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Response inhibition is an important component of adaptive behavior. Substantial prior research has focused on reactiveinhibition, 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 proactiveinhibition, 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.

The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent.

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.

THE thalamic connectivity and basal forebrain cholinergic input to the posterior parietal cortex (PPC) of Long-Evans rats was examined using combined retrograde tracing and immunocytochemical methods. As in previous studies, the PPC could be distinguished by its input from the lateral posterior, lateral dorsal, and posterior nuclei of the thalamus, but not the lateral geniculate nucleus or ventrobasal complex. These nuclei were also observed to receive reciprocal projections from the ipsilateral PPC. Cholinergic neurons innervating the PPC were primarily localized to the substantia innominata/nucleus basalis region. The implications of these data for possible functions of the cholinergic input to PPC are discussed.

THE role of the basal forebrain cholinergic system in learning and memory has held considerable interest since the discovery of cholinergic neurodegeneration in the basal forebrain in Alzheimer's disease. Contrary to expectation, selective removal of basal forebrain cholinergic neurons projecting to either hippocampus or neocortex fails to impair learning in a spatial task widely used to study hippocampal/cortical function. If cholinergic neurons contribute to learning and memory by integrated regulation of hippocampal and cortical processing, combined removal of hippocampal and cortical cholinergic projections might be necessary to produce impairment. However, this combined lesion failed to impair spatial learning. These data argue against the view that basal forebrain cholinergic deficiency plays a prominent role in disorders of learning and memory.

Neurobiological models are important for identifying the effects of aging that contribute to cognitive decline and for developing interventions to either prevent those changes or restore more optimal function. As a starting point, this paper considers one type of approach using cholinergic deficiency within the hippocampal system as a model for age-related spatial learning impairment. It is suggested that this approach, based on producing a target lesion in the brain, is inadequate for investigating the aging process. As an alternative, a systems-level approach to the development of more useful and accurate models of neurobiological aging is advocated. Copyright 1994, 1999 Academic Press