Beyond their immune function, microglia have key homeostatic functions in the brain. It is now well accepted that they control the life of synapses in different contexts: during development, in experience-dependent plasticity processes and pathologies.
The main objective of this proposal is to determine the role of microglia in remodeling nucleus accumbens-(NAc) glutamatergic transmission, through the maturation of newly formed silent synapses. This process underlies critical circuit mechanisms promoting cocaine craving (a risk factor for drug relapse), a feature of cue-associated cocaine memories.
Our central hypothesis, based on the current literature and our preliminary results (see below), is: microglia-neuron interactions dependent on fractalkine/CX3CR1 signaling contribute to the maturation and plasticity of silent glutamatergic synapses in the NAc, which embed critical memory traces that promote cue-induced cocaine craving.
To verify this hypothesis, we will combine behavioral measures, whole-cell patch clamp recordings, biochemical approaches and pharmacological interventions in mice and rats. Our proposal is based on the following 3 main aims: 1) Determine the effects of microglial depletion on glutamatergic transmission in the NAc during forced abstinence from cocaine-induced conditioned place preference (CPP). 2) Determine the role of fractalkine/CX3CR1 signaling on the electrophysiological properties of excitatory synapses in acute slices of NAc after forced abstinence from cocaine-induced CPP. 3) Determine the causal role of fractalkine/CX3CR1 signaling in modulating incubated cocaine craving after forced abstinence from cocaine-self administration (the gold standard procedure employed to study drug addiction-related neurobiological mechanisms).
We believe that our proposal, combining behavioral, electrophysiological and biochemical approaches, will offer a new perspective to address a question of great social and clinical relevance.
