Daulton Myers - PhD Candidate, Neuroscience Graduate Program
The anterior cingulate cortex (ACC) is a heterogenous structure that is strongly connected with the amygdala and contains subdivisions critical for unique limbic and cognitive functions. The subgenual ACC (sgACC, Brodmann area 25/14c), implicated in major depression in humans, is a key node of the salience network and is important for arousal state modulation and valuation of sensory information. The perigenual ACC (pgACC, Brodmann area 32/24b), which is positioned dorsal to the sgACC, is important for a host of cognitive functions including decision-making and conflict monitoring. Despite known functional differences in sgACC and pgACC, the main cortical and thalamic drivers of the ACC subregions are not fully understood in higher species. Our preliminary data in macaque suggests each region is unique. sgACC is weighted towards prefrontal cortical (PFC) and thalamic afferents carrying information about motivational states and the value of sensory cues, including midline thalamic nuclei and Brodmann area 13. In contrast, pgACC receives unique inputs from mediodorsal (MD) thalamus and Brodmann area 9/46 that carry information important for spatial and temporal localization of salient stimuli. In Aim 1, I will use paired retrograde tracer injections and compare ensembles of prefrontal cortical and thalamic afferents to the macaque sgACC and pgACC within the same animals. I hypothesize that unique combinations of inputs drive sgACC and pgACC, with sgACC being weighted towards key areas of the arousal network and pgACC being weighted towards cortical and thalamic areas important for goal-directed behavior and decision-making.
The amygdala is critical for ACC function, but its specific inputs to sgACC and pgACC are not clear. The basal nucleus of the amygdala, a 'cortical-like' nucleus critical for detection of salient cues such as facial expression and facial identity, has strong inputs to the ACC. The basal nucleus of the amygdala is enlarged in primates compared to rodents and is subdivided into a dorsal magnocellular division (Bmc), a ventral parvicellular division (Bpc), and an intermediate subdivision (Bi). These cellular divisions are based on size and density of glutamatergic pyramidal neurons. Since glutamatergic projection neurons are specialized at the molecular level, it is possible that glutamatergic neurons in the basal nucleus exhibit distinct transcriptional profiles that encode their projection targets. In Aim 2A, I will use long-read single-nucleus RNA sequencing to characterize the transcriptional profiles of glutamatergic neurons in the macaque basal nucleus of the amygdala. I hypothesize that a gradient of excitatory neuron subtype-specific gene expression will be revealed, with unique glutamatergic neuron types present in the Bmc, Bi, and Bpc. In Aim 2B, an atlas of differentially express genes in the basal nucleus subdivisions will be validated with spatial transcriptomics (RNAScope).
While the sgACC and pgACC act as discrete functional and connectional hubs, preliminary data show that they receive a common input from the Bi, which may function to coordinate responses to salient social stimuli. I hypothesize that excitatory Bi neurons projecting to sgACC and pgACC will exhibit distinct transcriptional profiles compared to neurons that do not target the ACC. In Aim 3, information from transcriptomic studies (Aim 2) will be used to determine the molecular features of Bi-ACC projection neurons. Using cases from Aim 1, retrogradely labeled neurons in the basal nucleus of the amygdala projecting to sgACC and pgACC will be double labeled for fluorescent in situ hybridization (RNAScope). These results will then be integrated with the results of Aim 1 for a comprehensive analysis of sgACC and pgACC connectivity. Overall, this will provide insight on how the unique functions of sgACC and pgACC are established and coordinated to guide decision-making in the presence of salient social stimuli, and will be informative for understanding ACC dysregulation in psychiatric disorders.
Dec 17, 2024 @ 9:00 a.m.
Medical Center | K307 (3-6408)
Hybrid EventHost: Julie Fudge, MD