Mouse models of fear-related disorders: Cell-type-specific manipulations in amygdala

Abstract

Fear conditioning is a model system used to study threat responses, fear memory and their dysregulation in a variety of organisms. Newly developed tools such as optogenetics, Cre recombinase and DREADD technologies have allowed researchers to manipulate anatomically or molecularly defined cell subtypes with a high degree of temporal control and determine the effect of this manipulation on behavior. These targeted molecular techniques have opened up a new appreciation for the critical contributions different subpopulations of cells make to fear behavior and potentially to treatment of fear and anxiety disorders. Here we review progress to date across a variety of techniques to understand fear-related behavior through the manipulation of different cell subtypes within the amygdala.

Keywords: amygdala; cell subtype manipulation; fear conditioning; fear extinction.

Figure 1. Location of different subregions of the amygdala

A. Nissl stain of coronal brain section from mouse (Image Credit: Allen Brain Atlas). B. Schematic diagram of amygdala complex (Adapted from Lee et al., 2013 (94). Abbreviations: Lad (Lateral amygdala dorsal), LAvm (Lateral amygdala ventromedial), LAvl (Lateral amygdala ventrolateral), ITCd (Intercalated cells dorsal), ITCv (Intercalated cells ventral), IITC (Lateral Intercalated cells), BL (Basolateral amygdala), BM (Basomedial amygdala), CEl (Central lateral amygdala), CEm (Central medial amygdala).

Figure 2. Distribution patterns of key neuronal cell populations in the amygdala

Distribution patterns of FoxP2 (Forkhead box protein P2), DRD1 (Dopamine receptor D1), PKCδ (Protein kinase C delta), Tac2 (Tachykinin 2), Nts (Neurotensin), GRP (Calcitonin Gene Related Peptide), CCK (Cholecystokinin), Cb1 (Cannabinoid receptor type 1), Sst (Somatostatin), CRF (Corticotropin Releasing Factor), Thy1 (Thy1 cell surface antigen) in the amygdala. Images from in situ hybridizations from Allen Brain Atlas as well as Ressler lab.

Figure 3. Disruption of GABAAα1 or NR1 genes within CRF neurons result in differential effects on fear acquisition and extinction

A.) CRF GABAAα1 deficient mice (Cre+/fGABAAα1) show no difference from Cre-/fGABAAα1 mice during fear conditioning. B.) However, Cre+/fGABAAα1 show significant deficits in extinction memory compared to Cre-/fGABAAα1 controls, consistent with enhanced activation of CRF neurons through disrupted GABA processing. Alternatively, disruption of CRF NR1 containing neurons (Cre+/ fNR1+) facilitates (C) fear acquisition and (D) fear retention compared to Cre-/fNR1+ controls, consistent with our data for compensatory increased glutamatergic AMPA signaling in CRF neurons. When CRF NR1 neurons were disrupted with virus infusion into the CeA (LV pCRF-CRE/ fNR1+), (E) fear acquisition and (F) fear retention were similarly significantly enhanced compared to GFP infused controls (LV pCRF-GFP/ fNR1+).

Figure 4. Schematic diagram of Select Neuronal Populations in Amygdala

Shown are a number of different neuronal populations that have been identified via cellular markers at the mRNA or protein level, or via their function through physiological, optogenetic, and chemogenetic manipulations. Although the list is neither comprehensive or fully understood, we have attempted to outline some of the more intriguing populations discussed in this review, outlining their location within the different subdivisions of the amygdala on the left and their subcellular marker and function if known, based on the reviewed literature on the right. Abbreviations: CS-conditioned stimulus; US-unconditioned stimulus; LA- Lateral Amygdala; BL-Basolateral amygdala; BM-Basomedial amygdala; ITC-Intercalated neurons of the amygdala; CeL-Centrolateral amygdala; CeM-Centromedial amygdala; GRP-Gastrin Releasing Peptide¹⁰⁹; Parv-Parvalbumin; SST-somatostatin; MOR-mu opiate receptor; CRF-corticotropin releasing factor; PKCd – protein kinase C, delta; Tac2 – tachykinin 2; VP – vasopressin.