The present experiments investigated the role of the prelimbic-infralimbic areas in behavioral flexibility using a place-response learning paradigm. All rats received a bilateral cannula implant aimed at the prelimbic-infralimbic areas. To examine the role of the prelimbic-infralimbic areas in shifting strategies, rats were tested on a place and a response discrimination in a cross-maze. Some rats were tested on the place version first followed by the response version. The procedure for the other rats was reversed. Infusions of 2% tetracaine into the prelimbic-infralimbic areas did not impair acquisition of the place or response discriminations. Prelimbic-infralimbic inactivation did impair learning when rats were switched from one discrimination to the other (cross-modal shift). To investigate the role of the prelimbic-infralimbic areas in intramodal shifts (reversal learning), one group of rats was tested on a place reversal and another group tested on a response reversal. Prelimbic-infralimbic inactivation did not impair place or response intramodal shifts. Some rats that completed testing on a particular version in the cross-modal and intramodal experiments were tested on the same version in a new room for 3 d. The transfer tests revealed that rats use a spatial strategy on the place version and an egocentric response strategy on the response version. Overall, these results suggest that the prelimbic-infralimbic areas are important for behavioral flexibility involving cross-modal but not intramodal shifts.

Behavioral flexibility refers to the ability to shift strategies or response patterns with a change in environmental contingencies. The frontal lobe and basal ganglia are two brain regions implicated in various components for successfully adapting to changed environmental contingencies. This paper discusses a series of experiments that investigate the contributions of the rat prelimbic area, infralimbic area, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Orbitofrontal cortex inactivation did not impair initial learning of discrimination tests, but it impaired reversal learning due to perseverance in the previously learned choice pattern. Inactivation of the prelimbic area did not affect acquisition or reversal learning of different discrimination tests, but it selectively impaired learning when rats had to inhibit one strategy and shift to using a new strategy. However, comparable to orbitofrontal cortex inactivation, strategy-switching deficits following prelimbic inactivation resulted from a perseverance of the previously relevant strategy. Fewer studies have examined the infralimbic region, but there is some evidence suggesting that this region supports reversal learning by maintaining the reliable execution of a new choice pattern. Dorsomedial striatal inactivation impaired both reversal learning and strategy switching. The behavioral flexibility deficits following dorsomedial striatal inactivation resulted from the inability to maintain a new choice pattern once selected. Taken together, the results suggest that orbitofrontal and prelimbic subregions differentially contribute to behavioral flexibility, but they are both critical for the initial inhibition of a previously learned strategy, while the dorsomedial striatum plays a broader role in behavioral flexibility and supports a process that allows the reliable execution of a new strategy once selected.

BackgroundThe results from cross sectional and longitudinal studies show that periodontitis is closely associated with cognitive impairment (CI) and Alzhemer’s Disease (AD). Further, studies using animal model of periodontitis and human post-mortem brain tissues from subjects with AD strongly suggest that a gram-negative periodontal pathogen, Porphyromonas gingivalis (Pg) and/or its product gingipain is/are translocated to the brain. However, neuropathology resulting from Pg oral application is not known. In this work, we tested the hypothesis that repeated exposure of wild type C57BL/6 mice to orally administered Pg results in neuroinflammation, neurodegeneration, microgliosis, astrogliosis and formation of intra- and extracellular amyloid plaque and neurofibrillary tangles (NFTs) which are pathognomonic signs of AD.MethodsExperimental chronic periodontitis was induced in ten wild type 8-week old C57BL/6 WT mice by repeated oral application (MWF/week) of Pg/gingipain for 22 weeks (experimental group). Another 10 wild type 8-week old C57BL/6 mice received vehicle alone (control group) MWF per week for 22 weeks. Brain tissues were collected and the presence of Pg/gingipain was determined by immunofluorescence (IF) microscopy, confocal microscopy, and quantitative PCR (qPCR). The hippocampi were examined for the signs of neuropathology related to AD: TNFα, IL1β, and IL6 expression (neuroinflammation), NeuN and Fluoro Jade C staining (neurodegeneration) and amyloid beta1-42 (Aβ42) production and phosphorylation of tau protein at Ser396 were assessed by IF and confocal microscopy. Further, gene expression of amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), a disintegrin and metalloproteinase domain-containing protein10 (ADAM10) for α-secretase and presenilin1 (PSEN1) for ɣ-secretase, and NeuN (rbFox3) were determined by RT-qPCR. Microgliosis and astrogliosis were also determined by IF microscopy.ResultsPg/gingipain was detected in the hippocampi of mice in the experimental group by immunohistochemistry, confocal microscopy, and qPCR confirming the translocation of orally applied Pg to the brain. Pg/gingipain was localized intra-nuclearly and peri-nuclearly in microglia (Iba1+), astrocytes (GFAP+), neurons (NeuN+) and was evident extracellularly. Significantly greater levels of expression of IL6, TNFα and IL1β were evident in experimental as compared to control group (p<0.01, p<0.00001, p<0.00001 respectively). In addition, microgliosis and astrogliosis were evident in the experimental but not in control group (p <0.01, p<0.0001 respectively). Neurodegeneration was evident in the experimental group based on a fewer number of intact neuronal cells assessed by NeuN positivity and rbFOX3 gene expression, and there was a greater number of degenerating neurons in the hippocampi of experimental mice assessed by Fluoro Jade C positivity. APP and BACE1 gene expression were increased in experimental group compared with control group (p<0.05, p<0.001 respectively). PSEN1 gene expression was higher in ex...

Objective-Restricted and repetitive behaviors, and a pronounced preference for behavioral and environmental consistency, are distinctive characteristics of autism spectrum disorders (ASD). Whether these clinical features of ASD are related to fundamental neuropsychological impairments in behavioral flexibility remains to be clarified.Method-Forty-one individuals with ASD and 37 matched controls performed a probabilistic reversal learning task to assess behavioral flexibility. Participants learned to choose the correct stimulus location from a pair of locations to win points (acquisition). After making the correct choice over multiple trials, the rewarded stimulus location changed without warning (reversal). Feedback was provided on an 80:20 probabilistic schedule, with 80% of correct choices and 20% of incorrect choices randomly reinforced.Results-ASD and control participants performed comparably during acquisition. At reversal, ASD participants initially chose the new correct location as quickly as controls, but then more frequently reverted back to the previously preferred response. The ASD group also more frequently shifted back to the previous response choice immediately following intermittent nonreinforcement of the new correct response. The number of regressive errors was positively correlated with independently ascertained clinical ratings of restricted and repetitive behaviors, but not other core features of ASD.Conclusions-Restricted and repetitive behaviors in ASD are associated with neurocognitive deficits in flexible choice behavior. Preclinical research has established that frontostriatal circuitry supports flexibility on reversal learning tasks. Thus, alterations in this circuitry may contribute to behavioral rigidity in ASD and represent a target for therapeutic intervention.Correspondence concerning this article should be addressed to John A. Sweeney, UT Southwestern Medical Center, 5323 Harry Hines Blvd. M/C 9086, Dallas, TX 75390-9086. John.Sweeney@utsouthwestern.edu. NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2014 March 01. . Understanding of the latter symptom domain remains limited, despite it contributing significantly to clinical distress and behavioral problems (Bishop, Richler, Cain, & Lord, 2007;South, Ozonoff, & McMahon, 2005). Clarifying the cognitive bases of behavioral rigidity in ASD has the potential to provide clues as to its pathophysiology, improve its clinical assessment, and guide development of new treatments that can alleviate this core feature of ASD.One possibility is that a specific impairment in the ability to transition away from preferred behaviors to new, more adaptive ones contributes to the occurrence of restrictive and repetitive behaviors. Some prior studies suggest that these behaviors are related to broad deficits in executive function and cognitive control in ASD (Lopez, Lincoln, Ozonoff, & Lai, 2005;Mosconi et al., 2009). However, results are inconsistent, and the specific cognitive impairments that may con...

Several lines of evidence indicate that a modest increase in circulating glucose levels enhances memory. One mechanism underlying glucose effects on memory may be an increase in acetylcholine (ACh) release. The present experiment determined whether enhancement of spontaneous alternation performance by systemic glucose treatment is related to an increase in hippocampal ACh output. Samples of extracellular ACh were assessed at 12-min intervals using in vivo microdialysis with HPLC-EC. Twenty-four minutes after an intraperitoneal injection of saline or glucose (100, 250, or 1000 mg/kg), rats were tested in a four-arm cross maze for spontaneous alternation behavior combined with microdialysis collection. Glucose at 250 mg/kg, but not 100 or 1000 mg/kg, produced an increase in spontaneous alternation scores (69.5%) and ACh output (121.5% versus baseline) compared to alternation scores (44.7%) and ACh output (58.9%o versus baseline) of saline controls. The glucose-induced increase in alternation scores and ACh output was not secondary to changes in locomotor activity. Saline and glucose (100-1000 mg/kg) treatment had no effect on hippocampal ACh output when rats remained in the holding chamber. These findings suggest that glucose may enhance memory by directly or indirectly increasing the release ofACh. The results also indicate that hippocampal ACh release is increased in rats performing a spatial task. Moreover, because glucose enhanced ACh output only during behavioral testing, circulating glucose may modulate ACh release only under conditions in which cholinergic cells are activated.

These experiments examined the effects of dorsomedial striatal inactivation on the acquisition of a response and visual cue discrimination task, as well as a shift from a response to a visual cue discrimination, and vice versa. In Experiment 1, rats were tested on the response discrimination task followed by the visual cue discrimination task. In Experiment 2, the testing order was reversed. Infusions of 2% tetracaine did not impair acquisition of the response or visual cue discrimination but impaired performance when shifting from a response to a visual cue discrimination, and vice versa. Analysis of the errors revealed that the deficit was not due to perseveration of the previously learned strategy, but to an inability to maintain the new strategy. These results contrast with findings indicating that prelimbic inactivation impairs behavioral flexibility due to perseveration of a previously learned strategy. Thus, specific circuits in the prefrontal cortex and striatum may interact to enable behavioral flexibility, but each region may contribute to distinct processes that facilitate strategy switching.There have been several different theories regarding the function of the striatum in learning and memory over the past several

This study examined the effects of a dopamine D 1 antagonist, SCH23390, infused into the prelimbicinfralimbic areas on the acquisition of a response and visual-cue discrimination task, as well as a shift from a response to a visual-cue discrimination and vice versa. Each test was carried out in a cross-maze. The response discrimination required learning to always turn in the same direction (right or left) for a cereal reinforcement. The visual-cue discrimination required learning to always enter the arm with the visual cue. In experiment 1, rats were tested on the response discrimination task, followed by the visual-cue discrimination task. In experiment 2, the testing order was reversed. Bilateral infusions of SCH23390 (0.1 or 1 µg/0.5 µL) into the prelimbic-infralimbic areas did not impair acquisition of the response or visual-cue discrimination tasks. SCH23390 injections at 1 µg, but not 0.1 µg impaired performance when shifting from a response to a visual-cue discrimination, and vice versa. Analysis of the errors revealed that the deficit was due to perseveration of the previously learned strategy. These results suggest that activation of dopamine D 1 receptors in the prelimbic-infralimbic areas may be critical for the suppression of a previously relevant strategy and/or generating new strategies.There is accumulating evidence that separate prefrontal cortex regions influence distinct cognitive functions (Kolb et al. 1974;Eichenbaum et al. 1983;Seamans et al. 1995;Delatour and Gisquet-Verrier 1996Goldman-Rakic 1996;Kesner et al. 1996;Petrides 1996;Bussey et al. 1997;DeCoteau et al. 1997;Ragozzino et al. 1998Ragozzino et al. , 1999b GisquetVerrier et al. 2000;Kesner 2000;Ragozzino and Kesner 2001). Experiments in nonhuman primates have shown that different prefrontal cortex areas contribute to separate forms of cognitive flexibility (Dias et al. 1996(Dias et al. , 1997. Lesions of the lateral prefrontal cortex produce a selective impairment in extra-dimensional shifts for a visual-cue discrimination task (e.g., learning to make a choice based on shape, then learning to make a choice based on lines). However, lateral prefrontal cortex lesions do not impair reversal learning (e.g., learning to always choose a red object but not a blue object, then learning to choose the opposite colored object). Conversely, lesions of the orbital prefrontal cortex impair reversal learning but not extra-dimensional shifts (Dias et al. 1996(Dias et al. , 1997. Taken together, the evidence suggests that the lateral prefrontal cortex and orbital prefrontal cortex regions differentially contribute to cognitive flexibility based on the type of task demands.The findings from several studies in rodents suggest that the medial prefrontal cortex plays a critical role in behavioral flexibility (deBruin et al. 1994; Aggleton et al. 1995;Granon and Poucet 1995;Bussey et al. 1997;Joel et al. 1997; Ragozzino et al. 1999a,b;Birrell and Brown 2000;Delatour and Gisquet-Verrier 2000;Dias and Aggleton 2000). Recently, a series of experiments foun...

Phasic changes in dopamine activity play a critical role in learning and goal-directed behavior. Unpredicted reward and reward predictive cues evoke phasic increases in the firing rate of the majority of midbrain dopamine neurons – results that predict uniformly broadcast increases in dopamine concentration throughout the striatum. However, measurement of dopamine concentration changes during reward has cast doubt on this prediction. We systematically measured phasic changes in dopamine in four striatal subregions (nucleus accumbens shell (Shell) and core (Core), dorsomedial (DMS) and dorsolateral striatum (DLS)) in response to stimuli known to activate a majority of dopamine neurons. We used fast-scan cyclic voltammetry in awake and behaving rats, which measures changes in dopamine on a similar timescale to the electrophysiological recordings that established a relationship between phasic dopamine activity and reward. Unlike the responses of midbrain dopamine neurons, unpredicted food reward and reward-predictive cues evoked a phasic increase in dopamine that was subregion specific. In rats with limited experience, unpredicted food reward evoked an increase exclusively in the Core. In rats trained on a discriminative stimulus paradigm, both unpredicted reward and reward-predictive cues evoked robust phasic dopamine in the Core and DMS. Thus, phasic dopamine release in select target structures is dynamic and dependent on context and experience. Since the four subregions assayed receive different inputs and have differential projection targets, the regional selectivity of phasic changes in dopamine has important implications for information flow through the striatum and plasticity that underlies learning and goal-directed behavior.