The activity of discrete sets of neurons in the posterior insula correlates with the behavioral expression and extinction of conditioned fear

The interoceptive insular cortex is known to be involved in the perception of bodily states and emotions. Increasing evidence points to an additional role for the insula in the storage of fear memories. However, the activity of the insula during fear expression has not been studied. We addressed this issue by recording single units from the posterior insular cortex (pIC) of awake behaving rats expressing conditioned fear during its extinction. We found a set of pIC units showing either significant increase or decrease in activity during high fear expression to the auditory cue (“freezing units”). Firing rate of freezing units showed high correlation with freezing and outlasted the duration of the auditory cue. In turn, a different set of units showed either significant increase or decrease in activity during low fear state (“extinction units”). These findings show that expression of conditioned freezing is accompanied with changes in pIC neural activity and suggest that the pIC is important to regulate the behavioral expression of fear memory. NEW & NOTEWORTHY Here, we show novel single-unit data from the interoceptive insula underlying the behavioral expression of fear. We show that different populations of neurons in the insula codify expression and extinction of conditioned fear. Our data add further support for the insula as an important player in the regulation of emotions.

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THE INSULA: ISLAND OF REIL

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2015-312379.63 ◽

2015 ◽

Vol 86 (11) ◽

pp. e4.155-e4

Author(s):

Ray Wynford-Thomas ◽

Rob Powell

Keyword(s):

Speech Processing ◽

Brain Function ◽

Insular Cortex ◽

Normal Brain ◽

Temporal Epilepsy ◽

Normal Brain Function ◽

Temporal Structures ◽

Hypermotor Seizures ◽

Posterior Insula ◽

As Effects

Just as ‘no man is an island’, despite its misleading name, the insula is not an island. Sitting deeply within the cerebrum, the insular cortex and its connections play an important role in both normal brain function and seizure generation. Stimulating specific areas of the insula can produce somatosensory, viscerosensory, somatomotor and visceroautonomic symptoms, as well as effects on speech processing and pain. Insular onset seizures are rare, but may mimic both temporal and extra-temporal epilepsy and if not recognised, may lead to failure of epilepsy surgery. We therefore highlight the semiology of insular epilepsy by discussing three cases with different auras. Insular onset seizures can broadly be divided into three main types both anatomically and according to seizure semiology:1. Seizures originating in the antero-inferior insula present with laryngeal constriction, along with visceral and gustatory auras (similar to those originating in medial temporal structures).2. Antero-superior onset seizures can have a silent onset, but tend to propagate rapidly to motor areas causing focal motor or hypermotor seizures.3. Seizures originating in the posterior insula present with contralateral sensory symptoms.

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New Vistas on Amygdala Networks in Conditioned Fear

Journal of Neurophysiology ◽

10.1152/jn.00153.2004 ◽

2004 ◽

Vol 92 (1) ◽

pp. 1-9 ◽

Cited By ~ 542

Author(s):

Denis Paré ◽

Gregory J. Quirk ◽

Joseph E. Ledoux

Keyword(s):

Brain Stem ◽

Conditioned Fear ◽

Current Model ◽

Central Nucleus ◽

Projection Neurons ◽

Conditioned Freezing ◽

Fear Potentiated Startle ◽

Classically Conditioned ◽

The Brain ◽

Critical Site

It is currently believed that the acquisition of classically conditioned fear involves potentiation of conditioned thalamic inputs in the lateral amygdala (LA). In turn, LA cells would excite more neurons in the central nucleus (CE) that, via their projections to the brain stem and hypothalamus, evoke fear responses. However, LA neurons do not directly contact brain stem-projecting CE neurons. This is problematic because CE projections to the periaqueductal gray and pontine reticular formation are believed to generate conditioned freezing and fear-potentiated startle, respectively. Moreover, like LA, CE may receive direct thalamic inputs communicating information about the conditioned and unconditioned stimuli. Finally, recent evidence suggests that the CE itself may be a critical site of plasticity. This review attempts to reconcile the current model with these observations. We suggest that potentiated LA outputs disinhibit CE projection neurons via GABAergic intercalated neurons, thereby permitting associative plasticity in CE. Thus plasticity in both LA and CE would be necessary for acquisition of conditioned fear. This revised model also accounts for inhibition of conditioned fear after extinction.

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The parieto-insular vestibular cortex in humans: more than a single area?

Journal of Neurophysiology ◽

10.1152/jn.00907.2017 ◽

2018 ◽

Vol 120 (3) ◽

pp. 1438-1450 ◽

Cited By ~ 24

Author(s):

Sebastian M. Frank ◽

Mark W. Greenlee

Keyword(s):

Nonhuman Primate ◽

Visual Motion ◽

Insular Cortex ◽

Vestibular Cortex ◽

Anatomical Structures ◽

The Core ◽

Primate Brain ◽

Cortex Area ◽

Posterior Insula ◽

And Function

Here, we review the structure and function of a core region in the vestibular cortex of humans that is located in the midposterior Sylvian fissure and referred to as the parieto-insular vestibular cortex (PIVC). Previous studies have investigated PIVC by using vestibular or visual motion stimuli and have observed activations that were distributed across multiple anatomical structures, including the temporo-parietal junction, retroinsula, parietal operculum, and posterior insula. However, it has remained unclear whether all of these anatomical areas correspond to PIVC and whether PIVC responds to both vestibular and visual stimuli. Recent results suggest that the region that has been referred to as PIVC in previous studies consists of multiple areas with different anatomical correlates and different functional specializations. Specifically, a vestibular but not visual area is located in the parietal operculum, close to the posterior insula, and likely corresponds to the nonhuman primate PIVC, while a visual-vestibular area is located in the retroinsular cortex and is referred to, for historical reasons, as the posterior insular cortex area (PIC). In this article, we review the anatomy, connectivity, and function of PIVC and PIC and propose that the core of the human vestibular cortex consists of at least two separate areas, which we refer to together as PIVC+. We also review the organization in the nonhuman primate brain and show that there are parallels to the proposed organization in humans.

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Convergent coding of recent and remote fear memory in the basolateral amygdala

10.1101/2021.09.27.462008 ◽

2021 ◽

Author(s):

Jianfeng Liu ◽

Michael S. Totty ◽

Laila Melissari ◽

Stephen Maren

Keyword(s):

Basolateral Amygdala ◽

Conditioned Fear ◽

Fear Memory ◽

Remote Memory ◽

Storage Site ◽

Long Term Storage ◽

Behavioral Design ◽

Within Subjects ◽

Conditioned Freezing ◽

Evoked Activity

Animals must learn to anticipate recently encountered threats as well as dangers experienced long ago. In both rodents and humans, the basolateral amygdala (BLA) is essential for the encoding and retrieval conditioned fear memories. Although the BLA is a putative storage site for aversive memory, recent evidence suggests that these memories undergo time-dependent reorganization and no longer require the BLA after the passage of time. To explore this question, we systematically examined the role for the BLA in recent and remote fear memory using optogenetic, electrophysiological, and calcium imaging methods in male and female Long-Evans rats. Critically, we used a behavioral design that permits within-subjects comparison of recent and remote memory at the same time point. We found that BLA c-Fos expression was similar after the retrieval of recent (1 day) or remote (2 weeks) fear memories. Extracellular recordings in awake, behaving animals revealed that the majority of BLA neurons encoded both recent and remote memories, suggesting substantial overlap in the allocation of temporally distinct events. Fiber photometric recordings of BLA principal neurons also revealed similar patterns of CS-evoked activity to recent and remote CSs. Consistent with these results, continuous or CS-specific optogenetic inhibition of BLA principal neurons impaired conditioned freezing to both recent and remote CSs. Collectively, these data reveal that single BLA neurons encode both recent and remote fear memories. This may underlie the broad generalization of fear memories across both space and time. Ultimately, these results provide robust evidence that the BLA is a long-term storage site for emotional memories.

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5‐HT depletion, but not 5‐HT1A antagonist, prevents the anxiolytic‐like effect of citalopram in rat contextual conditioned fear stress model

Acta Neuropsychiatrica ◽

10.1111/j.1601-5215.2012.00669.x ◽

2013 ◽

Vol 25 (2) ◽

pp. 77-84 ◽

Cited By ~ 6

Author(s):

Takahiro Masuda ◽

Hiroyuki Nishikawa ◽

Takeshi Inoue ◽

Hiroyuki Toda ◽

Shin Nakagawa ◽

...

Keyword(s):

Receptor Antagonist ◽

Selective Serotonin Reuptake Inhibitors ◽

Conditioned Fear ◽

Selective Serotonin ◽

Receptor Antagonists ◽

Shock Chamber ◽

Conditioned Fear Stress ◽

Way 100635 ◽

Conditioned Freezing ◽

Subtype Selective

ObjectiveSelective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety.MethodsRats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or dl‐p‐chlorophenylalanine (PCPA), various subtype‐selective serotonin (5‐HT) receptor antagonists: the 5‐HT1A receptor antagonist WAY 100635, the 5‐HT2A receptor antagonist MDL 100907, the 5‐HT2C receptor antagonist SB 242084, the 5‐HT3 receptor antagonist tropisetron, the 5‐HT4 receptor antagonist GR 125487, the 5‐HT6 receptor antagonist SB 258585 or the 5‐HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks.ResultsCitalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic‐like effect of citalopram was prevented completely by pretreatment with the 5‐HT‐depleting agent PCPA, but not by the 5‐HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype‐selective 5‐HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic‐like effect of citalopram.ConclusionThe anxiolytic‐like effect of citalopram in contextual CFS model depends on 5‐HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic‐like effect of citalopram.

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Knockdown of the astrocytic glucocorticoid receptor in the central nucleus of the amygdala diminishes conditioned fear expression and anxiety

Behavioural Brain Research ◽

10.1016/j.bbr.2020.113095 ◽

2021 ◽

Vol 402 ◽

pp. 113095

Author(s):

Lucja Wiktorowska ◽

Wiktor Bilecki ◽

Magdalena Tertil ◽

Lucja Kudla ◽

Lukasz Szumiec ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Conditioned Fear ◽

Central Nucleus ◽

Fear Expression

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Locus coeruleus toggles reciprocal prefrontal firing to reinstate fear

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814278116 ◽

2019 ◽

Vol 116 (17) ◽

pp. 8570-8575 ◽

Cited By ~ 7

Author(s):

Thomas F. Giustino ◽

Paul J. Fitzgerald ◽

Reed L. Ressler ◽

Stephen Maren

Keyword(s):

Locus Coeruleus ◽

Freezing Behavior ◽

Therapeutic Interventions ◽

Single Unit Activity ◽

Noradrenergic Neurons ◽

Number Of Factors ◽

Conditioned Freezing ◽

Noradrenergic Modulation ◽

Spike Firing ◽

Fear Expression

The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neurons, which are critical for inhibiting fear responses, and facilitates activity in prelimbic (PL) neurons involved in fear expression. Pharmacogenetic activation of noradrenergic neurons in the locus coeruleus mimics this shift in reciprocal IL–PL spike firing, increases the expression of conditioned freezing behavior, and causes relapse of extinguished fear. Noradrenergic modulation of mPFC firing represents a mechanism for relapse and a potential target for therapeutic interventions to reduce pathological fear.

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Venlafaxine facilitates between-session extinction and prevents reinstatement of auditory-cue conditioned fear

Behavioural Brain Research ◽

10.1016/j.bbr.2012.02.023 ◽

2012 ◽

Vol 230 (1) ◽

pp. 268-273 ◽

Cited By ~ 19

Author(s):

Cheng-hao Yang ◽

Hai-shui Shi ◽

Wei-li Zhu ◽

Ping Wu ◽

Li-li Sun ◽

...

Keyword(s):

Conditioned Fear ◽

Auditory Cue

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Surgical strategy to avoid ischemic complications of the pyramidal tract in resective epilepsy surgery of the insula: technical case report

Journal of Neurosurgery ◽

10.3171/2017.1.jns161278 ◽

2018 ◽

Vol 128 (4) ◽

pp. 1173-1177 ◽

Cited By ~ 4

Author(s):

Naoki Ikegaya ◽

Akio Takahashi ◽

Takanobu Kaido ◽

Yuu Kaneko ◽

Masaki Iwasaki ◽

...

Keyword(s):

Seizure Control ◽

Pyramidal Tract ◽

Focal Cortical Dysplasia ◽

Insular Cortex ◽

Motor Deficits ◽

Corona Radiata ◽

Ischemic Complications ◽

Posterior Insula ◽

Functional Preservation ◽

Perforating Arteries

Surgical treatment of the insula is notorious for its high probability of motor complications, particularly when resecting the superoposterior part. Ischemic damage to the pyramidal tract in the corona radiata has been regarded as the cause of these complications, resulting from occlusion of the perforating arteries to the pyramidal tract through the insular cortex. The authors describe a strategy in which a small piece of gray matter is spared at the bottom of the periinsular sulcus, where the perforating arteries pass en route to the pyramidal tract, in order to avoid these complications. This method was successfully applied in 3 patients harboring focal cortical dysplasia in the posterior insula and frontoparietal operculum surrounding the periinsular sulcus. None of the patients developed permanent postoperative motor deficits, and seizure control was achieved in all 3 cases. The method described in this paper can be adopted for functional preservation of the pyramidal tract in the corona radiata when resecting epileptogenic pathologies involving insular and opercular regions.

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