Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate

Abstract

The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

Intrinsic functional connectivity of the central extended amygdala

“…Anatomically, the Ce and the BST are both poised to trigger or orchestrate key signs of fear and anxiety-including alterations in arousal, behavioral inhibition, and neuroendocrine activity-via dense monoand polysynaptic projections to brainstem and subcortical effector regions (Fox et al, 2015a;Freese & Amaral, 2009;Fudge et al, 2017).…”

“…The EAc encompasses a collection of subcortical regions with similar cellular compositions, neurochemistry, gene expression, and structural connectivity and it encompasses the bed nucleus of the stria terminalis (BST), the central nucleus of the amygdala (Ce), the sublenticular extended amygdala (SLEA), and portions of the accumbens shell (Alheid & Heimer, ; Fox, Oler, Tromp, Fudge, & Kalin, a; Oler et al, ; Yilmazer‐Hanke, ). It has long been recognized that the amygdala is connected to the BST via two major fiber bundles—the ventral amygdalofugal pathway (VA) and the stria terminalis (ST) (Avery et al, ; Kamali et al, ; Nauta, ) (Figure c)—and more recent tracing studies have identified a third, indirect pathway centered on the SLEA (Ce ↔ SLEA ↔ BSTL) (deCampo & Fudge, ; Fudge et al, ; Oler et al, ). Anatomically, the Ce and the BST are both poised to trigger or orchestrate key signs of fear and anxiety—including alterations in arousal, behavioral inhibition, and neuroendocrine activity—via dense mono‐ and polysynaptic projections to brainstem and subcortical effector regions (Fox et al, a; Freese & Amaral, ; Fudge et al, ).…”

“…It has long been recognized that the amygdala is connected to the BST via two major fiber bundles—the ventral amygdalofugal pathway (VA) and the stria terminalis (ST) (Avery et al, ; Kamali et al, ; Nauta, ) (Figure c)—and more recent tracing studies have identified a third, indirect pathway centered on the SLEA (Ce ↔ SLEA ↔ BSTL) (deCampo & Fudge, ; Fudge et al, ; Oler et al, ). Anatomically, the Ce and the BST are both poised to trigger or orchestrate key signs of fear and anxiety—including alterations in arousal, behavioral inhibition, and neuroendocrine activity—via dense mono‐ and polysynaptic projections to brainstem and subcortical effector regions (Fox et al, a; Freese & Amaral, ; Fudge et al, ).…”

“…Fear and anxiety reflect functional circuits that extend well beyond the borders of the EAc (Chang, Gianaros, Manuck, Krishnan, & Wager, ; Fox & Shackman, in press; Kragel, Knodt, Hariri, & LaBar, ; Nummenmaa & Saarimaki, in press ; Pessoa, ; Shackman & Fox, ; Shackman, Fox, & Seminowicz, ; Wager et al, ). Anatomically, the BST and the Ce are embedded within a complex web of mono‐ and polysynaptically connected brain regions (Figure a) (Carrive & Morgan, ; Fox et al, a; Freese & Amaral, ; Fudge et al, ; Oler et al, ; Ongur & Price, ). This structural backbone includes subcortical regions, such as the periaqueductal gray (PAG), that are responsible for triggering specific signs of fear and anxiety (Amano et al, ; Assareh, Sarrami, Carrive, & McNally, ; Bandler, Price, & Keay, ; Chen et al, ; Fadok et al, ; Faull & Pattinson, ; Motta, Carobrez, & Canteras, ; Nashold, Wilson, & Slaughter, ; Richardson & Akil, ; Satpute et al, ; Tovote et al, ).…”

“…Abbreviations: BL 5 basolateral nucleus of the amygdala; BM 5 basomedial nucleus of the amygdala; BST 5 bed nucleus of the stria terminalis; Ce 5 central nucleus of the amygdala; EAc 5 central division of the extended amygdala; La 5 lateral nucleus of the amygdala; Me 5 medial nucleus of the amygdala; SLEA 5 sublenticular extended amygdala [Color figure can be viewed at wileyonlinelibrary.com] the accumbens shell (Alheid & Heimer, 1988;Fox, Oler, Tromp, Fudge, & Kalin, 2015a;Oler et al, 2017;Yilmazer-Hanke, 2012). It has long been recognized that the amygdala is connected to the BST via two major fiber bundles-the ventral amygdalofugal pathway (VA) and the stria terminalis (ST) (Avery et al, 2014;Kamali et al, 2015Kamali et al, , 2016Nauta, 1961) (Figure 1c)-and more recent tracing studies have identified a third, indirect pathway centered on the SLEA (Ce $ SLEA $ BSTL) (deCampo & Fudge, 2013;Fudge et al, 2017;Oler et al, 2017).…”