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The Basolateral Amygdala-Medial Prefrontal Cortex Circuitry Regulates Behavioral Flexibility During Appetitive Reversal Learning

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The Basolateral Amygdala-Medial Prefrontal Cortex Circuitry Regulates Behavioral Flexibility During Appetitive Reversal Learning Behavioral Neuroscience © 2019 American Psychological Association 2020, Vol. 134, No. 1, 34–44 ISSN: 0735-7044 http://dx.doi.org/10.1037/bne0000349 The Basolateral Amygdala-Medial Prefrontal Cortex Circuitry Regulates Behavioral Flexibility During Appetitive Reversal Learning Sara E. Keefer Gorica D. Petrovich University of Maryland School of Medicine Boston College Environmental cues can become predictors of food availability through Pavlovian conditioning. Two forebrain regions important in this associative learning are the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Recent work showed the BLA-mPFC pathway is activated when a cue reliably signals food, suggesting the BLA informs the mPFC of the cue’s value. The current study tested this hypothesis by altering the value of 2 food cues using reversal learning and illness-induced devaluation paradigms. Rats that received unilateral excitotoxic lesions of the BLA and mPFC contralaterally placed, along with ipsilateral and sham controls, underwent discriminative conditioning, followed by reversal learning and then devaluation. All groups successfully discriminated between 2 auditory stimuli that were followed by food delivery (conditional stimulus [CS]ϩ) or not rewarded (CSϪ), demonstrating this learning does not require BLA-mPFC communication. When the outcomes of the stimuli were reversed, the rats with disconnected BLA-mPFC (contralateral condition) showed increased responding to the CSs, especially to the rCSϩ (original CSϪ) during the first session, suggesting impaired cue memory recall and behavioral inhibition compared to the other groups. For devaluation, all groups successfully learned conditioned taste aversion; however, there was no evidence of cue devaluation or differences between groups. Interestingly, at the end of testing, the nondevalued contralateral group was still responding more to the original CSϩ (rCSϪ) compared to the devalued contralateral group. These results suggest a potential role for BLA-mPFC communication in guiding appropriate responding during periods of behavioral flexibility when the outcomes, and thus the values, of learned cues are altered. Keywords: basolateral amygdala, medial prefrontal cortex, appetitive learning, reversal learning, devaluation Behavioral flexibility is the ability to appropriately alter one’s Using various paradigms, a plethora of studies have shown the behavior in response to an environmental change (Brown & Tait, BLA is critical for appetitive associative learning (for review, see 2014). To respond appropriately, the subject must recall previously Wassum & Izquierdo, 2015). The anterior part of the BLA is the learned information about available cues and integrate that mem- first forebrain region activated during cue-food learning (Cole, ory with current environmental demands. One example of adaptive Powell, & Petrovich, 2013). Interestingly, even though the BLA is learning and behavioral flexibility is attending to and deciphering activated early during learning, it does not appear to be essential between cues that signal the availability of food. The current study for the acquisition of appetitive conditioning (Balleine, Killcross, examined if communication between the basolateral area of the & Dickinson, 2003; Corbit & Balleine, 2005; Hatfield, Han, Con- amygdala (BLA) and medial prefrontal cortex (mPFC) underlies ley, Gallagher, & Holland, 1996; Holland, Petrovich, & Gallagher, behavioral flexibility when there is a change in the value of food 2002; Parkinson, Robbins, & Everitt, 2000); instead, it is needed and its associated cues. when the acquired information supports new learning (Blundell, This document is copyrighted by the American Psychological Association or one of its allied publishers. Hall, & Killcross, 2001; Corbit & Balleine, 2005; Hatfield et al., This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. 1996; Ishikawa, Ambroggi, Nicola, & Fields, 2008; Nomura, Izaki, Takita, Tanaka, & Hori, 2004; Schoenbaum, Chiba, & This article was published Online First December 12, 2019. Gallagher, 1999; Setlow, Gallagher, & Holland, 2002; for reviews, X Sara E. Keefer, Department of Anatomy and Neurobiology, Univer- see Everitt, Cardinal, Parkinson, & Robbins, 2003; Holland, Hat- sity of Maryland School of Medicine; Gorica D. Petrovich, Department of field, & Gallagher, 2001; Holland & Petrovich, 2005; Holland et Psychology, Boston College. al., 2002; Petrovich, 2013; Wassum & Izquierdo, 2015). In par- We thank Megan Ebner, Amanda Jenkins, Marissa Kellogg, Sophia ticular, the BLA is necessary for driving behavioral responding Ramos-Bartolomei, Antonio Santos, and Hannah Yoon for technical assis- when the value of the cue changes. The BLA neurons respond to tance. This research was supported by the National Institute of Health cue value alterations (Tye, Cone, Schairer, & Janak, 2010) and are Grant R01DK085721 to Gorica D. Petrovich. Correspondence concerning this article should be addressed to Sara E. necessary for successful reversal learning (Churchwell, Morris, Keefer, Department of Anatomy and Neurobiology, University of Mary- Heurtelou, & Kesner, 2009; Schoenbaum, Setlow, Nugent, Sad- land School of Medicine, 20 Penn Street, Baltimore, MD 21201. E-mail: doris, & Gallagher, 2003) and cue value updating during devalu- [email protected] ation (Balleine et al., 2003; Corbit & Balleine, 2005; Coutureau, 34 AMYGDALA-PREFRONTAL CORTEX IN BEHAVIORAL FLEXIBILITY 35 Marchand, & Di Scala, 2009; Hatfield et al., 1996; Johnson, intramuscularly) of ketamine (50 mg/ml) and xylazine (10 mg/ml) Gallagher, & Holland, 2009; Ostlund & Balleine, 2008; Parkes & prior to stereotaxic frame (Kopf Instruments) placement. Rats Balleine, 2013). received a unilateral 0.3-␮l injection into the mPFC (coordinates The mPFC has topographically organized, reciprocal connec- from bregma: anteroposterior, ϩ3.0 mm; mediolateral, Ϯ0.7 mm; tions with the BLA (Gabbott, Warner, Jays, Salway, & Busby, dorsoventral, Ϫ4.5 mm) and two 0.1-␮l injections into either the 2005; Hoover & Vertes, 2007; for review, see Reppucci & contralateral or ipsilateral BLA depending on group allocation Petrovich, 2016). The mPFC is critical in adaptive behaviors and (coordinates from bregma: anteroposterior, Ϫ2.3 to 2.5 mm; me- executive control (Dalley, Cardinal, & Robbins, 2004; O’Doherty, diolateral, Ϯ5.0 mm; dorsoventral, Ϫ8.4 to 8.7 mm) using a 1-␮l 2011), as well as control of feeding behavior (Blasio, Steardo, 32-gauge Hamilton Neuros syringe driven by a Quintessential Sabino, & Cottone, 2014; Land et al., 2014; Mena, Sadeghian, & Stereotaxic Injector (Stoelting) at a rate of 0.1 ␮l/min. Excitotoxic Baldo, 2011; Mena, Selleck, & Baldo, 2013; Petrovich, Ross, lesions were induced by injecting 0.15M N-methyl-D-aspartate Holland, & Gallagher, 2007). Two subregions of the mPFC, the (Sigma-Aldrich) in a phosphate-buffered saline (PBS) solution, prelimbic (PL) and infralimbic (ILA) areas, are activated during whereas sham lesions received contralateral injections of PBS cue-food learning (Burgos-Robles, Bravo-Rivera, & Quirk, 2013; alone. The syringe was left in place for 4 min after each infusion Cole, Hobin, & Petrovich, 2015; Moorman & Aston-Jones, 2015; to allow for diffusion of solution. After infusions, the scalp was Warren et al., 2016), and BLA neurons that directly communicate clipped closed and coated with triple antibiotic cream, and rats with the mPFC are activated when cue-food associations are well were given chewable Rimadyl tablets (Bio Serv, Frenchtown, NJ; learned, suggesting that the BLA can inform the mPFC of the 2 mg/one tablet/100 g body weight) for 2 days following surgery. associative value of a conditioned cue (Keefer & Petrovich, 2017). Rats recovered for at least 1 week prior to behavioral testing and In turn, the mPFC is important for altering behavioral responding were monitored and weighed daily. during satiety-induced devaluation (Coutureau et al., 2009), sug- gesting the mPFC may be needed to integrate previously learned Apparatus information with current cue value to appropriately alter behavior. All habituation and training occurred within the same set of Therefore, the current study investigated if communication be- behavioral chambers (30 ϫ 28 ϫ 30 cm; Coulbourn Instruments) tween the BLA and mPFC is necessary in appetitive Pavlovian located in a separate room from where the colony was housed. The discriminative cue learning and behavioral flexibility when learned chambers had aluminum tops and sides, and one side contained a information about the cues is altered. We abolished communica- recessed food cup (3.2 ϫ 4.2 cm). The front and back of the tion between the BLA and mPFC using a contralateral disconnec- chambers were clear Plexiglas with a hinged front. The floor had tion approach. This method lesions the BLA in one hemisphere stainless steel rods 5 mm wide and 15 mm apart. Each chamber and the mPFC in the other hemisphere, functionally disconnecting was contained within an isolation cubicle (79 ϫ 53 ϫ 53 cm; communication between the structures in both hemispheres but Coulbourn Instruments) composed of monolithic rigid foam walls allowing one of each region to interact within other circuitries. We and a ventilation fan (55 dB). Video cameras were attached to the assessed flexibility using two well-known paradigms, reversal rear wall of each isolation cubicle and connected to a recording learning and illness-induced devaluation, to observe
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