Estradiol and Sex Differences in Generalized Fear

2020 ◽  
pp. 433-455
Author(s):  
Jordan M. Adkins ◽  
Aaron M. Jasnow ◽  
Joseph F. Lynch
Keyword(s):  
Sex Differences ◽  
Anxiety Disorders ◽  
Critical Role ◽  
Fear Extinction ◽  
Anterior Cingulate ◽  
Female Rats ◽  
Fear Learning ◽  
Ca1 Region ◽  
Glutamatergic Signaling ◽  
Fear Generalization

In the United States, the prevalence of psychiatric disorders has reached nearly epidemic proportions. Years of research has focused on the link between 17β‎-estradiol and the sex differences observed in anxiety disorders. Evidence suggests that estradiol plays a critical role in the way female rodents and women respond in various tasks assessing anxiety-like behaviors, fear learning, and fear extinction. One hallmark feature of many anxiety disorders is the tendency to express fear to nonthreatening contexts or cues. This generalized fear supports spreading of fear responses and can serve to maintain anxiety states. This chapter reviews the literature linking estradiol to anxiety behavior in female rodents and anxiety in women, including research on estradiol in fear learning and fear extinction. The chapter also presents data suggesting that female rats generalize fear at a faster rate than males, and this is due to estradiol. Through a series of experiments, the authors determine that estradiol promotes contextual fear generalization in female rats through activation of cytosolic estrogen receptor beta (ERβ‎) within the dorsal CA1 region of the hippocampus (dCA1). Additionally, estradiol promotes fear generalization likely through augmented glutamatergic signaling within the dCA1 and anterior cingulate cortex (ACC). However, in males, estradiol (and testosterone) function to reduce fear generalization and do so by activation of both ERβ‎ and ERα‎ within the dCA1. Understanding the neural mechanisms underlying the critical role of estradiol in context fear generalization will yield the knowledge and information necessary for developing novel, sex-specific, treatments for anxiety disorders.

scholarly journals Control of fear extinction by hypothalamic melanin-concentrating hormone–expressing neurons

2020 ◽  
Vol 117 (36) ◽  
pp. 22514-22521
Author(s):  
Cristina Concetti ◽  
Edward F. Bracey ◽  
Daria Peleg-Raibstein ◽  
Denis Burdakov
Keyword(s):  
Anxiety Disorders ◽  
Real Time ◽  
Fear Extinction ◽  
Fear Learning ◽  
Slowing Down ◽  
Aversive Events ◽  
Neural Substrate ◽  
Melanin Concentrating Hormone ◽  
Sensory Responses ◽  
Fear Behavior

Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone–expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.

scholarly journals Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis

2011 ◽  
Vol 300 (2) ◽  
pp. F433-F440 ◽  
Author(s):  
Jun Liu ◽  
Nikhil Sharma ◽  
Wei Zheng ◽  
Hong Ji ◽  
Helen Tam ◽  
...  
Keyword(s):  
Sex Differences ◽  
Protein Expression ◽  
Critical Role ◽  
Urine Volume ◽  
Urine Osmolality ◽  
Receptor Expression ◽  
Female Rats ◽  
Male Rats ◽  
Water Loading ◽  
Mrna And Protein Expression

The renal vasopressin V2 receptor (V2R) plays a critical role in physiological and pathophysiological processes associated with arginine vasopressin (AVP)-induced antidiuresis. Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V2R. In normal Sprague-Dawley rat kidneys, V2R mRNA and protein expression was 2.6- and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V2R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V2R mRNA and protein in female kidneys was reduced to a greater degree (−63% and −73%, respectively) than in males (−32% and −48%, respectively). By the end of the 5-day escape period, renal V2R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V2R expression seen in the basal state. Our results demonstrate that female rats express significantly more V2R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V2R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP.

Developmental Neurobiology of Anxiety and Related Disorders

2017 ◽  
Author(s):  
Emily M. Cohodes ◽  
Dylan G. Gee
Keyword(s):  
Anxiety Disorders ◽  
Anterior Cingulate ◽  
Fear Learning ◽  
Childhood And Adolescence ◽  
Dynamic Changes ◽  
Pediatric Anxiety ◽  
Signal Change ◽  
Pediatric Anxiety Disorders ◽  
And Function ◽  
Amygdala Reactivity

The majority of anxiety disorders emerge during childhood and adolescence, a developmental period characterized by dynamic changes in frontolimbic circuitry. Frontolimbic circuitry plays a key role in fear learning and has been a focus of recent efforts to understand the neurobiological correlates of anxiety disorders across development. Although less is known about the neurobiological underpinnings of anxiety disorders in youth than in adults, studies of pediatric anxiety have revealed alterations in both the structure and function of frontolimbic circuitry. The amygdala, prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampus contribute to fear conditioning and extinction, and interactions between these regions have been implicated in anxiety during development. Specifically, children and adolescents with anxiety disorders show altered amygdala volumes and exhibit heightened amygdala activation in response to neutral and fearful stimuli, with the magnitude of signal change in amygdala reactivity corresponding to the severity of symptomatology. Abnormalities in the PFC and ACC and their connections with the amygdala may reflect weakened top-down control or compensatory efforts to regulate heightened amygdala reactivity associated with anxiety. Taken together, alterations in frontolimbic connectivity are likely to play a central role in the etiology and maintenance of anxiety disorders. Future studies should aim to translate the emerging understanding of the neurobiological bases of pediatric anxiety disorders to optimize clinical interventions for youth.

scholarly journals Fear Extinction-Based Inter-Individual and Sex Differences in Pain-Related Vocalizations and Anxiety-like Behaviors but Not Nocifensive Reflexes

2021 ◽  
Vol 11 (10) ◽  
pp. 1339
Author(s):  
Peyton Presto ◽  
Guangchen Ji ◽  
Riley Junell ◽  
Zach Griffin ◽  
Volker Neugebauer
Keyword(s):  
Sex Differences ◽  
Neuropathic Pain ◽  
Field Tests ◽  
Fear Extinction ◽  
Female Rats ◽  
Chronic Neuropathic Pain ◽  
Pain Mechanisms ◽  
Pain Models ◽  
Neuropathic Pain Model ◽  
Individual And Sex Differences

Inter-individual and sex differences in pain responses are recognized but their mechanisms are not well understood. This study was intended to provide the behavioral framework for analyses of pain mechanisms using fear extinction learning as a predictor of phenotypic and sex differences in sensory (mechanical withdrawal thresholds) and emotional-affective aspects (open field tests for anxiety-like behaviors and audible and ultrasonic components of vocalizations) of acute and chronic pain. In acute arthritis and chronic neuropathic pain models, greater increases in vocalizations were found in females than males and in females with poor fear extinction abilities than females with strong fear extinction, particularly in the neuropathic pain model. Female rats showed higher anxiety-like behavior than males under baseline conditions but no inter-individual or sex differences were seen in the pain models. No inter-individual and sex differences in mechanosensitivity were observed. The data suggest that vocalizations are uniquely suited to detect inter-individual and sex differences in pain models, particularly in chronic neuropathic pain, whereas no such differences were found for mechanosensitivity, and baseline differences in anxiety-like behaviors disappeared in the pain models.

scholarly journals Individual Differences in Conditioned Fear and Extinction in Female Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Sarah C. Tryon ◽  
Iris M. Sakamoto ◽  
Devin M. Kellis ◽  
Kris F. Kaigler ◽  
Marlene A. Wilson
Keyword(s):  
Individual Differences ◽  
Conditioned Fear ◽  
Fear Extinction ◽  
Freezing Behavior ◽  
Female Rats ◽  
Fear Learning ◽  
Initial Exposure ◽  
Testing Environment ◽  
Wide Range ◽  
Distress Vocalizations

The inability to extinguish a traumatic memory is a key aspect of post-traumatic stress disorder (PTSD). While PTSD affects 10–20% of individuals who experience a trauma, women are particularly susceptible to developing the disorder. Despite this notable female vulnerability, few studies have investigated this particular resistance to fear extinction observed in females. Similar to humans, rodent models of Pavlovian fear learning and extinction show a wide range of individual differences in fear learning and extinction, although female rodents are considerably understudied. Therefore, the present study examined individual differences in fear responses, including freezing behavior and ultrasonic vocalizations (USVs), of female Long–Evans rats during acquisition of fear conditioning and cued fear extinction. Similar to prior studies in males, female rats displayed individual variation in freezing during cued fear extinction and were divided into extinction competent (EC) and extinction resistant (ER) phenotypes. Differences in freezing between ER and EC females were accompanied by shifts in rearing during extinction, but no darting was seen in any trial. Freezing behavior during fear learning did not differ between the EC and ER females. Vocalizations emitted in the 22 and 50 kHz ranges during fear learning and extinction were also examined. Unlike vocalizations seen in previous studies in males, very few 22 kHz distress vocalizations were emitted by female rats during fear acquisition and extinction, with no difference between ER and EC groups. Interestingly, all female rats produced significant levels of 50 kHz USVs, and EC females emitted significantly more 50 kHz USVs than ER rats. This difference in 50 kHz USVs was most apparent during initial exposure to the testing environment. These results suggest that like males, female rodents show individual differences in both freezing and USVs during fear extinction, although females appear to vocalize more in the 50 kHz range, especially during initial periods of exposure to the testing environment, and emit very few of the 22 kHz distress calls that are typically observed in males during fear learning or extinction paradigms. Overall, these findings show that female rodents display fear behavior repertoires divergent from males.

scholarly journals Fear extinction learning and anandamide: an fMRI study in healthy humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer Spohrs ◽  
Martin Ulrich ◽  
Georg Grön ◽  
Michael Prost ◽  
Paul Lukas Plener ◽  
...  
Keyword(s):  
Treatment Options ◽  
Endocannabinoid System ◽  
Anxiolytic Effect ◽  
Fear Extinction ◽  
Anterior Cingulate ◽  
Fear Learning ◽  
Neural Activation ◽  
Extinction Learning ◽  
Healthy Humans ◽  
And Task

AbstractAnxiety- and trauma-related disorders are severe illnesses with high prevalence. Current treatment options leave room for improvement and the endocannabinoid system (ECS) has become a key target in psychopharmacological research. Rodent models suggest an anxiolytic effect of endocannabinoids and demonstrated that the ECS is involved in the modulation of fear learning and aversive memory consolidation. So far, one prominent target was inhibition of fatty acid amino hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide (AEA). Research in humans remains scarce, but genetic studies have found that the single-nucleotide polymorphism (SNP) FAAH C385A (rs324420) is associated with lower catabolic performance of FAAH and increased levels of AEA. Translational research on the ECS in fear learning processes is rare, yet crucial to understand the mechanisms involved. To address this lack of research, we designed a fear conditioning, extinction learning paradigm with 51 healthy, male humans who underwent functional magnetic resonance imaging (fMRI) before analysing baseline and task-related changes of AEA, as well as the FAAH polymorphism (rs324420). The results indicate higher AEA levels in AC-heterozygotes than in CC-individuals (SNP rs324420), but no difference between the groups during extinction learning. However, neural activation of the anterior cingulate cortex and anterior insular cortex during extinction learning correlated positively with AEA baseline levels, and task-related changes in AEA were found particularly during fear extinction, with a modulatory effect on neural activation related to extinction learning. Results indicate a putative role for AEA in fear extinction learning. Pre-treatment with AEA-enhancing drugs could promote extinction learning during psychotherapeutic interventions.

Effects of an Anxiety-Specific Psychometric Factor on Fear Conditioning and Fear Generalization

2017 ◽  
Vol 225 (3) ◽  
pp. 200-213 ◽  
Author(s):  
Christian Baumann ◽  
Miriam A. Schiele ◽  
Martin J. Herrmann ◽  
Tina B. Lonsdorf ◽  
Peter Zwanzger ◽  
...  
Keyword(s):  
Risk Factor ◽  
Anxiety Disorders ◽  
Fear Conditioning ◽  
Longitudinal Design ◽  
Principal Component ◽  
Anxiety And Depression ◽  
Specific Factor ◽  
High Anxious ◽  
Two Factors ◽  
Fear Generalization

Abstract. Conditioning and generalization of fear are assumed to play central roles in the pathogenesis of anxiety disorders. Here we investigate the influence of a psychometric anxiety-specific factor on these two processes, thus try to identify a potential risk factor for the development of anxiety disorders. To this end, 126 healthy participants were examined with questionnaires assessing symptoms of anxiety and depression and with a fear conditioning and generalization paradigm. A principal component analysis of the questionnaire data identified two factors representing the constructs anxiety and depression. Variations in fear conditioning and fear generalization were solely associated with the anxiety factor characterized by anxiety sensitivity and agoraphobic cognitions; high-anxious individuals exhibited stronger fear responses (arousal) during conditioning and stronger generalization effects for valence and UCS-expectancy ratings. Thus, the revealed psychometric factor “anxiety” was associated with enhanced fear generalization, an assumed risk factor for anxiety disorders. These results ask for replication with a longitudinal design allowing to examine their predictive validity.

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