Early Graduate Career: Could one of neuroscience’s most celebrated facts—the amygdala is the brain’s “fear” center—turn out to be wrong?

Early in my doctoral training, I led and was involved in multiple projects developing translational measures of affective processing in rhesus macaques. I also worked to establish the contributions of various influences to changes in monkeys’ affective processing, including neural perturbation, aging, and social context. I showed that complete excitotoxic lesions of the macaque amygdala produced deficits in affective processing of threatening reptilian stimuli but failed to impact the processing of other threatening objects and a human experimenter (a). This work built on decades of neuropsychology experiments testing the impacts of amygdala lesions on affective processing, refining our knowledge of amygdala function in threat processing. I also showed that chronic social housing conditions have a significant impact on threat processing, with individually housed monkeys exhibiting a depression-like phenotype and monkeys housed in restricted contact exhibiting an anxiety-like phenotype (b). This work has substantial implications for the interpretation of a variety of existing non-human primate studies as well as considerations of future study conditions and animal welfare. Finally, we showed that age significantly impacys threat processing in monkeys. Like older people, older monkeys exhibit a less profound attentional bias to threatening stimuli than younger monkeys (c). This work is critical to understanding the neural basis of socioemotional changes that occur in older people and renders the macaque a key model for investigating such changes and attempting interventions. I later showed that both the insula and anterior cingulate cortex exhibit significant volume loss in older macaques (d), just as they do in older humans, providing a putative substrate for these functional changes that are conserved across species.

(a) Charbonneau JA, Bennett JL, Bliss-Moreau E. (2022). Amygdala or hippocampus damage only minimally impacts affective responding to threat. Behavioral Neuroscience, 136(1), 30-45. PMCID: PMC8863583

(b) Charbonneau JA, Amaral DG, Bliss-Moreau E. (2022). Social housing status impacts rhesus monkeys’ affective responding in classical threat processing tasks. Scientific Reports, 12(1), 4140. PMCID: PMC8907189.

(c) Santistevan AC, Fiske O, Moabab G, Charbonneau JA, Isaacowitz DM, Bliss-Moreau E. (2024). See no evil: Attentional bias toward threat is diminished in aged monkeys. Emotion, 24(2), 303-315. PMCID: PMC10879459.

(d) Charbonneau JA, Davis B, Raven EP, Patwardhan B, Grebosky C, Halteh L, Bennett JL, Bliss-Moreau E. (2024). Brain Structure and Function, 229(8), 2029-2043. PMCID: PMC11483197.

Late Graduate Career: “How is the brain organized to sense the body’s internal world and what happens when that organization is disrupted?”

My primary doctoral project investigated interoception in rhesus macaques, focusing on the insular cortex, the primary brain region for processing interoceptive signals. I used multimodal neuroimaging—functional, diffusion, and structural MRI—to establish the organization of the macaque insula (a). I found strong evidence for highly similar organization between macaques and humans, with a tripartite division of function and a primary anterior-posterior organizational axis. This work had a clear basis in the histological parcellation of the insula I had previously established (b). In this histological work, I showed that the anterior insula specifically is highly plastic, and capable of expanding to absorb functions of the highly connected anterior cingulate cortex (ACC) following excitotoxic lesions of the ACC. In the behavioral domain, I showed that rhesus monkeys exhibit human-like cardiac interoception, directing their overt attention more to stimuli that were asynchronous with their cardiac rhythm (c). To tie together my anatomical and behavioral findings, I conducted an interoceptive functional neuroimaging study to assess neural responses to affective touch in anesthetized macaques. I showed that even under anesthesia, slow, affective touch (a putatively interoceptive input activating C-tactile fibers) elicits significantly greater activation of the interoceptive-allostatic network (insula, ACC, and amygdala) relative to fast, discriminative touch (d). This paralleled activation observed in awake humans, providing compelling evidence for evolutionarily conserved interoceptive processing.

(a) Charbonneau JA, Raven EP, Katsumi Y, Santistevan AC, Taylor C, Bliss-Moreau E. (2024). Imaging Neuroscience, 2, 1-25. PMCID: Not yet available.

(b) Charbonneau JA, Bennett JL, Chau K, Bliss-Moreau E. (2023). Cerebral Cortex, 33(8), 4334-4349. PMCID: PMC10110454.

(c) Charbonneau JA, Maister L, Tsakiris M, Bliss-Moreau E. (2022). Proceedings of the National Academy of Sciences, 119(6), e2119868119. PMCID: PMC9169786.

(d) Charbonneau JA, Santistevan AC, Raven EP, Bennett JL, Russ BE, Bliss-Moreau E. (2024). Proceedings of the National Academy of Sciences, 121(18), e2322157121. PMCID: PMC11067024.

Unpublished: How much of what we feel begins in the body, and how much of what we think we know about the emotional brain is built on shakier ground than we realized?

My PhD research extended work on affective science and the brain in three directions. The first was theoretically proposing a shared framework for the science of interoception—how the brain reads and responds to signals from the body. Most interoception research relies on people reporting their own bodily awareness, which makes it hard to study the underlying biology. I have developed precise, testable definitions that work across species, laying the groundwork for the kind of mechanistic, causal research needed to understand how signals from the body shape our feelings, perceptions, and sense of self (a).

A second prior project of mine took a fresh look at one of neuroscience's most well-worn claims: that the amygdala is the brain's "fear center." Through a meta-analysis of nearly a century of lesion studies in nonhuman primates, this work examined what actually happens to fear and threat-related behavior when the amygdala is taken offline. By applying systematic, quantitative methods to a literature rarely subjected to this kind of scrutiny, the manuscript offers a rigorous reassessment of how much of the fear story the amygdala actually owns (b).

Finally, I have argued that Alzheimer's disease deserves to be understood, at least in part, as a disorder of affect—of mood and emotional life—not only as a disorder of memory and cognition. The prevailing view holds that emotional changes in Alzheimer's are a downstream consequence of cognitive decline. In this manuscript, I, alongside my coauthors, review evidence suggesting that affective changes may in fact come first, and that the brain systems responsible for generating mood and emotion are disrupted early in the disease. If true, this shifts the picture considerably: affective symptoms could serve as earlier warning signs, emotional and cognitive symptoms may require different interventions, and addressing emotional suffering in Alzheimer's patients and their caregivers deserves to be a treatment priority in its own right (c).

(a) Charbonneau JA, Bliss-Moreau (in prep). Toward a shared lexicon for interoceptive science: A framework for harmonizing human and nonhuman animal research.

(b) Charbonneau JA, Bliss-Moreau E (in prep). A meta-analytic reevaluation of the primate amygdala’s role in affective processing.

(c) Charbonneau JA, Carp SB, Bliss-Moreau E (in prep). Alzheimer’s disease as an affective disorder: Rethinking the temporal sequence of symptom and its implication for early intervention.