Titolo della tesi: Ventral striatal control of spatial memory consolidation in the hippocampus
New spatial representations are initially encoded in a labile form by the hippocampus (HPC). These representations can either be lost or stabilized into permanent memories. According to the system consolidation theory, memories are first stored in the HPC and then gradually transferred and consolidated within the neocortex for long-term storage. Although this view has dominated memory research for a long time, the temporally limited role of the HPC formation has been challenged based on evidence demonstrating that this brain structure might play a role also in retrieval of remote memories. Further issue still unexplored are the subcortical circuits, sustaining consolidation of remote memories. Indeed although the crucial role of the HPC is well established, the early stages of consolidation have been shown to depend upon coordinated activity of a network of brain regions including not only the HPC but also key subcortical structures. In this framework, neural activity in the ventral striatum (VS) has recently emerged as a fundamental event in this process. To better elucidate this issue, we investigated the temporal involvement of the VS and the HPC in remote spatial memory consolidation and retrieval. We found that NBQX infusion in the HPC, but not VS, impaired remote spatial memory recall. On the other hand, post-training DREADD’s inhibition of VS impaired remote spatial memory consolidation. There is a suggestion that signals originating from the VTA to the HPC play a significant role in this process. Based on the result that remote memory consolidation requires VS post-learning activity, we tested the hypothesis that the VTA’s influence on memory persistence in the HPC could be modulated by inputs from the VS. Utilizing transgenic mice expressing a Cre-dependent reporter dTomato, we verified the existence of an indirect pathway from the VS to the HPC via the VTA. For this purpose, we injected AAV1-CRE, possessing anterograde trans-synaptic properties, into the VS. Simultaneously, a second AAV8 for the CREdependent expression of the inhibitory DREADD hM4d and the fluorescent reporter mCitrine was administered into the VTA. This allowed the identification of VTA neurons receiving direct inputs from the VS projecting to the HPC. Having established this circuit, we investigated whether its inhibition could modulate memory stability in CD1 mice. Employing the same experimental strategy described above to express hM4d in VTA neurons receiving VS inputs and projecting to the HPC, we tested the effects of focal HPC administration of CNO immediately after training in the Morris maze. The inhibition of this circuit significantly impaired mice's ability to locate the platform 24 hours after training. This study underscores a bottom-up modulation of memory stability in the HPC by the VS through the VTA, emphasizing the role of the VS in shaping the persistence of memories.