Neuronal circuits of fear memory and fear extinction

e-Neuroforum ◽  
2013 ◽  
Vol 19 (3) ◽  
Author(s):  
C.T. Wotjak ◽  
H.-C. Pape
Keyword(s):  
Anxiety Disorders ◽  
Molecular Mechanisms ◽  
Fear Extinction ◽  
Intervention Strategies ◽  
Laboratory Animals ◽  
Mammalian Brain ◽  
Synaptic Circuits ◽  
Fear And Anxiety ◽  
High Degree ◽  
Synaptic Circuitry

AbstractThe paradigm“eat or be eaten” has proven to be a critical guiding element during the evolution of both humans and animals. This helps to explain the fact that the ability to de­tect danger or a threat has been highly con­served throughout evolution and thus exhib­its a high degree of homology between spe­cies. Studies in laboratory animals thereby enable the identification of key neurochem­ical, cellular and molecular mechanisms un­derlying fear and anxiety, and important­ly, permit conclusions to be drawn regard­ing the situation in humans. This, in turn, pro­vides a highly valuable basis for further im­provements in prognosis, diagnosis, preven­tion and therapy of anxiety disorders. The present article focuses on one aspect cen­tral to translational anxiety research: the neu­ronal substrates and circuits of fear memo­ry and fear extinction. Following a brief intro­duction into the principles of fear condition­ing, the synaptic circuits that underlie the ac­quisition and extinction of fear memories in the mammalian brain will be described. His­torically established principles will be system­atically compared with novel findings on the detailed synaptic circuitry of the fear matrix. Knowledge of the neuronal substrates and circuitry will significantly improve our under­standing of pathologically transformed states of fear and anxiety and thereby help to derive novel intervention strategies for the treat­ment of anxiety disorders.

Prefrontal Cortex Regulation of Emotion and Anxiety

2013 ◽  
pp. 580-592
Author(s):  
Bronwyn M. Graham ◽  
Mohammed R. Milad
Keyword(s):  
Emotion Regulation ◽  
Prefrontal Cortex ◽  
Anxiety Disorders ◽  
Functional Activity ◽  
Fear Extinction ◽  
Top Down ◽  
Structural Abnormalities ◽  
Psychiatric Conditions ◽  
Fear And Anxiety ◽  
Regulation Of Emotion

The ability to appropriately regulate fear and anxiety is considered a top-down process involving higher-level cortical structures. Here, we review evidence that the prefrontal cortex (PFC) is critically involved in many laboratory emotion regulation tasks in both rodents and humans, including behavioral or experiential forms of regulation like fear extinction, and cognitive forms of regulation like reappraisal. We also discuss research demonstrating that failures in emotion regulation, as observed in many psychiatric conditions like anxiety disorders, are associated with PFC structural abnormalities and/or aberrant PFC functional activity. We conclude that the PFC may act as a common gateway between higher-level cortical structures and limbic/brainstem areas to mediate the appropriate control of emotions, irrespective of the regulation strategy (i.e., behavioral or cognitive) employed.

Dispositional negativity, cognition, and anxiety disorders: An integrative translational neuroscience framework

2019 ◽  
Author(s):  
Juyoen Hur ◽  
Melissa D. Stockbridge ◽  
Andrew S. Fox ◽  
Alexander J. Shackman
Keyword(s):  
Risk Factor ◽  
Anxiety Disorders ◽  
Executive Control ◽  
Intervention Strategies ◽  
Attentional Biases ◽  
Translational Neuroscience ◽  
Adult Personality ◽  
Fundamental Dimension ◽  
To Come ◽  
Underlying Mechanisms

When extreme, anxiety can become debilitating. Anxiety disorders, which often first emerge early in development, are common and challenging to treat, yet the underlying mechanisms have only recently begun to come into focus. Here, we review new insights into the nature and biological bases of dispositional negativity, a fundamental dimension of childhood temperament and adult personality and a prominent risk factor for the development of pediatric and adult anxiety disorders. Converging lines of epidemiological, neurobiological, and mechanistic evidence suggest that dispositional negativity increases the likelihood of psychopathology via specific neurocognitive mechanisms, including attentional biases to threat and deficits in executive control. Collectively, these observations provide an integrative translational framework for understanding the development and maintenance of anxiety disorders in adults and youth and set the stage for developing improved intervention strategies.

scholarly journals An architectonic type principle in the development of laminar patterns of cortico-cortical connections

2021 ◽  
Author(s):  
Sarah F. Beul ◽  
Alexandros Goulas ◽  
Claus C. Hilgetag
Keyword(s):  
Structural Connectivity ◽  
Macaque Monkey ◽  
Brain Regions ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Cortical Connections ◽  
Cortical Projections ◽  
Structural Connections ◽  
High Degree ◽  
The Brain

AbstractStructural connections between cortical areas form an intricate network with a high degree of specificity. Many aspects of this complex network organization in the adult mammalian cortex are captured by an architectonic type principle, which relates structural connections to the architectonic differentiation of brain regions. In particular, the laminar patterns of projection origins are a prominent feature of structural connections that varies in a graded manner with the relative architectonic differentiation of connected areas in the adult brain. Here we show that the architectonic type principle is already apparent for the laminar origins of cortico-cortical projections in the immature cortex of the macaque monkey. We find that prenatal and neonatal laminar patterns correlate with cortical architectonic differentiation, and that the relation of laminar patterns to architectonic differences between connected areas is not substantially altered by the complete loss of visual input. Moreover, we find that the degree of change in laminar patterns that projections undergo during development varies in proportion to the relative architectonic differentiation of the connected areas. Hence, it appears that initial biases in laminar projection patterns become progressively strengthened by later developmental processes. These findings suggest that early neurogenetic processes during the formation of the brain are sufficient to establish the characteristic laminar projection patterns. This conclusion is in line with previously suggested mechanistic explanations underlying the emergence of the architectonic type principle and provides further constraints for exploring the fundamental factors that shape structural connectivity in the mammalian brain.

scholarly journals Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food

2021 ◽  
Vol 18 (7) ◽  
pp. 3332
Author(s):  
Olga V. Naidenko ◽  
David Q. Andrews ◽  
Alexis M. Temkin ◽  
Tasha Stoiber ◽  
Uloma Igara Uche ◽  
...  
Keyword(s):  
Immune System ◽  
High Throughput ◽  
Environmental Protection Agency ◽  
High Throughput Screening ◽  
Molecular Mechanisms ◽  
Specific Activity ◽  
Laboratory Animals ◽  
In Vitro Assays ◽  
Toxicological Studies

The development of high-throughput screening methodologies may decrease the need for laboratory animals for toxicity testing. Here, we investigate the potential of assessing immunotoxicity with high-throughput screening data from the U.S. Environmental Protection Agency ToxCast program. As case studies, we analyzed the most common chemicals added to food as well as per- and polyfluoroalkyl substances (PFAS) shown to migrate to food from packaging materials or processing equipment. The antioxidant preservative tert-butylhydroquinone (TBHQ) showed activity both in ToxCast assays and in classical immunological assays, suggesting that it may affect the immune response in people. From the PFAS group, we identified eight substances that can migrate from food contact materials and have ToxCast data. In epidemiological and toxicological studies, PFAS suppress the immune system and decrease the response to vaccination. However, most PFAS show weak or no activity in immune-related ToxCast assays. This lack of concordance between toxicological and high-throughput data for common PFAS indicates the current limitations of in vitro screening for analyzing immunotoxicity. High-throughput in vitro assays show promise for providing mechanistic data relevant for immune risk assessment. In contrast, the lack of immune-specific activity in the existing high-throughput assays cannot validate the safety of a chemical for the immune system.

scholarly journals Fear and Anxiety in COVID-19: Preexisting Anxiety Disorders

2021 ◽  
Author(s):  
Roz Shafran ◽  
Stanley Rachman ◽  
Maureen Whittal ◽  
Adam Radomsky ◽  
Anna Coughtrey
Keyword(s):  
Anxiety Disorders ◽  
Fear And Anxiety

scholarly journals BMP signaling alters aquaporin-4 expression in the mouse cerebral cortex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazuya Morita ◽  
Naoyuki Matsumoto ◽  
Kengo Saito ◽  
Toshihide Hamabe-Horiike ◽  
Keishi Mizuguchi ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Molecular Mechanisms ◽  
Water Movement ◽  
Water Channel ◽  
Bmp Signaling ◽  
Aquaporin 4 ◽  
Mammalian Brain ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
Mouse Cerebral Cortex

AbstractAquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.

scholarly journals The Saccharomyces cerevisiae RAD6 Group Is Composed of an Error-Prone and Two Error-Free Postreplication Repair Pathways

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1633-1641 ◽  
Author(s):  
Wei Xiao ◽  
Barbara L Chow ◽  
Stacey Broomfield ◽  
Michelle Hanna
Keyword(s):  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Signal Transducer ◽  
Repair Pathway ◽  
Polyubiquitin Chain ◽  
Postreplication Repair ◽  
Translesion Dna Synthesis ◽  
Radiation Repair ◽  
Repair Pathways ◽  
High Degree

Abstract The RAD6 postreplication repair and mutagenesis pathway is the only major radiation repair pathway yet to be extensively characterized. It has been previously speculated that the RAD6 pathway consists of two parallel subpathways, one error free and another error prone (mutagenic). Here we show that the RAD6 group genes can be exclusively divided into three rather than two independent subpathways represented by the RAD5, POL30, and REV3 genes; the REV3 pathway is largely mutagenic, whereas the RAD5 and the POL30 pathways are deemed error free. Mutants carrying characteristic mutations in each of the three subpathways are phenotypically indistinguishable from a single mutant such as rad18, which is defective in the entire RAD6 postreplication repair/tolerance pathway. Furthermore, the rad18 mutation is epistatic to all single or combined mutations in any of the above three subpathways. Our data also suggest that MMS2 and UBC13 play a key role in coordinating the response of the error-free subpathways; Mms2 and Ubc13 form a complex required for a novel polyubiquitin chain assembly, which probably serves as a signal transducer to promote both RAD5 and POL30 error-free postreplication repair pathways. The model established by this study will facilitate further research into the molecular mechanisms of postreplication repair and translesion DNA synthesis. In view of the high degree of sequence conservation of the RAD6 pathway genes among all eukaryotes, the model presented in this study may also apply to mammalian cells and predicts links to human diseases.

Memory impairment induced by amphetamine derivatives in laboratory animals and in humans: a review

2012 ◽  
Vol 3 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Jordi Camarasa ◽  
Teresa Rodrigo ◽  
David Pubill ◽  
Elena Escubedo
Keyword(s):  
Illicit Drugs ◽  
Molecular Mechanisms ◽  
Memory Performance ◽  
Laboratory Animals ◽  
Club Drugs ◽  
Synthetic Drugs ◽  
History Of ◽  
Amphetamine Derivatives ◽  
Considerable Body

AbstractThe 20th century brought with it the so-called club drugs (the most notorious being amphetamine derivatives), which are used by young adults at all-night dance parties. Methamphet­amine and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) are synthetic drugs with stimulant and psychoactive properties that belong to the amphetamine family. Here, we have reviewed the literature about the cognitive impairment induced by these two amphetamine derivatives and the preclinical and clinical outcomes. Although there is controversial evidence about the effect of methamphetamine and MDMA on learning and memory in laboratory animals, results from published papers demonstrate that amphetamines cause long-term impairment of cognitive functions. A large number of pharmacological receptors have been studied and screened as targets of amphetamine-induced cognitive dysfunction, and extensive research efforts have been invested to provide evidence about the molecular mechanisms behind these cognitive deficits. In humans, there is a considerable body of evidence indicating that methamphetamine and MDMA seriously disrupt memory and learning processes. Although an association between the impairments of memory performance and a history of recreational amphetamine ingestion has also been corroborated, a number of methodological difficulties continue to hamper research in this field, the most important being the concomitant use of other illicit drugs.

Vestibulo-ocular function in anxiety disorders

2007 ◽  
Vol 16 (4-5) ◽  
pp. 209-215
Author(s):  
Joseph M. Furman ◽  
Mark S. Redfern ◽  
Rolf G. Jacob
Keyword(s):  
Panic Disorder ◽  
Anxiety Disorders ◽  
Semicircular Canal ◽  
Constant Velocity ◽  
Vertical Axis ◽  
Velocity Storage ◽  
Movement Response ◽  
Ocular Reflex ◽  
Axis Rotation ◽  
High Degree

Previous studies of vestibulo-ocular function in patients with anxiety disorders have suggested a higher prevalence of peripheral vestibular dysfunction compared to control populations, especially in panic disorder with agoraphobia. Also, our recent companion studies have indicated abnormalities in postural control in patients with anxiety disorders who report a high degree of space and motion discomfort. The aim of the present study was to assess the VOR, including the semicircular canal-ocular reflex, the otolith-ocular reflex, and semicircular canal-otolith interaction, in a well-defined group of patients with anxiety disorders. The study included 72 patients with anxiety disorders (age 30.6 +/− 10.6 yrs; 60 (83.3% F) and 29 psychiatrically normal controls (age 35.0 +/minus; 11.6 yrs; 24 (82.8% F). 25 patients had panic disorder; 47 patients had non-panic anxiety. Patients were further categorized based on the presence (45 of 72) or absence (27 of 72) of height phobia and the presence (27 of 72) or absence (45 of 72) of excessive space and motion discomfort (SMD). Sinusoidal and constant velocity earth-vertical axis rotation (EVAR) was used to assess the semicircular canal-ocular reflex. Constant velocity off-vertical axis rotation (OVAR) was used to assess both the otolith-ocular reflex and static semicircular canal-otolith interaction. Sinusoidal OVAR was used to assess dynamic semicircular canal-otolith interaction. The eye movement response to rotation was measured using bitemporal electro-oculography. Results showed a significantly higher VOR gain and a significantly shorter VOR time constant in anxiety patients. The effect of anxiety on VOR gain was significantly greater in patients without SMD as compared to those with SMD. Anxiety patients without height phobia had a larger OVAR modulation. We postulate that in patients with anxiety, there is increased vestibular sensitivity and impaired velocity storage. Excessive SMD and height phobia seem to have a mitigating effect on abnormal vestibular sensitivity, possibly via a down-weighting of central vestibular pathways.

The interplay of genotype and environment in the development of fear and anxiety

e-Neuroforum ◽  
2013 ◽  
Vol 19 (3) ◽  
Author(s):  
N. Sachser ◽  
K.-P. Lesch
Keyword(s):  
Individual Differences ◽  
Environmental Factors ◽  
Anxiety Disorders ◽  
Candidate Gene ◽  
Early Development ◽  
Genetic Variants ◽  
External Influences ◽  
Postnatal Environment ◽  
Fear And Anxiety

AbstractIndividual differences in fear, anxiety, and the etiology of anxiety disorders develop dur­ing ontogeny. They are due to both genet­ic and environmental factors. With regard to the role of the environment, the organism is most susceptible to external influences dur­ing early development. Accordingly, stressors that impinge on the maternal organism dur­ing pregnancy evoke high levels of anxiety in the offspring later in life, as does an adverse early postnatal environment. However, anxi­ety-related circuits in the central nervous sys­tem retain their plasticity in adulthood, i.e., levels of anxiety can also be modified by ex­perience across the entire successive lifespan. Notably, the effects of external stressors on the individual’s level of anxiety are modulat­ed by genotype. Such genotype-by-environ­ment interactions are particularly well stud­ied in relation to genetic variants that modu­late the function of the serotonin transport­er. Thus, this review focuses on this candidate gene to elucidate the interplay of genotype and environment in the development of fear and anxiety.

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