NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis

Glangetas, Christelle; Massi, Léma; Fois, Giulia R.; Jalabert, Marion; Girard, Delphine; Diana, Marco; Yonehara, Keisuke; Roska, Botond; Xu, Chun; Lüthi, Andreas; Caillé, Stéphanie; Georges, François

doi:10.1038/ncomms14456

Cited by 46 publications

(41 citation statements)

References 44 publications

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“…The amygdala, PFC, and hippocampus have strong connections with the BNST (Canteras and Swanson, 1992); deCampo and Fudge, 2013; Dong et al, 2001; Glangetas et al, 2017; Johnson et al, 2019; McDonald et al, 1999; Reichard et al, 2017; Reynolds and Zahm, 2005; Torrisi et al, 2015; Vertes, 2004; Weller and Smith, 1982; Wood et al, 2019). In line with previous work, the expression of freezing (whether elicited by a forward or, in our case, backward CS) increased the number of Fos-positive neurons in these regions (Herry et al, 2008; Jin and Maren, 2015; Knapska and Maren, 2009; Lemos et al, 2010; Wang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

Goode

Ressler

Acca

et al. 2019

eLife

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The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.

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Section: Discussionmentioning

confidence: 99%

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

Goode

Ressler

Acca

et al. 2019

eLife

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“…Inhibition of vHPC-LHA projections in mice increases open arm exploration in the EPM, while modulation of vHPC-amygdala projections has no effect on anxiety, but modulates learned fear [29]. In contrast, outputs from the vHPC to lateral septum [30] and BNST [36] are anxiolytic in the EPM. Activation of the vHPC-BNST pathway may serve to interface the vHPC with the hypothalamic-pituitary-adrenal axis to decrease the release of stress hormones [37,38].…”

Section: Box 2 Classification Of Biomarkersmentioning

confidence: 95%

Circuit-Based Biomarkers for Mood and Anxiety Disorders

Xia

Kheirbek

2020

Trends in Neurosciences

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Mood and anxiety disorders are complex heterogeneous syndromes that manifest in dysfunctions across multiple brain regions, cell types, and circuits. Biomarkers using brain-wide activity patterns in humans have proven useful in distinguishing between disorder subtypes and identifying effective treatments. In order to improve biomarker identification, it is crucial to understand the basic circuitry underpinning brain-wide activity patterns. Leveraging a large repertoire of techniques, animal studies have examined roles of specific cell types and circuits in driving maladaptive behavior. Recent advances in multiregion recording techniques, data-driven analysis approaches, and machine-learning-based behavioral analysis tools can further push the boundary of animal studies and bridge the gap with human studies, to assess how brain-wide activity patterns encode and drive emotional behavior. Together, these efforts will allow identifying more precise biomarkers to enhance diagnosis and treatment. Distributed Neural Circuits Underly Mood and Anxiety Disorders Mood and anxiety disorders disrupt basic functions of individuals' lives, and are among the leading causes of disability [1]. In the USA, it is estimated that at a given timepoint, 10-20% of adults are impacted, and 20-30% of adults will experience a mood or anxiety disorder at some point in their lives (https://www.hcp.med.harvard.edu/ncs). However, most existing treatments are not effective [2,3]; largely due to a lack of clear understanding of disease etiology. The search for effective treatment is further complicated by the fact that mood and anxiety disorders are heterogeneous syndromes with various subtypes, where patients present diverse symptoms even for the same disorder, and often respond differently to the same treatment [4-7]. Highlights Mood and anxiety disorders are complex neural-circuit-based conditions that arise from dysfunctions across multiple cell types, brain regions, and circuits. Recent efforts in identifying circuit-based biomarkers using brain-wide activity patterns have shown promising results in stratifying disorder subtypes and identifying effective treatments for patients with mood and anxiety disorders.

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“…The hippocampus exerts inhibitory control over stress hormone release (via the hypothalamic-pituitary-adrenal [HPA] axis) through its glutamatergic projections to the BNST (Cullinan et al 1993;Forray and Gysling 2004). Thus, projections from the hippocampus to the BNST may modulate anxiety (and perhaps BNST-dependent fear) not by driving defensive responses per se but by reducing stress responses in particular contexts (Glangetas et al 2017; also, see Gorka et al 2017). The PFC, particularly the infralimbic (IL) region of the PFC, projects strongly to the BNST -this circuit (along with BNST-projecting cells from the neighboring orbitofrontal cortex) may be involved in both reward (Jalabert et al 2009;Reisiger et al 2014) and threat processing (Spencer et al 2005;Fox et al 2010;Motzkin et al 2015).…”

Section: Neural Circuits For Aversive Learning and Memorymentioning

confidence: 99%

Role of the bed nucleus of the stria terminalis in aversive learning and memory

Goode

2017

Learn. Mem.

115

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Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective forebrain"-including the amygdala, ventral hippocampus, and medial prefrontal cortex-and the hypothalamic and brainstem areas that have been implicated in neuroendocrine, autonomic, and behavioral responses to actual or anticipated threats. However, the precise contribution of the BNST to defensive behavior is unclear, both in terms of the antecedent stimuli that mobilize BNST activity and the consequent defensive reactions. For example, it is well known that the BNST is essential for contextual fear conditioning, but dispensable for fear conditioning to discrete conditioned stimuli (CSs), at least as indexed by freezing behavior. However, recent evidence suggests that there are circumstances in which contextual freezing may persist independent of the BNST. Furthermore, the BNST is involved in the reinstatement (or relapse) of conditioned freezing to extinguished discrete CSs. As such, there are critical gaps in understanding how the BNST contributes to fundamental processes involved in Pavlovian fear conditioning. Here, we attempt to provide an integrative account of BNST function in fear conditioning. We discuss distinctions between unconditioned stress and conditioned fear and the role of BNST circuits in organizing behaviors associated with these states. We propose that the BNST mediates conditioned defensive responses-not based on the modality or duration of the antecedent threat or the duration of the behavioral response to the threat-but rather as consequence the ability of an antecedent stimulus to predict when an aversive outcome will occur (i.e., its temporal predictability). We argue that the BNST is not uniquely mobilized by sustained threats or uniquely involved in organizing sustained fear responses. In contrast, we argue that the BNST is involved in organizing fear responses to stimuli that poorly predict danger will occur, no matter the duration, modality, or complexity of those stimuli. The concepts discussed in this review are critical to understanding the contribution of the human BNST to fear and anxiety disorders.

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NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis

Cited by 46 publications

References 44 publications

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

Circuit-Based Biomarkers for Mood and Anxiety Disorders

Role of the bed nucleus of the stria terminalis in aversive learning and memory

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