The nonapeptide, oxytocin (OT), known for its role in social bonding and attachment formation, has demonstrated anxiolytic properties in animal models and human studies. However, its role in the ...regulation of fear responses appears more complex, brain site-specific, sex-specific, and dependent on a prior stress history. Studies have shown that OT neurons in the hypothalamus are activated during cued and contextual fear conditioning and during fear recall, highlighting the recruitment of endogenous oxytocin system in fear learning. OT is released into the extended amygdala, which contains the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), both critical for the regulation of fear and anxiety-like behaviors. Behavioral studies report that OT in the CeA reduces contextual fear responses; whereas in the BNST, OT receptor (OTR) neurotransmission facilitates cued fear and reduces fear responses to un-signaled, diffuse threats. These ostensibly contrasting behavioral effects support growing evidence that OT works to promote fear discrimination by reducing contextual fear or fear of diffuse threats, yet strengthening fear responses to imminent and predictable threats. Recent studies from the basolateral nucleus of the amygdala (BLA) support this notion and show that activation of OTR in the BLA facilitates fear discrimination by increasing fear responses to discrete cues. Also, OTR transmission in the CeA has been shown to mediate a switch from passive freezing to active escape behaviors in confrontation with an imminent, yet escapable threat but reduce reactivity to distant threats. Therefore, OT appears to increase the salience of relevant threat-signaling cues yet reduce fear responses to un-signaled, distant, or diffuse threats. Lastly, OTR signaling has been shown to underlie emotional discrimination between conspecifics during time of distress, social transmission of fear, and social buffering of fear. As OT has been shown to enhance salience of both positive and negative social experiences, it can also serve as a warning system against potential threats in social networks. Here, we extend the social salience hypothesis by proposing that OT enhances the salience of relevant environmental cues also in non-social contexts, and as such promotes active defensive behaviors.
Oxytocin (OT) is a hypothalamic neuropeptide that modulates fear and anxiety-like behaviors. Dorsolateral bed nucleus of the stria terminalis (BNSTdl) plays a critical role in the regulation of fear ...and anxiety, and expresses high levels of OT receptor (OTR). However, the role of OTR neurotransmission within the BNSTdl in mediating these behaviors is unknown. Here, we used adult male Sprague-Dawley rats to investigate the role of OTR neurotransmission in the BNSTdl in the modulation of the acoustic startle response, as well as in the acquisition and consolidation of conditioned fear using fear potentiated startle (FPS) paradigm. Bilateral intra-BNSTdl administration of OT (100 ng) did not affect the acquisition of conditioned fear response. However, intra-BNSTdl administration of specific OTR antagonist (OTA), (d(CH2)51, Tyr(Me)2, Thr4, Orn8, des-Gly-NH29)-vasotocin, (200 ng), prior to the fear conditioning session, impaired the acquisition of cued fear, without affecting a non-cued fear component of FPS. Neither OTA, nor OT affected baseline startle or shock reactivity during fear conditioning. Therefore, the observed impairment of cued fear after OTA infusion resulted from the specific effect on the formation of cued fear. In contrast to the acquisition, neither OTA nor OT affected the consolidation of FPS, when administered after the completion of fear conditioning session. Taken together, these results reveal the important role of OTR neurotransmission in the BNSTdl in the formation of conditioned fear to a discrete cue. This study also highlights the role of the BNSTdl in learning to discriminate between threatening and safe stimuli.
•Oxytocin receptor (OTR) transmission in the BNST facilitates acquisition of cued fear.•OTRs in the BNST do not contribute to consolidation of cued fear.•Manipulation of OTR in the BNST does not affect baseline startle or non-cued fear.
The neuropeptide oxytocin (OT) plays an important role in the regulation of social and anxiety-like behavior. Our previous studies have shown that OT neurons send projections from the hypothalamus to ...the dorsolateral bed nucleus of the stria terminalis (BNST
), a forebrain region critically involved in the modulation of anxiety-like behavior. Importantly, these OT terminals in the BNST
express presynaptic corticotropin releasing factor (CRF) receptor type 2 (CRFR2). This suggests that CRFR2 might be involved in the modulation of OT release. To test this hypothesis, we measured OT content in microdialysates collected from the BNST
of freely-moving male Sprague-Dawley rats following the administration of a selective CRFR2 agonist (Urocortin 3) or antagonist (Astressin 2B, As2B). To determine if type 1 CRF receptors (CRFR1) are also involved, we used selective CRFR1 antagonist (NBI35965) as well as CRF, a putative ligand of both CRFR1 and CRFR2. All compounds were delivered directly into the BNST
via reverse dialysis. OT content in the microdialysates was measured with highly sensitive and selective radioimmunoassay. Blocking CRFR2 with As2B caused an increase in OT content in BNST
microdialysates, whereas CRFR2 activation by Urocortin 3 did not have an effect. The As2B-induced increase in OT release was blocked by application of the CRFR1 antagonist demonstrating that the effect was dependent on CRFR1 transmission. Interestingly, CRF alone caused a delayed increase in OT content in BNST
microdialysates, which was dependent on CRF2 but not CRF1 receptors. Our results suggest that members of the CRF peptide family modulate OT release in the BNST
via a fine-tuned mechanism that involves both CRFR1 and CRFR2. Further exploration of mechanisms by which endogenous OT system is modulated by CRF peptide family is needed to better understand the role of these neuropeptides in the regulation of anxiety and the stress response.
Available pharmacotherapies for anxiety disorders and post-traumatic stress-disorder (PTSD) have limited efficacy, but no new anxiolytic drug has been approved for treatment since the 1980s. In this ...issue of Neuropharmacology on “Fear, anxiety and PTSD: from cellular mechanisms to translational approaches”, we review the currently recommended pharmacotherapy for PTSD and discuss promising pharmacotherapies being revisited or newly developed. Novel strategies for pharmaceuticals in PTSD treatment include the use of serotonergic psychedelics as low-dose adjunct therapies combined with psychotherapy. We also discuss the use of glucocorticoids targeting the temporal window shortly following trauma exposure to interfere with fear memory consolidation. Although many factors have impeded progress in pharmacotherapy development for anxiety disorders and PTSD, we highlight three: (1) the sparsity of preclinical studies investigating the neurobiology of fear processing in female animal models despite the higher prevalence of anxiety disorders in women, (2) the poor implementation of the knowledge of how stress affects fear circuitry development across the lifetime into clinical practice, and (3) our paucity of knowledge of canonical fear circuitry in adaptive vs. maladaptive fear processing. Finally, we emphasize the functional link between interoceptive signals and emotion regulation and discuss how these interoceptive signals may be an inroad into PTSD treatment, which is often accompanied by cardiovascular dysregulation. A better understanding of the neurobiological underpinnings of adaptive and maladaptive fear processing is critical for identifying risk factors that will spur the development of sex- and developmental trauma-specific interventions, ushering in a new era of precision medicine for anxiety disorders and PTSD.
head blight (FHB) caused by fungi of the genus
is one of the most dangerous crop diseases, which has a wide geographic distribution and causes severe economic losses in the production of major cereal ...species. The infection leads to the accumulation of mycotoxins in grains, which compromises its suitability for human and animal consumption. The study demonstrated that grain samples from warmer regions of Poland, including Sulejów and Tomaszów Bolesławicki (results differed across years of the study), were colonized mainly by
and were most highly contaminated with deoxynivalenol (DON). Samples from Northeastern Poland, i.e., Ruska Wieś, which is located in a cooler region, were characterized by a predominance of
species typical of the cold climate, i.e.,
and
. A Spearman's rank correlation analysis revealed that the severity of grain infection with
/
was affected by the mean daily temperature and high humidity in May, and the corresponding values of the correlation coefficient were determined at R = 0.54 and R = 0.50. Competitive interactions were observed between the
/
genotype and DON-producing
and
, because the severity of grain infections caused by these pathogens was bound by a negative correlation.
Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are adaptive and facilitate ...survival. Selecting appropriate defensive strategy depends on intensity, proximity, temporal threat threshold, and past experiences. Hypothalamic corticotropin-releasing factor (CRF) is a major driver of an acute stress response, whereas extrahypothalamic CRF mediates stress-related affective behaviors. In this review, we shift the focus from a monolithic role of CRF as an anxiogenic peptide to comprehensively dissecting contributions of distinct populations of CRF neurons in mediating defensive behaviors. Direct interrogation of CRF neurons of the central amygdala (CeA) or the bed nucleus of the stria terminalis (BNST) show they drive unconditioned defensive responses, such as vigilance and avoidance of open spaces. Although both populations also contribute to learned fear responses in familiar, threatening contexts, CeA-CRF neurons are particularly attuned to the ever-changing environment. Depending on threat intensities, they facilitate discrimination of salient stimuli predicting manageable threats, and prevent their generalization. Finally, hypothalamic CRF neurons mediate initial threat assessment and active defense such as escape to shelter. Overall, these three major populations of CRF neurons demonstrate divergent, yet complementary contributions to the versatile defense system: heightened vigilance, discriminating salient threats, and active escape, representing three legs of the defense tripod. Despite the ‘CRF exhaustion’ in the field of affective neuroscience, understanding contributions of specific CRF neurons during adaptive defensive behaviors is needed in order to understand the implications of their dysregulation in fear- and anxiety-related psychiatric disorders.
This article is part of the Special Issue on “Fear, Anxiety and PTSD”.
•BNST-CRF and CeA-CRF neurons promote avoidance and vigilance in open spaces.•BNST-CRF and CeA-CRF neurons mediate learned fear responses in known, threatening contexts.•CeA-CRF neurons facilitate discrimination of threat salience and immediate extinction deficit.•PVN-CRF neurons mediate threat assessment and active escape to shelter.•All three CRF neuron populations are needed to successfully cope with a threat.
Despite its relatively well-understood role as a reproductive and pro-social peptide, oxytocin (OT) tells a more convoluted story in terms of its modulation of fear and anxiety. This nuanced story ...has been obscured by a great deal of research into the therapeutic applications of exogenous OT, driving more than 400 ongoing clinical trials. Drawing from animal models and human studies, we review the complex evidence concerning OT’s role in fear learning and anxiety, clarifying the existing confusion about modulation of fear versus anxiety. We discuss animal models and human studies demonstrating the prevailing role of OT in strengthening fear memory to a discrete signal or cue, which allows accurate and rapid threat detection that facilitates survival. We also review ostensibly contrasting behavioral studies that nonetheless provide compelling evidence of OT attenuating sustained contextual fear and anxiety-like behavior, arguing that these OT effects on the modulation of fear vs. anxiety are not mutually exclusive. To disambiguate how endogenous OT modulates fear and anxiety, an understudied area compared to exogenous OT, we survey behavioral studies utilizing OT receptor (OTR) antagonists. Based on emerging evidence about the role of OTR in rat dorsolateral bed nucleus of stria terminalis (BNST) and elsewhere, we postulate that OT plays a critical role in facilitating accurate discrimination between stimuli representing threat and safety. Supported by human studies, we demonstrate that OT uniquely facilitates adaptive fear but reduces maladaptive anxiety. Last, we explore the limited literature on endogenous OT and its interaction with corticotropin-releasing factor (CRF) with a special emphasis on the dorsolateral BNST, which may hold the key to the neurobiology of phasic fear and sustained anxiety.
Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation ...(LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub-threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs.
The inability to discriminate between threat and safety is a hallmark of stress-induced psychiatric disorders, including post-traumatic stress disorder. Dorsolateral bed nucleus of the stria ...terminalis (BNST
) is critically involved in the modulation of fear and anxiety, and has been proposed to regulate discrimination between signaled (cued, predictable) and unsignaled (unpredictable) threats. We recently showed that oxytocin receptors (OTRs) in the BNST
facilitate acquisition of cued fear measured in a fear-potentiated startle (FPS). In the current study, using in vivo microdialysis in awake male Sprague-Dawley rats, a double immunofluorescence approach with confocal microscopy, as well as retrograde tracing of hypothalamic BNST-projecting OT neurons, we investigated whether fear conditioning activates OT system and modulates OT release. To determine the role of OTR in fear memory formation, we also infused OTR antagonist or OT into the BNST
before fear conditioning and measured rats' ability to discriminate between cued (signaled) and non-cued (unsignaled) fear using FPS. In contrast to acute stress (exposure to forced swim stress or foot shocks alone), cued fear conditioning increases OT content in BNST
microdialysates. In addition, fear conditioning induces moderate activation of OT neurons in the paraventricular nucleus of the hypothalamus and robust activation in the supraoptic and accessory nuclei of the hypothalamus. Application of OT into the BNST
facilitates fear learning toward signaled, predictable threats, whereas blocking OTR attenuates this effect. We conclude that OTR neurotransmission in the BNST
plays a pivotal role in strengthening fear learning of temporally predictable, signaled threats.
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