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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]

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]

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]

• 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]

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]

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]

Abstract: The glia-derived molecule kynurenic acid (KYNA) is an antagonist of α7 nicotinic acetylcholine receptors and the glycineB binding site on NMDA receptors. KYNA levels are elevated in the brain and cerebrospinal fluid of persons with schizophrenia and Alzheimer''s disease, both of which are characterized by deficits in contextual learning and memory. The present study tested the hypothesis that increases in KYNA concentration would impair contextual fear conditioning but spare cue-specific fear conditioning. Rats in each experiment received injections of vehicle solution or l-kynurenine (L-KYN, 100mg/kg), the precursor for KYNA. Administration of L-KYN has been shown to produce clinically relevant increases in KYNA concentration. In Experiment 1, L-KYN-treated rats exhibited impaired contextual fear memory compared to control rats, while fear conditioning to a discrete auditory cue was unaffected. In Experiment 2, rats were trained to discriminate between two different training environments, one in which foot shock was delivered and one that was not paired with foot shock. Although both groups of rats eventually learned the discrimination, learning was slower in L-KYN-treated rats. The results of Experiment 3 demonstrated that the deficits in context discrimination could not be explained by the preferential use of an elemental learning strategy by L-KYN-treated rats. Together, these findings indicate that elevated concentration of endogenous KYNA interferes with contextual learning and memory and support the notion that increased concentration of KYNA may contribute to cognitive dysfunction. In addition, these data provide new insight into how novel ‘gliotransmitters’ may modulate neuronal function and behavior. [Copyright &y& Elsevier]

Abstract: Theories of the neurobiological basis of Attention-Deficit/Hyperactivity Disorder (ADHD) have largely focused on dysregulation of central dopaminergic function. However, other neurotransmitter systems may be implicated in specific cognitive deficits in ADHD. Interest in the potential involvement of nicotinic cholinergic systems in ADHD has arisen in part from the observation that adolescents and adults with ADHD smoke cigarettes at significantly higher rates than people without this disorder. In addition, several studies report that nicotine alleviates ADHD symptoms, and recent neuro-genetics studies indicate that cholinergic systems may be altered in persons with ADHD. In this review, we describe the evidence for a role of central nicotinic cholinergic systems in cognitive deficits in ADHD. We also propose mechanisms by which alterations in cholinergic function may contribute directly and/or indirectly to these deficits. Finally, we identify specific paradigms and models to guide future investigations into the specific involvement of nicotinic cholinergic systems in ADHD, possibly leading to the development of more effective pharmacotherapies for ADHD. [Copyright &y& Elsevier]

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]

Extinction of fear to a Pavlovian conditioned stimulus (CS) is known to be context-specific. When the CS is tested outside the context of extinction, fear returns, or renews. Several studies have demonstrated that renewal depends upon the hippocampus, although there are also studies where renewal was not impacted by hippocampal damage, suggesting that under some conditions context encoding and/or retrieval of extinction depends upon other regions. One candidate region is the retrosplenial cortex (RSC), which is known to contribute to contextual and spatial learning and memory. Using a conditioned-suppression paradigm, Experiment 1 tested the impact of pre-training RSC lesions on renewal of extinguished fear. Consistent with previous studies, lesions of the RSC did not impact acquisition or extinction of conditioned fear to the CS. Further, there was no evidence that RSC lesions impaired renewal, indicating that contextual encoding and/or retrieval of extinction does not depend upon the RSC. In Experiment 2, post-extinction lesions of either the RSC or dorsal hippocampus (DH) also had no impact on renewal. However, in Experiment 3, both RSC and DH lesions did impair performance in an object-in-place procedure, an index of place memory. RSC and DH contributions to extinction and renewal are discussed. [ABSTRACT FROM AUTHOR]

Abstract: This study examined the effects of a standard breast cancer chemotherapeutic protocol on learning and memory in rats. Ovariectomized rats were treated once a week for 3 weeks with a combination of cyclophosphamide and doxorubicin prior to training in a classical fear conditioning task. Training took place 1 week after the final treatment. During the training session, an auditory stimulus (a tone) was paired with a mild foot-shock. The resulting conditioned fear to the tone (cue-specific fear) and to the training environment (contextual fear) was measured in subsequent test sessions. Chemotherapy did not affect the acquisition of the conditioned response (freezing) during the training session or the expression of fear during the tone test session. In contrast, rats treated with cyclophosphamide and doxorubicin exhibited decreased freezing during the context test session, suggestive of a specific deficit in hippocampal-related learning and memory. Together, these data indicate that administration of cyclophosphamide and doxorubicin may have toxic effects on the hippocampus and results in specific learning deficits shortly after treatment has ended. [Copyright &y& Elsevier]

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]

Abstract: Hibernation is a unique and highly regulated physiological state characterized by profound, albeit periodically reversible, depression in body temperature, metabolism, and consciousness. Hippocampal synapses undergo pronounced remodeling in concert with torpor and arousal. During hibernation, the number of postsynaptic densities, apical dendritic branches, and spine densities decreases substantially in the hippocampus. Upon arousal these parameters increase beyond pre-hibernation levels and peak within 2–3h. By 24h after arousal, dendritic parameters remain elevated but have started to subside, consistent with pruning and differentiation. The present study examined the functional consequences of these natural changes in synaptic structure. Wild-caught Arctic ground squirrels (AGS) were trained in a hippocampal-dependent contextual fear conditioning task at 3h, 24h, or 4 weeks after arousal (warm-adapted euthermic control group). All groups acquired the fear conditioned response similarly on the training day. During a subsequent retention test session, AGS in the 24h group exhibited enhanced expression of contextual fear compared to the other two groups. These data suggest that the morphological and biochemical changes occurring at 24h after arousal from hibernation affect hippocampal-dependent learning and memory. The natural change in synaptic structure during hibernation may provide a unique opportunity to assess the neural substrates underlying cognitive enhancement. [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]