Cholinergic rescue of neurocognitive insult following third-trimester equivalent alcohol exposure in rats.

Neonatal ethanol exposure during the third trimester equivalent of human pregnancy in the rat significantly impairs hippocampal and prefrontal neurobehavioral functioning. Postnatal day [PD] 4-9 ethanol exposure in rats disrupts long-term context memory formation, resulting in abolished post-shock and retention test freezing in a variant of contextual fear conditioning called the Context Preexposure Facilitation Effect (CPFE). This behavioral impairment is accompanied by disrupted medial prefrontal, but not dorsal hippocampal expression of the immediate early genes (IEGs) c-Fos, Arc, Egr-1, and Npas4 (Heroux, Robinson-Drummer, Kawan, Rosen, & Stanton, 2019). The current experiment examined if systemic administration of the acetylcholinesterase inhibitor physostigmine (PHY) prior to context learning would rescue prefrontal IEG expression and freezing in the CPFE. From PD4-9, Long-Evans rats received oral intubation of ethanol (EtOH; 5.25 g/kg/day) or sham-intubation (SI). Rats received a systemic injection of saline (SAL) or PHY (0.01 mg/kg) prior to all three phases (Experiment 1) or just context exposure (Experiment 2) in the CPFE from PD31-33. A subset of rats were sacrificed 30 min after context learning to assay changes in IEG expression in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and ventral hippocampus (vHPC). Administration of PHY prior to all three phases or just context learning rescued both post-shock and retention test freezing in the CPFE in EtOH rats without altering performance in SI rats. EtOH-SAL rats had significantly reduced mPFC but not dHPC expression of c-Fos, Arc, Egr-1, and Npas4. EtOH-PHY treatment rescued mPFC expression of c-Fos in ethanol-exposed rats and increased Arc and Npas4 regardless of dosing condition. While there was no effect of PHY on dHPC or vHPC expression of Arc, Egr-1, or Npas4, this treatment significantly boosted hippocampal expression of c-Fos regardless of ethanol treatment. These findings implicate impaired cholinergic and prefrontal function in cognitive deficits arising from 3rd-trimester equivalent alcohol exposure.

Medial prefrontal and ventral hippocampal contributions to incidental context learning and memory in adolescent rats.

The Context Preexposure Facilitation Effect (CPFE) is a contextual fear conditioning (CFC) paradigm in which context learning, context-shock learning, and retrieval of contextual fear occur in three distinct phases. The medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and ventral hippocampus (vHPC) are required for the acquisition and/or consolidation of a context representation during incidental context exposure (Heroux et al., 2017; Robinson-Drummer et al., 2016; Rudy & Matus-Amat, 2006). This exposure also induces the expression of the immediate early genes (IEGs) c-Fos, Arc, Egr-1, and Npas4 in these regions (Heroux et al., 2018, 2019). Despite these studies, it is still unclear how mPFC and vHPC contribute to incidental context learning and memory. The current study examined whether prefrontal or ventral hippocampal inactivation during context preexposure interferes with long-term context memory and IEG activity in the mPFC, vHPC, dHPC and the ventral midline thalamus (VMT, a region connected to both the mPFC and HPC). Adolescent Long-Evans rats were given intra-mPFC (Experiment 1) or intra-vHPC (Experiment 2) infusions of the GABAA receptor agonist muscimol or PBS prior to context preexposure, and then were sacrificed 30 min later and whole mPFC, dHPC, vHPC, and VMT were collected and assayed for IEG mRNA expression via qPCR. Prefrontal or ventral hippocampal inactivation during context exposure abolished subsequent post-shock and retention test freezing in behaviorally-tested littermates of the sacrificed groups. In Experiment 1, prefrontal inactivation reduced expression of c-Fos, Arc, Egr-1, and Npas4 in the mPFC, c-Fos, Arc, and Npas4 in the vHPC, and c-Fos in the VMT, to the level of behaviorally-naïve home-cage controls. Prefrontal inactivation did not alter IEG expression in the dHPC during context exposure. In Experiment 2, ventral hippocampal inactivation impaired expression of all IEGs in the mPFC, dHPC, and vHPC, with no effect in the VMT. Taken together, these results suggest that context memory processes on the preexposure day of the CPFE may depend on mPFC-vHPC circuitry not typically emphasized in studies of incidental or configural learning and memory.

Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE).

The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases (context preexposure, immediate-shock training, and retention). The current study examined changes in the expression of plasticity-associated immediate early genes (IEGs) during context and contextual fear memory formation on the preexposure and training days of the CPFE, respectively. Using adolescent Long-Evans rats, preexposure and training day expression of the IEGs c-Fos, Arc, Egr-1, and Npas4 in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and basolateral amygdala (BLA) was analyzed using qPCR as an extension of previous studies from our lab examining Egr-1 via in situ hybridization (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014). In Expt. 1, context preexposure induced expression of c-Fos, Arc, Egr-1 and Npas4 significantly above that of home-cage (HC) controls in all three regions. In Expt. 2, immediate-shock was followed by a post-shock freezing test, resulting in increased mPFC c-Fos expression in a group preexposed to the training context but not a control group preexposed to an alternate context, indicating expression related to associative learning. This was not seen with other IEGs in mPFC or with any IEG in dHPC or BLA. Finally, when the post-shock freezing test was omitted in Expt. 3, training-related increases were observed in prefrontal c-Fos, Arc, Egr-1, and Npas4, hippocampal c-Fos, and amygdalar Egr-1 expression. These results indicate that context exposure in a post-shock freezing test re-engages IEG expression that may obscure associatively-induced expression during contextual fear conditioning. Additionally, these studies suggest a key role for long-term synaptic plasticity in the mPFC in supporting the CPFE.

Novelty and fear conditioning induced gene expression in high and low states of anxiety.

Emotional states influence how stimuli are interpreted. High anxiety states in humans lead to more negative, threatening interpretations of novel information, typically accompanied by activation of the amygdala. We developed a handling protocol that induces long-lasting high and low anxiety-like states in rats to explore the role of state anxiety on brain activation during exposure to a novel environment and fear conditioning. In situ hybridization of the inducible transcription factor Egr-1 found increased gene expression in the lateral nucleus of the amygdala (LA) following exposure to a novel environment and contextual fear conditioning in high anxiety-like rats. In contrast, low state anxiety-like rats did not generate Egr-1 increases in LA when placed in a novel chamber. Egr-1 expression was also examined in the dorsal hippocampus and prefrontal cortex. In CA1 of the hippocampus and medial prefrontal cortex (mPFC), Egr-1 expression increased in response to novel context exposure and fear conditioning, independent of state anxiety level. Furthermore, in mPFC, Egr-1 in low anxiety-like rats was increased more with fear conditioning than novel exposure. The current series of experiments show that brain areas involved in fear and anxiety-like states do not respond uniformly to novelty during high and low states of anxiety.

Differential involvement of the medial prefrontal cortex across variants of contextual fear conditioning.

The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases. In contrast, learning about the context and the context-shock association happens concurrently in standard contextual fear conditioning (sCFC). By infusing the GABAA receptor agonist muscimol into medial prefrontal cortex (mPFC) in adolescent Long-Evans rats, the current set of experiments examined the functional role of the mPFC in each phase of the CPFE and sCFC. In the CPFE, the mPFC is necessary for the following: acquisition and/or consolidation of context memory (Experiment 1), reconsolidation of a context memory to include shock (Experiment 2), and expression of contextual fear memory during a retention test (Experiment 3). In contrast to the CPFE, inactivation of the mPFC prior to conditioning in sCFC has no effect on acquisition, consolidation, or retention of a contextual fear memory (Experiment 4). Interestingly, the mPFC is not required for acquiring a context-shock association (measured by post-shock freezing) in the CPFE or sCFC (Experiment 2b and 4). Taken together, these results indicate that the mPFC is differentially recruited across stages of learning and variants of contextual fear conditioning (CPFE versus sCFC). More specifically, separating out learning about the context and the context-shock association necessitates activation of the medial prefrontal cortex during early learning and/or consolidation.

Changes in dam and pup behavior following repeated postnatal exposure to a predator odor (TMT): A preliminary investigation in Long-Evans rats.

The present study investigated whether repeated early postnatal exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) alters behavioral responses to the stimulus later in life, at postnatal day (PN30). Long-Evans rat pups with their mothers were exposed for 20 min daily to TMT, water, or a noxious odor, butyric acid (BTA), during the first three weeks of life. Mothers exposed to TMT displayed more crouching and nursing behavior than those exposed to BTA, and TMT exposed pups emitted more ultrasonic vocalizations than BTA exposed pups. At PN30, rats were tested for freezing to TMT, water, or BTA. Rats exposed to TMT during the postnatal period displayed less freezing to TMT than rats exposed postnatally to water or BTA. Our data indicate that early-life experience with a predator cue has a significant impact on later fear responses to that same cue, highlighting the programming capacity of the postnatal environment on the development of behavior.

Influence of metabolic syndrome factors and insulin resistance on the efficacy of ezetimibe/simvastatin and atorvastatin in patients with metabolic syndrome and atherosclerotic coronary heart disease risk.

BACKGROUND: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS. METHODS: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg). RESULTS: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups. CONCLUSION: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).

Egr-1 increases in the prefrontal cortex following training in the context preexposure facilitation effect (CPFE) paradigm.

The context pre-exposure facilitation effect (CPFE) is a modified form of standard contextual fear conditioning that dissociates learning about the context during a preexposure phase from learning the context-shock association during an immediate shock training phase conducted on separate days. Fear conditioning in the CPFE is an associative process in which only animals that are preexposed to the same context they are later given an immediate shock in demonstrate freezing when tested for conditioned fear memory. Previous research has shown that the hippocampus and amygdala are necessary for different phases of the CPFE, but whether other brain regions are also involved is unknown. The present study examined expression of the immediate-early gene early growth response gene 1 (Egr-1; also called Zif268, Ngfi-a, Krox-24) in the dorsal hippocampus, lateral nucleus of the amygdala, retrosplenial cortex, and several prefrontal cortex regions (infralimbic and prelimbic medial prefrontal cortex, anterior cingulate, and orbitofrontal cortex) following each phase of the CPFE in juvenile rats. Animals preexposed to the conditioning context displayed fear conditioned freezing during a retention test whereas rats preexposed to an alternate context did not. Following context preexposure, Egr-1 mRNA was elevated in context and alternate context exposed animals compared to home-cage control rats in almost all regions analyzed. Following the context-shock training phase, fear conditioned rats displayed significantly more Egr-1 mRNA expression in the infralimbic, prelimbic, and orbitofrontal cortices compared to the alternate context preexposed control rats. These differences in Egr-1 expression were not found in amygdala between the preexposed context and alternate context rats. No sex differences were observed following preexposure or training in any regions analyzed. The findings suggest that increased expression of Egr-1 within the prefrontal cortex is associated with contextual fear conditioning in the CPFE paradigm.

Consistency of effect of ezetimibe/simvastatin compared with intensified lipid-lowering treatment strategies in obese and non-obese diabetic subjects.

PURPOSE: This post hoc analysis assessed switching to ezetimibe/simvastatin 10/20 mg vs doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg in subgroups of obese (BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) diabetic subjects. METHODS: This was a randomized, double-blind, 12-week study of adults 18-79 years with cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. Percent change in LDL-C and other lipids was estimated. RESULTS: In obese subjects (n = 466), percent changes in LDL-C and most other lipids were greater with ezetimibe/simvastatin vs doubling the baseline statin dose or switching to rosuvastatin. In non-obese subjects (n = 342), percent changes in LDL-C, total cholesterol, non-HDL-C, Apo B and Apo A-I were greater with ezetimibe/simvastatin vs doubling the baseline statin dose or switching to rosuvastatin; and treatment with ezetimibe/simvastatin resulted in greater changes in triglycerides vs rosuvastatin and HDL-C vs doubling the baseline statin dose. The safety profiles were generally similar. CONCLUSIONS: Regardless of baseline obesity status, switching to ezetimibe/simvastatin was more effective at reducing LDL-C, total cholesterol, non-HDL-C, and Apo B vs doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg.

Cortisol and PTSD symptoms among male and female high-exposure 9/11 survivors.

Only a few studies have examined cortisol response to trauma-related stressors in relation to posttraumatic stress disorder (PTSD). We followed a sample of high-exposure survivors of the attacks on September 11, 2001 (9/11; 32 men and 29 women) and examined their cortisol response after recalling the escape from the attack, 7 and 18 months post-9/11. PTSD symptoms and saliva cortisol levels were assessed before and after trauma recollection. Hierarchical regression analyses revealed that PTSD symptoms and male sex predicted increased cortisol response following recollections. For men, elevated cortisol was associated with greater severity of reexperiencing symptoms (p < .001) and lower severity of avoidance symptoms (p < .001). For women, recall-induced cortisol was minimal and unrelated to PTSD symptoms (p = .164 and p = .331, respectively). These findings suggest that augmented cortisol response to trauma-related stressors may be evident in men reporting symptoms of PTSD. Thus, as cortisol abnormalities related to PTSD symptoms appear sex-specific, future research on mechanisms of sex differences in response to trauma is warranted.

Hyperexcitability: From Normal Fear to Pathological Anxiety and Trauma.

Hyperexcitability in fear circuits is suggested to be important for development of pathological anxiety and trauma from adaptive mechanisms of fear. Hyperexcitability is proposed to be due to acquired sensitization in fear circuits that progressively becomes more severe over time causing changing symptoms in early and late pathology. We use the metaphor and mechanisms of kindling to examine gains and losses in function of one excitatory and one inhibitory neuropeptide, corticotrophin releasing factor and somatostatin, respectively, to explore this sensitization hypothesis. We suggest amygdala kindling induced hyperexcitability, hyper-inhibition and loss of inhibition provide clues to mechanisms for hyperexcitability and progressive changes in function initiated by stress and trauma.

Ontogeny and neural substrates of the context preexposure facilitation effect.

Contextual fear conditioning emerges around post-natal day (PD) 23 in the rat. This is thought to reflect hippocampus-dependent conjunctive learning, which binds the individual features of the context into a unified representation (Rudy, 1993). However, context conditioning can also be supported by hippocampus-independent, feature-based simple associations (Rudy, 2009) and these may operate at PD 23-24 (Pugh & Rudy, 1996). To address this issue, we studied the ontogeny of a variant of contextual fear conditioning, termed the context-preexposure-facilitation-effect (CPFE), in which exposure to context and (immediate) foot shock occur on successive occasions. This variant requires conjunctive as opposed to feature-based simple associations (Rudy, 2009). We tested PD 17, 24, and 31 rats on the CPFE vs. conventional context conditioning (Exp. 1) and on the CPFE with stronger reinforcement (Exp. 2). The CPFE emerged on PD 24 regardless of reinforcer strength and in parallel with context conditioning. Infusions of the NMDA-receptor antagonist, MK-801, into the dorsal hippocampus just before pre-exposure on PD 24 eliminated the CPFE, whereas infusions occurring after pre-exposure had no effect (Exp. 3). These findings demonstrate a role of hippocampal NMDA receptors in the CPFE as early as PD 24 and implicate conjunctive learning mechanisms in the ontogeny of contextual fear conditioning.

Nicotine and Delta(9)-tetrahydrocannabinol withdrawal induce Narp in the central nucleus of the amygdala.

The central nucleus of the amygdala plays a key role in mediating aversive responses to drug withdrawal, effects thought to contribute to continued drug use. In previous studies, we found that the immediate early gene Narp, which encodes a secreted protein that binds to AMPA receptors, is induced in this nucleus following opiate withdrawal. Furthermore, Narp deletion alters the acquisition and extinction of aversive conditioning induced by opiate withdrawal. We now report that Narp is also induced in the central nucleus following withdrawal from other drugs of abuse, nicotine and Delta(9)-tetrahydrocannabinol, indicating that Narp is a common component of the transcriptional response triggered by drug withdrawal.

Neonatal ethanol exposure impairs long-term context memory formation and prefrontal immediate early gene expression in adolescent rats.

Fetal alcohol exposure leads to severe disruptions in learning and memory involving the hippocampus and prefrontal cortex in humans. Animal model research on FASD has documented impairment of hippocampal neuroanatomy and function but animal studies of cognition involving the prefrontal cortex are sparse. We have found that a variant of contextual fear conditioning in which both the hippocampus and prefrontal cortex is required, the Context Preexposure Facilitation Effect (CPFE), is particularly sensitive to neurobehavioral disruption caused by neonatal ethanol exposure during the third trimester equivalent of human pregnancy in the rat (i.e., PD4-9). In the CPFE, learning about the context, acquiring a context-shock association, and retrieving contextual fear are temporally separated across three days. The current study asked whether neonatal alcohol exposure impairs context learning, consolidation, or retrieval and examined prefrontal and hippocampal molecular signaling as correlates of this impairment. Long-Evans rats that received oral intubation of ethanol (AE; 5.25 g/kg/day, split into two doses) or underwent sham-intubation (SI) from PND4-9 were tested on the CPFE on PD31-33. Extending our previous reports, ethanol abolished both post-shock and retention test freezing in the CPFE. Assays (qPCR) of immediate early gene expression revealed that ethanol disrupted prefrontal but not hippocampal expression of c-Fos, Arc, Egr-1, and Npas4 during context learning. Finally, ethanol-exposed animals were unimpaired in a standard contextual fear conditioning procedure in which learning about the context and acquiring a context-shock association occurs concurrently. These findings implicate impaired prefrontal function in cognitive deficits arising from 3rd-trimester equivalent alcohol exposure in the rat.

Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: a model for animal phobias.

Specific phobias, including animal phobias, are the most common anxiety disorders, and have a strong innate and genetic component. Research on the neurobiology and environmental constraints of innate fear of predators in rodents may be useful in elucidating mechanisms of animal phobias in humans. The present article reviews research on innate fear in rats to trimethylthiazoline (TMT), an odor originally isolated from fox feces. TMT induces unconditioned freezing and other defensive responses that are regulated by the dose of TMT and the shape of the testing environment. Contextual conditioning induced by TMT occurs, but is constrained by the environment. Lesion studies indicate the amygdala circuitry subserving fear conditioning is not necessary for unconditioned fear to TMT. Additionally, a medial hypothalamic defensive circuit also appears not necessary for unconditioned freezing to TMT, whereas circuits that include the medial nucleus of the amygdala and the bed nucleus of the stria terminalis are essential. The importance of these findings of innate predator odor fear in rodents to animal phobias in humans is discussed.

Chronic corticosterone administration does not potentiate unconditioned freezing to the predator odor, trimethylthiazoline.

Chronic high levels of corticosterone (CORT) are known to facilitate learning and memory of aversive events. Whether this effect of chronic CORT also generalizes to unconditioned or unlearned fear behavior is not known. The present study investigated whether high levels of chronic CORT enhance unconditioned fear to a predator odor, trimethylthiazoline (TMT), an innate fear stimulus to rodents. TMT induces a dose-related freezing response, a prototypical behavior to fearful stimuli, in rats. The first experiment demonstrated that dose-related freezing to repeated exposures of TMT does not habituate, sensitize or produce contextually conditioned fear, and therefore can be used to measure the effects of chronic CORT on unconditioned fear to repeated exposures of TMT. In Experiment 2, 21-day release corticosterone pellets (200mg) were implanted subcutaneously in male, Sprague-Dawley rats. Control rats received sham implantation. On days when TMT was not present, chronic CORT rats froze significantly more than sham rats. However, while TMT-induced freezing in both chronic CORT and sham rats, freezing during exposure to TMT was not further enhanced in chronic CORT rats. Thus, chronic CORT appears to increase fear as measured by freezing, possibly by enhancing vigilance, but does not facilitate fear behavior induced by the innate fear stimulus, TMT.

Impairment of the context preexposure facilitation effect in juvenile rats by neonatal alcohol exposure is associated with decreased Egr-1 mRNA expression in the prefrontal cortex.

The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which learning about the context (preexposure) and associating the context with a shock (training) occur on separate occasions. The CPFE is sensitive to a range of neonatal alcohol doses (Murawski & Stanton, 2011). The current study examined the impact of neonatal alcohol on Egr-1 mRNA expression in the infralimbic (IL) and prelimbic (PL) subregions of the mPFC, the CA1 of dorsal hippocampus (dHPC), and the lateral nucleus of the amygdala (LA), following the preexposure and training phases of the CPFE. Rat pups were exposed to a 5.25 g/kg/day single binge-like dose of alcohol (Group EtOH) or were sham intubated (SI; Group SI) over postnatal days (PD) 7-9. In behaviorally tested rats, alcohol administration disrupted freezing. Following context preexposure, Egr-1 mRNA was elevated in both EtOH and SI groups compared with baseline control animals in all regions analyzed. Following both preexposure and training, Group EtOH displayed a significant decrease in mPFC Egr-1 mRNA expression compared with Group SI. However, this decrease was greatest after training. Training day decreases in Egr-1 expression were not found in LA or CA1 in Group EtOH compared with Group SI. A second experiment confirmed that the EtOH-induced training-day deficits in mPFC Egr-1 mRNA expression were specific to groups which learned contextual fear (vs. nonassociative controls). Thus, memory processes that engage the mPFC during the context-shock association may be most susceptible to the teratogenic effects of neonatal alcohol. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

A neuroendocrine mechanism for sustaining fear.

Fear is an adaptive response to recognition of a potentially dangerous event. Glucocorticoids are essential for maintaining a wide variety of behavioral events by their regulation of numerous genes; one such gene encodes corticotrophin-releasing hormone (CRH). CRH is involved in diverse behavioral responses to changing environmental demands. In this review, we focus on one aspect of glucocorticoid regulation of CRH--namely, fear-related responses to diverse classes of adverse events, such as those represented by contextual and cue-specific stimuli. Three extra-hypothalamic forebrain sites appear crucial for fear-related behavioral responses: the amygdala and the bed nucleus of the stria terminalis for sustaining adaptive fear-related behaviors, and the medial prefrontal cortex for modulating fear-related behaviors. Central regulation of CRH by glucocorticoids is important for adaptive and sustained fear-related behaviors, and its aberration is associated with anxiety and depressive disorders.

Differences in Cortisol Response to Trauma Activation in Individuals with and without Comorbid PTSD and Depression.

Background: Although depression symptoms are often experienced by individuals who develop posttraumatic stress disorder (PTSD) following trauma exposure, little is know about the biological correlates associated with PTSD and depression co-morbidity vs. those associated with PTSD symptoms alone. Methods: Here we examined salivary cortisol responses to trauma activation in a sample of 60 survivors of the World Trade Center attacks on September 11, 2001. Participants recalled the escape from the attacks 7 months post 9/11. Salivary cortisol levels were measured before and after their recollection of the trauma. PTSD, depression, and somatic symptoms were also assessed. From the behavioral assessment scales, the participants were grouped into three conditions: those with comorbid PTSD and depressive symptoms, PTSD alone symptoms, or no-pathology. Results: Baseline and cortisol response levels differed between the comorbid, PTSD alone, and no-pathology groups. Individuals endorsing co-morbid symptoms had higher PTSD and somatic symptom severity and their cortisol response decreased following their trauma reminder while a trend of an elevated response to the trauma was found in the PTSD alone group. Our findings show distinct psychological and biological correlates related to the endorsement of PTSD with and without depression comorbidity. Conclusions: The findings suggest that comorbidity symptoms manifestation entails a separate trauma induced condition from PTSD. Future research on biological correlates of comorbid PTSD and depression is warranted.

Immediate-early gene expression in the central nucleus of the amygdala is not specific for anxiolytic or anxiogenic drugs.

The lateral, basal, and central nuclei of the amygdala are part of a circuitry that instantiates many fear and anxious behaviors. One line of support indicates that immediate-early gene (IEG) expression (e.g., c-fos and egr-1 (zif268)) is increased in these nuclei following fear conditioning. Other research finds that anxiogenic drugs working through various mechanisms induce IEG expression in the central nucleus of the amygdala (CeA) suggesting that expression is a neural marker for fear and anxiety. However, several studies have also found that anxiolytic drugs induce IEG expression in the CeA. Expression of egr-1 in the CeA and lateral nucleus of the amygdala following administration of anxiolytic and anxiogenic benzodiazepine and serotonin agonists and antagonists was investigated. The first experiment determined behaviorally active anxiolytic and anxiogenic doses for two anxiogenic drugs (FG 7142 and mCPP) and two anxiolytic drugs (diazepam and buspirone). The effects of anxiogenic and anxiolytic doses of these drugs on egr-1 expression in the amygdala were then tested in a second experiment. All four drugs increased egr-1 in the CeA indicating that increased egr-1 mRNA expression in the CeA is not specific to anxiolytic or anxiogenic effects of the drugs. We suggest that IEG expression in the CeA may be due to activation of circuits that are associated with systemic physiological homeostasis perturbed by a number of drugs including anxiogenic and anxiolytic compounds.