Dissociable effects of advanced age on prefrontal cortical and medial temporal lobe ensemble activity.

The link between age-related cellular changes within brain regions and larger scale neuronal ensemble dynamics critical for cognition has not been fully elucidated. The present study measured neuron activity within medial prefrontal cortex (PFC), perirhinal cortex (PER), and hippocampal subregion CA1 of young and aged rats by labeling expression of the immediate-early gene Arc. The proportion of cells expressing Arc was quantified at baseline and after a behavior that requires these regions. In addition, PER and CA1 projection neurons to PFC were identified with retrograde labeling. Within CA1, no age-related differences in neuronal activity were observed in the entire neuron population or within CA1 pyramidal cells that project to PFC. Although behavior was comparable across age groups, behaviorally driven Arc expression was higher in the deep layers of both PER and PFC and lower in the superficial layers of these regions. Moreover, age-related changes in activity levels were most evident within PER cells that project to PFC. These data suggest that the PER-PFC circuit is particularly vulnerable in advanced age.

Medial prefrontal-perirhinal cortical communication is necessary for flexible response selection.

The ability to use information from the physical world to update behavioral strategies is critical for survival across species. The prefrontal cortex (PFC) supports behavioral flexibility; however, exactly how this brain structure interacts with sensory association cortical areas to facilitate the adaptation of response selection remains unknown. Given the role of the perirhinal cortex (PER) in higher-order perception and associative memory, the current study evaluated whether PFC-PER circuits are critical for the ability to perform biconditional object discriminations when the rule for selecting the rewarded object shifted depending on the animal's spatial location in a 2-arm maze. Following acquisition to criterion performance on an object-place paired association task, pharmacological blockade of communication between the PFC and PER significantly disrupted performance. Specifically, the PFC-PER disconnection caused rats to regress to a response bias of selecting an object on a particular side regardless of its identity. Importantly, the PFC-PER disconnection did not interfere with the capacity to perform object-only or location-only discriminations, which do not require the animal to update a response rule across trials. These findings are consistent with a critical role for PFC-PER circuits in rule shifting and the effective updating of a response rule across spatial locations.

Age-related impairments in object-place associations are not due to hippocampal dysfunction.

Age-associated cognitive decline can reduce an individual's quality of life. As no single neurobiological deficit can account for the wide spectrum of behavioral impairments observed in old age, it is critical to develop an understanding of how interactions between different brain regions change over the life span. The performance of young and aged animals on behaviors that require the hippocampus and cortical regions to interact, however, has not been well characterized. Specifically, the ability to link a spatial location with specific features of a stimulus, such as object identity, relies on the hippocampus, perirhinal and prefrontal cortices. Although aging is associated with dysfunction in each of these brain regions, behavioral measures of functional change within the hippocampus, perirhinal and prefrontal cortices in individual animals are often not correlated. Thus, how dysfunction of a single brain region within this circuit, such as the hippocampus, impacts behaviors that require communication with the perirhinal and prefrontal cortices remains unknown. To address this question, young and aged rats were tested on the interregion dependent object-place paired association task, as well as a hippocampal-dependent test of spatial reference memory. This particular cohort of aged rats did not show deficits on the hippocampal-dependent task, but were significantly impaired at acquiring object-place associations relative to young. These data suggest that behaviors requiring functional connectivity across different regions of the memory network may be particularly sensitive to aging, and can be used to develop models that will clarify the impact of systems-level dysfunction in the elderly.