Changing strengths of learned associations: neuronal ensemble mechanism

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The ability to learn and remember the changing meanings about learned associations of biologically significant experiences and sensory stimuli is crucial for survival. For example, animals respond to external cues that predict the availability of natural rewards (e.g. food). However, they will learn to inhibit responding to these cues if the same cues fail to predict their availability. For many decades, a major goal of neuroscience has been to reveal the precise location and physiological nature of representations about these associations in the brain. Recent studies implicate the role of a minority of sparsely distributed, activated neurons called 'neuronal ensembles' in forming mental representations about learned associations about salient experiences and associated environmental cues. Although it is established that these ensembles play a causal role in mediating these associations, we do not fully understand the mechanisms that are involved in their formation. Also, little is known about what happens to these neurons once the original meaning of the learned associations change, such as when a cue no longer predicts food availability. A likely site where these changes occur to encode the meaning of these associations at neuronal ensembles is at the synapse, the key sites of neuronal communication. It is thought that enduring changes at the synapse akin to 'neuronal rewiring' underlie the formation of new associative representations. However, the precise nature of this rewiring process, especially with regards to how neuronal ensembles establish and maintain these associations, is largely unknown due to the technical challenges in identifying and recording from activated neurons. The aim of this grant is to elucidate the mechanisms that modulate the strength of learned associations between natural rewards and associated environmental cues at the synaptic and local circuit level in neuronal ensembles. We will accomplish this by using an animal model of associative learning, where a mouse learns how to associate a tone cue with sucrose delivery. Once this association forms, a tone cue elicits a conditioned approach response towards the sucrose delivery receptacle. Conversely, this response is inhibited following a procedure called 'extinction learning' when the animal learns that the cue does not predict sucrose delivery. It is widely believed for this type of learning that the original associative memory is not erased but rather suppressed, since exposure to sucrose can re-trigger the approach response. At the neuronal level, a sucrose predictive cue elicits activation of a minority of neurons in the prefrontal cortex. This brain area is important for motivated behaviours, such as securing food sources, and these activated neurons are believed to encode information about sucrose and its associated cues. We will selectively record from these neurons using transgenic mice in which these activated neurons can be identified and physiologically characterised. We will examine structural alterations at their synapses to reveal the changes in neuronal wiring, after mice have learned that the cue predicts or no longer predicts sucrose delivery. We will also examine changes in 'connectivity' or the ability of one ensemble member to communicate with another, a process that may facilitate activation of the entire ensemble representation. Finally, we will characterize the behavioural role of these neurons that undergo rewiring by silencing their activity and testing this effect on conditioned approach responses, and whether the mice can relearn the original conditioning task.Understanding these neuronal mechanisms will shed light on basic associative learning processes that are integral to healthy cognitive functioning. Moreover, it will reveal specific alterations at synapses on behaviourally relevant neurons and could potentially reveal new therapeutic targets.