scholarly journals The Role of Central Amygdala Corticotropin-Releasing Factor in Predator Odor Stress-Induced Avoidance Behavior and Escalated Alcohol Drinking in Rats

2019 ◽  
Author(s):  
Marcus M. Weera ◽  
Allyson L. Schreiber ◽  
Elizabeth M. Avegno ◽  
Nicholas W. Gilpin
Keyword(s):  
Alcohol Drinking ◽  
Avoidance Behavior ◽  
Conditioned Avoidance ◽  
Corticotropin Releasing Factor ◽  
Predator Odor ◽  
Central Amygdala ◽  
Post Traumatic Stress ◽  
Conditioned Place Avoidance ◽  
Place Avoidance ◽  
Post Traumatic

ABSTRACTPost-traumatic stress disorder (PTSD) is characterized by avoidance of trauma-associated stimuli and amygdala hyperreactivity, and is highly co-morbid with alcohol use disorder (AUD). Our lab uses a predator odor (bobcat urine) stress model that produces conditioned avoidance of an odor-paired context in a subset of rats, mirroring avoidance symptoms that manifest in some but not all humans exposed to trauma. We previously showed that after predator odor stress, Avoiders exhibit escalated alcohol drinking, higher aversion-resistant operant alcohol responding, hyperalgesia, and greater anxiety-like behavior compared to unstressed Controls. We also showed that systemic antagonism of corticotropin-releasing factor-1 receptors (CRFR1) reduced escalation of alcohol drinking in rats not indexed for avoidance, that corticotropin-releasing factor (CRF) infusions into the central amygdala (CeA) produced conditioned place avoidance in stress-naïve rats, and that intra-CeA infusion of a CRFR1 antagonist reduced hyperalgesia in Avoiders. Here, we show that avoidance behavior is persistent after repeated predator odor exposure and is resistant to extinction. In addition, Avoiders showed lower weight gain than Controls after predator odor re-exposure. In the brain, higher avoidance was correlated with higher number of c-Fos+ cells and CRF immunoreactivity in the CeA. Finally, we show that intra-CeA CRFR1 antagonism reversed post-stress escalation of alcohol drinking and reduced avoidance behavior in Avoiders. Collectively, these findings suggest that elucidation of the mechanisms by which CRFR1-gated CeA circuits regulate avoidance behavior and alcohol drinking may lead to better understanding of the neural mechanisms underlying co-morbid PTSD and AUD.

scholarly journals The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Olivia B. Levine ◽  
Mary Jane Skelly ◽  
John D. Miller ◽  
Jean K. Rivera-Irizarry ◽  
Sydney A. Rowson ◽  
...  
Keyword(s):  
Synaptic Input ◽  
Alcohol Drinking ◽  
Avoidance Behavior ◽  
Corticotropin Releasing Factor ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Synaptic Excitation ◽  
Per Se ◽  
Paraventricular Thalamus ◽  
Crf Neurons

AbstractBed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

scholarly journals Increased Behavioral Deficits and Inflammation in a Mouse Model of Co-Morbid Traumatic Brain Injury and Post-Traumatic Stress Disorder

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142097956
Author(s):  
Arman Fesharaki-Zadeh ◽  
Jeremy T. Miyauchi ◽  
Karrah St. Laurent-Arriot ◽  
Stella E. Tsirka ◽  
Peter J. Bergold
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Stress Disorder ◽  
Barnes Maze ◽  
Post Traumatic Stress ◽  
Place Avoidance ◽  
Post Traumatic

Comorbid post-traumatic stress disorder with traumatic brain injury (TBI) produce more severe affective and cognitive deficits than PTSD or TBI alone. Both PTSD and TBI produce long-lasting neuroinflammation, which may be a key underlying mechanism of the deficits observed in co-morbid TBI/PTSD. We developed a model of co-morbid TBI/PTSD by combining the closed head (CHI) model of TBI with the chronic variable stress (CVS) model of PTSD and examined multiple behavioral and neuroinflammatory outcomes. Male C57/Bl6 mice received sham treatment, CHI, CVS, CHI then CVS (CHI → CVS) or CVS then CHI (CVS → CHI). The CVS → CHI group had deficits in Barnes maze or active place avoidance not seen in the other groups. The CVS → CHI, CVS and CHI → CVS groups displayed increased basal anxiety level, based on performance on elevated plus maze. The CVS → CHI had impaired performance on Barnes Maze, and Active Place Avoidance. These performance deficits were strongly correlated with increased hippocampal Iba-1 level an indication of activated MP/MG. These data suggest that greater cognitive deficits in the CVS → CHI group were due to increased inflammation. The increased deficits and neuroinflammation in the CVS → CHI group suggest that the order by which a subject experiences TBI and PTSD is a major determinant of the outcome of brain injury in co-morbid TBI/PTSD.

scholarly journals Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking

2019 ◽  
Author(s):  
Lucas Albrechet-Souza ◽  
Connor L. Schratz ◽  
Nicholas W. Gilpin
Keyword(s):  
Sex Differences ◽  
Traumatic Stress ◽  
Alcohol Drinking ◽  
Stress Reactivity ◽  
Acoustic Startle ◽  
Predator Odor ◽  
Female Rats ◽  
Post Traumatic Stress ◽  
Male And Female Rats ◽  
Odor Exposure

AbstractBackgroundAlcohol misuse and post-traumatic stress disorder (PTSD) are highly comorbid and treatment outcomes are worse in individuals with both conditions. Although more men report experiencing traumatic events than women, the lifetime prevalence of PTSD is twice as high in females. Despite these data trends in humans, preclinical studies of traumatic stress reactivity have been performed almost exclusively in male animals.MethodsThis study was designed to examine sex differences in traumatic stress reactivity in alcohol-naïve rats and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks. Rats were exposed to predator odor (bobcat urine) and tested for avoidance of the odor-paired context 24 hours later; unstressed Controls were never exposed to odor. Two days after stress, we measured physiological arousal using the acoustic startle response (ASR) test. We also measured anxiety-like behavior using the elevated plus-maze (EPM) and circulating corticosterone levels before and immediately after odor exposure.ResultsMale and female rats exposed to predator odor displayed blunted weight gain 24 hours post-stress, but only a subset of stressed animals exhibited avoidance behavior. Chronic intermittent alcohol drinking increased the proportion of Avoiders in males and predator odor exposure increased ASR in these animals. Predator odor stress reduced ASR in females relative to unstressed females and stressed males, regardless of alcohol drinking history. Bobcat urine exposure did not promote persistent anxiety-like behavior, but alcohol-experienced males exhibited reduced activity in the EPM in comparison to alcohol-experienced females.Furthermore, predator odor increased circulating corticosterone levels in females relative to males and baseline.ConclusionsWe report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, chronic moderate alcohol drinking increased traumatic stress reactivity in males but not females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior.

scholarly journals Inhibitory Corticotropin-Releasing Factor Neurons in the Dorsomedial Prefrontal Cortex Promote Stress-Resilient Behavior in Male Rodents

2020 ◽  
Author(s):  
Elena Maria Vidrascu ◽  
Madeline Mae Robertson
Keyword(s):  
Prefrontal Cortex ◽  
Corticotropin Releasing Factor ◽  
Post Traumatic Stress ◽  
Negative Effects ◽  
Adverse Experiences ◽  
Important Regulator ◽  
Response To Stress ◽  
Stress Response System ◽  
Post Traumatic ◽  
Resilient Behavior

Adaptive behavior in response to adverse experiences facilitates faster recovery and less time spent engaging in maladaptive behaviors that contribute to psychopathology, including anxiety, depression, and post-traumatic stress disorder. Dysregulation of activity in the prefrontal cortex (PFC) has been implicated in these disorders, as well as in diminished cognitive flexibility, with stress further exacerbating these negative effects. Corticotropin-releasing factor is an important regulator of the stress-response system and may have a differential involvement in individuals who are especially susceptible to negative stress-related outcomes. A recent study by Chen et al. (Neuron 106: 301-315, 2020) has identified a novel subtype of GABAergic CRF interneurons in the dorsomedial PFC that, upon activation, can promote active responses and resilient behavior in response to stress.

scholarly journals Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

2020 ◽  
Author(s):  
Ryan E. Tyler ◽  
Ben Weinberg ◽  
Dennis Lovelock ◽  
Laura Ornelas ◽  
Joyce Besheer
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Dorsal Hippocampus ◽  
Synaptic Function ◽  
Predator Odor ◽  
Male Rats ◽  
Prelimbic Cortex ◽  
Post Traumatic Stress ◽  
Early Stress ◽  
Post Traumatic

AbstractPersistent changes in brain stress and glutamatergic function are associated with post-traumatic stress disorder (PTSD). Rodent exposure to the predator odor trimethylthiazoline (TMT) is an innate stressor that produces lasting behavioral consequences relevant to PTSD. As such, the goal of the present study was to assess early (6 hours and 2 days) and late (4 weeks) changes to gene expression (RT-PCR) related to stress and excitatory function following TMT exposure in male, Long-Evans rats. During TMT exposure, rats engaged in stress reactive behaviors, including digging and immobility. Further, the TMT group displayed enhanced exploration and mobility in the TMT-paired context one week after exposure, suggesting a lasting contextual reactivity. Gene expression analyses revealed upregulated FKBP5 6 hours post-TMT in the hypothalamus and dorsal hippocampus. Two days after TMT, GRM3 was downregulated in the prelimbic cortex and dorsal hippocampus, but upregulated in the nucleus accumbens. This may reflect an early stress response (FKBP5) that resulted in later glutamatergic adaptation (GRM3). Finally, four weeks after TMT exposure, several differentially expressed genes known to mediate excitatory tripartite synaptic function were observed. Specifically in the prelimbic cortex (GRM5, DLG4 and SLC1A3 upregulated), infralimbic cortex (GRM2 downregulated, Homer1 upregulated), nucleus accumbens (GRM7 and SLC1A3 downregulated), dorsal hippocampus (FKBP5 and NR3C2 upregulated, SHANK3 downregulated) and ventral hippocampus (CNR1, GRM7, GRM5, SHANK3, and Homer1 downregulated). These data demonstrate that TMT exposure stress induces early and late stress and excitatory molecular adaptations, which may help us understand the persistent glutamatergic dysfunction observed in PTSD.

scholarly journals Measuring maladaptive avoidance: from animal models to clinical anxiety

2022 ◽  
Author(s):  
Tali M. Ball ◽  
Lisa A. Gunaydin
Keyword(s):  
Animal Models ◽  
Anxiety Disorders ◽  
Avoidance Behavior ◽  
Post Traumatic Stress ◽  
Obsessive Compulsive ◽  
Psychosocial Impairment ◽  
Compulsive Disorder ◽  
Post Traumatic ◽  
Underlying Processes ◽  
New Framework

AbstractAvoiding stimuli that predict danger is required for survival. However, avoidance can become maladaptive in individuals who overestimate threat and thus avoid safe situations as well as dangerous ones. Excessive avoidance is a core feature of anxiety disorders, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). This avoidance prevents patients from confronting maladaptive threat beliefs, thereby maintaining disordered anxiety. Avoidance is associated with high levels of psychosocial impairment yet is poorly understood at a mechanistic level. Many objective laboratory assessments of avoidance measure adaptive avoidance, in which an individual learns to successfully avoid a truly noxious stimulus. However, anxiety disorders are characterized by maladaptive avoidance, for which there are fewer objective laboratory measures. We posit that maladaptive avoidance behavior depends on a combination of three altered neurobehavioral processes: (1) threat appraisal, (2) habitual avoidance, and (3) trait avoidance tendency. This heterogeneity in underlying processes presents challenges to the objective measurement of maladaptive avoidance behavior. Here we first review existing paradigms for measuring avoidance behavior and its underlying neural mechanisms in both human and animal models, and identify how existing paradigms relate to these neurobehavioral processes. We then propose a new framework to improve the translational understanding of maladaptive avoidance behavior by adapting paradigms to better differentiate underlying processes and mechanisms and applying these paradigms in clinical populations across diagnoses with the goal of developing novel interventions to engage specific identified neurobehavioral targets.

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