Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning

Abstract

Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging-related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging.