Neurochemically distinct populations of the bed nucleus of stria terminalis modulate innate fear response to weak threat evoked by predator odor stimuli

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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Alcohol Drinking Alters Stress Response to Predator Odor via Extended Amygdala Kappa Opioid Receptor Signaling in Male Mice

10.1101/773481 ◽

2019 ◽

Author(s):

Lara S. Hwa ◽

Sofia Neira ◽

Meghan E. Flanigan ◽

Christina M. Stanhope ◽

Melanie M. Pina ◽

...

Keyword(s):

Opioid Receptor ◽

Stress Responses ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

Stria Terminalis ◽

Receptor Signaling ◽

Kappa Opioid ◽

Bed Nucleus ◽

Heavy Alcohol

AbstractMaladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST compared to drinking or stress alone. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal from heavy drinking. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.Impact StatementHeavy alcohol drinking primes dynorphin / kappa opioid systems in the bed nucleus of the stria terminalis to alter stress responses in mice.

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Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice

eLife ◽

10.7554/elife.59709 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Lara S Hwa ◽

Sofia Neira ◽

Meghan E Flanigan ◽

Christina M Stanhope ◽

Melanie M Pina ◽

...

Keyword(s):

Opioid Receptor ◽

Stress Responses ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

Stria Terminalis ◽

Receptor Signaling ◽

Kappa Opioid ◽

Bed Nucleus ◽

Heavy Alcohol

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here, we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.

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Behavioral and brain mechanisms mediating conditioned flight behavior in rats

10.1101/2021.01.29.428848 ◽

2021 ◽

Author(s):

Michael S. Totty ◽

Naomi Warren ◽

Isabella Huddleston ◽

Karthik R. Ramanathan ◽

Reed L. Ressler ◽

...

Keyword(s):

Compound Stimulus ◽

Female Rats ◽

Flight Behavior ◽

Central Nucleus ◽

Stria Terminalis ◽

Conditioning Context ◽

Bed Nucleus ◽

Contextual Fear ◽

Male And Female Rats ◽

Innate Fear

ABSTRACTEnvironmental contexts and associative learning can inform animals of potential threats, though it is currently unknown how contexts bias defensive transitions. Here we investigated context-dependent flight responses in the Pavlovian serial-compound stimulus (SCS) paradigm. We show here that SCS-evoked flight behavior in male and female rats is dependent on contextual fear. Flight was reduced in the conditioning context after context extinction and could be evoked in a different shock-associated context. Although flight was exclusive to white noise stimuli, it was nonetheless associative insofar as rats that received an equal number of unpaired USs did not show flight-like behavior. Finally, we found that inactivation of either the central nucleus of the amygdala (CeA) or bed nucleus of the stria terminalis (BNST) attenuated both contextual fear and flight responses. This work demonstrates that contextual fear summates with cued and innate fear to drive a high fear state and freeze-to-flight transitions.

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