Connectivity between the central nucleus of the amygdala and the bed nucleus of the stria terminalis in the non-human primate: neuronal tract tracing and developmental neuroimaging studies

Abstract

The lateral division of the bed nucleus of the stria terminalis (BSTL) and central nucleus of the amygdala (Ce) form the two poles of the ‘central extended amygdala’, a theorized subcortical macrostructure important in threat-related processing. Our previous work in nonhuman primates, and humans, demonstrating strong resting fMRI connectivity between the Ce and BSTL regions, provides evidence for the integrated activity of these structures. To further understand the anatomical substrates that underlie this coordinated function, and to investigate the integrity of the central extended amygdala early in life, we examined the intrinsic connectivity between the Ce and BSTL in non-human primates using ex vivo neuronal tract tracing, and in vivo diffusion-weighted imaging and resting fMRI techniques. The tracing studies revealed that BSTL receives strong input from Ce; however, the reciprocal pathway is less robust, implying that the primate Ce is a major modulator of BSTL function. The sublenticular extended amygdala (SLEAc) is strongly and reciprocally connected to both Ce and BSTL, potentially allowing the SLEAc to modulate information flow between the two structures. Longitudinal early-life structural imaging in a separate cohort of monkeys revealed that extended amygdala white matter pathways are in place as early as 3 weeks of age. Interestingly, resting functional connectivity between Ce and BSTL regions increases in coherence from 3 to 7 weeks of age. Taken together, these findings demonstrate a time period during which information flow between Ce and BSTL undergoes postnatal developmental changes likely via direct Ce->BSTL and/or Ce <-> SLEAc <-> BSTL projections.

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

“…To reduce animal use, some of the injections placed in the amygdala and CEA (Study 2) were mapped as parts of other studies (Cho et al , 2013; Decampo and Fudge, 2013; Oler et al , 2016). All experiments were carried out in accordance with National Institute of Health guidelines.…”

Contributions of the Central Extended Amygdala to Fear and Anxiety

“…Classic tracing studies showed that VA fibers project through the SLEA region of the substantial innominata, directly connecting the Ce to the BST (Novotny, 1977). In parallel, the ST exits the caudal amygdala to arch dorsally and rostrally over the thalamus, carrying with it a second set of projections from the Ce to BSTL (Klingler and Gloor, 1960;Freese and Amaral, 2009;Oler et al, 2016b). More recent tracing and diffusion imaging studies in monkeys have not only confirmed that the Ce and BSTL are structurally interconnected via these two direct pathways (primarily Ce ¡ BSTL) but have also identified a novel indirect pathway in the SLEA (Ce 7 SLEA 7 BSTL) (deCampo and Fudge, 2013;Oler et al, 2016b).…”

“…In parallel, the ST exits the caudal amygdala to arch dorsally and rostrally over the thalamus, carrying with it a second set of projections from the Ce to BSTL (Klingler and Gloor, 1960;Freese and Amaral, 2009;Oler et al, 2016b). More recent tracing and diffusion imaging studies in monkeys have not only confirmed that the Ce and BSTL are structurally interconnected via these two direct pathways (primarily Ce ¡ BSTL) but have also identified a novel indirect pathway in the SLEA (Ce 7 SLEA 7 BSTL) (deCampo and Fudge, 2013;Oler et al, 2016b). In both monkeys and humans, the Ce and BST also show persistently high levels of physiological coupling Avery et al, 2014;Birn et al, 2014;Torrisi et al, 2015;Oler et al, 2016b), suggesting that they represent an evolutionarily conserved functional circuit.…”

Resting‐state fMRI effective connectivity between the bed nucleus of the stria terminalis and amygdala nuclei

“…Both BNST and amygdala are strongly interconnected on a structural level (Sah, Faber, Lopez De Armentia, & Power, ; Waraczynski, ). The BNST is connected to the amygdala via the ventral amygdalofugal pathway and the stria terminalis (Sun, Roberts, & Cassell, ) and thus shows structural connections to the LB, CM, and SF (Cooke & Simerly, ; Oler et al, ; Weller & Smith, ). Particularly, the CM and the BNST have been proposed to belong to the medial extended amygdala due to their high similarity with respect to embryological origin, cell type, afferent, and efferent connections (Bienkowski & Rinaman, ; Bupesh, Abellán, & Medina, ; Dong, Petrovich, & Swanson, ; Sah et al, ) and timing of impulses to the brainstem (Nagy & Paré, ).…”