Biology subjects

Fox, A. S.

Publications and source records attributed to Fox, A. S..

17 recordsLinked to original sources

bioRxiv2026

Extended amygdala function is governed by threat probability, not uncertainty

Anxiety is a universal experience that arises as we anticipate negative events that may or may not happen. When extreme, anxiety is a major cause of distress, suffering, and disability-adjusted life years, with nearly one in four individuals experiencing clinically relevant anxiety in their lifetime1-3. Elucidating the biological basis of anxiety has the potential to help people understand, cope with, and ultimately receive improved treatments for their anxiety. The canonical neuroscientific model of anxiety posits that distinct regions of the extended amygdala (EA) elicit distress that is conditional on threat uncertainty4. Here, we refute this model using a precise computational framework to disambiguate specific dimensional facets of threat uncertainty in a racially diverse sample of 104 individuals. We show that self-report, psychophysiological, and neural correlates of threat anticipation are much more strongly associated with threat probability than uncertainty per se. Importantly, EA regions, including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), were most reliably associated with threat probability--contrary to the canonical model. Re-examination of the pioneering experiments that motivated the canonical model reveal a previously unappreciated confound between probability and uncertainty, suggesting the novel hypothesis that EA regions differ in their sensitivity to low-probability threats. Our fMRI data support this, showing that BST is more sensitive to low-probability threats than Ce. Moreover, lesion experiments in rhesus monkeys (Macaca mulatta) demonstrate that BST causally contributes to defensive behavior in low-probability threat contexts. Together, these data reconcile previous empirical inconsistencies, provide a fresh theoretical perspective on the neurobiology of anxiety, and underscore the theoretical importance of a formal lingua franca for coordinated cross-species emotion research.

neuroscience↗

bioRxiv2025

Fear, anxiety, and the extended amygdala- Absence of evidence for strict functional segregation

Since the time of Freud, the distinction between fear and anxiety has been a hallmark of influential models of emotion and emotional illness, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) and Research Domain Criteria (RDoC). Fear and anxiety disorders are common, debilitating, and challenging to treat, underscoring the importance of developing accurate models of the underlying neurobiology. Although there is consensus that the extended amygdala (EA) plays a central role in orchestrating responses to threat, the respective contributions of its two major subdivisions--the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)--remain contentious. To help adjudicate this debate, we performed a harmonized mega-analysis of fMRI data acquired from 295 adults as they completed a well-established threat-anticipation paradigm. Contrary to popular double-dissociation models, results demonstrated that the Ce responds to temporally uncertain threat and the BST responds to certain threat. In direct comparisons, the two regions showed statistically indistinguishable responses, with strong Bayesian evidence of regional equivalence. In contrast, frontocortical regions responded preferentially to uncertain-threat anticipation. Together, these observations underscore the need to reformulate conceptual models that posit a strict segregation of temporally certain and uncertain threat processing in the EA.

neuroscience↗

bioRxiv2024

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying neurobiology remains contentious. Leveraging a translationally relevant fMRI paradigm and theory-driven modeling approach in 220 adult humans, we demonstrate that certain- and uncertain-threat anticipation recruit a shared circuit that encompasses the central extended amygdala (EAc), periaqueductal gray, midcingulate, and anterior insula. This circuit exhibits persistently elevated activation when threat is uncertain and distal, and transient bursts of activation just before certain encounters with threat. Although there is agreement that the EAc plays a critical role in orchestrating responses to threat, confusion persists about the respective contributions of its major subdivisions, the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce). Here we used anatomical regions-of-interest to demonstrate that the BST and Ce exhibit statistically indistinguishable threat dynamics. Both regions exhibited activation dynamics that run counter to popular models, with the Ce showing sustained responses to uncertain-and-distal threat and the BST showing phasic responses to certain-and-imminent threat. For many scientists, feelings are the hallmark of fear and anxiety. Here we used an independently validated multivoxel brain signature to covertly probe the moment-by-moment dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research. SIGNIFICANCE STATEMENT"Fear" is widely viewed as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Prior work has begun to reveal the neural systems recruited by certain and uncertain anticipated threats, but has yet to rigorously plumb the moment-by-moment dynamics anticipated by theory. Here we used a novel combination of neuroimaging techniques to demonstrate that certain and uncertain threat recruit a common threat-anticipation circuit. Activity in this circuit and covert measures of distress showed similar patterns of context-dependent dynamics, exhibiting persistent increases when anticipating uncertain-threat encounters and transient surges just before certain encounters. These observations provide fresh insights into the neurobiology of fear and anxiety, laying the groundwork for more ambitious clinical and mechanistic research.

neuroscience↗

bioRxiv2023

The Quest for Dynamic Consistency: A Comparison of OpenSim Tools for Residual Reduction in Simulations of Human Running

The use of synchronous kinematic and kinetic data in simulations of human running will typically lead to dynamic inconsistencies (i.e. residual forces and moments) being present. Minimising the residual forces and moments in such simulations is important to ensure plausible model outputs (e.g. joint moments, muscle forces) are obtained. A variety of approaches suitable for residual reduction are available in OpenSim, however a detailed comparison of these is yet to be conducted. This study compared a variety of OpenSim tools applicable for residual reduction in simulations of human running. A series of approaches (i.e. singular and iterative Residual Reduction Algorithm, MocoTrack, AddBiomechanics) designed to reduce residual forces and moments were examined using an existing dataset of 10 male participants running on a treadmill at 5.0 m{middle dot}s-1 (n = 3 gait cycles per participant). The computational time, resultant residual forces and moments, and output joint kinematics and kinetics from each approach were compared. A computational cost to residual reduction trade-off was identified, where lower residual forces and moments were achieved using approaches that required longer computational times. All of the tested approaches regularly reduced residual forces below recommended thresholds, however only the MocoTrack approach could consistently achieve acceptable levels for residual moments. The AddBiomechanics and MocoTrack approaches produced variable lower and upper body kinematics, respectively, versus the remaining approaches; with minimal other qualitative differences were identified between joint kinematics from each approach. Joint kinetics were qualitatively similar between approaches, however MocoTrack generated much noisier joint kinetic signals. The MocoTrack approach was the most consistent and best performing approach for reducing residuals to near-zero levels, at the cost of longer computational times and potentially noisier joint kinetic signals. This study provides OpenSim users with evidence to inform decision-making at the residual reduction step of their modelling and simulation workflow when analysing human running.

bioengineering↗

bioRxiv2023

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala

Neuroticism/Negative Emotionality (N/NE)--the tendency to experience anxiety, fear, and other negative emotions--is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are non-fungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing mechanistic research. SIGNIFICANCE STATEMENTNeuroticism/Negative Emotionality (N/NE) is a core dimension of mammalian temperament. Elevated levels of N/NE confer risk for a panoply of adversities--from reduced wealth and divorce to depression and death--yet the underlying neurobiology remains unclear. Here we show that N/NE is associated with heightened activation in the bed nucleus of the stria terminalis (BST) during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST reactivity during the certain anticipation of threat or the acute presentation of threat-related faces, two popular probes of the emotional brain. These findings refine our understanding of what has been termed the single most important psychological risk factor in public health, with implications for on-going biobank and therapeutics research.

neuroscience↗

bioRxiv2023

Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates

Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds and rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and ex vivo human brain slices although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. Vasculature-secreted Hevin (a synaptogenic protein) rescued synaptic deficits in a mouse model.

bioengineering↗

bioRxiv2022

Measurement error associated with gait cycle selection in treadmill running at various speeds

A common approach in biomechanical analysis of running technique is to average data from several gait cycles to compute a representative mean. However, the impact of the quantity and selection of gait cycles on biomechanical measures is not well understood. We examined the effects of gait cycle selection on kinematic data by: (i) comparing representative means calculated from varying numbers of gait cycles to global means from the entire capture period; and (ii) comparing representative means from varying numbers of gait cycles sampled from different parts of the capture period. We used a public dataset (n = 28) of lower limb kinematics captured during a 30-second period of treadmill running at three speeds (2.5m {middle dot} s-1, 3.5m {middle dot} s-1 and 4.5m {middle dot} s-1). Ground truth values were determined by averaging data across all collected strides and compared to representative means calculated from random samples (1,000 samples) of n (range = 5--30) consecutive gait cycles. We also compared representative means calculated from n (range = 5--15) consecutive gait cycles randomly sampled (1,000 samples) from within the same data capture period. The mean, variance and range of the absolute error of the representative mean compared to the ground truth mean progressively reduced across all speeds as the number of gait cycles used increased. Similar magnitudes of error were observed between the 2.5m {middle dot} s-1 and 3.5m {middle dot} s-1 speeds at comparable gait cycle numbers -- where the maximum errors were < 1.5 degrees even with a small number of gait cycles (i.e. 5-10). At the 4.5m {middle dot} s-1 speed, maximum errors typically exceeded 2-4 degrees when a lower number of gait cycles were used. Subsequently, a higher number of gait cycles (i.e. 25-30) was required to achieve low errors (i.e. 1-2 degrees) at the 4.5m {middle dot} s-1 speed. The mean, variance and range of absolute error of representative means calculated from different parts of the capture period was consistent irrespective of the number of gait cycles used. The error between representative means was low (i.e. <1.5 degrees) and consistent across the different number of gait cycles at the 2.5m {middle dot} s-1 and 3.5m {middle dot} s-1 speeds, and consistent but larger (i.e. up to 2-4 degrees) at the 4.5m {middle dot} s-1 speed. Our findings suggest that selecting as many gait cycles as possible from a treadmill running bout will minimise potential error. Analysing a small sample (i.e. 5-10 cycles) will typically result in minimal error (i.e. < 2 degrees), particularly at lower speeds (i.e. 2.5m {middle dot} s-1 and 3.5m {middle dot} s-1). Researchers and clinicians should consider the balance between practicalities of collecting and analysing a smaller number of gait cycles against the potential error when determining their methodological approach. Irrespective of the number of gait cycles used, we recommend that the potential error introduced by the choice of gait cycle number be considered when interpreting the magnitude of effects in treadmill-based running studies.

scientific communication and education↗

bioRxiv2022

Rhesus Infant Nervous Temperament Predicts Peri-Adolescent Central Amygdala Metabolism & Behavioral Inhibition Measured by a Machine-Learning Approach

Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc)--a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST)--as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders--and how this relationship is mediated by alterations in the EAc--could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.

neuroscience↗

bioRxiv2022

Intravenous gene transfer throughout the brain of infant Old World primates using AAV

Adeno-associated viruses (AAVs) can enable robust and safe gene delivery to the mammalian central nervous system (CNS). While the scientific community has developed numerous neurotropic AAV variants for systemic gene-transfer to the rodent brain, there are few AAVs that efficiently access the CNS of higher order primates. We describe here AAV.CAP-Mac, an engineered AAV variant that enables systemic, brain-wide gene delivery in infants of two Old World primate species--the rhesus macaque (Macaca mulatta) and the green monkey (Chlorocebus sabaeus). We identified CAP-Mac using a multi-species selection strategy, initially screening our library in the adult common marmoset (Callithrix jacchus) and narrowing our pool of test-variants for another round of selection in infant macaques. In individual characterization, CAP-Mac robustly transduces human neurons in vitro and Old World primate neurons in vivo, where it targets all lobes of cortex, the cerebellum, and multiple subcortical regions of disease relevance. We use CAP-Mac for Brainbow-like multicolor labeling of macaque neurons throughout the brain, enabling morphological reconstruction of both medium spiny neurons and cortical pyramidal cells. Because of its broad distribution throughout the brain and high neuronal efficiency in infant Old World primates compared to AAV9, CAP-Mac shows promise for researchers and clinicians alike to unlock novel, noninvasive access to the brain for efficient gene transfer.

bioengineering↗

bioRxiv2021

Anxiety-related frontocortical activity is associated with dampened stressor reactivity in the real world

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes--from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys has begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here we used a combination of approaches-- including neuroimaging assays of threat anticipation and emotional face perception and >10,000 momentary assessments of emotional experience--to demonstrate that individuals showing greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experience lower levels of stressor-dependent distress in their daily lives (n=202-208). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world. STATEMENT OF RELEVANCEAnxiety, sadness, and other negative emotions are hallmarks of the human condition. When extreme, they contribute to a variety of adverse outcomes--from physical and mental illness to divorce and premature death--pointing to the need to develop a better understanding of the underlying brain circuitry. Recent work has begun to reveal the neural systems governing negative affect, but the relevance of these tantalizing laboratory discoveries to the real world has remained unclear. Here we used a combination of brain imaging and smartphone-based survey techniques to show that individuals marked by greater activation in a cingulo-opercular circuit during an anxiety-promoting laboratory paradigm tend to experience diminished distress in response to everyday stressors. These observations provide new insights into the brain systems most relevant to moment-by-moment fluctuations in negative mood, underscoring the importance of more recently evolved cortical association areas.

neuroscience↗

bioRxiv2020

U-Net Model for Brain Extraction on Non-human Primates

Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been designed for and applied to human data and are often challenged by non-human primates (NHP) data. Amongst recent attempts to improve performance on NHP data, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied to multi-site samples in NHP imaging. To overcome this challenge, we used a transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred this to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across a heterogeneous sample from multiple sites in the PRIME-DE with less computational cost (20s~10min). We also demonstrated the transfer-learning process enables the macaque model to be updated for use with scans from chimpanzees, marmosets, and other mammals (e.g. pig). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction.

neuroscience↗

bioRxiv2020

Infant Inhibited Temperament in Primates Predicts Adult Behavior, is Heritable, and is Associated with Anxiety Relevant Genetic Variation

An anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV near CTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p-values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.

genetics↗

bioRxiv2020

Simulating the impact of glenohumeral capsulorrhaphy on movement kinematics and muscle function in activities of daily living

This study aimed to use a predictive simulation framework to examine shoulder kinematics, muscular effort and task performance during functional upper limb movements under simulated selective glenohumeral capsulorrhaphy. A musculoskeletal model of the torso and upper limb was adapted to include passive restraints that simulated the changes in shoulder range of motion stemming from selective glenohumeral capsulorrhaphy procedures (anteroinferior, anterosuperior, posteroinferior, posterosuperior, and total anterior, inferior, posterior and superior). Predictive muscle-driven simulations of three functional movements (upward reach, forward reach and head touch) were generated with each model. Shoulder kinematics (elevation, elevation plane and axial rotation), muscle cost (i.e. muscular effort) and task performance time were compared to a baseline model to assess the impact of the capsulorrhaphy procedures. Minimal differences in shoulder kinematics and task performance times were observed, suggesting that task performance could be maintained across the capsulorrhaphy conditions. Increased muscle cost was observed under the selective capsulorrhaphy conditions, however this was dependent on the task and capsulorrhaphy condition. Larger increases in muscle cost were observed under the capsulorrhaphy conditions that incurred the greatest reductions in shoulder range of motion (i.e. total inferior, total anterior, anteroinferior and total posterior conditions) and during tasks that required shoulder kinematics closer to end range of motion (i.e. upward reach and head touch). The elevated muscle loading observed could present a risk to joint capsule repair. Appropriate rehabilitation following glenohumeral capsulorrhaphy is required to account for the elevated demands placed on muscles, particularly when significant range of motion loss presents.

bioengineering↗

bioRxiv2020

Anxiety and the neurobiology of uncertain threat anticipation

When extreme, anxiety--a state of distress and arousal prototypically evoked by uncertain danger--can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for functional MRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically co-localized in fronto-cortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with fronto-cortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala--the two major subdivisions of the extended amygdala--play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety. SIGNIFICANCE STATEMENTAnxiety--an emotion prototypically associated with the anticipation of uncertain harm--has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended-amygdala occupies center-stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear. RESOURCE SHARINGRaw data are available at the National Institute of Mental Healths Data Archive. Key statistical maps are or will be publicly available at NeuroVault.org.

neuroscience↗

bioRxiv2019

Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early Life Anxious Temperament

Children exhibiting extreme anxious temperament (AT) are at an increased risk to develop anxiety and depression. Work in young rhesus monkeys mechanistically links the central nucleus of the amygdala (Ce) to AT. Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT s molecular underpinnings by focusing on lateral Ce (CeL) neurons. We found 528 AT-related transcripts, including protein kinase C type-delta (PKC{delta}), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKC{delta} neurons in the rhesus CeL, compared their distribution to the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis (BSTLd). These findings present evidence in the primate of a CeL to BSTLd circuit that maybe relevant to understanding human anxiety and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.

neuroscience↗

bioRxiv2018

Acute alcohol administration dampens threat-related activation in the central extended amygdala

Alcohol abuse is common, imposes a staggering burden on public health, and is challenging to treat, underscoring the need to develop a deeper understanding of the underlying neurobiology. When administered acutely, ethyl alcohol reduces threat reactivity in humans and other animals, and there is growing evidence that threat-dampening and related negative reinforcement mechanisms support the etiology and recurrence of alcohol and other kinds of substance misuse. Converging lines of evidence motivate the hypothesis that these effects are mediated by the central extended amygdala (EAc)--including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)--but the relevance of this circuitry to acute alcohol effects in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband imaging data were acquired from 49 social drinkers while they performed an fMRI-optimized emotional-faces/places paradigm after consuming alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to threat-related emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from anatomically defined Ce and BST regions-of-interest. Analyses revealed a similar pattern of dampening across the two regions. In short, alcohol acutely dampens reactivity to threat-related faces in humans and it does so similarly across the two major divisions of the EAc. These observations provide a framework for understanding the translational relevance of addiction models derived from work in rodents, inform on-going debates about the functional organization of the EAc, and set the stage for bi-directional translational models aimed at developing improved treatment strategies for alcohol abuse and other addictions.

neuroscience↗

bioRxiv2017

Intrinsic functional connectivity of the central extended amygdala

The central extended amygdala (EAc)--including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)--plays a key role in orchestrating states of fear and anxiety and is implicated in the development and maintenance of anxiety disorders, depression, and substance abuse. Although it is widely thought that these disorders reflect the coordinated actions of large-scale functional circuits in the brain, the architecture of the EAc functional network, and the degree to which the BST and the Ce show distinct patterns of intrinsic functional connectivity, remains incompletely understood. Here, we leveraged a combination of approaches to trace the connectivity of the BST and the Ce in 130 psychiatrically healthy, racially diverse, community-dwelling adults with enhanced power and precision. Multiband imaging, high-precision data registration techniques, and spatially unsmoothed data were used to maximize anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala ( substantia innominata), the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed significant coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed significantly stronger connectivity with prefrontal territories--including the vmPFC, anterior MCC and pregenual anterior cingulate cortex--as well as the thalamus, striatum, and the periaqueductal gray. The only regions showing stronger functional connectivity with the Ce were located in the anterior hippocampus and dorsal amygdala. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and highlight the value of several new approaches to image registration which may be particularly useful for researchers working with de-identified neuroimaging data.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC=\"FIGDIR/small/178533_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (61K):\norg.highwire.dtl.DTLVardef@10ce93corg.highwire.dtl.DTLVardef@a467ceorg.highwire.dtl.DTLVardef@19b4550org.highwire.dtl.DTLVardef@e38e2a_HPS_FORMAT_FIGEXP M_FIG Intrinsic functional connectivity of bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce) in 130 psychiatrically healthy adults.\n\nC_FIG HIGHLIGHTSO_LIBST and Ce implicated in normal and pathological fear and anxiety\nC_LIO_LITraced the intrinsic functional connectivity of the BST and the Ce in 130 adults\nC_LIO_LIMultiband imaging, high-precision registration, unsmoothed data, newly developed seeds\nC_LIO_LIBST and Ce show robust coupling with one another, hippocampus, insula, MCC, and vmPFC\nC_LIO_LIBST shows stronger coupling with prefrontal/cingulate territories and brainstem/PAG\nC_LI

neuroscience↗