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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]

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]

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 posterior parietal cortex (PPC) is a component of a major cortico-hippocampal circuit that is involved in relational learning, yet the specific contribution of PPC to hippocampal-dependent learning is unresolved. To address this, two experiments were carried out to test the effects of PPC damage on tasks that involve forming associations between multiple sensory stimuli. In Experiment 1, sham or electrolytic lesions of the PPC were made before rats were tested on a three-phase sensory preconditioning task. During the first phase, half of the training trials consisted of pairings of an auditory stimulus followed by a light. During the other trials, a second auditory stimulus was presented alone. In the next phase of training, the same light was paired with food, but no auditory stimuli were presented. During the final phase of the procedure both auditory stimuli were presented in the absence of reinforcement during a single test session. As is typically observed during the test session, control rats exhibited greater conditioned responding to the auditory cue that was previously paired with light compared to the unpaired cue. In contrast, PPC-lesioned rats responded equally to both auditory cues. In Experiment 2, PPC-lesioned and control rats were trained in a compound feature negative discrimination task consisting of reinforced presentations of a tone-alone and non-reinforced simultaneous presentations of a light-tone compound stimulus. Control rats but not rats with damage to the PPC successfully learned the discrimination. Collectively, these results support the idea that the PPC contributes to relational learning involving multimodal sensory stimuli, perhaps by regulating the attentional processing of conditioned stimuli [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]

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: 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 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]

Abstract: The endocannabinoid system appears to have an important role in specific aspects of learning and memory, yet there has been no systematic study of the role of cannabinoid receptors in contextual fear conditioning. The present study examined the effects of cannabinoid CB1 receptor blockade on the acquisition, consolidation, and expression of contextual fear using the selective cannabinoid CB1 receptor antagonist AM251. AM251 produced a decrease in the expression of contextual fear when administered prior to training, testing, or both. This effect was observed when footshock was signaled by an auditory cue but not in an unsignaled shock version of the task. Moreover, blocking cannabinoid CB1 receptors had no effect on consolidation of contextual memory regardless of the conditioning paradigm. These data indicate that inhibition of cannabinoid CB1 receptors produces specific deficits in processing contextual information and that the effects of CB1 antagonists on contextual learning may differ from effects on other types of learning. [Copyright &y& Elsevier]

The effects of voluntary physical exercise on attentional function and social behavior were examined in male and female spontaneously hypertensive rats (SHR), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). Rats in the exercise groups had free access to a running wheel for 2 weeks and then all rats received nonreinforced presentations of a visual stimulus (light) during the 1st training session, followed by daily sessions in which the light was paired with food. Nonexercising male and female SHR rats exhibited more unconditioned orienting behavior than Wistar-Kyoto rats. SHRs also exhibited impaired conditioning when the light was paired with food. Exercise reduced orienting in female SHRs but not in male SHRs. In the social interaction task, nonexercising male and female SHRs interacted more with an unfamiliar rat than Wistar-Kyoto rats. Exercise reduced the number of social interactions in female SHRs but not male SHRs. There were no differences in general locomotor activity observed between the nonexercising and exercising SHRs. These data indicate that exercise may preferentially benefit female SHRs, and has implications for using exercise as an intervention for ADHD and for understanding sex differences in the effects of exercise on behavior. [ABSTRACT FROM AUTHOR]

Abstract: The effect of nicotine on conditioned inhibition was examined using a serial feature negative discrimination task. Nicotine (0.35 mg/kg) or vehicle was administered before each of the 16 training sessions. On some trials in each session, a tone was presented and followed by food reward. On other trials, the tone was preceded by a visual stimulus and not reinforced. Nicotine-treated rats exhibited greater discrimination between the two trial types as evidenced by less frequent responding during non-reinforced trials, and learned the discrimination in fewer sessions than vehicle-treated rats. In contrast, there were no group differences in responding during the reinforced trials. [Copyright &y& Elsevier]

• Damage to retrosplenial cortex produces anterograde and retrograde context amnesia. • Strong training procedures cannot overcome anterograde deficits. • The results differ from the effects of hippocampal damage using the same procedures. Contextual fear conditioning relies upon a network of cortical and subcortical structures, including the hippocampus and the retrosplenial cortex (RSC). However, the contribution of the hippocampus is parameter-dependent. For example, with "weak" training procedures, lesions of the hippocampus produce both retrograde and anterograde context amnesia. However, with "strong" training procedures (e.g., more trials and/or higher levels of footshock), lesions of the hippocampus produce retrograde context amnesia but not anterograde amnesia (Wiltgen et al., 2006). Likewise, prior studies have shown that with weak training, RSC lesions produce both retrograde and anterograde context amnesia (Keene & Bucci, 2008). The purpose of the current study was to examine the effects of RSC damage on contextual fear conditioning following strong training. In Experiment 1, lesions of the RSC resulted in both retrograde and anterograde context amnesia following strong training using the same unsignaled fear conditioning procedures described by Wiltgen et al. (2006). In Experiment 2, using a signaled fear conditioning procedure, we replicated these effects on context memory observing both retrograde and anterograde context amnesia. In contrast, there were no lesion effects on tone-fear memory. Thus, unlike lesions of the hippocampus, lesions of RSC produce both retrograde and anterograde context amnesia even when rats undergo strong fear conditioning. These findings suggest that the RSC has an essential role in contextual fear conditioning and that other systems or pathways are unable to compensate for the loss of RSC function. [ABSTRACT FROM AUTHOR]