Anterior cingulate cortex and its input to the basolateral amygdala control innate fear response

Jhang, Jinho; Lee, Hyoeun; Kang, Min Soo; Lee, Han Sol; Park, Hyungju; Han, Jin‐Hee

doi:10.1038/s41467-018-05090-y

Cited by 130 publications

(91 citation statements)

References 49 publications

(76 reference statements)

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“…Recent studies have reported that the amygdala plays a central role in processing innate fear of predator odors and looming visual threats (Jhang et al, 2018;Salay et al, 2018;Wei et al, 2015). We thus tested some of our recorded BLA neurons upon exposure to cat odor, looming objects, as well as loud noises.…”

Section: Resultsmentioning

confidence: 99%

“…Congruent with this idea, a physical therapy study showed that vestibular exercise can improve acrophobia symptoms (Whitney et al, 2005). Another possibility for the reduced responses in the enclosed high place is a regulation by cortical inputs, such as from the anterior cingulate cortex, which plays a role in the inhibition of innate fear (Jhang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, recent studies revealed that the thalamus-to-BLA and anterior cingulate-to-BLA pathways are important for innate fear responses to visual threats (Salay et al, 2018;Wei et al, 2015) and a predator odor, respectively (Jhang et al, 2018). These findings raise the possibility that the BLA may also process the innate fear of heights.…”

Section: Introductionmentioning

confidence: 97%

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Encoding Fear of Heights by Basolateral Amygdala Neurons

Lin

Wang

2020

Preprint

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Fear of heights is evolutionarily important for survival, yet it is unclear how and which brain regions encode such height threats. Given the importance of the basolateral amygdala (BLA) in processing both learned and innate fear, we investigated how BLA neurons may respond to high place exposure in freely behaving mice. We found that a discrete set of BLA neurons exhibited robust firing increases when the mouse was either exploring or placed on a high place, accompanied by increased heart rate and freezing. Importantly, these high-place fear neurons were only activated under height threats but not mild anxiogenic conditions. Furthermore, after a fear conditioning procedure, these high-place fear neurons developed conditioned responses to the context, but not the cue, indicating a convergence in encoding of dangerous/risky contextual information. Our results provide insights into the neural representation of the fear of heights and may have implications for treatment of excessive fear disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Encoding Fear of Heights by Basolateral Amygdala Neurons

Lin

Wang

2020

Preprint

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“…This allowed for maximal separation of PL and IL but caused spread of the virus into the anterior cingulate (Cg) and dorsal peduncular (DP) cortices in some cases. Recently, the anterior cingulate cortex and its input to the basolateral amygdala has been implicated in mediating innate freezing response to predator odors (Jhang et al, 2018), which is similar to the role the PL plays in learned fears (Corcoran and Quirk, 2007). Although the projection from the dorsal peduncular cortex to the BLA has not been directly characterized, the DP is thought to play a role similar to the IL and is often included when examining conditioned responses such as fear and drug seeking (Peters et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Differentially Modulates Glutamate Release from Dorsal and Ventral Prefrontal Cortical Inputs onto Rat Basolateral Amygdala Principal Neurons

McGinnis

Parrish

Chappell

et al. 2019

Preprint

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The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have strong reciprocal connectivity. Projections from the BLA to the mPFC can bidirectionally modulate anxiety-related behaviors but it is unclear if the same is true for mPFC to BLA projections. Our laboratory is specifically interested in withdrawal-related anxiety-like behavior and the underlying synaptic plasticity. Here, we use optogenetics and chemogenetics to characterize the neurophysiological and behavioral alterations produced by chronic ethanol exposure and withdrawal on dorsal mPFC/prelimbic (dmPFC/PL) and ventral mPFC (vmPFC/IL) terminals in the BLA. We exposed adult male Sprague-Dawley rats to chronic intermittent ethanol (CIE) using vapor chambers, measured anxiety-like behavior on the elevated zero maze (EZM), and used electrophysiology to record glutamatergic and GABAergic responses in BLA principal neurons. We found that 24-hour withdrawal following a 7-day CIE exposure significantly increased the glutamate release probability from PL/dmPFC terminals, but significantly decreases the glutamate release probability from IL/vmPFC terminals. Chemogenetic inhibition of PL/dmPFC terminals in the BLA attenuated the increased withdrawal-dependent, anxiety-like behavior. These data demonstrate that chronic ethanol exposure and withdrawal strengthens the PL/dmPFC -BLA pathway but weakens the IL/vmPFC -BLA pathway. Moreover, we provide novel evidence that the PL/dmPFC -BLA pathway can modulate anxiety-like behavior. These findings suggest that mPFC-BLA circuits known to regulate the acquisition of aversive behaviors are up-regulated by chronic ethanol while those involved with the extinction of these behaviors are down-regulated. Significance StatementAccumulating evidence suggests that the medial prefrontal cortex and its projections to the basolateral amygdala bidirectionally modulate fear-related behaviors. Since the neuronal circuits for fear and anxiety are thought to overlap, we sought to examine the role of prelimbic and infralimbic subdivisions of the medial prefrontal cortex and their inputs to the basolateral amygdala in regulating anxiety. Specifically, we focused on alcohol withdrawal-induced anxietylike behavior, which is a commonly reported cause of relapse in human alcoholics. In our study, we used optogenetics and chemogenetics to demonstrate, for the first time, that withdrawal from chronic ethanol exposure strengthens prelimbic synapses, but weakens infralimbic synapses in the basolateral amygdala and that inhibiting glutamate release from prelimbic terminal in the basolateral amygdala reduces anxiety-like behavior.

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“…The BLA is critical for fear learning and anxiety-like behavior, but is also implicated in novelty responses (Balderston et al 2011;Jhang et al 2018). LC-NE signaling within the BLA elicits anxiety-like behavior in canonical anxiety tests as well measures of social anxiety (McCall et al 2017;Siuda et al 2016), but the role of the LC-NE à BLA circuit in neophobia has not been described.…”

Section: Ne-deficient Mice Show Reduced C-fos Induction In Select Tarmentioning

confidence: 99%

Noradrenergic circuits in the forebrain control affective responses to novelty

Lustberg

Tillage

Bai

et al. 2020

Preprint

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Rationale: In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated.Objective: We sought to define the role of central NE transmission in neophilic and neophobic behaviors. Methods:We assessed dopamine b-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions.Results: Dbh -/-mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh -/-mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory a2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh -/-mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala. Conclusion:These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.

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Anterior cingulate cortex and its input to the basolateral amygdala control innate fear response

Cited by 130 publications

References 49 publications

Encoding Fear of Heights by Basolateral Amygdala Neurons

Encoding Fear of Heights by Basolateral Amygdala Neurons

Chronic Ethanol Differentially Modulates Glutamate Release from Dorsal and Ventral Prefrontal Cortical Inputs onto Rat Basolateral Amygdala Principal Neurons

Noradrenergic circuits in the forebrain control affective responses to novelty

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