Conditioned Fear Responses Research Articles

SUN-235 Deficient Fear Extinction in PRKAR1A-Defective Mice

Background: The role of the cAMP/PKA signaling in molecular pathways involved in fear memory is well established: PKA is required for fear memory formation and is a constraint for fear extinction. Previously we reported that a Prkar1a heterozygote (HZ) mouse that was developed in our lab to investigate Carney complex (CNC), the disease caused by PRKAR1A mutations, showed brain region-specific increased PKA activity that was associated with anxiety-like behavioral phenotype and threat bias (Keil, 2010, 2013). We hypothesized that Prkar1a+/- (HZ) mice would have deficits in fear extinction behavior. Brain derived neurotrophic factor (BDNF) has a critical role in formation of fear memory and its transcription is regulated by PKA/CREB. A mouse model with down regulation of PKA provides an opportunity for the first time to investigate the effect of altered PKA signaling on fear conditioning and extinction.Method: Fear conditioning, fear extinction learning, and fear extinction recall were tested in adult male HZ and wild-type (WT) mice as follows: fear conditioning training followed 24hr later by extinction training (new context), then 24hr later by extinction recall training. Percentage of time freezing was used to assess conditioned fear response. We measured BDNF gene expression in brain regions after completion of extinction recall training.Results: As expected, fear conditioning (learning) behavior was similar in HZ and WT mice. However, HZ mice showed a significant deficit in the early phase of fear extinction learning compared to WT. There was no difference in extinction recall between genotypes. Alterations in BDNF gene expression in the prefrontal cortex and amygdala was associated with deficit in fear extinction.Conclusion: Mice with a downregulation of Prkar1a gene demonstrate intact fear conditioning but impaired fear extinction learning, consistent with prior studies that report that PKA inhibition is necessary to facilitate extinction learning. Prkar1a+/- mice provide a valuable model to investigate impaired fear extinction to identify mechanisms for therapeutic targets for anxiety and trauma-related disorders.

Effects of Alcohol and Cocaine in a Mutant Mouse Model of Predisposition to Post-Traumatic Stress Disorder.

Comorbidity between drug abuse and post-traumatic stress disorder (PTSD), a stress-related dysregulation of fear responses, is very high. While some drugs are known to increase fear and anxiety, there are only few data regarding interactions between voluntary drug consumption and fear memory. The spontaneous chronic consumption of either alcohol or cocaine under a 3-week free-choice progressive paradigm of alcohol (3/6/10%) or cocaine (0.2/0.4/0.6 mg/ml), was assessed in VGV transgenic mice, having full 5-HT2C receptor editing and displaying PTSD-like behaviors. The consequences of these drug consumptions on the potentiated contextual and cued fear conditioning responses of VGV mice were assessed. The effects of drugs on hippocampal brain-derived neurotrophic factor (Bdnf) mRNA were measured as its expression was previously found to be decreased in VGV mice. Chronic alcohol consumption was similar in WT and VGV mice. In the alcohol condition, fear acquisition was not different at the end of the learning session and cue-fear extinction was facilitated. Regarding cocaine, in contrast to WT mice, VGV mice did not increase their drug consumption along with increasing doses, an effect that might be related with enhanced drug stimuli discrimination via increased 5-HT2C receptors. Cocaine-intake VGV mice did not display the contextual fear generalization usually observed in control VGV mice. In addition, Bdnf expression was upregulated after either chronic alcohol or cocaine intake. Altogether, these results suggest that both chronic alcohol and cocaine voluntary oral consumptions can exert some therapeutic-like effects in a mutant model of PTSD predisposition.

Inhibition of Serotonin Reuptake in the Medial Prefrontal Cortex during Acquisition of a Condition Reflex Fear Reaction Promotes Formation of Generalized Fear

Intracerebral microdialysis studies of Sprague–Dawley rats showed that acquisition of a conditioned reflex fear reaction (combination of a conditioned sound signal CS+ and an unavoidable electrocutaneous stimulus) was accompanied by an increase in the level of extracellular serotonin in the medial prefrontal cortex. Administration of the selective serotonin transporter inhibitor fluoxetine (1 μM) into the medial prefrontal cortex during acquisition of the conditioned reflex fear reaction magnified the increase in extracellular serotonin in these structures seen during this test and, secondly, strengthened freezing of the animals at 1 day (the measure of fear) in response to the differential signal CS–, not associated with pain stimulation (test for generalization of fear), but had no effect on freezing in the same animals in response to the conditioned stimulus CS+, previously combined with pain stimulation (test for expression of the fear reaction). These data provide the first evidence that stimulation of the serotoninergic system of the medial prefrontal cortex during acquisition of a condition reflex fear reaction promotes subsequent generalization of this conditioned reflex reaction without affecting its formation.

Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress.

Post-traumatic stress disorder (PTSD) is characterized by persistent fear memory of remote traumatic events, mental re-experiencing of the trauma, long-term cognitive deficits, and PTSD-associated hippocampal dysfunction. Extinction-based therapeutic approaches acutely reduce fear. However, many patients eventually relapse to the original conditioned fear response. Thus, understanding the underlying molecular mechanisms of this condition is critical to developing new treatments for patients. Mutations in the neuropsychiatric risk gene CACNA1C, which encodes the Cav1.2 isoform of the L-type calcium channel, have been implicated in both PTSD and highly comorbid neuropsychiatric conditions, such as anxiety and depression. Here, we report that male mice with global heterozygous loss of cacna1c exhibit exacerbated contextual fear that persists at remote time points (up to 180 days after shock), despite successful acute extinction training, reminiscent of PTSD patients. Because dopamine has been implicated in contextual fear memory, and Cav1.2 is a downstream target of dopamine D1-receptor (D1R) signaling, we next generated mice with specific deletion of cacna1c from D1R-expressing neurons (D1-cacna1cKO mice). Notably, D1-cacna1cKO mice also show the same exaggerated remote contextual fear, as well as persistently elevated anxiety-like behavior and impaired spatial memory at remote time points, reminiscent of chronic anxiety in treatment-resistant PTSD. We also show that D1-cacna1cKO mice exhibit elevated death of young hippocampal neurons, and that treatment with the neuroprotective agent P7C3-A20 eradicates persistent remote fear. Augmenting survival of young hippocampal neurons may thus provide an effective therapeutic approach for promoting durable remission of PTSD, particularly in patients with CACNA1C mutations or other genetic aberrations that impair calcium signaling or disrupt the survival of young hippocampal neurons.

Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures

Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients’ pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.

Differential Effects of Nicotine and Nicotine Withdrawal on Fear Conditioning in Male Rats.

BackgroundTobacco use is prevalent in individuals who are routinely exposed to stress. However, little is known about how nicotine affects responses to trauma. We examined in rats how nicotine exposure affects fear conditioning, a procedure often used to study stress-related psychiatric illness.MethodsWe examined 2 methods of nicotine exposure: self-administration, modeling voluntary use, and experimenter-programmed subcutaneous administration, modeling medicinal administration (nicotine patch). For self-administered nicotine, rats trained to self-administer nicotine i.v. were fear conditioned (via light cue preceding foot-shock) either immediately after a 12-hour self-administration session or 12 hours later during a period with somatic signs of nicotine withdrawal. For experimenter-delivered nicotine, rats were conditioned after 1–21 days of nicotine delivered by programmable (12 hours on) subcutaneous mini-pumps. Tests to evaluate acoustic startle responses to the conditioning environment (context-potentiated startle) and in the presence or absence of the light cue (fear-potentiated startle) occurred after a 10-day period.ResultsRats fear conditioned immediately after nicotine self-administration showed reduced responses to the shock-associated context, whereas those trained during nicotine withdrawal showed exaggerated responses. Experimenter-programmed nicotine produced effects qualitatively similar to those seen with self-administered nicotine.ConclusionsSelf-administration or experimenter-programmed delivery of nicotine immediately before exposure to aversive events can reduce conditioned fear responses. In contrast, exposure to aversive events during nicotine withdrawal exacerbates fear responses. These studies raise the possibility of developing safe and effective methods to deliver nicotine or related drugs to mitigate the effects of stress while also highlighting the importance of preventing withdrawal in nicotine-dependent individuals.

Using loss- and gain-of-function approaches to target amygdala-projecting serotonergic neurons in the dorsal raphe nucleus that enhance anxiety-related and conditioned fear behaviors.

The central serotonergic system originating from the dorsal raphe nucleus (DR) plays a critical role in anxiety and trauma-related disorders such as posttraumatic stress disorder. Although many studies have investigated the role of serotonin (5-HT) within pro-fear brain regions such as the amygdala, the majority of these studies have utilized non-selective pharmacological approaches or poorly understood lesioning techniques which limit their interpretation. Here we investigated the role of amygdala-projecting 5-HT neurons in the DR in innate anxiety and conditioned fear behaviors. To achieve this goal, we utilized (1) selective lesion of 5-HT neurons projecting to the amygdala with saporin toxin conjugated to anti-serotonin transporter (SERT) injected into the amygdala, and (2) optogenetic excitation of amygdala-projecting DR cell bodies with a combination of a retrogradely transported canine adenovirus-expressing Cre-recombinase injected into the amygdala and a Cre-dependent-channelrhodopsin injected into the DR. While saporin treatment lesioned both local amygdalar 5-HT fibers and neurons in the DR as well as reduced conditioned fear behavior, optical activation of amygdala-projecting DR neurons enhanced anxious behavior and conditioned fear response. Collectively, these studies support the hypothesis that amygdala-projecting 5-HT neurons in the DR represent an anxiety and fear-on network.

Effects of Decreases in Dopamine (D1 and D2) Receptor Expression in the Basolateral Amygdala of Rats on Conditioned Defensive Reflexes

RNA interference studies using lentivirus transduction were performed to investigate the effects of decreased expression of dopamine receptors (D1R and D2R) in the basolateral nucleus of the amygdala on the acquisition and extinction of conditioned defensive reflexes in rats. Immunohistochemical staining showed that transduction affected both neurons (mean 19%) and astrocytes (73%). As compared with controls, rats with decreased D1R expression showed degraded acquisition and facilitated extinction of a conditioned defensive reflex to sound, with acceleration of extinction of a passive avoidance reflex, and slowing of learning to seek a hidden platform in the Morris water maze by 1–2 days. In conditioned reflex fear, the behavior of rats with prolonged freezing changed more than that of rats with short periods of freezing when D1R expression in the amygdala was decreased. In rats with decreased D2R expression, extinction of the classical defensive reflex and the passive avoidance reflex was quicker. These results provide evidence of differences in the roles of D1R and D2R in the amygdala – functioning of D1R, in contrast to D2R, is important for acquisition of defensive refl exes and the manifestation of conditioned refl ex fear in the form of prolonged freezing. The activity of both D2R and D1R is significant for the resistance of reflexes to extinction.

Effects of verbal instructions and physical threat removal prior to extinction training on the return of conditioned fear

Instructions given prior to extinction training facilitate the extinction of conditioned skin conductance (SCRs) and fear-potentiated startle responses (FPSs) and serve as laboratory models for cognitive interventions implemented in exposure-based treatments of pathological anxiety. Here, we investigated how instructions given prior to extinction training, with or without the additional removal of the electrode used to deliver the unconditioned stimulus (US), affect the return of fear assessed 24 hours later. We replicated previous instruction effects on extinction and added that the additional removal of the US electrode slightly enhanced facilitating effects on the extinction of conditioned FPSs. In contrast, extinction instructions hardly affected the return of conditioned fear responses. These findings suggest that instruction effects observed during extinction training do not extent to tests of return of fear 24 hours later which serve as laboratory models of relapse and improvement stability of exposure-based treatments.

How Much Is Enough? Trauma Recall and the Exposure Therapy Process.

Theoretical models of posttraumatic stress disorder (PTSD) as well as exposure therapy (EXP) methodology suggest that trauma recall is crucial to altering the conditioned fear response associated with PTSD. However, it is unclear whether limited recall of the trauma event attenuates treatment outcomes. This study examined whether the extent of difficulty recalling aspects of a traumatic event affected fear activation, habituation, number of sessions, session length, and diagnostic outcomes in 166 Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans. Extent of trauma recall difficulty neither attenuated veterans' ability to achieve fear activation and habituation nor affected treatment outcomes. Findings suggest that even veterans who reported greater difficulty recalling their trauma event can engage successfully and benefit from EXP. This research is the first to examine trauma event recall in the context of the EXP process and contributes to the current body of literature that aims to address the question: "For whom do treatments work?"

A brief literature review retraining amygdala to substitute its irrational conditioned fear and anxiety responses with new learning experiences

A brief literature review retraining amygdala to substitute its irrational conditioned fear and anxiety responses with new learning experiences

Генерализация страха обстановки зависит от активности серотониновой системы медиальной префронтальной коры

The medial prefrontal cortex (mPFC) is involved in the regulation of fear generalization. We have previously shown that generalized fear formation to auditory cues is under the control of the mPFC serotonin system, as its pharmacological activation during a conditioned fear response acquisition (CFR - a fear model) enhances fear expression to safe auditory stimuli during testing. The aim of this work was to find out whether the mPFC serotonin system is involved in the contextual fear generalization. Using in vivo intracranial microdialysis in Sprague-Dawley rats, it was shown that placing animals in a potentially dangerous box A, in which they had previously acquired CFR (the paired presentation of a conditioned cue and inescapable footshock) was accompanied by an increase in the mPFC extracellular serotonin level and caused animals animals' freezing (a contextual fear measure). Placing the same animals in a safe differentiation box B also led to the extracellular serotonin level rise in the mPFC and caused animals' freezing (a measure of contextual fear generalization). The intra-mPFC infusion of a selective serotonin reuptake inhibitor fluoxetine (1 μM) during the fear response elaboration enhanced, during testing, animals' freezing in differentiation box B but did not affect animals' freezing in box A. The fluoxetine administration during training did not change the testing-induced extracellular serotonin levels rise in the mPFC in boxes A and B. The data indicate that activation of the mPFC serotonin system during fear formation affects the degree of contextual fear generalization. In addition, they suggest that one of the neurochemical manifestations of contextual fear generalization may be an increased activity of the mPFC serotonin system in the safe environment.

Social buffering enhances extinction of conditioned fear responses by reducing corticosterone levels in male rats

The presence of an affiliative conspecific reduces stress responses to a wide variety of stimuli, which is termed “social buffering.” We previously reported that social buffering in male rats ameliorated behavioral responses, as well as hypothalamic-pituitary-adrenal axis activation, elicited by an auditory conditioned stimulus (CS). In addition, subjects that experienced social buffering did not show stress responses when re-exposed to the CS the next day in the absence of an accompanying rat. However, the mechanisms underlying this enhancement of between-session extinction are poorly understood. In Experiment 1, we compared corticosterone levels at 0, 10, and 15 min after extinction training. Subjects that experienced social buffering had lower corticosterone levels than subjects that trained alone at the end of extinction training. However, corticosterone levels at 10 and 15 min after training were not affected by the experience of social buffering. These results suggest that a lower level of corticosterone during extinction training had an important role in the enhancement of extinction. To directly assess this, in Experiment 2, we manipulated the corticosterone level during extinction training. We found that a subcutaneous injection of corticosterone before extinction training blocked the enhancement of extinction by social buffering. These results demonstrate that the enhancement is caused by a low level of corticosterone during the training. Taken together, we suggest that social buffering enhances extinction of conditioned fear responses by reducing corticosterone levels in male rats.

Loss of NRF2 leads to impaired mitochondrial function, decreased synaptic density and exacerbated age-related cognitive deficits

Activation of the antioxidant regulatory transcription factor NRF2 (Nuclear factor erythroid-derived 2) regulates cellular bioenergetics and improves neuronal health in aging. Yet how NRF2 participates in maintaining synaptic, mitochondrial and cognitive function has not been fully elucidated. This study investigates how loss of NRF2 affects neuronal metabolism, synaptic density and cognitive performance in aged mice. Dendritic arborization as well as synaptic and mitochondrial gene expression was evaluated in hippocampal neurons isolated from mice lacking NRF2 (NRF2KO) and from wild-type (WT) C57BL6 mice. Mitochondrial function of these neurons was evaluated using the Seahorse XF platform. Additionally learning, memory and executive function were assessed in 20month old NRF2KO and age-matched WT mice using conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) tests. Hippocampal bioenergetics was profiled using mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial and synaptic genes. NRF2KO neurons had reduced dendritic complexity and diminished synaptic gene expression. This was accompanied by impaired mitochondrial function and decreased mitochondrial gene expression. Similar mitochondrial deficits were observed in the brains of aged NRF2KO mice. These animals also had significantly impaired cognitive performance and reduced synaptic gene expression as well. These data point to a role for NRF2 in maintaining mitochondrial and cognitive function during aging and suggest that the transcription factor may be a viable target for cognitive enhancing interventions. Because mitochondrial dysfunction and cognitive impairment also occur together in many neurodegenerative conditions there may be broad therapeutic potential of NRF2 activating agents.

Fear renewal requires nitric oxide signaling in the lateral amygdala

Fear renewal is defined as return of the conditioned fear responses after extinction when a conditioned stimulus (CS) is given outside of the extinction context. Previously, we have suggested that extinction induces S-nitrosylation of GluA1 in the lateral amygdala (LA), and that the extinction-induced S-nitrosylation of GluA1 lowers the threshold of GluA1 phosphorylation (at Ser 831) which is required for fear renewal. This fits nicely with the fact that fear renewal is induced by weak stimuli. However, it has not been tested whether S-nitrosylation of GluA1 in the LA is indeed required for fear renewal. In the present study, we used three different chemicals to impede protein S-nitrosylation via distinct mechanisms. Fear renewal was inhibited by microinjection of 7-Nitroindazole (nNOS inhibitor), and ZL006 (a blocker of PSD-95-nNOS interaction) before fear renewal. Furthermore, fear renewal was also attenuated by microinjection of a strong antioxidant (N-acetyl cysteine), which scavenges reactive oxygen including nitric oxide, into the LA before each extinction training. These findings suggest that protein S-nitrosylation is required for fear renewal.

Dorsomedial Medullary Catecholaminergic Neurons Couple Hypoxia to Emotional and Hormonal State

SummaryIn response to hypoxic threat, animals experience aversive feelings to engage behaviors which aid in restoring physiological balance. However, the pathways that connect interoception of tissue-oxygenation to the emotional brain remain largely unknown. Dorsomedial medullary catecholaminergic neurons (dMC) receive interoceptive information and project to the limbic areas that control fear, but their role in interoception and emotional state is unknown. Here, we use fiber photometry to show that dMC neurons are active during hypoxia and hypercapnia. Silencing of dMC neurons shows that they are necessary for deep inhalation during, and avoidance of respiratory threat. Optogenetic stimulation of dMC neurons was capable of generating both innate and conditioned fear responses. By simultaneous stimulation of dMC neurons while silencing axonal projections, we found that hypoxia induced hormonal stress is mediated by the paraventricular hypothalamic and lateral parabrachial nucleus outputs, whereas aversive behaviors are exclusively mediated by outputs to the lateral parabrachial nucleus. Collectively, these findings demonstrate a neural circuit that transforms interoceptive information into behavioral and hormonal response by engaging functionally and anatomically distinct connections.

Temporal dynamics of conditioned skin conductance and pupillary responses during fear acquisition and extinction

Fear acquisition manifests in the development of conditioned fear responses (CRs), whereas a decrement in CRs as a consequence of unconditioned stimulus (UCS) omission is referred to as extinction learning. Time windows for CR scoring in physiological readouts are subject to discussion, especially regarding the subdivision of skin conductance responses (SCRs) into first- (FIR) and second-interval responses (SIR). However, distinct temporal CR trajectories within or across measures may reflect specific characteristics of the underlying associative processes. In this study, 41 participants underwent fear acquisition and extinction, while SCRs and pupillary responses were recorded and separated into different time bins to explore the temporal dynamics of CRs across both learning phases. For SCRs, we observed a shift from early (FIR) to late (SIR) time intervals during fear acquisition most likely reflecting subsequent learning processes, in which CS-UCS associations and their relative timing are formed. During extinction, only the FIR exhibited a CR decline and was thus able to track the learning progress. These results indicate that conditioned SCRs follow a dynamic temporal pattern that may be related to different learning dimensions. By contrast, pupillary CRs were generally better captured by a late pupillary response component, suggesting a rather stable temporal CR pattern for the pupil in both learning phases. Our findings underscore the importance of specifying CR quantification for different physiological readouts when evaluating learning performance in the context of fear acquisition and extinction and may motivate further investigation of time-specific CR patterns and their relation to specific associative dimensions.

Threat imminence dictates the role of the bed nucleus of the stria terminalis in contextual fear.

Recent work indicates that the bed nucleus of the stria terminalis (BNST) is critically involved in the regulation of conditioned fear responses to unpredictable threats. Here we examined whether the involvement of the BNST in contextual fear conditioning in male rats depends on the imminence of shock after placement in the conditioning chamber. Specifically, we hypothesized that the BNST supports contextual freezing after conditioning with delayed, but not imminent, footshock (relative to placement in the context). Rats were implanted with cannulae targeting the BNST and underwent a contextual fear conditioning procedure in which a single footshock unconditioned stimulus (US) was delivered either 1min or 9min after the rat was placed in the context; the rats received a total of four identical conditioning sessions over two days, all with equivalent exposure to the context. Contexts associated with either imminent or delayed US onsets produced distinct patterns of freezing and shock-induced activity but freezing in each case was context-dependent. Reversible inactivation of the BNST reduced the expression of contextual freezing in the context paired with delayed (9min), but not imminent (1min), footshock onset. Implications of these data are discussed in the light of recent conceptualizations of BNST function, as well as for anxiety behaviors.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid(RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RAusing the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11β-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11β-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VADrats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11β-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11β-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11β-HSD1.

Short-term but not long-term exposure to an enriched environment reduces unconditioned fear responses but not conditioned fear responses

Environmental enrichment (EE) has been shown to produce beneficial effects in animal models of a wide variety of neurological and psychiatric disorders. EE exhibits antidepressant function; reduces anxiety, improves spatial learning and memory impairment. EE can reduce sensitivity to loss of reward by reducing frustration-like emotional states and facilitates the extinction of conditioned fear. However, some studies related to the emotional effects of EE present controversial results such as reduction or increase in anxiety. The time of exposure to an enriched environment seems to be an important factor in the behavioral responses presented by animals subjected to aversive stimuli. The present study compared the effects of two and four week exposure to EE with young adult Wistar rats under the same conditions and protocol on fear behavioral parameters in the face of footshock (unconditioned fear) and on re-exposure to an environment after electrical shock pairing (conditioned fear). We showed that the EE with a duration of two weeks reduced the freezing response of the animals in an unconditioned fear situation, that is, with the aversive stimulus present in the environment, however, did not influence the same behavior in a conditioned fear situation. In addition, the short-term EE developed the locomotor and exploratory activity, identified by the high rearing behavior, which may also suggest a low level of anxiety in these animals. We can conclude that EE changes the unconditioned fear responses of young adult rats. In addition, the duration of EE interferes differently, being two weeks of treatment with EE sufficient to cause improvement in coping with unconditioned aversive situations. We suggest that the emotional benefits resulting from the welfare provided by EE can be abolished by the longer duration of this treatment, due to the already known effect of tolerance to lasting or abundant rewards.