Corrigendum: Genetic Identification of the Central Nucleus and Other Components of the Central Extended Amygdala in Chicken During Development

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.

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

10.1101/283358 ◽

2018 ◽

Author(s):

Juyoen Hur ◽

Claire M. Kaplan ◽

Jason F. Smith ◽

Daniel E. Bradford ◽

Andrew S. Fox ◽

...

Keyword(s):

Alcohol Abuse ◽

Negative Reinforcement ◽

Functional Organization ◽

Treatment Strategies ◽

Central Nucleus ◽

Imaging Data ◽

Bed Nucleus ◽

Emotional Faces ◽

Extended Amygdala ◽

Activation Data

ABSTRACTAlcohol 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.

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Distinctive Regulation of Emotional Behaviors and Fear-Related Gene Expression Responses in Two Extended Amygdala Subnuclei With Similar Molecular Profiles

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.741895 ◽

2021 ◽

Vol 14 ◽

Author(s):

Shuhei Ueda ◽

Masahito Hosokawa ◽

Koji Arikawa ◽

Kiyofumi Takahashi ◽

Mao Fujiwara ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Central Nucleus ◽

Emotional States ◽

Expression Change ◽

Extended Amygdala ◽

Threat Processing ◽

Molecular Profiles ◽

Fear And Anxiety

The central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNST) are the two major nuclei of the central extended amygdala that plays essential roles in threat processing, responsible for emotional states such as fear and anxiety. While some studies suggested functional differences between these nuclei, others showed anatomical and neurochemical similarities. Despite their complex subnuclear organization, subnuclei-specific functional impact on behavior and their underlying molecular profiles remain obscure. We here constitutively inhibited neurotransmission of protein kinase C-δ-positive (PKCδ+) neurons—a major cell type of the lateral subdivision of the CeA (CeL) and the oval nucleus of the BNST (BNSTov)—and found striking subnuclei-specific effects on fear- and anxiety-related behaviors, respectively. To obtain molecular clues for this dissociation, we conducted RNA sequencing in subnuclei-targeted micropunch samples. The CeL and the BNSTov displayed similar gene expression profiles at the basal level; however, both displayed differential gene expression when animals were exposed to fear-related stimuli, with a more robust expression change in the CeL. These findings provide novel insights into the molecular makeup and differential engagement of distinct subnuclei of the extended amygdala, critical for regulation of threat processing.

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The Extended Amygdala: Are the Central Nucleus of the Amygdala and the Bed Nucleus of the Stria Terminalis Differentially Involved in Fear versus Anxiety?

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1999.tb09273.x ◽

1999 ◽

Vol 877 (1 ADVANCING FRO) ◽

pp. 281-291 ◽

Cited By ~ 220

Author(s):

MICHAEL DAVIS ◽

CHANGJUN SHI

Keyword(s):

Central Nucleus ◽

Stria Terminalis ◽

Bed Nucleus ◽

Extended Amygdala

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Maternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner

Frontiers in Physiology ◽

10.3389/fphys.2021.775404 ◽

2021 ◽

Vol 12 ◽

Author(s):

Natalia Bonetti Bertagna ◽

Cristiane Aparecida Favoretto ◽

Ben Tagami Rodolpho ◽

Paola Palombo ◽

Thais Suemi Yokoyama ◽

...

Keyword(s):

Maternal Separation ◽

Fixed Ratio ◽

Progressive Ratio ◽

Ethanol Consumption ◽

Ethanol Intake ◽

Central Nucleus ◽

Control Group ◽

Dependent Manner ◽

Self Administration ◽

Extended Amygdala

Maternal separation (MS) stress is a predictive animal model for evaluating the effects of early stress exposure on alcohol use disorders (AUD). The extended amygdala (AMY) is a complex circuit involved in both stress- and ethanol-related responses. We hypothesized that MS stress may increase ethanol consumption in adulthood, as well as augment neuronal activity in extended AMY, in a sex-dependent manner. We aimed to investigate the influence of MS stress on the ethanol consumption of male and female mice, and the involvement of extended amygdala sub-nuclei in this process. The C57BL/6J pups were subjected to 180min of MS, from postnatal day (PND) 1 to 14. The control group was left undisturbed. On PND 45, mice (n=28) in cages were exposed to a bottle containing 20% ethanol (w/v) for 4h during the dark period of the light-dark cycle, for 3weeks. Afterward, mice underwent ethanol self-administration training in operant chambers under fixed ratio (FR) schedule. Then, subjects were tested under 2h sessions of a progressive-ratio (PR) schedule of reinforcement (the last ratio achieved was considered the breaking point), and at the end, a 4h session of FR schedule (binge-intake). An immunohistochemistry assay for Fos protein was performed in Nucleus Accumbens (NAcc), Bed Nucleus of Stria Terminalis (BNST), and AMY. Our results showed that in the third week of training, the female MS group consumed more ethanol than the respective control group. The MS group presented increased breakpoint parameters. Female control group and male MS group were more resistant to bitter quinine taste. Increased Fos-immunoreactive neurons (Fos-IR) were observed in the central nucleus of AMY, but not in NAcc nor BNST in male maternal-separated mice. Maternal separation stress may influence ethanol intake in adulthood, and it is dependent on the sex and reinforcement protocol.

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Intrinsic functional connectivity of the central extended amygdala

10.1101/178533 ◽

2017 ◽

Author(s):

Rachael M. Tillman ◽

Melissa D. Stockbridge ◽

Brendon M. Nacewicz ◽

Salvatore Torrisi ◽

Andrew S. Fox ◽

...

Keyword(s):

Functional Connectivity ◽

High Precision ◽

Community Dwelling ◽

Central Nucleus ◽

Stria Terminalis ◽

Bed Nucleus ◽

Extended Amygdala ◽

Intrinsic Functional Connectivity ◽

Multiband Imaging ◽

Fear And Anxiety

ABSTRACTThe 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.GRAPHICAL ABSTRACTIntrinsic functional connectivity of bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce) in 130 psychiatrically healthy adults.HIGHLIGHTSBST and Ce implicated in normal and pathological fear and anxietyTraced the intrinsic functional connectivity of the BST and the Ce in 130 adultsMultiband imaging, high-precision registration, unsmoothed data, newly developed seedsBST and Ce show robust coupling with one another, hippocampus, insula, MCC, and vmPFCBST shows stronger coupling with prefrontal/cingulate territories and brainstem/PAG

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The value of extended amygdala structures in emotive effects of narcogenic with diverse chemical structure

Research Results in Pharmacology ◽

10.3897/rrpharmacology.5.38389 ◽

2019 ◽

Vol 5 (3) ◽

pp. 11-19

Author(s):

Roman O. Roik ◽

Andrei A. Lebedev ◽

Petr D. Shabanov

Keyword(s):

Nucleus Accumbens ◽

Dopamine Receptors ◽

Conditioned Reinforcement ◽

Gaba Receptors ◽

Sch 23390 ◽

Central Nucleus ◽

D1 Receptors ◽

Nucleus Accumbens Shell ◽

Bed Nucleus ◽

Extended Amygdala

Introduction: Studies on the mechanisms of the reinforcing action of opioid and non-opioid narcotics confirmed the existence in the brain of a specialized system named the extended amygdala. Materials and methods: To clarify the value of the extended amygdala structures (bed nucleus, central nucleus of the amygdala and nucleus accumbens shell) in the mechanisms of unconditioned and conditioned reinforcement activated by various narcogenic, this paper carried out a neuropharmacological analysis of these effects, using blockade of dopamine receptors, GABA, opioids and CRF receptors within these brain structures, as well as an analysis of behavioral responses by self-stimulation (unconditioned reinforcement) and conditioned place preference (CPP) (conditioned reinforcement). Results and discussion: The central amygdala and the bed nucleus have a controlling influence on the hypothalamus, which is predominantly of CRF-, GABA- and dopaminergic nature. Through D1 dopamine receptors,, a direct positive (activating) effect on the lateral hypothalamus is made. The D2 receptor blockade of the nucleus accumbens prevents narcogenic from exerting the reinforcing properties, which are primarily stimulating. The blockade of the D1 receptors of the nucleus accumbens by SCH-23390 prevents the expression of unconditioned and conditioned reinforcing properties of predominantly opiates and opioids. The blockade of GABAA receptors in the nucleus accumbens with bicuculline prevents the manifestation of the primary and secondary reinforcing properties (CPP) of psychostimulant drugs (amphetamine), without affecting the effects of opiates and opioids (fentanyl and leu-enkephalin). Conclusion: The pharmacological analysis proves that CRF, dopamine and GABA receptors are most important for the correction of reinforcement activated by various narcogenic.

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