John F. Sheridan

Residential segregation is associated with differential exposure to air pollution. Hippocampus structure and function are highly susceptible to pollutants and associated with posttraumatic stress disorder (PTSD) development. Therefore, we investigated associations between residential segregation, air pollutants, hippocampal neurobiology, and PTSD in recent trauma survivors. Participants (N = 278; 34% non-Hispanic white, 46% Non-Hispanic Black, 16% Hispanic) completed multimodal neuroimaging two weeks after trauma. Yearly averages of air pollutants (PM_2.5 and NO₂) and racial/economic segregation (Index of Concentration at the Extremes) were derived from each participant's address. Linear models assessed if air pollutants mediated associations between segregation and hippocampal volume, threat reactivity, or parahippocampal cingulum fractional anisotropy (FA) after covarying for age, sex, income, and 2-week PTSD symptoms. Further models evaluated if pollutants or segregation prospectively predicted PTSD symptoms six months post-trauma. We found that non-Hispanic Black participants lived in neighborhoods with significantly greater segregation and air pollution compared to Hispanic and non-Hispanic white participants (ps < 0.001). PM_2.5 concentration was positively correlated with threat reactivity (r(276) = 0.16, p < 0.006), while NO₂ concentration was positively correlated with hippocampus volume (r(276) = 0.17, p < 0.005) and negatively correlated with white matter tract FA (r(276) = -0.18, p < 0.003). There was a significant indirect effect of NO₂ between segregation and FA values (β = 0.08, 95% CI[0.01, 0.15]), and an indirect effect of PM_2.5 between segregation and threat reactivity (β = -0.08, 95% CI[-0.14, -0.01]). There was no direct effect of segregation on hippocampal features. Pollutants and segregation were not associated with PTSD symptoms. In conclusion, residential segregation is associated with greater air pollution exposure, which is in turn associated with variability in hippocampal features among recent trauma survivors. Further research is needed to assess relationships between other environmental factors and trauma and stress-related disorders.

Stress-related conditions disrupt cognition and emotion regulation and can result in psychiatric illness, but the neural circuit-level changes that can explain these broad effects remain unclear. To address this issue, we paired population-grounded discovery with out-of-sample testing. Using resting-state fMRI from > 14,000 healthy adults in the UK Biobank, we derived connectivity profiles tied to cognition (reaction time, numeric memory), and proxies of emotion dysregulation (neuroticism, anhedonia). We then applied the profiles to a trauma-exposed cohort (N = 306) to assess symptom relevance. Associations with stress, anxiety, and depression concentrated in a subset of circuit motifs, two of which recurred: (1) hyperintegration between the default mode and control/limbic interfaces, as well as (2) hypointegration between the default mode and visual interfaces, both tracked higher symptom burden. Static and dynamic analyses converged on the precuneus as a critical hub: stronger precuneus–visual coupling and greater occupancy of a precuneus-engaged dynamic state were related to lower symptoms, whereas the opposing state was related to higher burden. This novel hybrid approach—discover-then-project—thus yielded interpretable markers of circuit dysfunction that generalized to post-trauma psychopathology. Furthermore, the approach identified the precuneus as a potential target for mechanistically informed interventions.

Repeated social defeat (RSD) in mice causes sensitization of hippocampal neurons associated with enhanced contextual fear memory. Because enhanced fear memory is an integral component of posttraumatic stress disorder, the physiological basis of neuronal sensitization in the hippocampus after social defeat was investigated in male mice using two interventions: microglia depletion (CSF1R antagonist, PLX5622) and neuronal (Vglut2 ⁺ ) IL-1R1 ^−/− mice. Here, two single-nuclei (sn) RNAseq data sets using these interventions were integrated and compared. Social defeat altered the transcriptional profiles of CA1 (Satb2 ⁺ ), dentate gyrus (DG, Prox1 ⁺ ), and inhibitory (Pval ⁺ ) neurons, and these stress profiles were influenced by nIL-1R1, microglia, or both. In DG neurons, differentially expressed genes and canonical pathways related to cAMP response element (CREB), calcium/calmodulin kinases, bassoon, and glutamatergic signaling were robustly increased by RSD, and these were selectively dependent on nIL-1R1. Based on the snRNAseq data, neuronal stability and plasticity within the hippocampus were assessed. For instance, social defeat increased perineuronal nets around inhibitory (Pval ⁺ ) neurons in the DG, and these were influenced by both nIL-1R1 and microglia. In addition, RNAscope confirmed that bassoon RNA was amplified after social defeat in the CA1 and DG, and these increases were selectively dependent on nIL-1R1. Last, electrophysiological analyses showed that both spontaneous excitatory and inhibitory postsynaptic current amplitudes in the DG were influenced by social defeat in a nIL-1R1-dependent manner. Collectively, sensitization of dentate gyrus neurons after social defeat requires neuronal IL-1R1 and is associated with enhanced CREB-bassoon signaling and disruption of the excitatory/inhibitory input balance.

Traumatic stress exposures (TSEs) are common in life. Although most individuals recover after a TSE, a substantial subset develop adverse post-traumatic neuropsychiatric sequelae such as chronic post-traumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the Advancing Understanding of RecOvery afteR traumA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding, combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In Advancing Understanding of RecOvery afteR traumA study participants (n = 2480), using multinomial logistic regression modeling of 4 identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (odds ratio [OR] = 1.047, P < 0.001), the moderate pain class (OR = 1.031, P < 0.001), and the moderate recovery pain class (OR = 1.018, P = 0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison with SPS alone, neonatal limited bedding combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197) = 3.22, P < 0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP.

Background: Chronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner. Methods: We utilized blood-plasma samples and pain questionnaire data from men (n=99) and (n=223) women enrolled in AURORA , a multi-site emergency department (ED)-based longitudinal study of TSE survivors. We measured CRP using Ella/ELISA from plasma samples collected in the ED (‘peritraumatic CRP’, n=322) and six months following TSE (n=322). Repeated measures mixed-effects models were used to assess the relationship between peritraumatic CRP and post-TSE chronic pain. Results: Peritraumatic CRP levels significantly predicted post-TSE chronic pain, such that higher levels of CRP were associated with lower levels of pain over time following TSE, but only in men (men:β=-0.24, p =0.037; women:β=0.05, p =0.470). By six months, circulating CRP levels had decreased by more than half in men, but maintained similar levels in women (t(290)=1.926, p =0.055). More men with a decrease in CRP levels had decreasing pain over time versus women (men:83% women:65%; Z=2.21, p =0.027). Conclusions: In men but not women, we found circulating peritraumatic CRP levels predict chronic pain outcomes following TSE and resolution of CRP levels in men over time might be associated with increased pain recovery. Further studies are needed to validate these results. Summary: Peritraumatic circulating CRP levels predicted pain recovery in men following TSE and decreases in CRP levels over time were greater in men compared to women.

Traumatic stress exposures (TSE) are common in life. While most individuals recover following a TSE, a substantial subset develop adverse posttraumatic neuropsychiatric sequelae such as chronic posttraumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the AURORA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding (NLB), combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In AURORA study participants (n=2,480), using multinomial logistic regression modeling of four identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (OR=1.047, p p p =0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison to SPS alone NLB combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197)=3.22, p <0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP. Summary: In humans and rats, early life adversity is associated with a greater duration of musculoskeletal pain and mechanical hypersensitivity following traumatic stress exposures during adulthood.

Chronic stress is associated with anxiety and cognitive impairment. Repeated social defeat (RSD) in mice induces anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes to the brain. Nonetheless, it is unclear how microglia communicate with other cells to modulate the physiological and behavioral responses to stress. Using single-cell (sc)RNAseq, we identify novel, to the best of our knowledge, stress-associated microglia in the hippocampus defined by RNA profiles of cytokine/chemokine signaling, cellular stress, and phagocytosis. Microglia depletion with a CSF1R antagonist (PLX5622) attenuates the stress-associated profile of leukocytes, endothelia, and astrocytes. Furthermore, RSD-induced social withdrawal and cognitive impairment are microglia-dependent, but social avoidance is microglia-independent. Furthermore, single-nuclei (sn)RNAseq shows robust responses to RSD in hippocampal neurons that are both microglia-dependent and independent. Notably, stress-induced CREB, oxytocin, and glutamatergic signaling in neurons are microglia-dependent. Collectively, these stress-associated microglia influence transcriptional profiles in the hippocampus related to social and cognitive deficits.

Chronic stress is associated with increased anxiety, cognitive deficits, and post-traumatic stress disorder. Repeated social defeat (RSD) in mice causes long-term stress-sensitization associated with increased microglia activation, monocyte accumulation, and enhanced interleukin (IL)-1 signaling in endothelia and neurons. With stress-sensitization, mice have amplified neuronal, immune, and behavioral responses to acute stress 24 days later. This is clinically relevant as it shares key aspects with post-traumatic stress disorder. The mechanisms underlying stress-sensitization are unclear, but enhanced fear memory may be critical. The purpose of this study was to determine the influence of microglia and IL-1R1 signaling in neurons in the development of sensitization and increased fear memory after RSD. Here, RSD accelerated fear acquisition, delayed fear extinction, and increased cued-based freezing at 0.5 day. The enhancement in contextual fear memory after RSD persisted 24 days later. Next, microglia were depleted with a CSF1R antagonist prior to RSD and several parameters were assessed. Microglia depletion blocked monocyte recruitment to the brain. Nonetheless, neuronal reactivity (pCREB) and IL-1β RNA expression in the hippocampus and enhanced fear memory after RSD were microglial-independent. Because IL-1β RNA was prominent in the hippocampus after RSD even with microglia depletion, IL-1R1 mediated signaling in glutamatergic neurons was assessed using neuronal Vglut2⁺/IL-1R1^−/− mice. RSD-induced neuronal reactivity (pCREB) in the hippocampus and enhancement in fear memory were dependent on neuronal IL-1R1 signaling. Furthermore, single-nuclei RNA sequencing (snRNAseq) showed that RSD influenced transcription in specific hippocampal neurons (DG neurons, CA2/3, CA1 neurons) associated with glutamate signaling, inflammation and synaptic plasticity, which were neuronal IL-1R1-dependent. Furthermore, snRNAseq data provided evidence that RSD increased CREB, BDNF, and calcium signaling in DG neurons in an IL-1R1-dependent manner. Collectively, increased IL-1R1-mediated signaling (monocytes/microglia independent) in glutamatergic neurons after RSD enhanced neuronal reactivity and fear memory.