The Role of Basal Forebrain Cholinergic Projections to the Anterior Cingulate Cortex in Cued and Contextual Fear Conditioned Suppression Paradigms

Basal forebrain corticopetal cholinergic neurons are critical for contextual and cued fear memory in the conditioned suppression paradigm, but neural mechanisms that alter these neurons in fear memory remain unknown. Interestingly, basal forebrain cholinergic lesions have no effect on behavioral performance in commonly-studied fear conditioning paradigms like Pavlovian conditioned freezing or fear-potentiated startle, yet impair fear memory in the conditioned suppression paradigm. Many studies conducted have experimented with lesions of cell bodies of corticopetal cholinergic neurons in the nucleus basalis magnocellularis (NBM), but there is a void in the literature defining which specific projections may be responsible for their discrepant role in different fear memory paradigms. The basal forebrain projects to the anterior cingulate cortex (ACC), a subregion of the medial prefrontal cortex. The ACC is a well-established portion of the fear circuit across all fear conditioning paradigms and has a clear role in decision-making in the conditioned suppression paradigm. Given the role in choice conflict that the ACC plays in operant tasks involved in the conditioned suppression paradigm, it is plausible that it may be a region that allows basal forebrain cholinergic neurons to alter a fear memory in the conditioned suppression paradigm. The goal of this study is to examine the specific roles that basal forebrain cholinergic projections to the ACC play in fear memory, specifically in the conditioned suppression paradigm. These lesions may target specific cholinergic input to the ACC from the NBM in the basal forebrain and this may isolate a specific fear circuit involved in fear memory in the conditioned suppression paradigm. Data have suggested that ACC lesioned animals demonstrate less fear-conditioned suppression over sham animals, but further experiments and cohorts of animals are required. If ACC cholinergic lesions are shown to produce deficits in fear memory in the conditioned suppression paradigm, it may suggest that the presence of the appetitive task, which only occurs in the conditioned suppression paradigm and not in any of the other commonly studied fear paradigms, may be able to elicit changes in functional connectivity to incorporate this projection from the NBM to the ACC to the fear circuit. Discrepancies in fear memory between fear conditioning paradigms demand to be addressed because assumptions about functional connectivity across different paradigms are assumed to be similar in the literature. If the notion of paradigmdependent functional connectivity presented here is true, deductions about this functional connectivity may only be made in the context of one fear paradigm and may not necessarily be applicable across paradigms. In other words, to say that Pavlovian fear conditioning and fear-potentiated startle are indicative of the broad neurobiology of fear memory would only be looking at a fraction of the reality behind how fear circuitry operates. In order to further the literature to propose holistic circuits, molecular processes and constructs that apply to all fear memory regardless of protocol or paradigm, it is necessary to investigate neural involvement across alternative fear paradigms, like conditioned suppression. This study supports the novel idea that neural circuitry that supports fear can expand with new learning tasks or events and therefore, may be more susceptible to change than previously considered, but future studies are require