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The retrosplenial cortex (RSP) and the posterior parietal cortex (PPC) are the primary sources of cortical sensory input to the postrhinal cortex (POR) in rodents. Together, these areas compose a major corticohippocampal circuit that is involved in processing visuospatial information. The POR has been implicated in contextual learning and memory, consistent with the type of information presumably being processed by this region. By comparison, little is known about the role of the RSP or the PPC in contextual learning. In the present study, rats were trained either before or after surgery in a standard signaled fear conditioning task in which an auditory cue was paired with foot shock. Contextual fear and tone-specific fear were assessed in subsequent test sessions. In Experiment 1, electrolytic damage to the RSP either before or immediately after training impaired the expression of contextual fear but not tone-specific fear. In contrast, electrolytic damage to the PPC had no effect on conditional fear to the context or the tone in Experiment 2. These findings indicate that the RSP, but not the PPC, contributes to the processing of contextual information by the POR corticohippocampal processing stream. [ABSTRACT FROM AUTHOR]

The role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information was examined with Pavlovian fear conditioning. Rats with electrolytic or neurotoxic lesions of the POR or PER were tested in 2 contextual fear conditioning paradigms. In Experiment 1, electrolytic lesions of the POR or PER produced impairments in contextual fear conditioning but not in conditioning to a phasic auditory conditioned stimulus. Neurotoxic lesions of the POR or PER likewise resulted in anterograde (Experiment 2) and retrograde (Experiment 3) deficits in fear conditioning to the training context in an unsignaled shock paradigm. The results suggest that operations performed on sensory information by the POR and PER are necessary to support contextual learning. [ABSTRACT FROM AUTHOR]

Technological advances over the last decade are changing the face of behavioral neuroscience research. Here we review recent work on the use of one such transformative tool in behavioral neuroscience research, chemogenetics (or Designer Receptors Exclusively Activated by Designer Drugs, DREADDS). As transformative technologies such as DREADDs are introduced, applied, and refined, their utility in addressing complex questions about behavior and cognition becomes clear and exciting. In the behavioral neuroscience field, remarkable new findings now regularly appear as a result of the ability to monitor and intervene in neural processes with high anatomical precision as animals behave in complex task environments. As these new tools are applied to behavioral questions, individualized procedures for their use find their way into diverse labs. Thus, "tips of the trade" become important for wide dissemination not only for laboratories that are using the tools but also for those who are interested in incorporating them into their own work. Our aim is to provide an up-to-date perspective on how the DREADD technique is being used for research on learning and memory, decision making, and goal-directed behavior, as well as to provide suggestions and considerations for current and future users based on our collective experience. [ABSTRACT FROM AUTHOR]

Male and female Long-Evans rats were tested in the Morris water maze at 6 months of age. A place training procedure, in which rats learned the position of a camouflaged platform, was followed by cue training, in which rats escaped to a visible platform. No sex difference was found in place learning ability. Search accuracy on probe trials, when the platform was unavailable, was also equivalent for the male and female groups. These results contrast with previous studies of rodents at younger ages, which have reported a male advantage in spatial learning. It is suggested that the age at which rats are assessed may be an important factor, possibly reflecting a different course in the relatively protracted maturation of the hippocampus in male and female rats. The results of this investigation are also discussed with reference to studies of sex differences for spatial abilities in humans. [ABSTRACT FROM AUTHOR]

During adolescence, individuals experience a broad range of dynamic environments as they strive to establish independence. Learning to respond appropriately in both new and previously encountered environments requires that an individual identify and learn the meaning of cues indicating that a behavior is appropriate, or alternatively, that it should be altered or inhibited. Although the ability to regulate goal-directed behavior continues to develop across adolescence, the specific circumstances under which adolescents experience difficulty with inhibitory control remain unclear. Here we review recent findings in our laboratory that address how adolescents learn to proactively inhibit a response. Much of our research has utilized a negative occasion setting paradigm, in which one cue (a feature) gates the meaning of a second cue (a target). The feature provides information that resolves the ambiguity of the target and indicates the appropriate behavioral response to the target. As such, we have been able to determine how adolescents learn about ambiguous stimuli, such as those whose meaning changes in accordance with other features of the surrounding environment. We consider why adolescents in particular exhibit difficulty in negative occasion setting compared to either pre-adolescents or adults. In addition, we review findings indicating that a balance in neural activity between orbitofrontal cortex and nucleus accumbens is necessary to support normal negative occasion setting. Finally, we consider aspects of associative learning that may contribute to adolescent inhibitory control, as well as provide insight into adolescent behavior as a whole. [ABSTRACT FROM AUTHOR]

Prior findings indicate that adolescent rats exhibit difficulty using negative occasion setters to guide behavior compared to adult rats (Meyer and Bucci, 2014). Here, additional groups of juvenile rats were trained in the same negative occasion setting procedure to further define the development of negative occasion setting. Beginning on either postnatal day (PND) 30, 40, or 50, rats received daily training sessions in which a tone was paired with food reinforcement on some trials, while on other trials a light preceded the tone and no reinforcement was delivered. We found that rats that began training on PND 50 required 10 training sessions to discriminate between the two types of trials, consistent with prior findings with young adult rats. Interestingly, rats in the PND 30 group (pre-adolescents) also required just 10 training sessions, in stark contrast to adolescent rats that began training on PND 35 (adolescents) and required 18 sessions (Meyer and Bucci, 2014). Rats that began training on PND 40 (adolescents) also required more sessions than the PND 30 group. These data indicate that the development of negative occasion setting is non-linear and have direct bearing on understanding the behavioral and neural substrates that underlie suboptimal behavioral control in adolescents. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that adolescents exhibit heightened sensitivity to rewards and reward-related cues compared to adults, and that adolescents are often unable to exert behavioral control in the face of such cues. Moreover, differences in reward processing during adolescence have been linked to heightened risk taking and impulsivity. However, little is known about the processes by which adolescents learn about the appetitive properties of environmental stimuli that signal reward. To address this, Pavlovian conditioning procedures were used to test for differences in excitatory conditioning between adult and adolescent rats using various schedules of reinforcement. Specifically, separate cohorts of adult and adolescent rats were trained under conditions of consistent (continuous) or intermittent (partial) reinforcement. We found that the acquisition of anticipatory responding to a continuously-reinforced cue proceeded similarly in adolescents and adults. In contrast, responding increased at a greater rate in adolescents compared to adults during presentations of a partially-reinforced cue. We subsequently compared the ability of adolescent and adult rats to dynamically adjust the representation of a reward-predictive cue during extinction trials, in which a secondary inhibitory representation is acquired for the previously-reinforced stimulus. We observed significant age differences in the ability to flexibly update cue representations during extinction, in that the appetitive properties of cues with a history of either continuous or partial reinforcement persisted to a greater extent in adolescents relative to adults. [ABSTRACT FROM AUTHOR]

Summary Contemporary models of behavioral regulation maintain that balanced activity between cognitive control areas (prefrontal cortex, PFC) and subcortical reward-related regions (nucleus accumbens, NAC) mediates the selection of appropriate behavioral responses, whereas imbalanced activity (PFC < NAC) results in maladaptive behavior [ 1–6 ]. Imbalance can arise from reduced engagement of PFC (via fatigue or stress [ 7 ]) or from excessive activity in NAC [ 8 ]. Additionally, a concept far less researched is that an imbalance can result from simultaneously low PFC activity and high NAC activity. This occurs during adolescence, when the maturation of PFC lags behind that of NAC and NAC is more functionally active compared to adulthood or pre-adolescence [ 2, 5, 9, 10 ]. Accordingly, activity is disproportionately higher in NAC than in PFC, which may contribute to impulsivity and risk-taking exhibited by adolescents [ 5, 6, 10–12 ]. Despite having explanatory value, support for this notion has been solely correlational. Here, we causally tested this using chemogenetics to simultaneously decrease neural activity in the orbitofrontal cortex (OFC) and increase activity in NAC in adult rats, mimicking the imbalance during adolescence. We tested the effects on negative occasion setting, an important yet understudied form of inhibitory learning that may be particularly relevant during adolescence. Rats with combined manipulation of OFC and NAC were impaired in learning to use environmental cues to withhold a response, an effect that was greater than that of either manipulation alone. These findings provide direct evidence that simultaneous underactivity in OFC and overactivity in NAC can negatively impact behavioral control and provide insight into the neural systems that underlie inhibitory learning. [ABSTRACT FROM AUTHOR]

Technological advances over the last decade are changing the face of behavioral neuroscience research. Here we review recent work on the use of one such transformative tool in behavioral neuroscience research, chemogenetics (or Designer Receptors Exclusively Activated by Designer Drugs, DREADDS). As transformative technologies such as DREADDs are introduced, applied, and refined, their utility in addressing complex questions about behavior and cognition becomes clear and exciting. In the behavioral neuroscience field, remarkable new findings now regularly appear as a result of the ability to monitor and intervene in neural processes with high anatomical precision as animals behave in complex task environments. As these new tools are applied to behavioral questions, individualized procedures for their use find their way into diverse labs. Thus, "tips of the trade" become important for wide dissemination not only for laboratories that are using the tools but also for those who are interested in incorporating them into their own work. Our aim is to provide an up-to-date perspective on how the DREADD technique is being used for research on learning and memory, decision making, and goal-directed behavior, as well as to provide suggestions and considerations for current and future users based on our collective experience. [ABSTRACT FROM AUTHOR]

The retrosplenial cortex (RSC) is reciprocally connected with the hippocampus and various parahippocampal cortical regions, suggesting that RSC is well-positioned to contribute to hippocampal-dependent memory. Consistent with this, substantial behavioral evidence indicates that RSC is essential for consolidating and/or retrieving contextual and spatial memories. In addition, there is growing evidence that RSC neurons undergo activity-dependent plastic changes during memory formation and retrieval. In this paper we review both the behavioral and cellular/molecular data and posit that the RSC has a particularly important role in the storage and retrieval of spatial and contextual memories perhaps due its involvement in binding together multiple cues in the environment. We identify remaining questions and avenues for future research that take advantage of emerging methods to selectively manipulate RSC neurons both spatially and temporally and to image the RSC in awake, behaving animals. [ABSTRACT FROM AUTHOR]

A wealth of data supports the notion that the hippocampus binds objects and events together in place and time. In support of this function, a cortical circuit that includes the retrosplenial cortex (RSC) and various structures in the parahippocampal region is thought to provide the hippocampus with essential information regarding the physical and temporal context in which the object/event occurs. However, it remains unclear if and how individual components of this so-called ‘where’ circuit make unique contributions to processing context-related information. Here we focus on the RSC and the postrhinal cortex (POR; homologous with parahippocampal cortex (PHC) in primates), two of the most strongly interconnected components of the where pathway and the foci of an increasing amount of recent research. Much of the behavioral evidence to date suggests that RSC and POR/PHC work closely together as a functional unit. We begin by briefly reviewing studies that have investigated the involvement of RSC and POR/PHC in contextual and spatial learning, both of which involve learning associations and relationships between the individual stimuli that compose an environment (i.e., where information). However, we propose that potential differences have been overlooked because most studies to date have relied on behavioral paradigms and experimental approaches that are not well suited for distinguishing between different aspects of information processing. We then consider the anatomical differences between RSC and POR/PHC and emerging behavioral evidence that gives rise to a working model of how these regions may differentially contribute to hippocampal-dependent learning and memory. We then discuss experimental designs and behavioral methods that may be useful in testing the model. Finally, approaches are described that may be valuable in probing the nature of information processing and neuroplasticity in the myriad of local circuits that are nested within the where pathway. [ABSTRACT FROM AUTHOR]

This study determined the duration of exercise and amount of methylphenidate that is needed to affect attentional function and social behavior in spontaneously hypertensive rats (SHR), a commonly used animal model of Attention-Deficit/Hyperactivity Disorder (ADHD). Attention was assessed by measuring the orienting response to repeated presentations of a nonreinforced visual cue. Social behavior was examined by allowing rats to freely explore a large arena containing an unfamiliar conspecific rat. Consistent with their hyper-responsive phenotype, nonexercising SHRs exhibited a high level of orienting behavior and little habituation, as well as hyper-social behavior compared with normo-active rats. Exercise or methylphenidate decreased orienting behavior and social behavior in a dose-dependent fashion. In addition, we found an additive effect of combining doses of exercise and methylphenidate that alone were ineffective in altering behavior. These data indicate that physical exercise and methylphenidate can reduce hyper-responsiveness to irrelevant stimuli and reduce hyper-social behavior in SHR. Moreover, subthreshold doses of methylphenidate can be used in combination with moderate amounts of exercise to reduce distractibility, supporting the notion that exercise may be useful as an adjunctive or replacement therapy in ADHD. [ABSTRACT FROM AUTHOR]

Few studies have considered the process by which individuals learn to omit a response, which is an essential aspect of adaptive behavior. Several lines of evidence indicate that two regions of the medial prefrontal cortex have disparate roles in behavioral flexibility. In particular, the prelimbic cortex (PL) is thought to facilitate the generation of a strategy to inhibit a prepotent response, whereas the infralimbic cortex (IL) appears to be more important for maintaining extensively trained inhibitory behaviors. The present experiments were designed to elucidate the contributions of PL and IL to the acquisition and maintenance of Pavlovian conditioned inhibition. In Experiment 1, damage to PL before training in a compound feature negative discrimination task impaired inhibitory learning. By comparison, lesions of IL had little effect. In Experiment 2, lesions of PL or IL occurred after overtraining, and damage to IL significantly impaired subsequent performance in the task, suggesting that this region is involved in the continued expression of Pavlovian conditioned inhibition after thorough training. PL may also be involved in maintaining inhibition, as evidenced by a marginally significant lesion-induced performance deficit. These data support the notion that PL and IL have distinguishable roles in modulating inhibition, while contributing important information about the specific role for PL in acquisition of an inhibitory response and IL in performance. [ABSTRACT FROM AUTHOR]

The advent of the selective cholinergic toxin, 192 IgG-saporin, dramatically shaped subsequent research on the role of the basal forebrain in learning and memory. In particular, several articles (including the authors' 1995 Behavioral Neuroscience paper; M. G. Baxter, D. J. Bucci, L. K., Gorman, R. G. Wiley, & M. Gallagher, 1995) revealed that selective removal of basal forebrain cholinergic neurons had surprisingly little effect on spatial learning and memory. Here, as part of the series commemorating the 30th anniversary of Behavioral Neuroscience, we describe how our earlier findings prompted a reconsideration of the cholinergic contribution to cognitive function and also led to several new research directions, including renewed interest in basal forebrain GABA-ergic neurons and cholinergic contributions to neurocognitive development. The authors also describe how the successful use of 192 IgG-saporin led to the development and popularity of a wide range of selective new neurotoxic agents. Finally, they consider the utility of the permanent lesion approach in the wake of new transgenic and optogenetic methods. [ABSTRACT FROM AUTHOR]

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory. [ABSTRACT FROM AUTHOR]

The hippocampus plays a central role in spatial and contextual learning and memory, however relatively little is known about the specific contributions of parahippocampal structures that interface with the hippocampus. The postsubiculum (PoSub) is reciprocally connected with a number of hippocampal, parahippocampal and subcortical structures that are involved in spatial learning and memory. In addition, behavioral data suggest that PoSub is needed for optimal performance during tests of spatial memory. Together, these data suggest that PoSub plays a prominent role in spatial navigation. Currently it is unknown whether the PoSub is needed for other forms of learning and memory that also require the formation of associations among multiple environmental stimuli. To address this gap in the literature we investigated the role of PoSub in Pavlovian fear conditioning. In Experiment 1 male rats received either lesions of PoSub or Sham surgery prior to training in a classical fear conditioning procedure. On the training day a tone was paired with foot shock three times. Conditioned fear to the training context was evaluated 24 hr later by placing rats back into theconditioning chamber without presenting any tones or shocks. Auditory fear was assessed on the third day by presenting the auditory stimulus in a novel environment (no shock). PoSub-lesioned rats exhibited impaired acquisition of the conditioned fear response as well as impaired expression of contextual and auditory fear conditioning. In Experiment 2, PoSub lesions were made 1 day after training to specifically assess the role of PoSub in fear memory. No deficits in the expression of contextual fear were observed, but freezing to the tone was significantly reduced in PoSub-lesioned rats compared to shams. Together, these results indicate that PoSub is necessary for normal acquisition of conditioned fear, and that PoSub contributes to the expression of auditory but not contextual fear memory. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Previous studies indicate that physical exercise improves contextual fear memory, as evidenced by increased freezing behavior when rats are returned to a training environment that was initially paired with footshock. However, freezing behavior could also be affected by fatigue, especially because rats were tested shortly after the end of the dark cycle, which is when most wheel running was likely to occur. In addition, exercise has been shown to have anxiolytic effects, further confounding interpretation of the effects of exercise on cognition when using aversive conditioning tasks. These factors were examined in the present study by comparing freezing behavior in exercising and nonexercising rats that were tested at different times in the light cycle. In addition, all rats were tested on an elevated plus maze to assess anxiety-like behavior and in an open-field apparatus to measure locomotor activity in order to directly examine interactions between freezing, anxietylike behavior, and locomotion. Consistent with prior studies, exercising rats exhibited more context freezing than did sedentary rats when tested early in the light cycle. However, the opposite pattern of results was obtained when testing occurred late in the light cycle, an effect driven by a difference in the amount of freezing exhibited by the sedentary control groups. Indeed, the levels of context freezing exhibited by exercising rats were comparable regardless of when the rats were tested during the light cycle. These data have implications for interpreting the effects of exercise on aversive conditioning. [ABSTRACT FROM AUTHOR]

Abstract: Physical exercise induces widespread neurobiological adaptations and improves learning and memory. Most research in this field has focused on hippocampus-based spatial tasks and changes in brain-derived neurotrophic factor (BDNF) as a putative substrate underlying exercise-induced cognitive improvements. Chronic exercise can also be anxiolytic and causes adaptive changes in stress-reactivity. The present study employed a perirhinal cortex-dependent object recognition task as well as the elevated plus maze to directly test for interactions between the cognitive and anxiolytic effects of exercise in male Long Evans rats. Hippocampal and perirhinal cortex tissue was collected to determine whether the relationship between BDNF and cognitive performance extends to this non-spatial and non-hippocampal-dependent task. We also examined whether the cognitive improvements persisted once the exercise regimen was terminated. Our data indicate that 4weeks of voluntary exercise every-other-day improved object recognition memory. Importantly, BDNF expression in the perirhinal cortex of exercising rats was strongly correlated with object recognition memory. Exercise also decreased anxiety-like behavior, however there was no evidence to support a relationship between anxiety-like behavior and performance on the novel object recognition task. There was a trend for a negative relationship between anxiety-like behavior and hippocampal BDNF. Neither the cognitive improvements nor the relationship between cognitive function and perirhinal BDNF levels persisted after 2weeks of inactivity. These are the first data demonstrating that region-specific changes in BDNF protein levels are correlated with exercise-induced improvements in non-spatial memory, mediated by structures outside the hippocampus and are consistent with the theory that, with regard to object recognition, the anxiolytic and cognitive effects of exercise may be mediated through separable mechanisms. [ABSTRACT FROM AUTHOR]

The medial prefrontal cortex of rats has a role in many aspects of cognitive function, including forms of inhibitory learning. Recent studies suggest that there is heterogeneity in the contributions of the prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex to response inhibition. The present study tested the effects of separate neurotoxic lesions of the PL or IL on a serial feature negative discrimination task (negative occasion setting). Rats received training sessions consisting of 16 trials: on 4 trials in each session, a tone was presented and followed by food reward; on the other 12 trials the tone was preceded by a visual stimulus and not reinforced, The results indicate that PL but not IL is necessary for learning the discrimination. We then tested the effects of these lesions on rats that were fast extensively trained in the task. Rats that had been trained for 30 days before receiving PL or IL lesions were still able to perform the task as well as controls after surgery. Thus, PL lesions disrupt acquisition but not performance of a serial feature negative discrimination. [ABSTRACT FROM AUTHOR]

ACh release into the rodent prefrontal cortex is predictive of successful performance of cue detection tasks, yet the cellular mechanisms underlying cholinergic modulation of cortical function are not fully understood. Prolonged ("tonic") muscarinic ACh receptor (mAChR) activation increases the excitability of cortical pyramidal neurons, whereas transient ("phasic") mAChR activation generates inhibitory and/or excitatory responses, depending on neuron subtype. These cholinergic effects result from activation of "M1-like" mAChRs (M1, M3, and M5 receptors), but the specific receptor subtypes involved are not known. We recorded from cortical pyramidal neurons from wild-type mice and mice lacking M1, M3, and/or M5 receptors to determine the relative contribution of M1-like mAChRs to cholinergic signaling in the mouse prefrontal cortex. Wild-type neurons in layer 5 were excited by tonic mAChR stimulation, and had biphasic inhibitory followed by excitatory, responses to phasic ACh application. Pyramidal neurons in layer 2/3 were substantially less responsive to tonic and phasic cholinergic input. Cholinergic effects were largely absent in neurons from mice lacking M1 receptors, but most were robust in neurons lacking M3, M5, or both M3 and M5 receptors. The exception was tonic cholinergic suppression of the afterhyperpolarization in layer 5 neurons, which was absent in cells lacking either M1 or M3 receptors. Finally, we confirm a role for M1 receptors in behavior by demonstrating cue detection deficits in M1-lacking mice. Together, our results demonstrate that M1 receptors facilitate cue detection behaviors and are both necessary and sufficient for most direct effects of ACh on pyramidal neuron excitability. [ABSTRACT FROM AUTHOR]

Abstract: Mounting evidence indicates that the retrosplenial cortex (RSP) has a critical role in spatial navigation. The goal of the present study was to characterize the specific nature of spatial memory deficits that are observed following damage to RSP. Rats with RSP lesions or sham lesions were first trained in a working memory task using an 8-arm radial arm maze. Rats were allowed 5min to visit each arm and retrieve food pellets and a 5-s delay was imposed between arm choices. Consistent with previous research, rats with RSP damage committed more errors than controls. In particular, RSP-lesioned rats committed more errors of omission (failing to visit an arm of the maze), but there were no lesion effects on errors of commission (revisiting an arm). Neither group of rats exhibited a turn bias (i.e., always turning a certain direction when choosing an arm). At the end of the training phase of the experiment, both groups had reached asymptote and committed very few errors. In the subsequent test phase, a longer delay (30-s) was imposed during some sessions. Both control and RSP-lesioned rats continued to make few errors during sessions with the standard 5-s delay, but RSP-lesioned rats were impaired at the 30-s delay and committed more errors of commission, consistent with an increase in taxing spatial working memory. [Copyright &y& Elsevier]

Abstract: The posterior parietal cortex (PPC) of rats has most recently been defined based on patterns of thalamic and cortical connectivity. The anatomical characteristics of this area suggest that it may be homologous to the PPC of primates and contribute to similar functions. This review summarizes evidence for and against a role for the rat PPC in attention and working memory and evaluates how the function of the rat PPC compares to that of primates on these dimensions. Theories of how the rat PPC contributes to behavior are presented, including the notion that PPC may serve as an interface between attention and learning. Finally, several avenues for future research are considered. [Copyright &y& Elsevier]

The majority of research regarding contextual learning and memory has focused on the contributions of the hippocampus and related medial temporal lobe structures. However, little is known about other possible cortical contributions to these processes. Our laboratory recently demonstrated that electrolytic lesions of the retrosplenial cortex (RSP), a posterior region of cingulate cortex, impaired contextual but not cue-specific fear conditioning. The present experiments further examined the role of RSP in contextual fear memory using fiber-sparing neurotoxic lesions and both signaled and unsignaled fear conditioning paradigms. Despite comparable acquisition of the conditioned fear response, rats with neurotoxic lesions of RSP exhibited impaired contextual memory relative to control animals in both the signaled and unsignaled paradigms. These results further suggest an important role for RSP in contextual learning and memory. [ABSTRACT FROM AUTHOR]

Lesions of retrosplenial cortex (RSP) disrupt spatial and contextual learning, suggesting that RSP may have a fundamental role in processing overlapping, or simultaneously presented stimuli. If so, then RSP lesions might also be expected to disrupt learning that requires the concurrent processing of phasic conditioned stimuli. In Experiment 1, rats were trained in a compound feature negative discrimination task in which a tone was presented and immediately followed by food on some trials, while on other trials a visual stimulus was simultaneously presented along with the tone and not reinforced. Normal rats learned to discriminate between the trials but RSP-lesioned rats exhibited low levels of conditioning on both types of trials. Experiment 2 demonstrated that this effect was not simply due to a general inability to form associations, since RSP-lesioned rats exhibited normal responding when the visual stimulus was presented alone and paired with food. These findings support the view that RSP has an important role in learning that involves the processing of simultaneously presented stimuli and have implications for understanding the functional relationship between the hippocampus and RSP. [ABSTRACT FROM AUTHOR]

Abstract: Pavlovian conditioning of a visual stimulus paired with food was examined in spontaneously hypertensive rats (SHR), which are a commonly used model for Attention-Deficit/Hyperactivity Disorder (ADHD), and in Wistar rats (normoactive control). In gonadally intact rats of both strains, males spent more time in the food cup following onset of the light than did females, indicating a stronger association of the conditioned stimulus (CS) with reward. Gonadectomy carried out in adulthood affected conditioning differently in the two strains. In Wistar rats, gonadectomy had no effect on conditioned responding in females, but reduced conditioned responding in males, effectively eliminating the sex difference in behavior. This result suggests that circulating androgens in male Wistar rats normally aid conditioning in this task. In contrast, gonadectomy enhanced conditioning in both sexes in the SHR rats, indicating that androgens and/or estrogens impair conditioned associations in this strain. These data indicate that gonadal steroids can influence conditioning in rats and that the valence of steroid action on this behavior is strain-dependent. To the extent that SHR serves as a model of ADHD in humans, the influence of steroids on associative learning may play a role in the expression of ADHD-like behaviors. [Copyright &y& Elsevier]

Abstract: Few studies have addressed potential differences in the nature of cognitive impairment observed in males and females with ADHD. In Experiment 1, we examined sex differences in conditioned inhibitory behaviour in spontaneously hypertensive rats (SHR strain), a purported animal model of ADHD. Rats were presented with two types of trials during each of the 15 conditioning sessions. On some trials an auditory stimulus (a tone) was presented and followed immediately by delivery of food reward. On the remaining trials the tone was preceded by presentation of a visual stimulus and on those trials food was not delivered after the tone was presented. As training progressed, conditioned responding during presentation of the tone increased on reinforced trials and decreased during the non-reinforced trials, indicative of successful discrimination and inhibition. Overall, female SHR rats exhibited less conditioned overall food cup behaviour compared to male rats. Female SHR rats also required more training sessions until they responded significantly more during presentation of the tone on reinforced trials versus non-reinforced trials. In addition, the magnitude of the discrimination was smaller in female SHR rats compared to males. In contrast, no sex differences were observed in WKY rats (commonly-used control strain) in Experiment 2. Importantly, there were no significant sex differences in baseline activity or motivation during either experiment, indicating that performance differences could not account for the observed results. These results suggest that male and female SHR rats differ in their ability to form conditioned associations and inhibit behavioural responses and may provide a useful model for sex differences in cognitive dysfunction specific to ADHD. [Copyright &y& Elsevier]

The retrosplenial cortex (RSP) and the posterior parietal cortex (PPC) are the primary sources of cortical sensory input to the postrhinal cortex (POR) in rodents. Together, these areas compose a major corticohippocampal circuit that is involved in processing visuospatial information. The POR has been implicated in contextual learning and memory, consistent with the type of information presumably being processed by this region. By comparison, little is known about the role of the RSP or the PPC in contextual learning. In the present study, rats were trained either before or after surgery in a standard signaled fear conditioning task in which an auditory cue was paired with foot shock. Contextual fear and tone-specific fear were assessed in subsequent test sessions. In Experiment 1, electrolytic damage to the RSP either before or immediately after training impaired the expression of contextual fear but not tone-specific fear. In contrast, electrolytic damage to the PPC had no effect on conditional fear to the context or the tone in Experiment 2. These findings indicate that the RSP, but not the PPC, contributes to the processing of contextual information by the POR corticohippocampal processing stream. [ABSTRACT FROM AUTHOR]

Changes in how well a conditioned stimulus (CS) predicts future events can alter the amount of attention paid to that cue. For example, the unexpected violation of a previously established relationship between a CS and another stimulus can increase attentional processing and subsequent conditioning to that cue [ J.M. Pearce & G. Hall (1980) Psych. Rev., 106, 532–552]. Previous lesion studies have implicated the central nucleus of the amygdala (CN) and basal forebrain corticopetal cholinergic system in mediating surprise-induced changes in attention. Here, expression of the immediate-early gene c-fos was used to determine which cortical targets of the basal forebrain cholinergic system are activated during an increase in attentional processing. Consistent with previous studies, increased Fos expression was observed in the posterior parietal cortex (PPC) when a visual stimulus no longer reliably predicted occurrence of a tone. Similar results were observed in the secondary auditory cortex; however, there were no significant changes in Fos expression in other auditory or visual cortices or in other cortical association areas that have been implicated in attentional function (frontal, cingulate or retrosplenial cortex). These findings support the notion that the PPC is the primary cortical component of a neural system mediating incremental changes in attention. In addition, an increase in Fos-positive cells was detected in the substantia innominata/nucleus basalis and the CN at the time of surprise. An opposite pattern of results was observed in the basal lateral nucleus of the amygdala, providing evidence for different stimulus-processing mechanisms in regions of the amygdala. [ABSTRACT FROM AUTHOR]

The behavioral and neural mechanisms of orienting behavior have interested experimental psychologists for the last several decades. For example, in the framework of associative learning, examining the brain substrates of orienting behavior has yielded significant insight into the neural basis of attentional function and learning. The present study describes a procedure by which the orienting response to a visual stimulus (rearing on the hind legs) can be monitored automatically, and it validates the procedure by comparing data generated by the automated procedure with data generated by the typical observational procedure. The automated procedure provides an inexpensive means of obtaining immediate, online assessment of rearing behavior during a conditioning session, reduces the possibility of experimenter bias, and significantly reduces the time required to evaluate observational data. [ABSTRACT FROM AUTHOR]

Abstract: Kynurenic acid (KYNA) is a tryptophan metabolite synthesized and released by glia and recently shown to be a non-competitive antagonist of α7 nicotinic acetylcholine receptors at physiologically relevant concentrations, and NMDA receptors at higher concentrations. KYNA concentration is elevated in individuals with schizophrenia and those with Alzheimer''s disease, two populations exhibiting cholinergic-related cognitive impairments. The present study investigated the effects of elevated KYNA concentration on conditioned stimulus processing in rats. For the first 2 days of the experiment, a subset of rats received intracerebroventricular infusions of either KYNA (0.1μM) or vehicle and were either returned to the home cage or received non-reinforced presentations of a visual stimulus. All rats subsequently received presentations of the same visual stimulus followed by food reward during a 6-day training phase. In vehicle-treated rats, pre-exposure to the visual stimulus reduced orienting behaviour to the light (standing on the hind legs and orienting towards the visual stimulus) when it was later reinforced (i.e., conditioned orienting). In contrast, pre-exposure to the visual cue or 2 days of KYNA pretreatment reduced conditioned orienting behaviour. Finally, the reduction of orienting in KYNA-treated rats following pre-exposure was not as robust as in vehicle-treated rats. These results suggest that elevated KYNA levels can alter specific aspects of attentional processing of environmental stimuli and are discussed in terms of the potential contribution of KYNA to cognitive function and dysfunction. [Copyright &y& Elsevier]

The central nucleus (CN) of the amygdala and basal forebrain cholinergic projections to the posterior parietal cortex (PPC) are involved in regulating changes in attentional processing of conditioned stimuli. In a previous study, lesions of the CN produced a deficit in conditioned orienting behavior (rearing on the hind legs) when a visual stimulus was paired with food. Unconditioned orienting (rearing to nonreinforced presentations of the stimulus) and conditioned food cup behavior were unaffected. The present study examined the contribution of the PPC to attentional orienting behavior. Damage to the PPC did not affect orienting behavior but produced deficits in food cup behavior. These findings help define the specific contributions of the PPC to attentional processing and associative learning. [ABSTRACT FROM AUTHOR]

The authors used an associative learning paradigm to assess the effects of perirhinal or postrhinal damage on attentional orienting. Control rats and rats with lesions of either the perirhinal or postrhinal cortex initially displayed high levels of orienting behavior (rearing) to presentations of a light cue. Continued nonreinforced presentations resulted in normal habituation of the response. In addition, orienting reemerged in control rats, indicating increased attentional processing of the cue. This conditioned orienting did not reemerge in rats with either perirhinal or postrhinal lesions, providing direct evidence that the rat perirhinal and postrhinal cortices each play a role in attention. These results are consistent with an emerging view that some structures within the medial temporal lobe have nonmnemonic functions. [ABSTRACT FROM AUTHOR]

Examines the effect of postrhinal (POR) cortex damage on contextual fear discrimination. Importance of POR in configural learning of contextual fear; Impairment of acquisition and expression of contextual fear; Role of POR in mnemonic processing of stimuli.

Features a study which examined the role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information with Pavlovian fear conditioning. Role of the operations performed on sensory information by the POR and PER; Methodology; Results and discussion.

Focuses on a study which indicated the changes in attentional processing of conditioned stimuli by the regulation of the cholinergic system and basal forebrain. Information on the relation between the cholinergic system amd altered processing of conditioned stimuli; Discussion and analysis.

Examines the effects of selective immunotoxic lesions of basal forebrain cholinergic neurons on place learning and memory in rats in the Morris water maze. Working memory function; Match-to-place memory task; Radioenzymatic determination of choline acetyltransferase activity; Age-related deficits in learning and memory.

Discusses the spatial learning in male and female long-Evans rats. Test in a water maze; Learning the position of a camouflaged platform; Cue training; Escape to a visible platform; Sex difference in learning ability; Maturation of the hippocampus in male and female rats.

This special issue on the cognitive functions of the retrosplenial cortex highlights progress that has been made in recent years in understanding the anatomy and function of the retrosplenial cortex in both animals and humans. The articles in this issue of Behavioral Neuroscience use a number of different approaches that together provide an up-to-date account of recent progress in understanding how the retrosplenial cortex contributes to cognition, with an emphasis on its functional role in spatial navigation and learning and memory. [ABSTRACT FROM AUTHOR]

Abstract: Kynurenic acid (KYNA) is a tryptophan metabolite that is present at high concentrations in the brains of persons with schizophrenia. This study tested the hypothesis that treatment with l-kynurenine (L-KYN), which increases KYNA concentration, would produce deficits in social behavior similar to those associated with schizophrenia. Rats treated with L-KYN throughout adolescence exhibited decreased social interaction when tested drug-free as adults. In contrast, neither acute nor chronic treatment during adulthood affected social behavior. These findings demonstrate that increases in KYNA concentration produce deficits in social behavior and that the adolescent brain is particularly susceptible to the effects of high KYNA concentration. [Copyright &y& Elsevier]

The perirhinal (PER) and postrhinal (POR) cortices, two components of the medial temporal lobe memory system, are reciprocally connected with the hippocampus both directly and via the entorhinal cortex. Damage to PER or POR before or shortly after training on a contextual fear conditioning task causes deficits in the subsequent expression of contextual fear, implicating these regions in the acquisition or expression of contextual memory. Here, we examined the contribution of PER and POR to the processing of remotely learned contextual information. Male Long-Evans rats were trained in an unsignaled contextual fear conditioning paradigm. After training, rats received bilateral neurotoxic lesions to PER or POR or sham control surgeries at three different training-to-lesion intervals: 1,28, or 100 d after training. Two weeks after surgery, lesioned and control rats were returned to the training context to assess contextual fear as measured by freezing. Rats with PER or POR damage froze significantly less in the training context than control rats but were not different from each other. The severity of the deficit did not differ across training-to- lesion intervals for any group. This pattern of deficits differs from that of posttraining hippocampal lesions, for which longer training-to- lesion intervals produce significantly more fear-conditioned contextual freezing than shorter training-to-lesion intervals. In the absence of such a retrograde gradient in the present study, our interpretation is that PER and POR have an ongoing role in the storage or retrieval of representations for context. Alternatively, these regions may be involved in a more extended consolidation process that becomes apparent beyond 100 d after learning. [ABSTRACT FROM AUTHOR]

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. [ABSTRACT FROM AUTHOR]

Extinguished responding will renew when the conditioned stimulus occurs outside the extinction context. Although studies of conditioned freezing have consistently demonstrated a role for the hippocampus in renewal, several studies have demonstrated intact renewal of conditioned suppression despite damage to the hippocampus (Frohardt, Guarraci, & Bouton, 2000; Todd, Jiang, DeAngeli, & Bucci, 2017; Wilson, Brooks, & Bouton, 1995). Because these prior studies have examined renewal when testing occurred in the original conditioning context ("Context A"), the present conditioned suppression experiments examined the role of the hippocampus when testing occurred in a context not associated with prior conditioning ("Context C"). In Experiments 1 and 2, conditioning occurred in Context A, and extinction in Context B. Renewal of conditioned suppression was observed when the extinguished conditioned stimulus (CS) was tested in Context C. However, renewal was attenuated in rats with lesions of the dorsal hippocampus (DH). Summation testing failed to detect conditioned inhibition in the extinction context, suggesting instead that the context acquired negative occasion-setting properties. Attenuated renewal was not due to an inability of DH lesioned rats to discriminate contexts (Experiment 3). These experiments thus demonstrate a role for the DH in renewal of conditioned suppression when testing occurs in a neutral context. [ABSTRACT FROM AUTHOR]

Rationale: Stress is related to cognitive impairments which are observed in most major brain diseases. Prior studies showed that the brain concentration of the tryptophan metabolite kynurenic acid (KYNA) is modulated by stress, and that changes in cerebral KYNA levels impact cognition. However, the link between these phenomena has not been tested directly so far. Objectives: To investigate a possible causal relationship between acute stress, KYNA, and fear discrimination. Methods: Adult rats were exposed to one of three acute stressors—predator odor, restraint, or inescapable foot shocks (ISS)—and KYNA in the prefrontal cortex was measured using microdialysis. Corticosterone was analyzed in a subset of rats. Another cohort underwent a fear discrimination procedure immediately after experiencing stress. Different auditory conditioned stimuli (CSs) were either paired with foot shock (CS+) or were non-reinforced (CS−). One week later, fear was assessed by re-exposing rats to each CS. Finally, to test whether stress-induced changes in KYNA causally impacted fear discrimination, a group of rats that received ISS were pre-treated with the selective KYNA synthesis inhibitor PF-04859989. Results: ISS caused the greatest increase in circulating corticosterone levels and raised extracellular KYNA levels by ~ 85%. The two other stressors affected KYNA much less (< 25% increase). Moreover, only rats that received ISS were unable to discriminate between CS+ and CS−. PF-04859989 abolished the stress-induced KYNA increase and also prevented the impairment in fear discrimination in animals that experienced ISS. Conclusions: These findings demonstrate a causal connection between stress-induced KYNA increases and cognitive deficits. Pharmacological manipulation of KYNA synthesis therefore offers a novel approach to modulate cognitive processes in stress-related disorders. [ABSTRACT FROM AUTHOR]

The retrosplenial cortex (RSC) is positioned at the interface between cortical sensory regions and the structures that compose the medial temporal lobe memory system. It has recently been suggested that 1 functional role of the RSC involves the formation of associations between cues in the environment (stimulus-stimulus [S-S] learning; Bucci & Robinson, 2014). This suggestion is based, in part, on the finding that lesions or temporary inactivation of the RSC impair sensory preconditioning. However, all prior studies examining the role of the RSC in sensory preconditioning have used cues from multiple modalities (both visual and auditory stimuli). The purpose of the present experiment was to determine whether the RSC contributes to unimodal sensory preconditioning. In the present study we found that both electrolytic and neurotoxic lesions of the RSC impaired sensory preconditioning with auditory cues. Together with previous experiments, these findings indicate that the RSC contributes to both multisensory and unimodal sensory integration, which suggests a general role for the RSC in linking sensory cues in the environment. [ABSTRACT FROM AUTHOR]

• Examines the role of the retrosplenial cortex in non-spatial learning and memory. • Describes retrosplenial connections relevant to cue-specific learning. • Suggests RSC involvement in cue-specific learning is tied to contextual processing. The retrosplenial cortex (RSC) contributes to spatial navigation, as well as contextual learning and memory. However, a growing body of research suggests that the RSC also contributes to learning and memory for discrete cues, such as auditory or visual stimuli. In this review, we summarize and assess the Pavlovian and instrumental conditioning experiments that have examined the role of the RSC in cue-specific learning and memory. We use the term cue-specific to refer to these putatively non-spatial conditioning paradigms that involve discrete cues. Although these paradigms emphasize behavior related to cue presentations, we note that cue-specific learning and memory always takes place against a background of contextual stimuli. We review multiple ways by which contexts can influence responding to discrete cues and suggest that RSC contributions to cue-specific learning and memory are intimately tied to contextual learning and memory. Indeed, although the RSC is involved in several forms of cue-specific learning and memory, we suggest that many of these can be linked to processing of contextual stimuli. [ABSTRACT FROM AUTHOR]

Although the retrosplenial cortex (RSC) is critically involved in spatial learning and memory, it appears to have more selective contributions to learning and memory for discrete cues. For example, damage to the RSC does not impair Pavlovian delay fear conditioning to a discrete auditory cue (e.g., tone), when RSC manipulation occurs just prior to, or shortly after, conditioning. In contrast, when lesions of the RSC occur following a substantial retention interval (e.g., 28 days), the RSC is necessary for retrieval of fear to the tone. Thus, the RSC makes time-dependent contributions to memory retrieval for discrete auditory cues. The purpose of the current experiment was to assess if the time-dependent involvement of the RSC in cue-specific fear memory extended to cues of other sensory modalities. Rats firsts underwent fear conditioning to a visual stimulus, and lesions of the RSC subsequently occurred 1 or 28 days later. Lesions of the RSC impaired fear expression when made 28 days after conditioning, but not when made 1 day following conditioning. Coupled with previous findings, the current results suggest the RSC is necessary for retrieval of remotely acquired cued fear memories across multiple modalities. [ABSTRACT FROM AUTHOR]

Substantial research has established that exposure to nicotine during adolescence can lead to long-term changes in neural circuitry and behavior. However, relatively few studies have considered the effects of nicotine use on cognition during this critical stage of brain development. This is significant because the influence of nicotine on cognitive performance during adolescence may contribute to the development of regular nicotine use. For example, improvements in cognitive functioning may increase the perceived value of smoking and facilitate impulses to smoke. To address this, the present research tested the effects of nicotine on a form of inhibitory learning during adolescence. Specifically, adolescent rats were exposed to nicotine as they were trained in a negative occasion setting paradigm, in which successful performance depends on learning the conditions under which it is, or is not, appropriate to respond to a target stimulus. Here, we found that nicotine administration enhances negative occasion setting in adolescents. In addition, nicotine increased the amount of orienting behavior directed toward the inhibitory stimulus, suggesting that improvements in this form of behavioral inhibition may be attributed to nicotine-induced increases in attentional processing. These results may help elucidate the factors that contribute to the onset as well as continued use of products containing nicotine during adolescence and provide insight to increase the effectiveness of interventions targeted at reducing the prevalence of adolescent smoking. [ABSTRACT FROM AUTHOR]

Cues associated with rewarding events acquire value themselves as a result of the incentive value of the reward being transferred to the cue. Consequently, presentation of a reward-paired cue can trigger reward-seeking behaviours towards the cue itself (i.e. sign-tracking). The ventral pallidum (VP) has been demonstrated to be involved in a number of motivated behaviours, both conditioned and unconditioned. However, its contribution to the acquisition of incentive value is unknown. Using a discriminative autoshaping procedure with levers, the effects of disrupting VP activity in rats on the emergence of sign-tracking was investigated using chemogenetics, i.e. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Transient disruption of VP neurons [activation of the inhibitory hM4D(Gi) DREADD through systemic injections of clozapine N-oxide (CNO) prior to each autoshaping session] impaired acquisition of sign-tracking (lever press rate) without having any effect on approach to the site of reward delivery (i.e. goal-tracking) or on the expression of sign-tracking after it was acquired. In addition, electrophysiological recordings were conducted in freely behaving rats following VP DREADD activation. The majority of VP units that were responsive to CNO injections exhibited rapid inhibition relative to baseline, a subset of CNO-responsive units showed delayed excitation, and a smaller subset displayed a mixed response of inhibition and excitation following CNO injections. It is argued that disruption of VP during autoshaping specifically disrupted the transfer of incentive value that was attributed to the lever cue, suggesting a surprisingly fundamental role for the VP in acquiring, compared with expressing, Pavlovian incentive values. [ABSTRACT FROM AUTHOR]

ABSTRACT The retrosplenial cortex (RSC) has an important role in contextual learning and memory. While the majority of experiments have focused on the physical context, the present study asked whether the RSC is involved in processing the temporal context. Rats were trained in a temporal discrimination procedure where the duration of the intertrial interval (ITI) signaled whether or not the next tone conditioned stimulus would be paired with food pellet reinforcement. When the tone was presented after a 16-min ITI it was reinforced, but when it was presented after a 4-min ITI it was not. Rats demonstrated successful discrimination in this procedure by responding more to the tone on reinforced trials than on non-reinforced trials. Pre-training electrolytic lesions of the RSC attenuated acquisition of the temporal discrimination. The results are the first to demonstrate a role for the RSC in processing temporal information and in turn extend the role of the RSC beyond the physical context to now include the temporal context. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Prior research has established that stimulating nicotinic acetylcholine receptors can facilitate learning and memory. However, most studies have focused on learning to emit a particular behavior, while little is known about the effects of nicotine on learning to withhold a behavioral response. The present study consisted of a dose response analysis of the effects of nicotine on negative occasion setting, a form of learned inhibition. In this paradigm, rats received one type of training trial in which presentation of a tone by itself was followed immediately by food reward. During the other type of trials, the tone was preceded by presentation of a light and no food was delivered after the tone. Rats gradually learned to approach the cup in anticipation of receiving food reward during presentations of the tone alone, but withheld that behavior when the tone was preceded by the light. Nicotine (0.35 mg/kg) facilitated negative occasion setting by reducing the number of sessions needed to learn the discrimination between trial types and by reducing the rate of responding on non-reinforced trials. Nicotine also increased the orienting response to the light, suggesting that nicotine may have affected the ability to withhold food cup behavior on non-reinforced trials by increasing attention to the light. In contrast to the effects of nicotine, rats treated with mecamylamine (0.125, 0.5, or 2 mg/kg) needed more training sessions to discriminate between reinforced and non-reinforced trials compared to saline-treated rats. The findings indicate that nicotinic acetylcholine receptors may be active during negative occasion setting and that nicotine can potentiate learned inhibition. [ABSTRACT FROM AUTHOR]