Rethinking memory acquisition: the rules of memory cooperation and competition

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Rethinking memory acquisition : the rules of Memory cooperation and competition

Publication . Madeira, Natalia

ABSTRACT Learning is a key process allowing individuals to adapt to the environment. It is now well accepted that information stored in the form of long-term memories (LTM) involves a process of consolidation, in which labile memories are stabilized as longlasting traces. Although one can consider each learning event as the acquisition of a “new” memory, considerable evidence indicates that new memories are formed in an interleaved fashion upon a large network of pre-existing knowledge. This implies that learning is highly influenced by previous experience and that previously consolidated memories can be reactivated during new learning. Once active, a previously acquired memory can be strengthened by the following event, by cooperation, or can be lost, by competition. The rules by which memory cooperation and competition are orchestrated and what determines which trace is stored as longterm memory, are completely unknown. To tackle these questions, we have studied the rules of synaptic cooperation and competition in the lateral amygdala (LA). The LA circuitry is very well characterized from the anatomical and behavioural point of view, with the possibility of linking cellular physiology with behaviour. We found that cortical and thalamic inputs into the amygdala engage in synaptic cooperation leading to the maintenance of transient forms of long-term potentiation (LTP) induced by either weak stimulation of thalamic or cortical synapses. Interestingly, the cooperation between cortical and thalamic inputs is bi-directional but asymmetric. We found that thalamic capture of plasticity-related proteins (PRPs) occurs in a time window that is much shorter than the cortical capture of PRPs. This suggests a restriction mechanism in thalamic cooperation, which we found to be due to an activity-dependent release of endocannabinoids. Cortical and thalamic synapses also engage in competition when the availability of PRPs is limited. Interestingly, inhibition of the endocannabinoid signaling favors competition. Additionally, we found that the time of thalamic and cortical activation is a crucial parameter for synaptic cooperation and competition. Our current hypothesis is that endocannabinoid signaling controls negatively the thalamic activity limiting the time of association with the cortical activation. Thalamic time restriction can be particularly relevant in the acquisition of discriminative forms of fear-learning. To test this hypothesis, we developed a behaviour protocol designed to probe memory cooperation and competition. Animals were exposed to two auditory stimuli one unpaired (CS-) and one paired with a footshock (CS+) separated by different time intervals. In our paradigm, during training, each stimulus is presented in blocks, in two different contexts representing two different events. We found, similarly to what we described at the synaptic level, that animals’ associate events if the time interval is less than 30 minutes, showing that memory cooperation follows the same temporal rule as synaptic cooperation. Interestingly, we also found that introducing a third stimulus, during training induces a form of memory competition that destabilizes the acquisition of a fear response to both events. Memory competition is also sensitive to the time at which the third stimulus is introduced. Taken together, we found that memory cooperation and competition follow the same temporal rules as synaptic competition in the lateral amygdala. It remains to be explored whether the same rules apply to remote versus recent events and whether different sensory modalities and/or neuronal circuits show different temporal rules.

2023-05-31Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

SFRH/BD/130911/2017