Fear Retention Research Articles

Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of relevance for the development of novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.

Demarcating the boundary conditions of memory reconsolidation: An unsuccessful replication

Disrupting memory reconsolidation provides an opportunity to abruptly reduce the behavioural expression of fear memories with long-lasting effects. The success of a reconsolidation intervention is, however, not guaranteed as it strongly depends on the destabilization of the memory. Identifying the necessary conditions to trigger destabilization remains one of the critical challenges in the field. We aimed to replicate a study from our lab, showing that the occurrence of a prediction error (PE) during reactivation is necessary but not sufficient for destabilization. We tested the effectiveness of a reactivation procedure consisting of a single PE, compared to two control groups receiving no or multiple PEs. All participants received propranolol immediately after reactivation and were tested for fear retention 24 h later. In contrast to the original results, we found no evidence for a reconsolidation effect in the single PE group, but a straightforward interpretation of these results is complicated by the lack of differential fear retention in the control groups. Our results corroborate other failed reconsolidation studies and exemplify the complexity of experimentally investigating this process in humans. Thorough investigation of the interaction between learning and memory reactivation is essential to understand the inconsistencies in the literature and to improve reconsolidation interventions.

Adult and adolescent C57BL/6J and DBA/2J mice are differentially susceptible to fear learning deficits after acute ethanol or MK-801 treatment

Ethanol and other drugs of abuse disrupt learning and memory processes, creating problems associated with drug use and addiction. Understanding individual factors that determine susceptibility to drug-induced cognitive deficits, such as genetic background, age, and sex, is important for prevention and treatment. Comparison of adolescent and adult mice of both sexes across inbred mouse strains can reveal age, sex, and genetic contributions to phenotypes. We treated adolescent and adult, male and female, C57BL/6J and DBA/2J inbred mice with ethanol (1 g/kg or 1.5 g/kg) or MK-801 (0.05 mg/kg or 0.1 mg/kg), an NMDA receptor antagonist, prior to fear conditioning training. Contextual and cued fear retention were tested one day and eight or nine days after training. After ethanol exposure, adult C57BL/6J mice experienced greater deficits in contextual learning than adult DBA/2J mice. C57BL/6 J adolescents were less susceptible to ethanol-induced contextual learning disruptions than C57BL/6J adults, and adolescent males of both strains exhibited greater ethanol-induced contextual learning deficits than adolescent females. After MK-801 exposure, adolescent C57BL/6J mice experienced more severe contextual learning deficits than adolescent DBA/2J mice. Both ethanol and MK-801 had greater effects on contextual learning than cued learning. Collectively, we demonstrate that genetic background contributes to contextual and cued learning outcomes after ethanol or MK-801 exposure. Further, we report age-dependent drug sensitivities that are strain-, sex-, and drug-specific, suggesting that age, sex, and genetic background interact to determine contextual and cued learning impairments after ethanol or MK-801 exposure.

047 Fear-Potentiated Startle and Sleep in Trauma-Exposed Men and Women with and without PTSD

Abstract Introduction Animal and human studies indicate that fear conditioning disrupts subsequent sleep, including REM sleep (REMS). REMS is thought to be central to fear information processing. We utilized an afternoon nap protocol to examine the effects of fear-potentiated startle (FPS), a variant of fear conditioning, on subsequent sleep integrity and REMS in trauma-exposed participants with varying levels of PTSD. We also examined the effects of changes in sleep integrity and REMS on subsequent retention and extinction of pre-sleep learning. Methods Participants (N=47) participated in 3 nap visits. The first was an adaptation nap. The second and third nap visits were counterbalanced: a stress-condition nap, during which participants underwent FPS procedures prior to a nap and assessment of retention of fear and safety signal learning and fear extinction after the nap, and a control visit during which participants had a nap opportunity without stressful procedures. Canonical correlation analysis assessed the relationship between FPS responses and change in subsequent sleep relative to a control nap, as well as the relationship between change in sleep from control to stress condition and both subsequent fear and safety learning retention, and subsequent extinction. Results Results demonstrated a relationship between fear learning and change in sleep and supported a relationship between safety signal learning and subsequent REMS, as well as differential conditioning and wake after sleep onset. Sleep did not predict measures of fear retention or extinction. PTSD symptoms did not predict fear learning or sleep measures. Conclusion These findings replicate prior work showing a relationship between safety learning and REMS, suggesting that this is a core mechanism through which stress impacts fear processing. Further research is critical to further understand this effect, and to examine how different aspects of fear learning impact different components of sleep. This study also demonstrates that nap studies can be a valuable approach for studying the stress-sleep relationship. Support (if any) VA Career Development Award to Dr. Richards (5IK2CX000871-05)

Prefrontal cortex PACAP signaling: organization and role in stress regulation

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuromodulatory peptide strongly implicated in nervous stress processing. Human polymorphism of the primary PACAP receptor (PAC1) is linked to psychiatric disorders, including posttraumatic stress disorder (PTSD). Prefrontal cortex PACAP signaling is associated with processing of traumatic stress and fear learning, suggesting a potential role in PTSD-related deficits. We used RNAscope to define the cellular location of PACAP and PAC1 in the infralimbic cortex (IL). Subsequent experiments used a pharmacological approach to assess the impact of IL PACAP infusion on behavioral and physiological stress response and fear memory. Adult male Sprague-Dawley rats were bilaterally microinjected with PACAP (1 ug) or vehicle into the IL, 30 minutes prior to forced swim test (FST). Blood was sampled at 15, 30, 60, and 120 minutes for analysis of hypothalamic pituitary adrenal (HPA) axis reactivity. Five days after, animals were tested in a 3-day passive avoidance paradigm with subsequent testing of fear retention two weeks later. We observed that PACAP is highly expressed in putative pyramidal neurons (identified by VGlut1 expression), while PAC1 is enriched in interneurons (identified by GAD). Pretreatment with PACAP increased active coping style in the FST, despite higher levels of ACTH and corticosterone. The treatment was also sufficient to cause an increase in anxiety-like behavior in a dark/light crossover test and enhanced retention of passive avoidance. Our data suggest that IL PACAP plays a role in driving stress responses and in processing of fear memories, likely mediated by inhibition of cortical drive.

Role of the reuniens and rhomboid thalamic nuclei in anxiety-like avoidance behavior in the rat.

The nucleus reuniens (RE) and rhomboid (RH) nuclei of the ventral midline thalamus are reciprocally connected with the prefrontal cortex (PFC) and the hippocampus (HF) and serve as key intermediaries between these structures, regulating cognitive and emotional behaviors. Regarding affective behavior, several recent reports have described the involvement of RE/RH in the acquisition and retention of conditioned fear, but little is known regarding their role (RE/RH) in anxiety-like behaviors. We examined the role of RH/RE on avoidance and defensive behaviors in male Long Evans rats using the elevated plus maze (EPM). We found that the reversible suppression of RE/RH with muscimol increased avoidance behavior to the open arms of the plus maze as shown by: (a) significant reductions in open arm entries; (b) reductions in the mean duration of time spent in the open arms; and (c) significant increases in retreats during open arm exploration. This was coupled with decreases in the number of head dips in the maze. Consistent with these behavioral effects, a single exposure of naïve rats to the plus maze produced significant increases in c-fos expression selectively in RE and RH of midline thalamic nuclei. We posit that RE/RH normally acts to optimize adaptive responses to anxiety-eliciting situations, and disruptions of RE/RH produce severe deficits in coping behaviors-or as shown here increases in avoidance/defensive behaviors. In sum, the present results establish a novel role for RE/RH in anxiety-like avoidance behavior. In addition to its role in attention, working memory, and executive control, RE/RH also regulates adaptative responses to not only fear but also to anxiogenic stimuli. As such, dysfunction of RE/RH may contribute to the amalgamation of symptoms common to many mental health disorders including anxiety, depression, schizophrenia, and PTSD.

Anodal tDCS applied to the left frontal cortex abrogates scopolamine-induced fear memory deficit via the dopaminergic system

Evidence suggests that transcranial direct current stimulation (tDCS) modulates conditioned fear memories and has effects on cognitive flexibility via the dopaminergic system. This study examines whether modulation of scopolamine‑induced fear memory deficit by anodal tDCS could be mediated by the dopaminergic system. The male NMRI mice received scopolamine, 30 min before fear conditioning, and showed impaired contextual memory retention. Mice subjected to left frontal anodal stimulation for 20 or 30 min, before fear conditioning, impaired fear memory retrieval. Anodal application for 20 min significantly decreased scopolamine response on fear retention, while the one applied for 30 min did not alter. Moreover, anodal stimulation for 30 min abolished scopolamine‑induced fear memory deficit. Dopaminergic antagonists SCH23390 and sulpiride, alone or in combination, prevented the abolishment effect of anodal stimulation on scopolamine‑induced fear memory deficit, whereas they did not alter the impairing effect of scopolamine at the dose of 2 mg/kg. Our data suggest that anodal stimulation for 30 min abrogates the impairing effect of scopolamine on fear memory retention. This influence could be prevented by dopaminergic antagonists, indicating the involvement of the dopaminergic system in the effect of anodal stimulation on scopolamine‑induced fear memory deficit.

The propensity for re-triggered predation fear in a prey fish

Variation in predation risk can drive variation in fear intensity, the length of fear retention, and whether fear returns after waning. Using Trinidadian guppies, we assessed whether a low-level predation threat could easily re-trigger fear after waning. First, we show that background risk induced neophobia after either multiple exposures to a low-level threat or a single exposure to a high-level threat. However, a single exposure to the low-level threat had no such effect. The individuals that received multiple background exposures to the low-level threat retained their neophobic phenotype over an 8-day post-risk period, and this response was intensified by a single re-exposure to the low-level threat on day 7. In contrast, the neophobia following the single high-level threat waned over the 8-day period, but the single re-exposure to the low-level threat on day 7 re-triggered the neophobic phenotype. Thus, despite the single low-level exposure being insufficient to induce neophobia, it significantly elevated existing fear and re-triggered fear that had waned. We highlight how such patterns of fear acquisition, retention, and rapid re-triggering play an important role in animal ecology and evolution and outline parallels between the neophobic phenotype in fishes and dimensions of post-traumatic stress in humans.

Temporally variable predation risk and fear retention in Trinidadian guppies

Abstract Predation fear is a unifying theme across vertebrate taxa. Here, we explored how the frequency and duration of predation risk affects postrisk fear behavior in Trinidadian guppies. We first exposed individuals to visual cues of potential predators for 3 days, either frequently (6×/day) or infrequently (1×/day). Each exposure lasted for either a relatively brief (5 min) or long (30 min) duration, whereas a control group consisted of no risk exposures. One day later, we quantified guppy behavior. All background risk treatments induced a fear response toward a novel odor (i.e., neophobia), and individuals previously exposed to frequent bouts of brief risk showed elevated baseline fear. Although neophobic responses were initially similar across risk treatments (1 day later), retention of this response differed. After 8 days, only individuals previously exposed to brief bouts of risk (both frequent and infrequent) maintained neophobic responses, whereas their initially higher level of baseline fear remained elevated but was no longer significantly different from the control. These results increase our understanding of temporal factors that affect the intensity and retention of fear that persists after risk exposure, which may have applications across vertebrates in relation to problems with fearful phenotypes.

Metoprolol decreases retention of fear memory and facilitates long-term depression in lateral amygdala

Posttraumatic stress disorder is a mental disorder with a known cause, yet effective behavioral and pharmacotherapies remain elusive for many afflicted patients. Propranolol is suggested to be effective as a fear-reducing agent when paired with behavioral therapy soon after trauma when psychological stress is high, possibly dampening or preventing the later development of posttraumatic stress disorder. In our previous study, we found propranolol efficaciously reduced fear retention induced by reactivation via β-adrenergic receptors in lateral amygdala. However, it is unclear which subtypes of β-adrenergic receptors dominate the function of adrenergic activation in lateral amygdala. In this study, we investigated the action of β1-adrenergic receptor antagonist-metoprolol and β2-adrenergic receptor antagonist-butoxamine on the retention of conditioned fear memory and synaptic adaptation in the lateral amygdala of rats. We found metoprolol not butoxamine attenuated the reactivation-induced strengthening of fear retention and restored the impaired long-term depression in lateral amygdala. Intra-amygdala infusion of metoprolol not butoxamine attenuated reactivation-induced enhancement of fear retention. Our results suggest that β1-adrenergic receptor antagonist-metoprolol may be more suitable for the treatment of posttraumatic stress disorder.

Inactivation of the dorsolateral periaqueductal gray matter impairs the promoting influence of stress on fear memory during retrieval

Exposure to stressful conditions induces long-lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. Moreover, the interaction of a stressful experience and the retrieval of an established fear memory trace enhance both fear expression and fear retention. Related to this, the stimulation of the dorsolateral part of the mesencephalic periaqueductal gray matter (dlPAG) prior to retrieval potentiates a fear memory trace previously acquired. Therefore, the question that arises is whether the dlPAG mediates the increased fear expression and fear retention after retrieval. Rats were subjected to a contextual fear conditioning paradigm using a single footshock, and 1 day later, rats were subjected to a stressful situation. As previously reported, there was an increase of freezing response only in those rodents that were re-exposed to the associated context at 1 and 5days after stress exposure. Muscimol intra-dlPAG prior to the restraint event prevented such increase. Conversely, Muscimol intra-dlPAG infusion immediately after the stress experience had no effect on the resulting fear memory. When the neuroendocrine response to stress was explored, intra-dlPAG infusion of muscimol prior to stress decreased Fos expression in the paraventricular nucleus and serum corticosterone levels. Moreover, this treatment prevented the enhancement of the density of hippocampal "mature" spines associated with fear memory. In conclusion, the present results suggest that the dlPAG is a key neural site for the negative valence instruction necessary to modulate the promoting influence of stress on fear memory.

Влияние микроинъекций агониста и антагониста рецепторов серотонина (5-НТ 2А/С) в миндалину крыс на тревожное поведение и условнорефлекторный страх

The role of amygdala 5-НТ2А/С receptors in the acquisition, expression, and extinction of conditioned fear as well as in anxiety was studied. Injections of 5-НТ2А/С antagonist (ketanserin, 0.5 µg/0.5 µl) into basolateral amygdala impaired fear expression in the form of freezing and its acquisition, but had no effect on anxiety. Injection of 5-НТ2А/С agonist (DOI, 1 µg/0.5 µl) caused panic-like behavior, increased the locomotor activity but decreased anxiety and fear expression in the form of freezing. Both agonist and antagonist facilitated fear extinction in high-freezing rats. These results suggest that 5-НТ2А/С serotonin receptors in amygdala play an important role in the expression and retention of conditioned fear.

The impact of maternal separation and isolation stress during stress hyporesponsive period on fear retention and extinction recall memory from 5-week- to 1-year-old rats.

The purpose of the present study was to determine whether age would disrupt fear retention and extinction memory in rats pre-exposed to maternal separation and isolation stress; these rats are called MS rats. MS stress was induced by exposing rat pups into maternal separation followed by isolation stress from peer groups (MS) daily/6h during stress hyporesponsive period, while controls rats that were undisturbed during this period are called NMS rats. 5, 8, 15 and 52weeks later, these animals were exposed to classical fear conditioning test by pairing auditory stimulus (conditioned stimulus, CS+) with electric footshock. 24h later, conditioned freezing response to CS+ was measured during fear retention, extinction and extinction recall trials. The normal ageing per se did not affect the formation of fear memory, retention and fear extinction memory. MS stress, on the other hand, disrupted fear memory at young adulthood age exhibiting increased freezing response to CS+ during retention test and reduced during fear extinction memory test when compared to NMS groups. On the other hand, rats at adolescence age exhibited reduced freezing during fear retention and enhanced freezing response to CS+ during extinction recall test. However, MS-induced changes in freezing response during fear retention and extinction tests were not seen in adulthood and 1-year-old age groups. These data demonstrate the young adulthood age is highly vulnerable to fear memory and extinction processes. The differences in freezing response to CS+ during fear conditioning from adolescence to old age, thus, appear to be related to the maturation of the limbic circuit.

Functional neuroimaging of associative learning and generalization in specific phobia

BackgroundTheoretical models have implicated classical fear conditioning, fear generalization, and extinction learning in the development of anxiety disorders. To date, it is largely unknown to what extent these mechanisms and the underlying neurobiology may be altered in specific phobia, a disorder characterized by focal fears. The current study systematically examined fear conditioning, fear generalization, extinction learning, and extinction recall in a sample of individuals with a specific phobia. MethodsParticipants with a specific phobia (SP) of spiders (n = 46) and healthy controls (HC) (n = 48) underwent a 3-day fMRI cue-conditioning protocol, including a fear acquisition and a fear generalization phase (day 1), an extinction learning phase (day 2), and an extinction recall phase (day 3). Stimuli were phobia-irrelevant, as geometrical shapes served as conditioned threat (CS+) and safety stimuli (CS-), and an electrical shock as the unconditioned stimulus (US). Self-reported fear, US expectancy, and blood-oxygen-level dependent responses were measured. ResultsBehavioral results only revealed enhanced CS+/CS-differentiation in fear scores during acquisition retention in SP. Some neural differences were observed during other task phases. During early fear acquisition, SP showed enhanced differential activation in the angular gyrus and lateral occipital cortex, and during extinction recall, more precuneus deactivation was found in SP compared to HC. There were no clear indications of altered neural fear generalization or extinction learning mechanisms in the SP group. ConclusionsResults indicate that spider phobia may be characterized by enhanced differential fear retention and altered brain activation patterns during fear acquisition and extinction recall. The findings provide insight into the nature of fear learning alterations in specific phobia, and how these may differ from those found in disorders characterized by broad anxious distress.

A more generalized fear response after a daytime nap.

The aim of this study was to examine how a daytime nap affected the consolidation of fear learning. Participants first underwent fear conditioning during which they were exposed to a large and a small circle. One of these was repeatedly paired with an electric shock (making it the CS+), whereas the other circle was never paired with the shock (the CS-). After a delay interval containing either a nap or wake, participants again viewed the CS+ and the CS- intermixed with eight novel circles that varied in size between the two stimuli seen before, as well as a blue triangle that served as a novel stimulus without prior fear relevance. We examined both fear retention (the difference between the CS+ and the CS-) and fear generalization (responses to the novel stimuli based on their similarity to the original CS+). Contrary to previous studies, results from the participants who acquired a differentiated fear response during the acquisition phase revealed that the wake group showed significantly larger skin conductance responses to the CS+ compared to the CS-, whereas no such difference was present in the sleep group. These results were not driven by differences in explicit memory or by differences in general reactivity. Analyzing responses to the novel stimuli revealed a tendency towards a more generalized response in the sleep group, with no differences between the CS+ and any other stimulus, whereas the wake group showed increased responses to the stimuli depending on their similarity to the original CS+. This effect was however only present when controlling for baseline differences in worry.

Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation. Interestingly, both TBI and PTSD can be produced by overlapping pathophysiological changes that disrupt neural connections termed the "connectome." The neural disruptions shared by PTSD and TBI and the comorbid condition include asymmetrical white matter tract abnormalities and gray matter changes in the basolateral amygdala, hippocampus, and prefrontal cortex. These neural circuitry dysfunctions result in behavioral changes that include executive function and memory impairments, fear retention, fear extinction deficiencies, and other disturbances. Pathophysiological etiologies can be identified using experimental models of TBI, such as fluid percussion or blast injuries, and for PTSD, using models of fear conditioning, retention, and extinction. In both TBI and PTSD, there are discernible signs of neuroinflammation, excitotoxicity, and oxidative damage. These disturbances produce neuronal death and degeneration, axonal injury, and dendritic spine dysregulation and changes in neuronal morphology. In laboratory studies, various forms of pharmacological or psychological treatments are capable of reversing these detrimental processes and promoting axonal repair, dendritic remodeling, and neurocircuitry reorganization, resulting in behavioral and cognitive functional enhancements. Based on these mechanisms, novel neurorestorative therapeutics using anti-inflammatory, antioxidant, and anticonvulsant agents may promote better outcomes for comorbid TBI and PTSD.

Inhibition of TrkB at the nucleus accumbens, using ANA-12, regulates basal and stress-induced orexin A expression within the mesolimbic system and affects anxiety, sociability and motivation

Repeated stress exposure can lead to the development of anxiety and mood disorders. An emerging biological substrate of depression and associated pathology is the nucleus accumbens (NAc), which through interactions with limbic, cognitive and motor circuits can regulate a variety of stress responses. Within these circuits, orexin neurons are involved in arousal and stress adaptability, effects proposed mediated via brain-derived neurotrophic factor signaling. This study tested the hypotheses that 1) repeated exposure to heterotypic stress alters social ability and preference and passive avoidant behaviors, 2) TrkB receptors at the NAc shell regulates stress-induced behavioral responses and orexin expression within the mesocorticolimbic system. Our findings indicate that ANA-12 (0.25 μg/0.5 μl) enhanced sociability during the social interaction test, although treatment had no effect on social preference. The development of conditioned place preference, and fear retention in the passive avoidance test were also facilitated by ANA-12. Biochemical assessments on brain tissues collected within 2 h of a forced swim exposure revealed that ANA-12 increased orexin A immunoreactivity (ir) in the hypothalamic perifornical area, while expression was reduced in the ventral portion of the hippocampal CA1 layer, irrespective of the stress condition. This contrasts changes at the VTA characterized by elevated versus reduced orexin A-ir in ANA-12-treated stress and non-stress rats, respectively. Colocalized orexin A- and tyrosine hydroxylase (TH)-ir at the VTA supports a different temporal expression post stress, TH-ir being unaffected 9 days post stress. These findings support a role for TrkB receptors in regulating basal and stress-induced social, cognitive and motivational behavior, and modulatory actions of BDNF, via TrkB signaling, on orexin A signaling upon stress exposure.

Galectin-3 Negatively Regulates Hippocampus-Dependent Memory Formation through Inhibition of Integrin Signaling and Galectin-3 Phosphorylation.

Galectin-3, a member of the galectin protein family, has been found to regulate cell proliferation, inhibit apoptosis and promote inflammatory responses. Galectin-3 is also expressed in the adult rat hippocampus, but its role in learning and memory function is not known. Here, we found that contextual fear-conditioning training, spatial training or injection of NMDA into the rat CA1 area each dramatically decreased the level of endogenous galectin-3 expression. Overexpression of galectin-3 impaired fear memory, whereas galectin-3 knockout (KO) enhanced fear retention, spatial memory and hippocampal long-term potentiation. Galectin-3 was further found to associate with integrin α3, an association that was decreased after fear-conditioning training. Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase (FAK) levels, effects that were blocked by co-transfection of the FAK phosphorylation-defective mutant Flag-FAKY397F. Notably, levels of serine-phosphorylated galectin-3 were decreased by fear conditioning training. In addition, blockade of galectin-3 phosphorylation at Ser-6 facilitated fear memory, whereas constitutive activation of galectin-3 at Ser-6 impaired fear memory. Interestingly galectin-1 plays a role in fear-memory formation similar to that of galectin-3. Collectively, our data provide the first demonstration that galectin-3 is a novel negative regulator of memory formation that exerts its effects through both extracellular and intracellular mechanisms.

Mixed evidence for the potential of non-invasive transcutaneous vagal nerve stimulation to improve the extinction and retention of fear

Extinction memories are fragile and their formation has been proposed to partially rely on vagus nerve activity. We tested whether stimulating the auricular branch of the vagus (transcutaneous VNS; tVNS) accelerates extinction and reduces spontaneous recovery of fear. Forty-two healthy students participated in a 3-day fear conditioning study, where we tested fear acquisition (day 1), fear extinction (day 2) and the retention of the extinction memory (day 3). During extinction, participants were randomly allocated to receive tVNS or sham stimulation concurrently with each CS presentation. During the acquisition and retention phases, all participants received sham stimulation. Indexes of fear included US-expectancy, startle blink EMG and skin conductance responses. Results showed successful acquisition and extinction of fear in all measures. tVNS facilitated the extinction of declarative fear (US expectancy ratings), but did not promote a stronger retention of the declarative extinction memory. No clear effects of tVNS on extinction and retention of extinction were found for the psychophysiological indexes. The present findings provide tentative indications that tVNS could be a promising tool to improve fear extinction and call for larger scale studies to replicate these effects.