Dr. Sean J. O’Sullivan is an MD/PhD postdoctoral scholar from Philadelphia. His PhD in neuroscience from Thomas Jefferson University focused on the molecular mechanisms of alcohol and opioid withdrawal.
Specifically, he took a systems neuroscience approach to understand the role of the gut microbiome in influencing the negative physical and emotional states that characterize alcohol and opioid withdrawal syndromes.
This work led to the generation of a novel hypothesis—interoceptive neuroinflammatory signaling involving gut dysbiosis and peripheral network decompensation secondary to abstinence in the context of allostasis drives neuroinflammation in the nucleus tractus solitarius (NTS) and amygdala during alcohol and opioid withdrawal which increases the severity of the withdrawal symptoms. He further conjectures that this interoceptive signaling constitutes an antireward pathway that motivates substance dependence via negative reinforcement.
He also investigated neuronal subphenotypes in the suprachiasmatic nucleus which is the principle circadian brain region. He further investigated how circadian rhythms affect gene expression in the NTS and amygdala.
In the Stanford Brain Stimulation Lab, Dr. O’Sullivan is part of the inpatient treatment team that is applying an accelerated transcranial magnetic stimulation (TMS) protocol (Stanford Accelerated Intelligent Neuromodulation Therapy [SAINT]) to hospitalized psychiatric patients. TMS is not currently available to psychiatric inpatients, and this work aims to make this innovative treatment available to those most in need. He is also leading a study researching the effects of TMS on a peripheral biomarker of depression known as L-acetyl-carnitine. He is in the process of applying for psychiatry residency and plans to integrate brain stimulation into his future clinical practice.
Nolan Williams, Postdoctoral Faculty Sponsor
Similarities in alcohol and opioid withdrawal syndromes suggest common negative reinforcement mechanisms involving the interoceptive antireward pathway.
Neuroscience and biobehavioral reviews
2021; 125: 355–64
Alcohol and opioids are two major contributors to so-called deaths of despair. Though the effects of these substances on mammalian systems are distinct, commonalities in their withdrawal syndromes suggest a shared pathophysiology. For example, both are characterized by marked autonomic dysregulation and are treated with alpha-2 agonists. Moreover, alcohol and opioids rapidly induce dependence motivated by withdrawal avoidance. Resemblances observed in withdrawal syndromes and abuse behavior may indicate common addiction mechanisms. We argue that neurovisceral feedback influences autonomic and emotional circuits generating antireward similarly for both substances. Amygdala is central to this hypothesis as it is principally responsible for negative emotion, prominent in addiction and motivated behavior, and processes autonomic inputs while generating autonomic outputs. The solitary nucleus (NTS) has strong bidirectional connections to the amygdala and receives interoceptive inputs communicating visceral states via vagal afferents. These visceral-emotional hubs are strongly influenced by the periphery including gut microbiota. We propose that gut dysbiosis contributes to alcohol and opioid withdrawal syndromes by contributing to peripheral and neuroinflammation that stimulates these antireward pathways and motivates substance dependence.
View details for DOI 10.1016/j.neubiorev.2021.02.033
View details for PubMedID 33647322
- Single-cell systems neuroscience: A growing frontier in mental illness BIOCELL 2021; 46 (1): 7-11
Single Cell Scale Neuronal and Glial Gene Expression and Putative Cell Phenotypes and Networks in the Nucleus Tractus Solitarius in an Alcohol Withdrawal Time Series
Frontiers in Systems Neuroscience
2021; 15: 131
View details for DOI 10.3389/fnsys.2021.739790
The Interoceptive Antireward Pathwayand Gut Dysbiosis in Addiction
Journal of Psychiatry Depression & Anxiety
View details for DOI 10.24966/PDA-0150/100040
Understanding the Regulation of Transcription in Mental Illness
2021; 5 (4): 7
View details for DOI 10.21926/obm.genet.2104143
Diurnal Patterns of Gene Expression in the Dorsal Vagal Complex and the Central Nucleus of the Amygdala - Non-rhythm-generating Brain Regions
FRONTIERS IN NEUROSCIENCE
2020; 14: 375
Genes that establish the circadian clock have differential expression with respect to solar time in central and peripheral tissues. Here, we find circadian-time-induced differential expression in a large number of genes not associated with circadian rhythms in two brain regions lacking overt circadian function: the dorsal vagal complex (DVC) and the central nucleus of the amygdala (CeA). These regions primarily engage in autonomic, homeostatic, and emotional regulation. However, we find striking diurnal shifts in gene expression in these regions of male Sprague Dawley rats with no obvious patterns that could be attributed to function or region. These findings have implications for the design of gene expression studies as well as for the potential effects of xenobiotics on these regions that regulate autonomic and emotional states.
View details for DOI 10.3389/fnins.2020.00375
View details for Web of Science ID 000537225600001
View details for PubMedID 32477043
View details for PubMedCentralID PMC7233260
Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
Profound transcriptional heterogeneity in anatomically adjacent single cells suggests that robust tissue functionality may be achieved by cellular phenotype diversity. Single-cell experiments investigating the network dynamics of biological systems demonstrate cellular and tissue responses to various conditions at biologically meaningful resolution. Herein, we explain our methods for gathering single cells from anatomically specific locations and accurately measuring a subset of their gene expression profiles. We combine laser capture microdissection (LCM) with microfluidic reverse transcription quantitative polymerase chain reactions (RT-qPCR). We also use this microfluidic RT-qPCR platform to measure the microbial abundance of gut contents.
View details for DOI 10.3791/60612
View details for Web of Science ID 000523286100036
View details for PubMedID 32202523
View details for PubMedCentralID PMC8015684
Single-Cell Glia and Neuron Gene Expression in the Central Amygdala in Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis
FRONTIERS IN NEUROSCIENCE
2019; 13: 665
Drug-seeking in opioid dependence is due in part to the severe negative emotion associated with the withdrawal syndrome. It is well-established that negative emotional states emerge from activity in the amygdala. More recently, gut microflora have been shown to contribute substantially to such emotions. We measured gene expression in single glia and neurons gathered from the amygdala using laser capture microdissection and simultaneously measured gut microflora in morphine-dependent and withdrawn rats to investigate drivers of negative emotion in opioid withdrawal. We found that neuroinflammatory genes, notably Tnf, were upregulated in the withdrawal condition and that astrocytes, in particular, were highly active. We also observe a decreased Firmicutes to Bacteroides ratio in opioid withdrawal indicating gut dysbiosis. We speculate that these inflammatory and gut microflora changes contribute to the negative emotion experienced in opioid withdrawal that motivates dependence.
View details for DOI 10.3389/fnins.2019.00665
View details for Web of Science ID 000473597100001
View details for PubMedID 31333398
View details for PubMedCentralID PMC6619439
Single-Cell Transcriptional Analysis Reveals Novel Neuronal Phenotypes and Interaction Networks Involved in the Central Circadian Clock
FRONTIERS IN NEUROSCIENCE
2016; 10: 481
Single-cell heterogeneity confounds efforts to understand how a population of cells organizes into cellular networks that underlie tissue-level function. This complexity is prominent in the mammalian suprachiasmatic nucleus (SCN). Here, individual neurons exhibit a remarkable amount of asynchronous behavior and transcriptional heterogeneity. However, SCN neurons are able to generate precisely coordinated synaptic and molecular outputs that synchronize the body to a common circadian cycle by organizing into cellular networks. To understand this emergent cellular network property, it is important to reconcile single-neuron heterogeneity with network organization. In light of recent studies suggesting that transcriptionally heterogeneous cells organize into distinct cellular phenotypes, we characterized the transcriptional, spatial, and functional organization of 352 SCN neurons from mice experiencing phase-shifts in their circadian cycle. Using the community structure detection method and multivariate analytical techniques, we identified previously undescribed neuronal phenotypes that are likely to participate in regulatory networks with known SCN cell types. Based on the newly discovered neuronal phenotypes, we developed a data-driven neuronal network structure in which multiple cell types interact through known synaptic and paracrine signaling mechanisms. These results provide a basis from which to interpret the functional variability of SCN neurons and describe methodologies toward understanding how a population of heterogeneous single cells organizes into cellular networks that underlie tissue-level function.
View details for DOI 10.3389/fnins.2016.00481
View details for Web of Science ID 000386091900001
View details for PubMedID 27826225
View details for PubMedCentralID PMC5079116