Physiopathology of brain-wide assemblies in adaptive memory

When making decisions, we often draw on previous experience. This ability to inform behaviour from memory relies on the fine-grained coordination of activity between nerve cells in the brain. The hippocampus is a region of the mammalian brain where the activity of such “cell assemblies” has been related to memory-guided behaviour. However, memories of important life events are expected to span multiple brain regions, with each region processing a particular dimension of information. This organisation of information representation could be at the heart of the complexity of the cognitive disabilities associated with natural ageing and certain neurological/psychiatric diseases. Here, we will first seek to provide a comprehensive mechanistic explanation of how cell activities distributed across multiple brain regions support complex, detail-rich memories. In this work, we will further consider unwanted memories related to drugs of abuse that underpin maladaptive responses, investigating how cross-brain-region communication drives the re-emergence of behaviourally-extinguished drug memory. We will finally identify brain mechanisms of inferential reasoning, a higher-order operation that allows individuals to deduce logical links between sets of information that have not been experienced together. This work is intended to provide principles of interventions to harness brain physiopathology of maladaptive memory.

Memory is central to adaptation, enabling individuals to infer from past experience how to respond to ever-changing situations. The idea that groups of neurons transiently synchronize their spiking activity to organize information-representing cell assemblies has laid the foundation of scientific investigations carried at the nexus between brain, memory and behaviour. Notably, past work has established how neural dynamics of assemblies in the hippocampus circuit serve memory-guided behaviour. However, memories of important, salient events are expected to span multiple brain circuits, with each circuit processing a particular dimension of mnemonic information. This organisational principle of neurally-distributed memory items could be at the heart of the complexity of the cognitive disabilities associated with natural ageing and certain neurological/psychiatric diseases. Here, we seek to obtain a comprehensive mechanistic explanation of how neuronal activities distributed across brain regions allow the division of representational labour involved in complex, detail-rich memories. We will perform this work while keeping in mind that not all memories serve adaptive behaviour. This is notably the case of strong memories related to drugs of abuse that underpin the expression of maladaptive responses. Throughout this programme, we will deploy a number of cutting-edge strategies, including cell-type-selective and input-defined optogenetic interventions as well as real-time manipulation of brain circuit dynamics, to establish causal links with behavioural phenotypes. We will first determine how temporally-patterned cooperation of neuronal spiking distributed across memory circuits allows brain-wide operations to serve optimal behaviour in situations of uncertainty caused by multiple information streams. We will then investigate how cross-brain-region communication relates to the renewal of behaviourally-extinguished drug-paired memory and associated re-occurrence of drug seeking. We will finally provide a comprehensive description of the macrocircuit and microcircuit mechanisms of inferential reasoning, a higher-order operation that allows combining discrete memory items to infer logical associations between sets of information that have not been directly experienced together. In doing so, our research programme will identify neuronal motifs and pathways supporting memory-guided behaviour. This work is intended to provide principles of interventions to harness network physiopathology of maladaptive memory.