Bridging the Gap : Towards a cell-type specific understanding of neural circuits underlying fear behaviors

McCullough, Kenneth M.; Morrison, Filomene G.; Ressler, Kerry J.

doi:10.1016/j.nlm.2016.07.025

Cited by 44 publications

(32 citation statements)

References 123 publications

(153 reference statements)

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“…Therefore, we used the hM4D system with intracranial infusions of CNO to identify the precise ACC circuit that regulates fear generalization. The ACC is known to convey sensory information to the BLA (Morozov et al, 2011;McCullough et al, 2016); therefore, we targeted ACC projection terminals in the BLA.…”

Section: Cno Administration Alone Has No Effect On Context Fear Genermentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Cno Administration Alone Has No Effect On Context Fear Genermentioning

confidence: 99%

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

et al. 2019

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“…Recent evidence suggests that distinct subpopulations play differential roles in fear and extinction learning ( Herry et al, 2008 ; Haubensak et al, 2010 ; Li et al, 2013a ; Kim et al, 2017 ). The characterization of molecularly identifiable neuronal populations is an important early step in developing improved treatments for fear and anxiety related disorders ( McCullough et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Quantified Coexpression Analysis of Central Amygdala Subpopulations

McCullough

Morrison

Hartmann

et al. 2018

eNeuro

116

118

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Molecular identification and characterization of fear controlling circuitries is a promising path towards developing targeted treatments of fear-related disorders. Three-color in situ hybridization analysis was used to determine whether somatostatin (SOM, Sst), neurotensin (NTS, Nts), corticotropin-releasing factor (CRF, Crf), tachykinin 2 (TAC2, Tac2), protein kinase c-␦ (PKC-␦, Prkcd), and dopamine receptor 2 (DRD2, Drd2) mRNA colocalize in male mouse amygdala neurons. Expression and colocalization was examined across capsular (CeC), lateral (CeL), and medial (CeM) compartments of the central amygdala. The greatest expression of Prkcd and Drd2 were found in CeC and CeL. Crf was expressed primarily in CeL, while Sst-, Nts-, and Tac2-expressing neurons were distributed between CeL and CeM. High levels of colocalization were identified between Sst, Nts, Crf, and Tac2 within the CeL, while little colocalization was detected between any mRNAs within the CeM. These findings provide a more detailed understanding of the molecular mechanisms that regulate the development and maintenance of fear and anxiety behaviors.

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“…The defensive strategies are critical for the survival of an organism. Although defensive behaviors are often adaptive, pathologic expression of these defensive behaviors often leads to inappropriate anxiety (Rosen and Schulkin, 1998;Bonne et al, 2004;McCullough et al, 2016). Indeed, anxiety-related disorders can be characterized by an inability to discriminate threat from safety (Dunsmoor et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Anterior Cingulate Cortex to Ventral Hippocampus Circuit Mediates Contextual Fear Generalization

et al. 2019

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Contextual fear memory becomes less context-specific over time, a phenomenon referred to as contextual fear generalization. Overgeneralization of contextual fear memory is a core symptom of post-traumatic stress disorder (PTSD), but circuit mechanisms underlying the generalization remain unclear. We show here that neural projections from the anterior cingulate cortex (ACC) to ventral hippocampus (vHPC) mediate contextual fear generalization in male mice. Retrieval of contextual fear in a novel context at a remote time point activated cells in the ACC and vHPC, as indicated by significantly increased C-fos ϩ cells. Using chemogenetic or photogenetic manipulations, we observed that silencing the activity of ACC or vHPC neurons reduced contextual fear generalization at the remote time point, whereas stimulating the activity of ACC or vHPC neurons facilitated contextual fear generalization at a recent time point. We found that ACC neurons projected to the vHPC unidirectionally, and importantly, silencing the activity of projection fibers from the ACC to vHPC inhibited contextual fear generalization at the remote time point. Together, our findings reveal an ACC to vHPC circuit that controls expression of fear generalization and may offer new strategies to prevent or reverse contextual fear generalization in subjects with anxiety disorders, especially in PTSD. Significance StatementOvergeneralization of contextual fear memory is a cardinal feature of PTSD, but circuit mechanisms underlying it remain unclear. Our study indicates that neural projections from the anterior cingulate cortex to ventral hippocampus control the expression of contextual fear generalization. Thus, manipulating the circuit may prevent or reverse fear overgeneralization in subjects with PTSD.

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Bridging the Gap : Towards a cell-type specific understanding of neural circuits underlying fear behaviors

Cited by 44 publications

References 123 publications

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

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

Quantified Coexpression Analysis of Central Amygdala Subpopulations

Anterior Cingulate Cortex to Ventral Hippocampus Circuit Mediates Contextual Fear Generalization

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