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

ABSTRACTThe 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.IMPACT STATEMENTThe bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to unpredictable threats, a function that may be central to pathological anxiety.

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

eLife ◽

10.7554/elife.46525 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 15

Author(s):

Travis D Goode ◽

Reed L Ressler ◽

Gillian M Acca ◽

Olivia W Miles ◽

Stephen Maren

Keyword(s):

Conditioned Fear ◽

Stria Terminalis ◽

Conditioned Stimuli ◽

Variable Intensity ◽

Reversible Inactivation ◽

Bed Nucleus ◽

Defensive Behaviors ◽

The Us ◽

Specific Factors ◽

Fear And Anxiety

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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Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1997.0149 ◽

1997 ◽

Vol 352 (1362) ◽

pp. 1675-1687 ◽

Cited By ~ 163

Author(s):

◽

Michael Davis ◽

David L. Walker ◽

Younglim Lee

Keyword(s):

Excitatory Amino Acid ◽

Conditioned Fear ◽

Acoustic Startle ◽

Acoustic Startle Reflex ◽

Stria Terminalis ◽

Bed Nucleus ◽

Amino Acid Receptors ◽

Sensory Modalities ◽

Behavioural Tests ◽

Fear And Anxiety

Neural stimuli associated with traumatic events can readily become conditioned so as to reinstate the memory of the original trauma. These conditioned fear responses can last a lifetime and may be especially resistant to extinction. A large amount of data from many different laboratories indicate that the amygdala plays a crucial role in conditioned fear. The amygdala receives information from all sensory modalities and projects to a variety of hypothalamic and brainstem target areas known to be critically involved in specific signs that are used to define fear and anxiety. Electrical stimulation of the amygdala elicits a pattern of behaviours that mimic natural or conditioned states of fear. Lesions of the amygdala block innate or conditioned fear and local infusion of drugs into the amygdala have anxiolytic effects in several behavioural tests. Excitatory amino acid receptors in the amygdala are critical for the acquisition, expression and extinction of conditioned fear.

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Threat imminence dictates the role of the bed nucleus of the stria terminalis in contextual fear

10.1101/696112 ◽

2019 ◽

Author(s):

Travis D. Goode ◽

Gillian M. Acca ◽

Stephen Maren

Keyword(s):

Unconditioned Stimulus ◽

Fear Conditioning ◽

Stria Terminalis ◽

Conditioning Procedure ◽

Conditioned Stimuli ◽

Reversible Inactivation ◽

Bed Nucleus ◽

Contextual Fear ◽

Context Dependent

ABSTRACTPrevious work indicates that the bed nucleus of the stria terminalis (BNST) is involved in defensive freezing to unpredictable Pavlovian conditioned stimuli (Goode et al., 2019). Here we show that the BNST mediates freezing to contexts paired with remote (unpredictable), but not imminent (predictable), footshock. Rats underwent a fear conditioning procedure in which a single footshock unconditioned stimulus (US) was delivered either 1 (imminent) or 9 minutes (remote) after placement in the context; each rat received a total of four conditioning trials over two days. Contexts associated with either imminent or remote USs produced distinct patterns of freezing and shock-induced activity but freezing in each case was context-dependent. Reversible inactivation of the BNST reduced the expression of contextual freezing in the context paired with remote, but not imminent, footshock. Implications of these data are discussed in light of recent conceptualizations of BNST function, as well as for anxiety behaviors.

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Reversible Inactivation of the Bed Nucleus of the Stria Terminalis Prevents Reinstatement But Not Renewal of Extinguished Fear

eNeuro ◽

10.1523/eneuro.0037-15.2015 ◽

2015 ◽

Vol 2 (3) ◽

pp. ENEURO.0037-15.2015 ◽

Cited By ~ 22

Author(s):

Travis D. Goode ◽

Janice J. Kim ◽

Stephen Maren

Keyword(s):

Stria Terminalis ◽

Reversible Inactivation ◽

Bed Nucleus

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Fear and Anxiety: Possible Roles of the Amygdala and Bed Nucleus of the Stria Terminalis

Cognition & Emotion ◽

10.1080/026999398379619 ◽

1998 ◽

Vol 12 (3) ◽

pp. 277-305 ◽

Cited By ~ 24

Author(s):

Michael Davis Young ◽

Lim Lee

Keyword(s):

Stria Terminalis ◽

Bed Nucleus ◽

Fear And Anxiety

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Extra-hypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

10.1101/2020.06.02.129981 ◽

2020 ◽

Author(s):

Natalia Duque-Wilckens ◽

Lisette Y. Torres ◽

Sae Yokoyama ◽

Vanessa A. Minie ◽

Amy M. Tran ◽

...

Keyword(s):

Social Stress ◽

Social Contexts ◽

Stria Terminalis ◽

Social Approach ◽

Bed Nucleus ◽

Defensive Behaviors ◽

Oxytocin Infusion ◽

Different Populations ◽

Social Vigilance ◽

Sensitive Population

AbstractOxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a social stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knock-down prevented stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extra-hypothalamic oxytocin neurons play a key role in controlling stress-induced social anxiety behaviors.

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CART neuropeptide modulates the extended amygdalar CeA-vBNST circuit to gate expression of innate fear

10.1101/096610 ◽

2016 ◽

Author(s):

Abhishek Rale ◽

Ninad Shendye ◽

Devika S Bodas ◽

Nishikant Subhedar ◽

Aurnab Ghose

Keyword(s):

Conditioned Fear ◽

Stria Terminalis ◽

Fear Response ◽

Bed Nucleus ◽

Freezing Response ◽

Central Processing ◽

Panic Disorders ◽

Local Levels ◽

Innate Fear ◽

Excitatory Drive

ABSTRACTInnate fear is critical for the survival of animals and is under tight homeostatic control. Deregulation of innate fear processing is thought to underlie pathological phenotypes including, phobias and panic disorders. Although central processing of conditioned fear has been extensively studied, the circuitry and regulatory mechanisms subserving innate fear remain relatively poorly defined.In this study, we identify cocaine- and amphetamine-regulated transcript (CART) neuropeptide signaling in the central amygdala (CeA) - ventral bed nucleus of stria terminalis (vBNST) axis as a key modulator of innate fear expression. 2,4,5-trimethyl-3-thiazoline (TMT), a component of fox faeces, induces a freezing response whose intensity is regulated by the extent of CART-signaling in the CeA neurons. Abrogation of CART activity in the CeA attenuates the freezing response and reduces activation of vBNST neurons. Conversely, ectopically elevated CART signaling in the CeA potentiates the fear response concomitant with enhanced vBNST activation. We show that local levels of CART signaling modulate the activation of CeA neurons by NMDA receptor-mediated glutamatergic inputs, in turn, regulating activity in the vBNST.This study identifies the extended amygdalar CeA-vBNST circuit as a CART modulated axis encoding innate fear. CART signaling regulates the glutamatergic excitatory drive in the CeA-vBNST circuit, in turn, gating the expression of the freezing response to TMT.

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