RESUMEN
Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.
Asunto(s)
Complejo Nuclear Basolateral , Trastornos por Estrés Postraumático , Ratas , Masculino , Animales , Miedo/fisiología , Extinción Psicológica/fisiología , Memoria/fisiología , Recuerdo Mental/fisiología , Complejo Nuclear Basolateral/fisiología , Trastornos de la MemoriaRESUMEN
The requirement of NMDA receptor (NMDAR) activity for memory formation is well described. However, the plasticity mechanisms for memory can be modified by experience, such that a future similar learning becomes independent of NMDARs. This effect has often been reported in learning events conducted with a few days interval. In this work, we asked whether the NMDAR-independency is permanent or the brain regions and plasticity mechanisms of experience-dependent learning may change over time. Considering that contextual memories undergo a gradual reorganization over time, becoming progressively independent from the hippocampus and dependent upon cortical regions, we investigated the brain regions mediating a new related learning conducted at a remote time-point, when the first memory was already cortically established. First, we demonstrated that anterior cingulate cortex was not able to support a learning subsequent to a previous systems-level consolidated memory; it did require at least one functional subregion of the hippocampus (ventral or dorsal). Moreover, after replicating findings showing that a few days interval between trainings induces a NMDAR-independent learning, we managed to show that a learning following a longer interval once again becomes dependent on NMDARs in the hippocampus. These findings suggest that while the previous memory grows independent from the hippocampus over time, an experience-dependent learning following a systems-consolidated memory once again engages the hippocampus and a NMDAR-dependent plasticity mechanism.
Asunto(s)
Hipocampo/fisiología , Aprendizaje/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Agonistas de Receptores de GABA-A/farmacología , Hipocampo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Masculino , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Muscimol/farmacología , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Long-lasting changes in dendritic spines provide a physical correlate for memory formation and persistence. LIM kinase (LIMK) plays a critical role in orchestrating dendritic actin dynamics during memory processing, since it is the convergent downstream target of both the Rac1/PAK and RhoA/ROCK pathways that in turn induce cofilin phosphorylation and prevent depolymerization of actin filaments. Here, using a potent LIMK inhibitor (BMS-5), we investigated the role of LIMK activity in the dorsal hippocampus during contextual fear memory in rats. We first found that post-training administration of BMS-5 impaired memory consolidation in a dose-dependent manner. Inhibiting LIMK before training also disrupted memory acquisition. We then demonstrated that hippocampal LIMK activity seems to be critical for memory retrieval and reconsolidation, since both processes were impaired by BMS-5 treatment. Contextual fear memory extinction, however, was not sensitive to the same treatment. In conclusion, our findings demonstrate that hippocampal LIMK activity plays an important role in memory acquisition, consolidation, retrieval, and reconsolidation during contextual fear conditioning.