scholarly journals Independence of Cued and Contextual Components of Fear Conditioning is Gated by the Lateral Habenula

2020 ◽  
Author(s):  
Tomas E. Sachella ◽  
Marina R. Ihidoype ◽  
Christophe Proulx ◽  
Jorge H. Medina ◽  
Pablo Mendez ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Fear Conditioning ◽  
Neuronal Activity ◽  
Fear Memory ◽  
Fear Learning ◽  
Training Context ◽  
Lateral Habenula ◽  
Extreme Form ◽  
Pathological Conditions

AbstractFear is an extreme form of aversion that, if inappropriately generalized, initiates pathological conditions such as panic or anxiety disorders. Fear conditioning (FC) is the best understood model of fear learning. FC forms two associations that independently link the cue and the training context to fear responses. The lateral habenula (LHb) encodes aversive information. However, how the LHb participates in fear learning has not been intensively studied. Here we studied the role of the LHb in FC learning using optogenetics and pharmacological tools in rats. We found that disrupting neuronal activity of the LHb during training abolishes independent expression of contextual and cued memories, yet memory is normally expressed when the cue is played in the training context. Our results show that neuronal activity at the LHb regulates independent expression of sub-components of a fear memory, assigning to that structure a previously uncharacterized role as regulator of fear memories.

scholarly journals Inhibition of the PI3 kinase cascade in corticolimbic circuit: temporal and differential effects on contextual fear and extinction

2013 ◽  
Vol 16 (4) ◽  
pp. 825-833 ◽  
Author(s):  
Milly Kritman ◽  
Mouna Maroun
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Fear Memory ◽  
Fear Learning ◽  
Contextual Fear ◽  
Pi3k Inhibition ◽  
Kinase Cascade ◽  
Differential Involvement ◽  
Phosphoinositide 3 Kinase

Abstract We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders.

Neurobiology of Anxiety Disorders

2020 ◽  
Author(s):  
Pooja Palkar ◽  
Eric Hollander
Keyword(s):  
Anxiety Disorders ◽  
Fear Conditioning ◽  
Endogenous Opioids ◽  
Aminobutyric Acid ◽  
Nmda Antagonists ◽  
Important Goal ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
New Learning

In recent years, advances in the fields of neuroimaging and experimental psychology increased our understanding of the basic mechanisms of classical conditioning and learning, contributing to our knowledge of the neurobiology of anxiety disorders. Research has shown that the amygdala is the cornerstone of fear circuitry and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Activation of the amygdala in response to disorder-relevant stimuli has been observed in anxiety disorders. The roles of the hippocampus, nucleus accumbens, periaqueductal gray, and insular and medial prefrontal cortices in response to fear have been identified as well. Neurotransmitters such as serotonin, dopamine, γ-aminobutyric acid, glutamate, and some neurosteroids play an important part in the neurobiology of anxiety disorders. Neuropeptides such as oxytocin, neuropeptide Y, galanin, and cholecystokinin have been shown to modulate stress response. Drugs such as N-methyl-d-aspartate (NMDA) antagonists and blockers of voltage-gated calcium channels in the amygdala are anxiolytic. Fear extinction, which entails new learning of fear inhibition, is the mechanism of effective antianxiety treatments such as d-cycloserine, a partial NMDA agonist. Extinction is thought to occur by the medial prefrontal cortex, which inhibits the lateral amygdala under hippocampal modulation. Harnessing extinction to delink neutral stimuli from aversive responses is an important goal of the psychotherapy and pharmacotherapy of anxiety disorders. Discovery of the role of microRNAs in the etiology of anxiety disorders and their possible utility as targets to treat these disorders is fascinating. In this review, we discuss the neurobiology of anxiety disorders, which will help us better manage them clinically. This review contains 5 figures, 6 tables, and 39 references. Key words: Amygdala, anxiety disorders, neurobiology, fear conditioning, neurocircuitry, neurotransmitters, neuropeptides, neurosteroids, endogenous opioids.

scholarly journals Fear Memory

2016 ◽  
Vol 96 (2) ◽  
pp. 695-750 ◽  
Author(s):  
Ivan Izquierdo ◽  
Cristiane R. G. Furini ◽  
Jociane C. Myskiw
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Inhibitory Avoidance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Term Potentiation ◽  
Mechanisms Of Memory

Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.

scholarly journals Dopamine and fear memory formation in the human amygdala

2021 ◽  
Author(s):  
Andreas Frick ◽  
Johannes Björkstrand ◽  
Mark Lubberink ◽  
Allison Eriksson ◽  
Mats Fredrikson ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Dopamine Release ◽  
Conditioned Fear ◽  
Fear Memory ◽  
Memory Formation ◽  
Fear Learning ◽  
Causative Role ◽  
Endogenous Dopamine ◽  
Positron Emission ◽  
Endogenous Dopamine Release

AbstractLearning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

scholarly journals microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

2019 ◽  
Author(s):  
Meghan E Jones ◽  
Stephanie E. Sillivan ◽  
Sarah Jamieson ◽  
Gavin Rumbaugh ◽  
Courtney A. Miller
Keyword(s):  
Basolateral Amygdala ◽  
Differential Susceptibility ◽  
Anxiolytic Effect ◽  
Bioinformatic Analysis ◽  
Fear Memory ◽  
Fear Learning ◽  
Small Rna Sequencing ◽  
Female Mice ◽  
The Impact

ABSTRACTmicroRNAs (miRNAs) have emerged as potent regulators of learning, recent memory and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memory, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue to identify miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was downregulated in the BLA. Further decreasing BLA mir-598-3p levels did not alter the expression or extinction of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 days post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton.

Fear learning and extinction

2019 ◽  
pp. 113-128
Author(s):  
Tina B Lonsdorf
Keyword(s):  
Anxiety Disorders ◽  
Fear Conditioning ◽  
Association Studies ◽  
Conditioned Fear ◽  
Significant Proportion ◽  
Genetic Association Studies ◽  
Individual Variability ◽  
Fear Learning ◽  
Treatment Programs ◽  
Return Of Fear

Experimental fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and serve as laboratory models for the development and treatment of anxiety disorders, respectively. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions as well as the return of fear and approximately one third of the variance in human fear conditioning and in the vulnerability for anxiety disorders can be attributed to genetic factors. The experimental paradigms of fear conditioning and extinction are particularly well suited for genetic association studies as these optimally investigate simple behavioral paradigms with sufficient inter-individual variability and clear heritability that elicit robust behavioral responses which are easy to measure and quantify and rely on a well-defined underlying neural circuitry. Understanding the molecular pathways that mediate conditioning and extinction might therefore make an important contribution to the study of anxiety pathophysiology and resilience. Because a significant proportion of patients do not respond to or tolerate standard treatments, such advances may ultimately open up new perspectives for pharmacological interventions (i.e. pharmacologically enhanced CBT) or the individualization of current prevention and treatment programs. In the future, translational work employing a synergy between molecular genetics, neuroimaging, psychophysiology and psychopharmacology will be powerful in unraveling the neurobiology of fear learning and extinction processes and the investigation of genetic polymorphisms in fear learning and extinction processes represents one avenue along this path.

scholarly journals Brief optogenetic inhibition of rat lateral or ventrolateral periaqueductal gray augments the acquisition of Pavlovian fear conditioning

2017 ◽  
Author(s):  
Neda Assareh ◽  
Elena E. Bagley ◽  
Pascal Carrive ◽  
Gavan P. McNally
Keyword(s):  
Fear Conditioning ◽  
Viral Vectors ◽  
Strong Support ◽  
Periaqueductal Gray ◽  
Fear Learning ◽  
Defensive Responses ◽  
Defensive Behaviors ◽  
The Relationship ◽  
Exact Timing

AbstractThe midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in expression of defensive behavior is well understood, the relationship between activity of PAG neurons and fear learning, the exact timing of PAG contributions to learning during the conditioning trial, and the contributions of different PAG columns to fear learning are poorly understood. We assessed the effects of optogenetic inhibition of lateral (LPAG) and ventrolateral (VLPAG) PAG neurons on fear learning. Using adenoassociated viral vectors expressing halorhodopsin (eNpHR3.0), we show that brief optogenetic inhibition of LPAG or VLPAG during delivery of the shock unconditioned stimulus (US) augments acquisition of contextual or cued fear conditioning and we also show that this inhibition augments post-encounter defensive responses to a non-noxious threat. Taken together, these results show that LPAG and VLPAG serve a key role in regulation of Pavlovian fear learning at the time of US delivery. These findings provide strong support for existing models which state that LPAG and VLPAG contribute to a fear prediction error signal determining variations in the effectiveness of the aversive US in supporting learning.

scholarly journals Secure attachment priming protects against relapse of fear in Young adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Metaxia Toumbelekis ◽  
Belinda J. Liddell ◽  
Richard A. Bryant
Keyword(s):  
Young Adults ◽  
Anxiety Disorders ◽  
Fear Conditioning ◽  
The Other ◽  
Fear Learning ◽  
Secure Attachment ◽  
Attachment Figure ◽  
Fear Potentiated Startle ◽  
Reinstatement Test

AbstractPrevious studies have shown that activating the attachment system attenuates fear learning. This study aimed to explore whether attachment priming can also impact on fear extinction processes, which underpin the management of anxiety disorders. In this study, 81 participants underwent a standard fear conditioning and extinction protocol on day 1 and returned 24 h later for an extinction recall and reinstatement test. Half the participants were primed to imagine their closest attachment figure prior to undergoing extinction training, while the other half were instructed to imagine a positive situation. Fear-potentiated startle and subjective expectancies of shock were measured as the primary indicators of fear. Attachment priming led to less relapse during the reinstatement test at the physiological but not subjective levels. These findings have translational potential to imply that activating awareness of attachment figures might augment long-term safety memories acquired in existing treatments to reduce relapse of fear.

scholarly journals Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex

2015 ◽  
Vol 309 (11) ◽  
pp. H1837-H1845 ◽  
Author(s):  
Peter Toth ◽  
Stefano Tarantini ◽  
Antonio Davila ◽  
M. Noa Valcarcel-Ares ◽  
Zsuzsanna Tucsek ◽  
...  
Keyword(s):  
Somatosensory Cortex ◽  
Neuronal Activity ◽  
Critical Role ◽  
Neurovascular Coupling ◽  
No Synthase ◽  
Functional Hyperemia ◽  
Inhibitory Effects ◽  
Pathological Conditions ◽  
Whisker Stimulation

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS−/−) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS−/− mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

scholarly journals Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner

2021 ◽  
Vol 15 ◽  
Author(s):  
Nicholas Chaaya ◽  
Joshua Wang ◽  
Angela Jacques ◽  
Kate Beecher ◽  
Michael Chaaya ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Mitogen Activated Protein Kinase ◽  
Limbic Cortex ◽  
Pavlovian Fear Conditioning ◽  
Bdnf Expression ◽  
Contextual Fear ◽  
Contextual Fear Memory

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n = 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.

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