Publicação
Role of laterodorsal tegmentum in motivation and reward
| Resumo: | The reward circuit is mainly comprised by dopaminergic projections arising from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), and has been shown to mediate different aspects of reward and reinforcement. Mesopontine neurons of the laterodorsal tegmentum (LDT) tightly modulate the activity of dopaminergic neurons of the VTA, controlling the release of dopamine in the NAc. Interestingly, a recent study has shown that the LDT also sends direct projections to the nucleus accumbens, suggesting both a direct and indirect role in modulating accumbal activity. In this thesis, we first show that prenatal glucocorticoid exposure (iuCG model) impacts the electrophysiological activity of the LDT-VTA circuit, culminating with a decrease in motivational drive. LDT basal activity was decreased in iuGC-exposed animals, and we observe a bidirectional effect in evoked activity: iuGC animals present a decrease in the magnitude of excitation and an increase in the magnitude of inhibition in the VTA after electrical stimulation of LDT. Importantly, optogenetic activation of LDT-VTA projections rescues this phenotype, suggesting that motivational levels are dependent on this circuit. In line with this, we further manipulated LDT-VTA circuit during multiple phases of reward using optogenetics. We showed that optical LDT-VTA stimulation is able to causally enhance choice preference for a laser-paired reward and induce intracranial selfstimulation. Next, we investigated the recently described LDT projections to the NAc. This region is comprised by two major populations of GABAergic medium spiny neurons (MSNs), canonically segregated into those expressing dopamine receptor D1 (D1-MSNs), and those expressing D2 (D2- MSNs). Using anatomical, electrophysiological and behavioural experiments, we confirmed the presence of direct cholinergic, glutamatergic and GABAergic projections from the LDT to the NAc, evoking a predominantly excitatory response in accumbal cells. Lastly, we show for the first time that selective activation of LDT-NAc projections enhances motivational drive and induces preference for a laser-associated lever, but only when paired with a food reward. We further demonstrate that specific activation of LDT-NAc cholinergic projections is sufficient for this shift in preference, suggesting that these projections enhance and narrow incentive motivation in rodents. In conclusion, with this work we showed that i) prenatal glucocorticoid exposure negatively impacts motivation due to impairments in LDT-VTA inputs, and that activation of this circuit rescues motivational deficits; ii) that LDT also controls NAc activity through direct projections of different natures; and iii) LDT-NAc (cholinergic) projections convey positive reinforcement signals. |
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| Autores principais: | Coimbra, Bárbara Guimarães Salazar |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | português |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | The reward circuit is mainly comprised by dopaminergic projections arising from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), and has been shown to mediate different aspects of reward and reinforcement. Mesopontine neurons of the laterodorsal tegmentum (LDT) tightly modulate the activity of dopaminergic neurons of the VTA, controlling the release of dopamine in the NAc. Interestingly, a recent study has shown that the LDT also sends direct projections to the nucleus accumbens, suggesting both a direct and indirect role in modulating accumbal activity. In this thesis, we first show that prenatal glucocorticoid exposure (iuCG model) impacts the electrophysiological activity of the LDT-VTA circuit, culminating with a decrease in motivational drive. LDT basal activity was decreased in iuGC-exposed animals, and we observe a bidirectional effect in evoked activity: iuGC animals present a decrease in the magnitude of excitation and an increase in the magnitude of inhibition in the VTA after electrical stimulation of LDT. Importantly, optogenetic activation of LDT-VTA projections rescues this phenotype, suggesting that motivational levels are dependent on this circuit. In line with this, we further manipulated LDT-VTA circuit during multiple phases of reward using optogenetics. We showed that optical LDT-VTA stimulation is able to causally enhance choice preference for a laser-paired reward and induce intracranial selfstimulation. Next, we investigated the recently described LDT projections to the NAc. This region is comprised by two major populations of GABAergic medium spiny neurons (MSNs), canonically segregated into those expressing dopamine receptor D1 (D1-MSNs), and those expressing D2 (D2- MSNs). Using anatomical, electrophysiological and behavioural experiments, we confirmed the presence of direct cholinergic, glutamatergic and GABAergic projections from the LDT to the NAc, evoking a predominantly excitatory response in accumbal cells. Lastly, we show for the first time that selective activation of LDT-NAc projections enhances motivational drive and induces preference for a laser-associated lever, but only when paired with a food reward. We further demonstrate that specific activation of LDT-NAc cholinergic projections is sufficient for this shift in preference, suggesting that these projections enhance and narrow incentive motivation in rodents. In conclusion, with this work we showed that i) prenatal glucocorticoid exposure negatively impacts motivation due to impairments in LDT-VTA inputs, and that activation of this circuit rescues motivational deficits; ii) that LDT also controls NAc activity through direct projections of different natures; and iii) LDT-NAc (cholinergic) projections convey positive reinforcement signals. |
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