Evoked Axonal Oxytocin Release in the Central Amygdala Attenuates Fear Response (original) (raw)

Selective sub-nucleus effects of intra-amygdala oxytocin on fear extinction

Behavioural Brain Research, 2020

There is growing evidence that the neuropeptide oxytocin (OT) modulates fear and extinction in humans and rodents through actions in corticolimbic circuits including the central amygdala (CeA). Prior studies have, however, been limited to subjects that exhibit intact basal extinction, rather than extinction-impaired populations that could potentially therapeutically benefit from viable OT-targeting treatments. Here, we assessed the effects of pre-extinction training infusion of OT into the CeA, or basolateral amygdala (BLA), on extinction in an inbred mouse strain (S1) model of impaired extinction. We found that intra-CeA OT, at a dose of 0.01 μg, enabled extinction memory formation, as evidenced by lesser freezing as compared to vehicle-infused controls on a drug-free retrieval test. Conversely, infusion of a higher, 1.0 μg OT dose, markedly reduced freezing and increased grooming during extinction training and produced elevated freezing on drug-free retrieval. Infusion of the 0.01 μg dose into the BLA was without behavioral effects. Together, our data show that OT acts in a dose-dependent manner within the CeA to promote extinction in otherwise extinction-deficient mice. These findings provide further support for the potential utility of OT as an adjunctive treatment to extinction-based therapies for trauma and anxiety disorders.

Freezing suppression by oxytocin in central amygdala allows alternate defensive behaviours and mother-pup interactions

eLife, 2017

When animals and their offspring are threatened, parents switch from self-defense to offspring protection. How self-defense is suppressed remains elusive. We postulated that suppression of the self-defense response, freezing, is gated via oxytocin acting in the centro-lateral amygdala (CeL). We found that rat dams conditioned to fear an odor, froze when tested alone, whereas if pups were present, they remained in close contact with them or targeted the threat. Furthermore, blocking oxytocin signaling in the CeL prevented the suppression of maternal freezing. Finally, pups exposed to the odor in the presence of the conditioned dam later froze when re-exposed alone. However, if oxytocin signaling in the dam had been blocked, pups failed to learn. This study provides a functional role for the well-described action of oxytocin in the central amygdala, and demonstrates that self-defense suppression allows for active pup protection and mother-pup interactions crucial for pup threat learning.

Oxytocin signaling in basolateral and central amygdala nuclei differentially regulates the acquisition, expression, and extinction of context-conditioned fear in rats

Learning & memory (Cold Spring Harbor, N.Y.), 2015

The present study investigated how oxytocin (OT) signaling in the central (CeA) and basolateral (BLA) amygdala affects acquisition, expression, and extinction of context-conditioned fear (freezing) in rats. In the first set of experiments, acquisition of fear to a shocked context was impaired by a preconditioning infusion of synthetic OT into the CeA (Experiment 1) or BLA (Experiment 2). In the second set of experiments, expression of context fear was enhanced by a pre- or post-extinction CeA infusion of synthetic OT (Experiments 3-6) or a selective OT receptor agonist, TGOT (Experiment 4). This enhancement of fear was blocked by coadministration of an OT receptor antagonist, OTA (Experiment 5) and context fear was suppressed by administration of the antagonist alone (Experiment 6). In the third set of experiments, expression of context fear was suppressed, not enhanced, by a preextinction BLA infusion of synthetic OT or a selective OT receptor agonist, TGOT (Experiments 7 and 8). T...

Oxytocin Modulation of Neural Circuits

Current Topics in Behavioral Neurosciences

Oxytocin is a hypothalamic neuropeptide first recognized as a regulator of parturition and lactation which has recently gained attention for its ability to modulate social behaviors. In this chapter, we review several aspects of the oxytocinergic system, focusing on evidence for release of oxytocin and its receptor distribution in the cortex as the foundation for important networks that control social behavior. We examine the developmental timeline of the cortical oxytocin system as demonstrated by RNA, autoradiographic binding, and protein immunohistochemical studies, and describe how that might shape brain development and behavior. Many recent studies have implicated oxytocin in cognitive processes such as processing of sensory stimuli, social recognition, social memory, and fear. We review these studies and discuss the function of oxytocin in the young and adult cortex as a neuromodulator of central synaptic transmission and mediator of plasticity.

Oxytocin Facilitates the Extinction of Conditioned Fear in Humans

Biological Psychiatry, 2014

BACKGROUND: Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala-medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear. METHODS: Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo. RESULTS: Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases. CONCLUSIONS: Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.

Oxytocin Acts on Astrocytes in the Central Amygdala to Promote a Positive Emotional State

SUMMARYOxytocin orchestrates social and emotional behaviors through modulation of neural circuits in brain structures such as the central amygdala (CeA). The long-standing dogma is that oxytocin signaling in the central nervous system occurs exclusively via direct actions on neurons. However, several findings over the last decades showed that astrocytes actively participate in the modulation of neuronal circuits. Here, we investigate the degree of astrocytes’ involvement in oxytocin functions. Using astrocyte’ specific gain and loss of function approaches, we demonstrate that CeA astrocytes not only directly respond to oxytocin, but are actually necessary for its effects on neuronal circuits and ultimately behavior. Our work identifies astrocytes as a crucial cellular substrate underlying the promotion of a positive emotional state by oxytocin. These results further corroborate that astrocytes are key regulators of neuronal circuits activity by responding to specific neuropeptidergi...

Oxytocin modulates neural circuitry for social cognition and fear in humans

The Journal of …, 2005

In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.

Oxytocin-induced excitation of neurones in the rat central and medial amygdaloid nuclei

Neuroscience, 2005

Central oxytocin plays an important role in regulating emotionality. The amygdala expresses gonadal steroid-sensitive oxytocin binding sites in both the central and medial sub-nuclei, although the densities markedly differ between these nuclei. These studies examined the in vitro electrophysiological effects of oxytocin in the two amygdaloid nuclei and compared responses in female rats in different reproductive states (virgin, pregnant and lactating). Oxytocin (10 ؊9 -10 ؊6 M) caused a concentration-dependent increase in the firing rate of 20 -36% of the neurones in both nuclei. Although autoradiographic studies using the oxytocin receptor antagonist [ 125 I]d(CH 2 ) 5 [Tyr(Me) 2 ,Thr 4 ,Orn 8 ,Tyr-NH 2 9 ]-vasotocin showed a higher density of binding in the central nucleus of the amygdala than medial nucleus of the amygdala, neurones in the central nucleus of the amygdala had a much lower sensitivity to oxytocin: equivalent responses obtained with 10 ؊6 M in the central nucleus of the amygdala and 10 ؊8 M in the medial nucleus of the amygdala, and neurones in the central nucleus of the amygdala were insensitive to concentrations below 10 ؊6 M. Furthermore, repeated applications of oxytocin induced homologous desensitization in the central nucleus of the amygdala, but not medial nucleus of the amygdala-a single application of oxytocin producing long duration suppression of responses. This indicates that oxytocin has contrasting modes of action in the amygdala. Studies made across the reproductive cycle showed that lactating animals exhibited a larger proportion of oxytocinresponsive neurones in the medial nucleus of the amygdala and a smaller proportion in the central nucleus of the amygdala, compared with virgin or pregnant animals, indicating a peripartum shift in relative activation within the amygdala. However, changes in responses were not accompanied by changes in the density of oxytocin binding sites. These data show that oxytocin has a markedly different efficacy on neuronal activation in the central and medial sub-nuclei of the amygdala. The relative shift in excitatory responses between these two nuclei may underlie some of the neuroendocrine, behavioral and anxiolytic effects which have been ascribed to oxytocin in the periparturient rat. © 2005 Published by Elsevier Ltd on behalf of IBRO. (C. D. Ingram). Abbreviations: aCSF, artificial cerebrospinal fluid; ANOVA, analysis of variance; BST, bed nuclei of the stria terminalis; BSTm, medial nucleus of the bed nuclei of the stria terminalis; BSTo, oval nucleus of the bed nuclei of the stria terminalis; BSTp, principal nucleus of the bed nuclei of the stria terminalis; CeA, central nucleus of the amygdala; MeA, medial nucleus of the amygdala; NMDA, N-methyl-D-aspartate; OTA, d(CH 2 ) 5 [Tyr(Me) 2 ,Thr 4 ,Orn 8 ,Tyr-NH 2 9 ]-vasotocin; sp/s, spikes/s; VLS, ventrolateral septum; VMH, ventromedial hypothalamus. Neuroscience 134 (2005) 345-354 0306-4522/05$30.00ϩ0.00

A thalamo-hypothalamic pathway that activates oxytocin neurons in social contexts in female rats

Endocrinology, 2016

Oxytocin is released from neurons in the paraventricular hypothalamic nucleus (PVN) in mothers upon suckling and during adult social interactions. However, neuronal pathways that activate oxytocin neurons in social contexts are not established yet. Neurons in the posterior intralaminar complex of the thalamus (PIL), which contain tuberoinfundibular peptide 39 (TIP39) and are activated by pup exposure in lactating mothers provide a candidate projection. Innervation of oxytocin neurons by TIP39 neurons was examined by double labeling in combination with electron microscopy and retrograde tract-tracing. Potential classical neurotransmitters in TIP39 neurons were investigated by in situ hybridization histochemistry. Neurons activated after encounter with a familiar conspecific female in familiar environment were mapped with the c-fos technique. PVN and the supraoptic nucleus oxytocin neurons were closely apposed by an average of 2.0 and 0.4 TIP39 terminals, respectively. Asymmetric (pre...