Hippocampal GABAB(1a) Receptors Constrain Generalized Contextual Fear

Abstract

Many anxiety disorders are characterized by generalization of fear responses to neutral or ambiguous stimuli. Therefore, a comprehensive understanding of the mechanisms contributing to generalized fear is essential for formulating successful treatments for anxiety disorders. Previous research shows that GABA-mediated presynaptic inhibition has a critical role in cued fear generalization, as animals with genetically deleted presynaptic GABA B(1a) receptors cannot discriminate between CS+ and CS − tones. Work from our laboratory has further identified that GABA B(1a) receptors are necessary for maintaining contextual memory precision, thereby constraining generalized contextual fear. We previously found that GABA B(1a) KO mice show generalized fear to a neutral context 24 h after training, but not 2 h after training. A similar pattern was observed with object location and recognition, suggesting that this receptor subtype affects consolidation and/or retrieval of precise contextual and spatial memories. Here we sought to specifically examine the involvement of GABA B(1a) receptors in consolidation or retrieval of a precise fear memory. To do so, we infused a selective GABA B(1a) receptor antagonist, CGP 36216, intracerebroventricularly (ICV), or locally into the dorsal hippocampus, ventral hippocampus, or anterior cingulate cortex (ACC), during consolidation and retrieval of context fear training. Blockade of GABA B(1a) receptors through ICV, dorsal hippocampal, or ventral hippocampal infusions 'after' training (consolidation) resulted in fear generalization to the neutral context when mice were tested 24, but not 6 h after training. Post-training infusions of CGP into the ACC, however, did not promote generalized fear. In addition, ICV, dorsal hippocampal, ventral hippocampal, or ACC infusions immediately 'before' testing (retrieval) did not result in context fear generalization. These data suggest that GABA-mediated presynaptic inhibition is not critical for retrieval of precise contextual memory, but rather has an important role in the long-term consolidation of precise contextual memories and constrains generalized fear responses.

Anterior Cingulate Cortex and Ventral Hippocampal Inputs to the Basolateral Amygdala Selectively Control Generalized Fear

“…Here, we discovered that rapidly generalized memories do not require the vHPC, whereas remote generalized memories do, showing an opposite role of that of the dHPC. Thus, our data, in combination with recent findings (Lynch et al, 2017;Zhou et al, 2017), suggest that transformation of a specific fear memory into a generalized form may actually involve a shift in control over memory recall from the dHPC to the vHPC over time.…”

Anterior cingulate cortex and dorsal hippocampal glutamate receptors mediate generalized fear in female rats

“…Here, we show for the first time that the ACC (Experiment 1.1) also serves as an important locus for the actions of estradiol on generalized fear in female rats. However, unlike our previous findings supporting a critical role for the vCA1 in generalized fear (Cullen et al, 2015;Lynch et al, 2017) estradiol did not influence generalization when directly infused into this region (Experiment 1.2). Given the influence of estradiol on learning and memory, LTP, and glutamatergic signaling, an aim of this study was to determine the role that glutamate receptors play in mediating the actions of estradiol on generalization.…”

“…Given our findings here, we predict that estradiol is acting within neural circuits that support memory recall to promote generalized fear to non-threatening contexts. In support of our previous neuroanatomical data (Cullen et al, 2015), we show that the ACC in addition to the dCA1 (Lynch et al, 2017;Lynch et al, 2016) are important loci for regulating a form of timeindependent generalization that is modulated by the presence of estradiol. Further, we show that AMPA and NMDA receptors in general, as well as the specific GluN2B-conatining NMDA receptors, are important mediators of the actions of estradiol on fear processing.…”

“…Similar increases in glutamatergic signaling have also produced contextual generalization for fear and non-fear tasks. For instance, genetic or pharmacological inactivation of presynaptic GABAb(1a) receptors, globally or within the dCA1, results in contextual fear generalization 24 hours after training (Cullen et al, 2014;Lynch et al, 2017). GABAb(1a) receptors are commonly found on presynaptic terminals of glutamatergic neurons, mediating glutamate release through presynaptic inhibition (Gassmann and Bettler, 2012).…”

Differential Dorsolateral Prefrontal Cortex Proteomic Profiles of Suicide Victims with Mood Disorders

“…GABRB1 is a subunit of the gamma-aminobutyric acid A receptor, which is a multi-subunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system [50]. GABRB1 has an important role in the long-term consolidation of precise contextual memories and constrains generalized fear responses [51]. There is also evidence for the involvement of the GABRB1 gene in thalamus volume and interactive effects on intelligence [50].…”