ß1-Integrins in the Developing Orbitofrontal Cortex Are Necessary for Expectancy Updating in Mice.

ABSTRACT

Navigating a changing environment requires associating stimuli and actions with their likely outcomes and modifying these associations when they change. These processes involve the orbitofrontal cortex (OFC). Although some molecular mediators have been identified, developmental factors are virtually unknown. We hypothesized that the cell adhesion factor ß1-integrin is essential to OFC function, anticipating developmental windows during which ß1-integrins might be more influential than others. We discovered that OFC-selective ß1-integrin silencing before adolescence, but not later, impaired the ability of mice to extinguish conditioned fear and select actions based on their likely outcomes. Early-life knock-down also reduced the densities of dendritic spines, the primary sites of excitatory plasticity in the brain, and weakened sensitivity to cortical inputs. Notwithstanding these defects in male mice, females were resilient to OFC (but not hippocampal) ß1-integrin loss. Existing literature suggests that resilience may be explained by estradiol-mediated transactivation of ß1-integrins and tropomyosin receptor kinase B (trkB). Accordingly, we discovered that a trkB agonist administered during adolescence corrected reward-related decision making in ß1-integrin-deficient males. In sum, developmental ß1-integrins are indispensable for OFC function later in life.SIGNIFICANCE STATEMENT The orbitofrontal cortex (OFC) is a subregion of the frontal cortex that allows organisms to link behaviors and stimuli with anticipated outcomes, and to make predictions about the consequences of one's behavior. Aspects of OFC development are particularly prolonged, extending well into adolescence, likely optimizing organisms' abilities to prospectively calculate the consequences of their actions and select behaviors appropriately; these decision making strategies improve as young individuals mature into adulthood. Molecular factors are not, however, well understood. Our experiments reveal that a cell adhesion protein termed "ß1-integrin" is necessary for OFC neuronal maturation and function. Importantly, ß1-integrins operate during a critical period equivalent to early adolescence in humans to optimize the ability of organisms to update expectancies later in life.