Hippocampal and amygdalar circuitry involved in contextual fear conditioning: Identification of functional subregions of the hippocampus in anxious mice and humans

Although clinical and basic science researchers have made significant progress in understanding different types of pathological anxiety and in developing better treatments for these disorders, integration of the animal model and human literature is incomplete. Relatively little is known about structural and functional differentiation along the longitudinal axis of the hippocampus in humans, and if the functions of these subregions resemble those of the homologous hippocampal subregions studied in rodent models. Furthermore, contextual fear conditioning, a behavioral paradigm for studying learned fear of an environment, has been studied in both mice and humans, but information on the contribution of specific hippocampal subregions to this behavior is limited.;These studies demonstrate that mice lacking the 5-HT1AR have a specific deficit in a modified contextual fear conditioning paradigm that includes an ambiguous context containing some threat cues and some novel neutral cues. 5-HT1AR KO mice do not discriminate between the threatening environment and the ambiguous environment, displaying as much fear behavior in the ambiguous environment as in the threatening environment. These results suggest that the 5- HT1AR may play a role in the assessment of the threat level of a complex environment, possibly through receptors located in the amygdala or hippocampus. Quantification of the expression of 5-HT1AR mRNA along the longitudinal axis of the human hippocampus shows a high level of expression in the most anterior region of the dentate gyrus, in agreement with a previous finding of high 1AR mRNA expression in the ventral dentate gyrus of the mouse. Functional magnetic resonance imaging of brain activity in the hippocampus during free navigation in an aversively conditioned virtual environment and in a neutral environment shows activity unique to navigation in an aversive environment in the anterior-intermediate hippocampus, and activity unique to navigation in a neutral environment in the posterior hippocampus. Examination of amygdala activity during viewing of consciously and subconsciously presented fearful faces shows common activation of dorsal amygdala of subjects regardless of their trait anxiety level, and a unique site of activation in the basolateral amygdala that is positively correlated with trait anxiety while viewing subconsciously presented fearful faces. Finally, probabilistic tracking of connectivity between the amygdala and hippocampus using diffusion tensor imaging reveals a gradient of connectivity between superior amygdala-posterior hippocampus and inferior amygdala-anterior hippocampus. This pattern is distributed over a wider region of the longitudinal axis of the hippocampus in individuals with high trait anxiety, including a higher probability of connection between the anterior hippocampus and basolateral amygdala in high anxiety individuals. The peak of connection probability for both high and low anxiety subjects falls slightly anterior to the midpoint of the hippocampus, in the same region as activation found in the functional experiment group during navigation in both aversive and neutral environments.;These results are discussed in the context of the existing literature on functional specialization along the longitudinal axis of the hippocampus, and the relevance of anatomical connectivity between the amygdala and hippocampus to understanding the biological basis of normal and pathological fear behaviors. Based on the structural, functional, and receptor expression data reported here, I propose a refinement of the known contextual fear conditioning circuit to include information about the longitudinal axis of the hippocampus and subregions of the amygdala, and highlight the applicability of this model in both mice and humans. The unique structural connectivity observed in humans with high trait anxiety suggests that the connectivity pattern between the basolateral amygdala and the anterior hippocampus may be a biomarker for the types of anxiety captured by the Spielberger trait anxiety scale, and furthermore, may also represent a possible biological basis for anxiety disorders in humans. (Abstract shortened by UMI.);This series of studies focuses on contextual fear conditioning behavior in an animal model of anxiety-like behavior, the 5-HT1AR knockout mouse, the detailed distribution of the 5-HT1AR in the hippocampus of both the rodent and human, functional brain imaging of unconditioned and contextually conditioned fear in humans, and finally in vivo structural imaging of connectivity patterns between the human amygdala and hippocampus and correlations of the subjects' trait anxiety levels with these patterns.