47,3 ? 0,9 mV vs. -41 ? 1,9 mV, respectivamente, p = 0,007) e na largura do disparo
(1,6 ? 0,08 vs. 2 ms ? 0,12 ms, respectivamente, p = 0,01). Al?m disso, realizamos
outro conjunto de experimentos in vitro, relativo ? conectividade das tr?s grandes
popula??es neuronais de MS / DBB que usam a acetilcolina, GABA ou glutamato
como neurotransmissores. O registro pareado de patch-clamp mostrou que
neur?nios glutamat?rgicos e GABA?rgicos realizam contatos intra-septais capazes
de produzir correntes sin?pticas em neur?nios p?s-sin?pticos do MS/DBB. A
probabilidade da conectividade entre diferentes popula??es neuronais foi
implementada em um modelo realista que corrobora que a rede ? altamente sens?vel
? gera??o de ritmo gama. Juntamente com os dados dispon?veis, o conjunto
completo de experi?ncias corrobora que a nicotina pode atuar como potenciador
cognitivo, e um substrato eletrofisiol?gico prov?vel ? atrav?s da indu??o de oscila??o
gama no circuito local do MS/DBB. / Nicotine administration in humans and rodents enhances memory and attention,
and also has a positive effect in Alzheimer's Disease. The Medial Septum / Diagonal
Band of Broca complex (MS/DBB) ? a main cholinergic system ? massively projects
to the hippocampus through the fimbria-fornix, and this pathway is called the septohippocampal
pathway. It has been demonstrated that the MS/DBB acts directly on
the local field potential (LFP) rhythmic organization of the hippocampus, especially in
the rhythmogenesis of Theta (4-8Hz) ? an oscillation intrinsically linked to
hippocampus mnemonic function. In vitro experiments gave evidence that nicotine
applied to the MS/DBB generates a local network Theta rhythm within the MS/DBB.
Thus, the present study proposes to elucidate the function of nicotine in the MS/DBB
on the septo-hippocampal pathway. In vivo experiments compared the effect of
MS/DBB microinfusion of saline (n=5) and nicotine (n=8) on Ketamine/Xylazine
anaesthetized mice. We observed power spectrum density in the Gamma range (35
to 55 Hz) increasing in both structures (Wilcoxon Rank-Sum test, p=0.038) but with
no change in coherence between these structures in the same range (Wilcoxon
Rank-Sum test, p=0.60). There was also a decrease in power of the ketamineinduced
Delta oscillation (1 to 3 Hz). We also performed in vitro experiments on the
effect of nicotine on membrane voltage and action potential. We patch-clamped 22
neurons in current-clamp mode; 12 neurons were responsive to nicotine, half of them
increased firing rate and other 6 decreased, and they significantly differed in action
potential threshold (-47.3?0.9 mV vs. -41?1.9 mV, respectively, p=0.007) and halfwidth
time (1.6?0.08 ms vs. 2?0.12 ms, respectively, p=0.01). Furthermore, we
performed another set of in vitro experiments concerning the connectivity of the three
major neuronal populations of MS/DBB that use acetylcholine, GABA or glutamate as
neurotransmitter. Paired patch-clamp recordings found that glutamatergic and
GABAergic neurons realize intra-septal connections that produce sizable currents in
MS/DBB postsynaptic neurons. The probability of connectivity between different
neuronal populations gave rise to a MS/DBB topology that was implemented in a
realistic model, which corroborates that the network is highly sensitive to the
generation of Gamma rhythm. Together, the data available in the full set of
experiments suggests that nicotine may act as a cognitive enhancer, by inducing
gamma oscillation in the local circuitry of the MS/DBB.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/20188 |
| Date | 24 February 2015 |
| Creators | G?is, Jos? Henrique Targino Dias |
| Contributors | 99944251615, http://lattes.cnpq.br/0683942077872227, Nascimento, George Carlos do, 19363737420, http://lattes.cnpq.br/1489371044894987, Figuerola, Wilfredo Blanco, 05579557779, http://lattes.cnpq.br/9912829629195282, Tort, Adriano Bretanha Lopes, Le?o, Richardson Naves |
| Publisher | Universidade Federal do Rio Grande do Norte, PROGRAMA DE P?S-GRADUA??O EM NEUROCI?NCIAS, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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