Summary Background Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic ...activity predicts risk of subsequent cardiovascular events. Methods Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent18 F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. Findings 293 patients (median age 55 years IQR 45·0–65·5) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7–4·8). Amygdalar activity was associated with increased bone-marrow activity ( r =0·47; p<0·0001), arterial inflammation ( r =0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27–1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation ( r =0·70; p=0·0083). Perceived stress was associated with amygdalar activity ( r =0·56; p=0·0485), arterial inflammation ( r =0·59; p=0·0345), and C-reactive protein ( r =0·83; p=0·0210). Interpretation In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. Funding None.
Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed ...for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility.
Display omitted
•vHC projects to the BA and the CEA via separate pathways with distinct behavioral roles•vHC inputs to the CEA contact output cells that target PAG and NST•vHC projection to the BA is required for contextual fear memory retrieval•vHC projection to the CEA is necessary for context-dependent cue fear memory retrieval
Two parallel hippocampal circuits link sensory memories with the context in which they are formed, helping the selection of appropriate behavioral responses to fear.
Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits ...underlying the “engram” of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.
Threat processing is central to understanding posttraumatic stress disorder and other fear- and stress-related disorders. Maddox et al. describe recent progress in this area, understanding the neural circuits underlying trauma-related memories encoded throughout the brain and the body.
Abstract Background Maternal inflammation during pregnancy increases risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the ...developing fetal brain is hypothesized as one potential mechanism, but has not been examined in humans. Methods Participants were N=86 adult women recruited in early pregnancy, and their infants born after 34-weeks gestation. A biological indicator of maternal inflammation (interleukin-6 IL-6), which has been shown to influence fetal brain development in animal models, was quantified serially in early, mid and late pregnancy. Structural and functional brain MRI was acquired in neonates shortly after birth. Infants’ amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24-months-of-age, children completed a snack delay task to assess impulse control. Results Higher average maternal IL-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24-months-of-age, and mediated the association between higher maternal IL-6 concentrations and lower impulse control. Conclusions These findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts.
Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the ...pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.
Display omitted
•Peripheral CD4+ T cells control stress-induced anxiety-like behavior•Mitochondrial fission in peripheral CD4+ T cell causes severe anxiety symptoms•T cell-derived xanthine acts on the oligodendrocytes in the left amygdala•IRF-1 controls purine synthesis in CD4+ T cells and triggers the onset of anxiety
Xanthine metabolism in CD4+ T cells is found to be central to mediating the effects of stress-induced anxiety like behavior in mice through its effects on oligodendrocyte proliferation and neuronal hyperactivation.
Maternal depressive symptoms influence neurodevelopment in the offspring. Such effects may appear to be gender-dependent. The present study examined contributions of prenatal and postnatal maternal ...depressive symptoms to the volume and microstructure of the amygdala in 4.5-year-old boys and girls. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at 26 weeks of gestation. Postnatal maternal depression was assessed at 3 months using the EPDS and at 1, 2, 3 and 4.5 years using the Beck's Depression Inventory-II. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 4.5-year-old children to extract the volume and fractional anisotropy (FA) values of the amygdala. Our results showed that greater prenatal maternal depressive symptoms were associated with larger right amygdala volume in girls, but not in boys. Increased postnatal maternal depressive symptoms were associated with higher right amygdala FA in the overall sample and girls, but not in boys. These results support the role of variation in right amygdala structure in transmission of maternal depression to the offspring, particularly to girls. The differential effects of prenatal and postnatal maternal depressive symptoms on the volume and FA of the right amygdala suggest the importance of the timing of exposure to maternal depressive symptoms in brain development of girls. This further underscores the need for intervention targeting both prenatal and postnatal maternal depression to girls in preventing adverse child outcomes.
Abstract Background Early life stress (ELS) can compromise development, with higher amounts of adversity linked to behavioral problems. To understand this linkage, a growing body of research has ...examined two brain regions involved with socioemotional functioning—amygdala and hippocampus. Yet empirical studies have reported increases, decreases, and no differences within human and nonhuman animal samples exposed to different forms of ELS. This divergence in findings may stem from methodological factors, nonlinear effects of ELS, or both. Methods We completed rigorous hand-tracing of the amygdala and hippocampus in three samples of children who experienced different forms of ELS (i.e., physical abuse, early neglect, or low socioeconomic status). Interviews were also conducted with children and their parents or guardians to collect data about cumulative life stress. The same data were also collected in a fourth sample of comparison children who had not experienced any of these forms of ELS. Results Smaller amygdala volumes were found for children exposed to these different forms of ELS. Smaller hippocampal volumes were also noted for children who were physically abused or from low socioeconomic status households. Smaller amygdala and hippocampal volumes were also associated with greater cumulative stress exposure and behavioral problems. Hippocampal volumes partially mediated the relationship between ELS and greater behavioral problems. Conclusions This study suggests ELS may shape the development of brain areas involved with emotion processing and regulation in similar ways. Differences in the amygdala and hippocampus may be a shared diathesis for later negative outcomes related to ELS.
Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying ...relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.
Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in ...learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning--a simple form of associative learning--through two distinct disinhibitory mechanisms. During an auditory cue, PV(+) interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM(+) interneurons, thereby enhancing auditory responses and promoting cue-shock associations. During an aversive footshock, however, both PV(+) and SOM(+) interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.
Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving ...5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HT
) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOM
neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HT
→SOM
pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HT
→SOM
→lateral habenula pathway may mediate at least some aspects of CDS.
PDF
