Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction.

The P2X ionotropic purinergic receptors, P2X2 and P2X3, are essential for transmission of taste information from taste buds to the gustatory nerves. Mice lacking both P2X2 and P2X3 purinergic receptors (P2X2/P2X3(Dbl-/-)) exhibit no taste-evoked activity in the chorda tympani and glossopharyngeal nerves when stimulated with taste stimuli from any of the 5 classical taste quality groups (salt, sweet, sour, bitter, and umami) nor do the mice show taste preferences for sweet or umami, or avoidance of bitter substances (Finger et al. 2005. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science. 310[5753]:1495-1499). Here, we compare the ability of P2X2/P2X3(Dbl-/-) mice and P2X2/P2X3(Dbl+/+) wild-type (WT) mice to detect NaCl in brief-access tests and conditioned aversion paradigms. Brief-access testing with NaCl revealed that whereas WT mice decrease licking at 300 mM and above, the P2X2/P2X3(Dbl-/-) mice do not show any change in lick rates. In conditioned aversion tests, P2X2/P2X3(Dbl-/-) mice did not develop a learned aversion to NaCl or the artificial sweetener SC45647, both of which are easily avoided by conditioned WT mice. The inability of P2X2/P2X3(Dbl-/-) mice to show avoidance of these taste stimuli was not due to an inability to learn the task because both WT and P2X2/P2X3(Dbl-/-) mice learned to avoid a combination of SC45647 and amyl acetate (an odor cue). These data suggest that P2X2/P2X3(Dbl-/-) mice are unable to respond to NaCl or SC45647 as taste stimuli, mirroring the lack of gustatory nerve responses to these substances.

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We have previously demonstrated that voluntary exercise facilitates discrimination learning in a modified T-maze. There is evidence implicating the dorsolateral striatum (DLS) as the substrate for this task. The present experiments examined whether changes in DLS dopamine receptors might underlie the exercise-associated facilitation. Infusing a D1R antagonist into the DLS prior to discrimination learning facilitated the performance of nonexercising rats but not exercising rats. Infusing a D2R antagonist impaired the performance of exercising rats but not nonexercising rats. Exercise-associated facilitation of this task may rely on an exercise-induced decrease in D1R and increase in D2R activation in the DLS. Executive functions, such as working memory, cognitive flexibility , abstract thinking, and planning (Lezak 1982), are often the targets of research looking at the effects of exercise on human brain function. Meta-analysis of studies engaging older participants (ages 60-85) in exercise intervention programs suggests that exercise can improve several measures of cognition, but that the largest effects are on executive function (Hillman et al. 2008). Set-shifting is a measure of discrimination and cognitive flexibility used in both humans and rodents. Our lab has demonstrated that rats require fewer trials to reach the learning criterion of the initial discrimination phase of a set-shift task following 2 wk of voluntary wheel running (Eddy et al. 2013). In rodents, the initial discrimination in a set-shift task involves the dorsolateral striatum (DLS) (Palencia and Ragozzino 2005). This suggests that exercise is affecting the DLS in some way. One likely candidate is the dopamine (DA) system. There is abundant evidence that exercise impacts the striatal DA system (Gilliam et al. 1984; MacRae et al. 1987; Fisher et al. 2004; Pet-zinger et al. 2007; Foley and Fleshner 2008; Gerecke et al. 2010; Vuckovic et al. 2010), but these effects have not been linked to effects on learning. Therefore, the purpose of the current experiments was to test the hypothesis that changes in DLS DA receptors are responsible for our previously observed exercise-associated improvement in DLS-dependent discrimination learning (Eddy et al. 2013). D1 receptors (D1Rs) and D2 receptors (D2Rs) were the focus of these studies, as they are the most highly expressed DA receptors in the striatum (Valjent et al. 2009). As a starting place for this line of research, we used receptor antagonists to block the effects of striatal DA release during our task, with the reasoning that exercising and nonexercising rats would be affected differently. Male Wistar rats (n ¼ 9-13/group) obtained from Harlan Laboratories were used. Rats were between 59-and 63-d old when they arrived in the colony, and were housed individually. Rats assigned to the exercise group were given unlocked running wheels following colony acclimation. Nonexercise animals were given identical wheels that were locked in place to control for environmental enrichment effects. Rats had 24-h ...

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