Heidi C. Meyer

The ontogeny of learned inhibition.

Previous studies have examined the maturation of learning and memory abilities during early stages of development. By comparison, much less is known about the ontogeny of learning and memory during later stages of development, including adolescence. In Experiment 1, we tested the ability of adolescent and adult rats to learn a Pavlovian negative occasion setting task. This procedure involves learning to inhibit a behavioral response when signaled by a cue in the environment. During reinforced trials, a target stimulus (a tone) was presented and immediately followed by a food reward. On nonreinforced trials, a feature stimulus (a light) was presented 5 sec prior to the tone and indicated the absence of reward following presentation of the tone. Both adult and adolescent rats learned to discriminate between two different trial types and withhold responding when the light preceded the tone. However, adolescent rats required more sessions than adults to discriminate between reinforced and nonreinforced trials. The results of Experiment 2 revealed that adolescents could learn the task rules but were specifically impaired in expressing that learning in the form of withholding behavior on nonreinforced trials. In Experiment 3, we found that adolescents were also impaired in learning a different version of the task in which the light and tone were presented simultaneously during the nonreinforced trials. These findings add to existing literature by indicating that impairments in inhibitory behavior during adolescence do not reflect an inability to learn to inhibit a response, but instead reflect a specific deficit in expressing that learning.

Contribution of the retrosplenial cortex to temporal discrimination learning.

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.

Neural and behavioral mechanisms of proactive and reactive inhibition

Response inhibition is an important component of adaptive behavior. Substantial prior research has focused on reactive inhibition, which refers to the cessation of a motor response that is already in progress. More recently, a growing number of studies have begun to examine mechanisms underlying proactive inhibition, whereby preparatory processes result in a response being withheld before it is initiated. It has become apparent that proactive inhibition is an essential component of the overall ability to regulate behavior and has implications for the success of reactive inhibition. Moreover, successful inhibition relies on learning the meaning of specific environmental cues that signal when a behavioral response should be withheld. Proactive inhibitory control is mediated by stopping goals, which reflect the desired outcome of inhibition and include information about how and when inhibition should be implemented. However, little is known about the circuits and cellular processes that encode and represent features in the environment that indicate the necessity for proactive inhibition or how these representations are implemented in response inhibition. In this article, we will review the brain circuits and systems involved in implementing inhibitory control through both reactive and proactive mechanisms. We also comment on possible cellular mechanisms that may contribute to inhibitory control processes, noting that substantial further research is necessary in this regard. Furthermore, we will outline a number of ways in which the temporal dynamics underlying the generation of the proactive inhibitory signal may be particularly important for parsing out the neurobiological correlates that contribute to the learning processes underlying various aspects of inhibitory control.

Age differences in appetitive Pavlovian conditioning and extinction in rats

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.

Inhibitory learning is modulated by nicotinic acetylcholine receptors

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.

Negative occasion setting in juvenile rats

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.

The contribution of medial prefrontal cortical regions to conditioned inhibition.

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.

Nicotine administration enhances negative occasion setting in adolescent rats.

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.

Setting the occasion for adolescent inhibitory control

HighlightsWe review factors contributing to the ontogeny of proactive inhibition.Difficulties using negative occasion setters are specific to adolescence.Adolescents differentially integrate the meanings and contingencies of multiple cues.Adolescent behavior may be biased towards individual rather than networks of cues.A functional balance between OFC and NAC is necessary for negative occasion setting. Abstract 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.