Medial prefrontal-perirhinal cortical communication is necessary for flexible response selection
Introduction
The capacity to update one’s actions based on environmental contingencies is critical for adaptive behaviors. Dysfunction in this type of cognitive flexibility is associated with schizophrenia (Enomoto, Tse, & Floresco, 2011), aging (Barense et al., 2002, Beas et al., 2013, Moore et al., 2003), and other disease states (Buckner, 2004, Cunha et al., 2013, Lavoie and Everett, 2001). Cognitive flexibility is supported by the dorsolateral prefrontal cortex in humans (Demakis, 2003, Owen et al., 1991) and other primates (Dias et al., 1996a, Dias et al., 1996b, Moore et al., 2009), and the homologous medial prefrontal cortex (mPFC) in rodents (Birrell and Brown, 2000, Bissonette and Powell, 2012, Floresco et al., 2008, Uylings et al., 2003). Specifically, the ability to extinguish a cue-driven behavior, one measure of cognitive flexibility, is mediated by increased neuronal activity within the infralimbic region of the rodent mPFC (Burgos-Robles et al., 2007, Milad and Quirk, 2002, Quirk and Mueller, 2008), and age-related decreases in the excitability of these neurons have been linked to flexibility impairments in old animals (Kaczorowski, Davis, & Moyer, 2012).
While the prefrontal cortex, and mPFC in particular, is unequivocally involved in behavioral flexibility (Logue & Gould, 2014), this brain region does not act in isolation to update response selection. In support of this idea, damage to the hippocampus has been shown to impair performance on attentional set-shifting tasks of behavioral flexibility (Cholvin et al., 2013, Malá et al., 2015). Furthermore, both mPFC and hippocampal activity are associated with the inhibition of an incorrect response (Lee & Byeon, 2014), and functional connectivity between the frontal cortices and medial temporal lobe is involved in dynamic task switching (Clapp et al., 2011, Wais and Gazzaley, 2014). While these data support that communication between the mPFC and hippocampus is important for behavioral flexibility, the anatomical projections between these areas are relatively sparse (Beckstead, 1979, Sesack et al., 1989, Vertes, 2002), suggesting that other cortical regions may be important for updating associations between sensory information and desirable outcomes.
A candidate brain region that could be critical for facilitating flexible response selection is the perirhinal cortex (PER), an area within the medial temporal lobe that receives direct input from all sensory modalities (Burwell and Amaral, 1998a, Suzuki and Amaral, 1994). The PER is involved in both memory (Buffalo et al., 1999, Suzuki et al., 1993) and higher-order sensory perception (Barense et al., 2007, Barense et al., 2012, Bartko et al., 2007a, Bartko et al., 2007b). Moreover, the PER shares reciprocal connections with the mPFC (Agster and Burwell, 2009, Burwell and Amaral, 1998a, Delatour and Witter, 2002, McIntyre et al., 1996, Sesack et al., 1989) and the hippocampus (Naber et al., 1999, Witter et al., 2000, Witter et al., 2000). Furthermore, communication within the mPFC-PER-hippocampal circuit is necessary for an animal’s ability to detect when the relationship between an object and its spatial location has changed (Barker et al., 2007, Barker and Warburton, 2008, Barker and Warburton, 2015). Thus, the PER is positioned to contribute stimulus-specific information as well as link activity patterns in the hippocampus to the mPFC in support of flexible behavior. Consistent with this idea, mPFC activity enhances interactions between the PER and entorhinal cortex (Paz, Bauer, & Pare, 2007). As PER-entorhinal cortical interactions are believed to gate the flow of information into the hippocampus (de Curtis & Pare, 2004), mPFC modulation of rhinal cortical activity is likely critical for higher cognitive function.
Although the mPFC is necessary for an animal’s ability to inhibit an incorrect response (Lee and Byeon, 2014, Lee and Solivan, 2008), and mPFC-PER communication is involved in an animal’s ability to detect novel object-place associations (Barker and Warburton, 2008, Barker and Warburton, 2015, Barker et al., 2007, Jo and Lee, 2010a, Jo and Lee, 2010b), it is not known if communication between these brain areas is critical for flexible behavior. The objective of the current experiments was to examine whether mPFC-PER communication is necessary for performance on the object-place paired association (OPPA) task (Jo & Lee, 2010b), which tests an animal’s ability to flexibly update which of two objects is rewarded based on an incrementally learned object-in-place rule that requires knowledge of both object identity and current spatial location. After rats acquired the biconditional association, the necessity of mPFC-PER communication was investigated by infusing the GABAA receptor agonist muscimol (MUS) into one hemisphere of the mPFC and the contralateral PER to reversibly disconnect these areas. This approach capitalizes on the fact that the mPFC and PER are densely connected within the same hemisphere, but not across hemispheres (Bedwell, Billett, Crofts, MacDonald, & Tinsley, 2015). Thus, unilateral mPFC and contralateral PER inactivation blocks communication between these areas. Importantly, because only one hemisphere of each region is inactivated, the PER and mPFC remain functional as independent entities.
Section snippets
Subjects and handling
Twelve male Fischer 344 rats (NIA colony at Taconic; 6-13 mo. old) were single housed and kept on a reverse 12-h light/dark cycle, with all testing occurring during the dark phase. After histological verification of cannula placement (see below), 9 rats were included in the current analyses. Upon arrival to the facility, rats acclimated to the colony room for 7 days. After acclimation, the rats were handled by the experimenters for several days before being placed on food restriction. Rats were
Muscimol selectively blocked activity-dependent arc expression in perirhinal and medial prefrontal cortices
To confirm the MUS infusion in the current study, the expression of the neural activity-dependent gene Arc was used to determine if MUS infusion blocked neuronal activity selectively in the PER and mPFC. Specifically, if MUS blocked PER/mPFC activity then the expression of Arc should be reduced in these brain areas compared to adjacent areas not targeted for inactivation: LEC, area TE and AC. To test this idea, 4 rats received ipsilateral infusions of MUS 30 min prior to performing the OPPA
Discussion
The current study examined the extent to which an animal’s ability to update the selection of a rewarded object when the correct choice is contingent on spatial location requires communication between medial prefrontal (mPFC) and perirhinal cortices (PER). Blocking neural activity with muscimol (MUS) infusions into either region bilaterally, resulted in significant impairments. This finding confirms previous reports that both regions are necessary for object-place paired association (OPPA) task
Funding
This work was supported by the Eveyln F. McKnight Brain Research Foundation, The National Institute on Aging at the National Institutes of Health (Claude D. Pepper Older Americans Independence Center Scholar Award Grant No. P30 AG028740 subaward to SNB, and Grant Nos. R01 AG049711 to SNB, and R01 AG029421 to JLB, R03 1R03AG049411 to APM and SNB), University of Florida Howard Hughes Medical Institute Science for Life, and the University of Florida Research Opportunity Seed Fund.
Acknowledgements
We would like to thank Michael G. Burke for maze construction, and Sofia Beas, Ph.D., Shannon Wall, Caitlin Orsini Ph.D., and Barry Setlow Ph.D. for help completing the experiments.
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