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Effects of optogenetic photoexcitation of infralimbic cortex inputs to the basolateral amygdala on conditioned fear and extinction.

ABSTRACT: Deficiencies in the ability to extinguish fear is a hallmark of Trauma- and stressor-related disorders, Anxiety disorders, and certain other neuropsychiatric conditions. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear is of significant translational relevance. Previous studies in rodents have shown that glutamatergic projections from the infralimbic prefrontal cortex (IL) to basolateral amygdala (BLA) play a crucial instructional role in the formation of extinction memories, and also indicate that variation in the strength of this input correlates with extinction efficacy. To further examine the relationship between the IL→BLA pathway and extinction we expressed three different titers of the excitatory opsin, channelrhodopsin (ChR2), in IL neurons and photostimulated their projections in the BLA during partial extinction training. The behavioral effects of photoexcitation differed across the titer groups: the low titer had no effect, the medium titer selectively facilitated extinction memory formation, and the high titer produced both an acute suppression of fear and a decrease in fear during (light-free) extinction retrieval. We discuss various possible explanations for these titer-specific effects, including the possibility of IL-mediated inhibition of BLA fear-encoding neurons under conditions of sufficiently strong photoexcitation. These findings further support the role of IL→BLA pathway in regulating fear and highlight the importance of methodological factors in optogenetic studies of neural circuits underling behavior.

SUBMITTER: Bukalo O

PROVIDER: S-EPMC8299731 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear.

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Selective Control of Fear Expression by Optogenetic Manipulation of Infralimbic Cortex after Extinction.

Project description:Evidence from rodent and human studies has identified the ventromedial prefrontal cortex, specifically the infralimbic cortex (IL), as a critical brain structure in the extinction of conditioned fear. However, how IL activity controls fear expression at the time of extinction memory retrieval is unclear and controversial. To address this issue, we used optogenetics to precisely manipulate the activity of genetically targeted cells and to examine the real-time contribution of IL activity to expression of auditory-conditioned fear extinction in mice. We found that inactivation of IL, but not prelimbic cortex, impaired extinction retrieval. Conversely, photostimulation of IL excitatory neurons robustly enhanced the inhibition of fear expression after extinction, but not before extinction. Moreover, this effect was specific to the conditioned stimulus (CS): IL activity had no effect on expression of fear in response to the conditioned context after auditory fear extinction. Thus, in contrast to the expectation from a generally held view, artificial activation of IL produced no significant effect on expression of non-extinguished conditioned fear. Therefore, our data provide compelling evidence that IL activity is critical for expression of fear extinction and establish a causal role for IL activity in controlling fear expression in a CS-specific manner after extinction.

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Reactivation of Recall-Induced Neurons in the Infralimbic Cortex and the Basolateral Amygdala After Remote Fear Memory Attenuation.

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Pharmacological stimulation of infralimbic cortex after fear conditioning facilitates subsequent fear extinction.

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Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats.

Project description:There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24?hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc.

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Project description:The paraventricular nucleus of the thalamus (PVT), which serves as a hub, receives dense projections from the medial prefrontal cortex (mPFC) and projects to the lateral division of central amygdala (CeL). The infralimbic (IL) cortex plays a crucial role in encoding and recalling fear extinction memory. Here, we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval. Silencing PVT neurons inhibited extinction retrieval at recent time point (24 h after extinction), while activating them promoted extinction retrieval at remote time point (7 d after extinction), suggesting a critical role of the PVT in extinction retrieval. In the mPFC-PVT circuit, projections from IL rather than prelimbic cortex to the PVT were dominant, and disrupting the IL-PVT projection suppressed extinction retrieval. Moreover, the axons of PVT neurons preferentially projected to the CeL. Silencing the PVT-CeL circuit also suppressed extinction retrieval. Together, our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.

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Fear extinction requires Arc/Arg3.1 expression in the basolateral amygdala.

Project description:BACKGROUND: Prolonged re-exposure to a fear-eliciting cue in the absence of an aversive event extinguishes the fear response to the cue, and has been clinically used as an exposure therapy. Arc (also known as Arg3.1) is implicated in synaptic and experience-dependent plasticity. Arc is regulated by the transcription factor cAMP response element binding protein, which is upregulated with and necessary for fear extinction. Because Arc expression is also activated with fear extinction, we hypothesized that Arc expression is required for fear extinction. FINDINGS: Extinction training increased the proportion of Arc-labeled cells in the basolateral amygdala (BLA). Arc was transcribed during latter part of extinction training, which is possibly associated with fear extinction, as well as former part of extinction training. Intra-BLA infusions of Arc antisense oligodeoxynucleotide (ODN) before extinction training impaired long-term but not short-term extinction memory. Intra-BLA infusions of Arc antisense ODN 3 h after extinction training had no effect on fear extinction. CONCLUSION: Our findings demonstrate that Arc is required for long-term extinction of conditioned fear and contribute to the understanding of extinction as a therapeutic manner.

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Interaction of basolateral amygdala, ventral hippocampus and medial prefrontal cortex regulates the consolidation and extinction of social fear.

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Project description:In Pavlovian fear conditioning, pairing a neutral cue with aversive foot shock endows a cue with fear-eliciting properties. Studies of Pavlovian fear conditioning measuring freezing have demonstrated the basolateral amygdala (BLA) to be critical to both fear learning and memory. The nucleus accumbens core (NAc), while not important to freezing, is important to the enhancement of instrumental responding by cues paired with food reward. In the present study we investigated the role of the BLA and the NAc in another property of fear cues, the ability to suppress instrumental responding for food rewards (conditioned suppression). Sham, BLA and NAc-lesioned rats received a fear discrimination procedure in which one visual cue (CS+) predicted foot shock while a second cue (CS-) did not. Conditioning took place over a baseline of instrumental responding, allowing for concurrent measure of freezing and instrumental suppression. NAc lesions left fear conditioning fully intact. BLA lesions impaired acquisition and discrimination of fear when assessed with conditioned freezing. However, BLA lesions only altered fear acquisition and left discrimination completely intact when assessed with conditioned suppression. These findings suggest a critical role for the BLA in fear when assessed with conditioned freezing but a diminished role when assessed with conditioned suppression.

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Optogenetic activation of presynaptic inputs in lateral amygdala forms associative fear memory.

Project description:In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we tested whether direct activation of presynaptic sensory inputs in LA, without the participation of upstream activity, is sufficient to form fear memory in mice. Photostimulation of axonal projections from the two main auditory brain regions, the medial geniculate nucleus of the thalamus and the secondary auditory cortex, was paired with aversive footshock. Twenty-four hours later the same photostimulation induced robust conditioned freezing and this fear memory formation was disrupted when glutamatergic synaptic transmission was locally blocked in the LA. Therefore, our results prove for the first time that synapses between sensory input areas and the LA, previously implicated as a crucial brain site for fear memory formation, actually are sufficient to serve as a conditioned stimulus. Our results strongly support the idea that the LA may be sufficient to encode and store associations between neutral cue and aversive stimuli during natural fear conditioning as a critical part of a broad fear memory engram.

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