β1-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 ␤1-integrin is essential to OFC function, anticipating developmental windows during which ␤1-integrins might be more influential than others. We discovered that OFC-selective ␤1-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) ␤1-integrin loss. Existing literature suggests that resilience may be explained by estradiol-mediated transactivation of ␤1-integrins and tropomyosin receptor kinase B (trkB). Accordingly, we discovered that a trkB agonist administered during adolescence corrected reward-related decision making in ␤1-integrin-deficient males. In sum, developmental ␤1-integrins are indispensable for OFC function later in life.

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

“…Since activation of β1 integrins is known to promote spine stabilization ( DePoy et al, 2019 ), integrin inactivation and loss of adhesion to the extracellular matrix likely contributes to spine pruning. Actin cytoskeletal remodeling resulting from these effector pathways serves to collapse the affected spines.…”

Sex and pubertal status influence dendritic spine density onto frontal corticostriatal projection neurons

“…Our study adds to a growing body of research demonstrating that spine density and dynamics change within agranular frontal cortices during adolescence (Zuo et al, 2005;Gourley et al, 2012;Johnson et al, 2016;Boivin et al, 2018), and provides novel evidence that spine pruning onto a projection-defined cell-type in the frontal cortex is sensitive to pubertal development. More work needs to be done in order to understand how spine pruning relates to changes in neural computation and cognitive processes during adolescence (Selemon, 2013), but recent studies have made progress, associating changes in spine density onto OFC neurons to alterations in goal-directed behavior (DePoy et al, 2019;Hinton et al, 2019). Data in humans suggests that pubertal status and circulating gonadal hormone levels influence working memory use during learning in both sexes (Master et al, 2019), sensitivity to immediate rewards during intertemporal decision-making in males (Laube et al, 2017), and a variety of social and affective behaviors in both sexes (Vijayakumar et al, 2018;Goddings et al, 2019).…”

Semaphorin3F Drives Dendritic Spine Pruning through Rho-GTPase Signaling

“…Loss of integrin-dependent adhesion to the extracellular matrix may be an early step in spine pruning, since activated β 1 integrins promote spine stabilization [18]. However, the downstream signaling events that cause spines to retract have not been elucidated.…”