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

Abstract

A common symptom of anxiety disorders is the overgeneralization of fear across a broad range of contextual cues. We previously found that the ACC and ventral hippocampus (vHPC) regulate generalized fear. Here, we investigate the functional projections from the ACC and vHPC to the amygdala and their role in governing generalized fear in a preclinical rodent model. A chemogenetic approach (designer receptor exclusively activated by designer drugs) was used to inhibit glutamatergic projections from the ACC or vHPC that terminate within the BLA at recent (1 d) or remote (28 d) time points after contextually fear conditioning male mice. Inactivating ACC or vHPC projections to the BLA significantly reduced generalized fear to a novel, nonthreatening context but had no effect on fear to the training context. Further, our data indicate that the ACC-BLA circuit supports generalization in a time-independent manner. We also identified, for the first time, a strictly time-dependent role of the vHPC-BLA circuit in supporting remote generalized contextual fear. Dysfunctional signaling to the amygdala from the ACC or the HPC could underlie overgeneralized fear responses that are associated with anxiety disorders. Our findings demonstrate that the ACC and vHPC regulate fear expressed in novel, nonthreatening environments via projections to the BLA but do so as a result of training intensity or time, respectively.

Reminders reinstate context-specificity to generalized remote memories in rats: relation to activity in the hippocampus and aCC

“…There is evidence suggesting that the ventral hippocampus and its projections to the medial prefrontal cortex, are required for the retrieval of the remote generalized context. Inactivation of the aCC and vHPC at this time prevents the expression of the generalized context memory, while leaving the context-specific memory intact (Cullen et al 2015;Ortiz et al 2019). While vHPC activity was not assessed in the present study, the results provide an interesting avenue for follow up studies investigating the role of the vHPC to determine how reactivating the remote memory via a Context-A reminder may alter the remote systems reconsolidation of generalized/schematic memories in the absence of a functional aCC and vHPC.…”

“…Over time, memories in rats that were once highly specific to the contextual cues present during memory acquisition are changed as the memory transforms from one that is critically dependent upon the hippocampus, to one that becomes supported by both the hippocampus and the prefrontal cortex, particularly anterior cingulate cortex (aCC) (Frankland et al 2004;Wiltgen and Silva 2007;Winocur et al 2007;Einarsson and Nader, 2012;Wheeler et al 2013;Cullen et al 2015;Einarsson et al 2015;Kitamura et al 2017;Vetere et al 2017;Sekeres et al 2018a;DeNardo et al 2019;Ortiz et al 2019). Reactivating an established 30 d old fear memory by presenting the contextual cues that were present during encoding reinstates context-specificity to the remote memory (Sekeres et al 2012), and renders the memory sensitive to hippocampal disruption during the postreactivation reconsolidation window (Debiec et al 2002).…”

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

“…The latter (ACC→NAc) connection is functionally reduced in first-episode schizophrenia ( Lin et al, 2018 ). The ACC also projects to further key structures of the extended vSub/VTA circuit, such as the amygdala and the vHC ( Figure 2 )—these connections are crucial for attribution of the appropriate levels of significance during associative learning ( Bian et al, 2019 ; Ortiz et al, 2019 ).…”

MouseCircuits.org: An online repository to guide the circuit era of disordered affect

“…Presumably, timedependence is due to different circuits mediating varying aspects of a behavior. For instance, the PL→BLA pathway is critical for fear retrieval at 6 hours post fear conditioning (115), but at 1 and 28 days, fear retrieval has shifted to the anterior cingulate cortex (ACC)→LA (116).…”