Chasing the addicted engram: identifying functional alterations in Fos-expressing neuronal ensembles that mediate drug-related learned behavior

Abstract

Given that addiction has been characterized as a disorder of maladaptive learning and memory, one critical question is whether there are unique physical adaptations within neuronal ensembles that support addiction-related learned behavior. The search for the physical mechanisms of encoding these and other memories in the brain, often called the engram as a whole, continues despite decades of research. As we develop new technologies and tools that allow us to study cue- and behavior-activated Fos-expressing neuronal ensembles, the possibility of identifying the engrams of learning and memory is moving into the realm of reality rather than speculation. It has become clear from recent studies that there are specific functional, electrophysiological alterations unique to Fos-expressing ensemble neurons that may participate in encoding memories. The ultimate goal is to identify the addicted engram and reverse the physical changes that support this maladaptive form of learning.

Figure 1.

(Top) Schematic representation of Fos-expressing neuronal ensembles before and after learning. The number of Fos-expressing neurons in the ensemble decreases with further training (Whitaker et al. 2017). (Middle) Example of spiking activity in Fos-expressing neurons before and after incorporation into a behaviorally relevant ensemble. Neuronal excitability increases after learning (Whitaker et al. 2017; Ziminski et al. 2017, 2018). (Bottom) Example of synaptic changes in a Fos neuron before and shortly after drug-based learning experience. There is an increase of silent synapses that contain NMDA receptors but no functional AMPA receptors (Koya et al. 2012; Whitaker et al. 2016).