Computational Modeling of Lateral Amygdala Neurons During Acquisition and Extinction of Conditioned Fear, Using Hebbian Learning

The amygdaloid complex located within the medial temporal lobe plays an important role in the acquisition and expression of learned fear associations (Quirk et al. 2003) and contains three main components: the lateral nucleus (LA), the basal nucleus (BLA), and the central nucleus (CE) (Faber and Sah, 2002). The lateral nucleus of the amygdala (LA) is widely accepted to be a key site of plastic synaptic events that contributes to fear learning (Pare, Quirk, LeDoux, 2004). There are two main types of neurons within the LA and the BLA: principal pyramidal-like cells which form projection neurons and are glutamatergic and local circuit GABAergic interneurons (Faber and Sah, 2002). In auditory fear conditioning, convergence of tone [conditioned stimulus (CS)] and foot-shock [unconditioned stimulus (US)] inputs potentiates the synaptic transmission containing CS information from the thalamus and cortex to LA, which leads to larger responses in LA in the presentation of subsequent tones only. The increasing LA responses disinhibit the CE neurons via the intercalated (ITC) cells, eliciting fear responses via excessive projections to brain stem and hypothalamic sites (Pare, Quirk, LeDoux, 2004). As a result, rats learn to freeze to a tone that predicts a foot-shock. Once acquired, conditioned fear associations are not always expressed and repeated presentation of the tone CS in the absence of US causes conditioned fear responses to rapidly diminish, a phenomenon termed fear extinction (Quirk et al. 2003). Extinction does not erase the CS-US association, instead it forms a new memory that inhibits conditioned response (Quirk et al. 2003)

Download Full-text

Acquisition of Fear and Extinction in Lateral Amygdala: A Modeling Study

ASME 2010 Dynamic Systems and Control Conference, Volume 1 ◽

10.1115/dscc2010-4218 ◽

2010 ◽

Author(s):

Sandeep Pendyam ◽

Dongbeom Kim ◽

Gregory J. Quirk ◽

Satish S. Nair

Keyword(s):

Pyramidal Neurons ◽

Conditioned Fear ◽

Fear Memory ◽

Fear Learning ◽

Cell Populations ◽

Storage Site ◽

Somatosensory Information ◽

Cortical Inputs ◽

Lateral Nucleus ◽

And Storage

The lateral nucleus of amygdala (LA) is known to be a critical storage site for conditioned fear memory. Synaptic plasticity at auditory inputs to the dorsal LA (LAd) is critical for the formation and storage of auditory fear memories. Recent evidence suggests that two different cell populations (transient- and long-term plastic cells) are present in LAd and are responsible for fear learning. However, the mechanisms involved in the formation and storage of fear are not well understood. As an extension of previous work, a biologically realistic computational model of the LAd circuitry is developed to investigate these mechanisms. The network model consists of 52 LA pyramidal neurons and 13 interneurons. Auditory and somatosensory information reaches LA from both thalamic and cortical inputs. The model replicated the tone responses observed in the two LAd cell populations during conditioning and extinction. The model provides insights into the role of thalamic and cortical inputs in fear memory formation and storage.

Download Full-text

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.

Download Full-text

Prefrontal somatostatin interneurons encode fear memory

10.1101/696377 ◽

2019 ◽

Author(s):

Kirstie A. Cummings ◽

Roger L. Clem

Keyword(s):

Specific Activity ◽

Conditioned Fear ◽

Gain Control ◽

Brain Regions ◽

Fear Learning ◽

Causal Mechanism ◽

Projection Neurons ◽

Synaptic Organization ◽

Cortical Projection ◽

Output Neurons

AbstractTheories stipulate that memories are encoded within networks of cortical projection neurons (PNs). Conversely, GABAergic interneurons (INs) are thought to function primarily to inhibit PNs and thereby impose network gain control, an important but purely modulatory role. However, we found that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex (mPFC) somatostatin interneurons (SST-INs), and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST- and parvalbumin (PV)-INs provides a potential circuit basis for SST-IN-evoked disinhibition of mPFC output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that rather than constrain mnemonic processing, potentiation of SST-IN activity represents an important causal mechanism for conditioned fear.

Download Full-text

Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear

Physiological Reviews ◽

10.1152/physrev.00037.2009 ◽

2010 ◽

Vol 90 (2) ◽

pp. 419-463 ◽

Cited By ~ 595

Author(s):

Hans-Christian Pape ◽

Denis Pare

Keyword(s):

Conditioned Fear ◽

Fear Memory ◽

Network Activity ◽

Fear Learning ◽

Learning Mechanisms ◽

Memory Extinction ◽

Basic Biology ◽

Learned Fear ◽

Neuronal Systems ◽

Neuronal Functions

The last 10 years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate in the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled with the fact that the underlying circuitry is evolutionarily well conserved, make it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses.

Download Full-text

Observational Fear Learning in Rats: Role of Trait Anxiety and Ultrasonic Vocalization

Brain Sciences ◽

10.3390/brainsci11040423 ◽

2021 ◽

Vol 11 (4) ◽

pp. 423

Author(s):

Markus Fendt ◽

Claudia Paulina Gonzalez-Guerrero ◽

Evelyn Kahl

Keyword(s):

Trait Anxiety ◽

Conditioned Fear ◽

Ultrasonic Vocalization ◽

Fear Learning ◽

Anxiety State ◽

Learning Procedure ◽

The Social ◽

Medium Level ◽

Male Wistar Rats

Rats can acquire fear by observing conspecifics that express fear in the presence of conditioned fear stimuli. This process is called observational fear learning and is based on the social transmission of the demonstrator rat’s emotion and the induction of an empathy-like or anxiety state in the observer. The aim of the present study was to investigate the role of trait anxiety and ultrasonic vocalization in observational fear learning. Two experiments with male Wistar rats were performed. In the first experiment, trait anxiety was assessed in a light–dark box test before the rats were submitted to the observational fear learning procedure. In the second experiment, ultrasonic vocalization was recorded throughout the whole observational fear learning procedure, and 22 kHz and 50 kHz calls were analyzed. The results of our study show that trait anxiety differently affects direct fear learning and observational fear learning. Direct fear learning was more pronounced with higher trait anxiety, while observational fear learning was the best with a medium-level of trait anxiety. There were no indications in the present study that ultrasonic vocalization, especially emission of 22 kHz calls, but also 50 kHz calls, are critical for observational fear learning.

Download Full-text

Fear conditioning and stimulus generalization in association with age in children and adolescents

European Child & Adolescent Psychiatry ◽

10.1007/s00787-021-01797-4 ◽

2021 ◽

Author(s):

Julia Reinhard ◽

Anna Slyschak ◽

Miriam A. Schiele ◽

Marta Andreatta ◽

Katharina Kneer ◽

...

Keyword(s):

Children And Adolescents ◽

Fear Conditioning ◽

Repeated Measures ◽

Conditioned Fear ◽

Fear Learning ◽

Stimulus Generalization ◽

Healthy Children ◽

Older Individuals ◽

Age Related ◽

Current Task

AbstractThe aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8–17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS−) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS−): four generalization stimuli depicting gradual morphs from CS+ to CS− in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS−, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

Download Full-text

Npas4a expression in the teleost forebrain is associated with stress coping style differences in fear learning

Scientific Reports ◽

10.1038/s41598-021-91495-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Matthew R. Baker ◽

Ryan Y. Wong

Keyword(s):

Neural Plasticity ◽

Coping Style ◽

Molecular Mechanisms ◽

Conditioned Fear ◽

Coping Styles ◽

Brain Regions ◽

Contextual Fear Conditioning ◽

Fear Learning ◽

Stress Coping ◽

Contextual Fear

AbstractLearning to anticipate potentially dangerous contexts is an adaptive behavioral response to coping with stressors. An animal’s stress coping style (e.g. proactive–reactive axis) is known to influence how it encodes salient events. However, the neural and molecular mechanisms underlying these stress coping style differences in learning are unknown. Further, while a number of neuroplasticity-related genes have been associated with alternative stress coping styles, it is unclear if these genes may bias the development of conditioned behavioral responses to stressful stimuli, and if so, which brain regions are involved. Here, we trained adult zebrafish to associate a naturally aversive olfactory cue with a given context. Next, we investigated if expression of two neural plasticity and neurotransmission-related genes (npas4a and gabbr1a) were associated with the contextual fear conditioning differences between proactive and reactive stress coping styles. Reactive zebrafish developed a stronger conditioned fear response and showed significantly higher npas4a expression in the medial and lateral zones of the dorsal telencephalon (Dm, Dl), and the supracommissural nucleus of the ventral telencephalon (Vs). Our findings suggest that the expression of activity-dependent genes like npas4a may be differentially expressed across several interconnected forebrain regions in response to fearful stimuli and promote biases in fear learning among different stress coping styles.

Download Full-text

Conditioned fear reactions are associated with gray matter density but not cortical microstructure

10.1101/2020.12.18.423236 ◽

2020 ◽

Author(s):

Christoph Fraenz ◽

Dorothea Metzen ◽

Christian J. Merz ◽

Helene Selpien ◽

Nikolai Axmacher ◽

...

Keyword(s):

Gray Matter ◽

Conditioned Fear ◽

Brain Networks ◽

Brain Regions ◽

Matter Density ◽

Fear Learning ◽

Future Research ◽

Fear Reaction ◽

Gray Matter Density ◽

Diffusion Weighted Images

AbstractResearch has shown that fear acquisition, in reaction to potentially harmful stimuli or situations, is characterized by pronounced interindividual differences. It is likely that such differences are evoked by variability in the macro- and microstructural properties of brain regions involved in the processing of threat or safety signals from the environment. Indeed, previous studies have shown that the strength of conditioned fear reactions is associated with the cortical thickness or volume of various brain regions. However, respective studies were exclusively targeted at single brain regions instead of whole brain networks. Here, we tested 60 young and healthy individuals in a differential fear conditioning paradigm while they underwent fMRI scanning. In addition, we acquired T1-weighted and multi-shell diffusion-weighted images prior to testing. We used task-based fMRI data to define global brain networks which exhibited increased BOLD responses towards CS+ or CS- presentations, respectively. From these networks, we obtained mean values of gray matter density, neurite density, and neurite orientation dispersion. We found that mean gray matter density averaged across the CS+ network was significantly correlated with the strength of conditioned fear reactions quantified via skin conductance response. Measures of neurite architecture were not associated with conditioned fear reaction in any of the two networks. Our results extend previous findings on the relationship between brain morphometry and fear learning. Most importantly, our study is the first to introduce neurite imaging to fear learning research and discusses how its implementation can be improved in future research.

Download Full-text

Refinement of the primate corticospinal pathway during prenatal development

10.1101/575936 ◽

2019 ◽

Author(s):

Ana Rita Ribeiro Gomes ◽

Etienne Olivier ◽

Herbert P. Killackey ◽

Pascale Giroud ◽

Michel Berland ◽

...

Keyword(s):

Occipital Cortex ◽

Prenatal Development ◽

Zona Incerta ◽

Central Nucleus ◽

Projection Neurons ◽

Subcortical Structures ◽

Corticospinal Pathway ◽

Contralateral Projection ◽

Order Of Magnitude ◽

Ipsilateral Projection

AbstractPerturbation of the developmental refinement of the corticospinal pathway leads to motor disorders. In non-primates developmental refinement is well documented, however in primates invasive investigations of the developing corticospinal pathway have been confined to neonatal and postnatal stages when refinement is relatively modest.Here, we investigated the developmental changes in the distribution of corticospinal projection neurons in cynomolgus monkey. Injections of retrograde tracer at the cervical levels of the spinal cord at embryonic day (E) 95 and E105 show that (i) areal distribution of back-labeled neurons is more extensive than in the neonate and dense labeling is found in prefrontal, limbic, temporal and occipital cortex; (ii) distributions of contra- and ipsilateral projecting corticospinal neurons are comparable in terms of location and numbers of labeled neurons, in contrast to the adult where the contralateral projection is an order of magnitude higher than the ipsilateral projection. Findings from one largely restricted injection suggest a hitherto unsuspected early innervation of the gray matter.In the fetus there was in addition dense labeling in the central nucleus of the amygdala, the hypothalamus, the subthalamic nucleus and the adjacent region of the zona incerta, subcortical structures with only minor projections in the adult control.

Download Full-text