Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats

Abstract

The prefrontal cortex (PFC) is critical for the ability to flexibly adapt established patterns of behavior in response to a change in environmental contingencies. Impaired behavioral flexibility results in maladaptive strategies such as perseveration on response options that no longer produce a desired outcome. Pharmacological manipulations of prefrontal cortical GABAergic signaling modulate behavioral flexibility in animal models, and prefrontal cortical interneuron dysfunction is implicated in impaired behavioral flexibility that accompanies neuropsychiatric disease. As deficits in behavioral flexibility also emerge during the normal aging process, the goal of this study was to determine the role of GABAergic signaling, specifically via prefrontal cortical GABA(B) receptors, in such age-related deficits. Young and aged rats were trained in a set shifting task performed in operant chambers. First, rats learned to discriminate between two response levers to obtain a food reward on the basis of a cue light illuminated above the correct lever. Upon acquisition of this initial discrimination, the contingencies were shifted such that rats had to ignore the cue light and respond on the levers according to their left/right positions. Both young and aged rats acquired the initial discrimination similarly; however, aged rats were impaired relative to young following the set shift. Among aged rats, GABA(B) receptor expression in the medial prefrontal cortex (mPFC) was strongly correlated with set shifting, such that lower expression was associated with worse performance. Subsequent experiments showed that intra-mPFC administration of the GABA(B) receptor agonist baclofen enhanced set shifting performance in aged rats. These data directly link GABAergic signaling via GABA(B) receptors to impaired behavioral flexibility associated with normal aging.

Discrimination performance in aging is vulnerable to interference and dissociable from spatial memory

“…Our finding also suggests the spatial discrimination test used in the current study taxes executive functions by requiring rats to store information regarding spatial locations for a single trial and then update that information across trials. Consistent with this observation, both working memory (Moss et al 2007;Beas et al 2013;Bañuelos et al 2014) and set-shifting (Moore et al 2003(Moore et al , 2006Beas et al 2013Beas et al , 2016Bañuelos et al 2014) are impaired by aging.…”

“…This requirement of rats to maintain a location in memory for a brief period and then update that location across trials likely engages prefrontal cortical circuits (Sloan et al 2006). Because prefrontal cortical function is also vulnerable to the effects of advanced age (Morrison and Baxter 2012;Beas et al 2013Beas et al , 2016Bañuelos et al 2014), deficits in spatial discrimination performance could potentially emerge from dysfunction of this brain area or its ability to interact with medial temporal lobe structures.…”

Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats

“…This task was originally developed by (Floresco et al, 2008a) and was used previously to demonstrate impaired cognitive flexibility in aged Fischer 344 rats (e.g., Beas et al, 2017, 2013). …”

“…Consistent with data from human subjects, aged rats displayed greater preference for large, delayed rewards compared to young (Simon et al, 2010). Other work from our laboratory with F344 rats has identified age-related deficits in tests of several forms of PFC-mediated executive function, including a delayed response task that assesses working memory and an attentional set-shifting task that assesses cognitive flexibility (Bañuelos et al, 2014; Beas et al, 2017, 2013). Cognitive flexibility is not as well characterized in the context of intertemporal choice; however, both an exaggerated ability to delay gratification and behavioral inflexibility are associated with the eating disorder anorexia nervosa (Steinglass et al, 2012; Tchanturia et al, 2004), suggesting the possibility that such relationships may exist.…”

“…In addition, tasks used to study intertemporal choice in rodents often incorporate a block design, which places demands on cognitive flexibility as response contingencies shift over the course of test sessions (Hamilton et al, 2015). As our laboratory has reported both an enhanced ability to delay gratification (Simon et al, 2010) and impaired cognitive flexibility (Beas et al, 2017, 2013) in aged rats, it is reasonable to hypothesize that cognitive inflexibility in aged subjects may in part mediate age-associated differences in intertemporal choice using the block task design (Breton et al, 2015). …”