Assessment of structural plasticity in adaptive behavior

The ability to adapt behavior to an ever-changing environment requires flexible control of behavior, which depends on the causal relationship between an action and its outcome (AO). With repetition, behavior becomes inflexible; actions are no longer sensitive to changes in A-O associations and are primarily elicited by retrospective events. At the neural level, this balance between flexible and inflexible behavior is underpinned by dynamic changes within corticostriatal circuits, particularly the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). While it is known that extensive instrumental training can lead to transitions between flexible and inflexible behavior, it remains unclear how external behavioral changes are translated into internal structural adaptations in the brain, particularly within the DLS. Considering that long-lasting behavioral changes require longlasting changes in the brain, it raises the question of which structural elements encode such persistence or flexibility. Dendritic spines, as dynamic postsynaptic compartments, are adequately positioned to register and store the outcomes of experience through morphological remodeling. Changes in spine morphology and density could reflect dynamic updating of synaptic connectivity as behavior shifts from flexible to inflexible control. In this study, we explored whether behavioral inflexibility is associated with alterations in the structural plasticity of striatal dSPN and iSPN neurons, and whether Interspersed Nuclear Elements -1 (L1) play a role in these alterations. Specifically, we conducted experiments to systematically compare dendritic spine density and morphology in the dorsolateral striatum in mice displaying flexible behavior and mice displaying inflexible behavior by performing 3D dendritic analysis in ImageJ software. Our findings show that the different training regimes of a reward-based behavioral paradigm can be reflected both in spine density and spine head volume. We found that the overtraining is associated with the increased density of stubby spines in dSPN cells and in mushroom spines in iSPN cells. Additionally, the changes in action-outcome contingency were reflected by reduced spine head volumes in the inflexible mice. We found that L1 downregulation in the overtrained animals has an influence on both spine density and spine 6 head volumes. These analyses provide insight into specific structural changes in different spine subtypes linked with the transition between behavioral flexibility and inflexibility. Understanding the structural synaptic mechanisms that underlie behavioral flexibility holds relevance for disorders described by behavioral rigidity, such as autism and OCD.