Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

Sabihi, Sara; Dong, Shuai; Maurer, Skyler; Post, Caitlin; Leuner, Benedetta

doi:10.1016/j.neuropharm.2017.06.024

Cited by 66 publications

(42 citation statements)

References 120 publications

(216 reference statements)

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“…By using an OTR antagonist, it has further been shown that endogenous OT has similar anxiolytic effects in the PL, as it has in the CeL (Nakajima et al 2014;Li et al 2016;Sabihi et al 2017). In addition, optogenetic and pharmacological activation of the OTR in the PL reduces anxiety-like behavior, in a genderdependent manner (Li et al 2016), further characterizing the differential role of different prefrontal-amygdala circuits during the modulation of fear memories in female and male rodents (Shansky et al 2010;Gruene et al 2015).…”

Section: Modulation Of Fear Circuits By Oxytocin In Preclinical Animamentioning

confidence: 95%

“…Indeed, OTRsand OT-binding sites have been found in those circuits, especially in the ACC, PL, and CeL (Huber et al 2005;Nakajima et al 2014;Burkett et al 2016;Li et al 2016;Sabihi et al 2017) (Jiménez et al 2015), that together constitute the fear retrieval network. The OTRs are expressed specifically by GABAergic interneurons in all of the brain regions involved in fear retrieval (Huber et al 2005;Owen et al 2013;Nakajima et al 2014;Marlin et al 2015;Sabihi et al 2017). Importantly, OT-positive fibers originating from the PVN project to these areas (Knobloch et al 2012), and, at least in the CeL, OT is released from these fibers as observed following optogenetic stimulation and application of an OTR antagonist.…”

Section: Modulation Of Fear Circuits By Oxytocin In Preclinical Animamentioning

confidence: 99%

“…In addition to acting as an acute anxiolytic to diminish fear responses, mainly in the CeA and other areas (Litvin et al 2016;Viviani et al 2011;de la Mora et al 2016;Sabihi et al 2017;Grund et al 2017;Menon et al 2018), OTcould also act on fear learning, and fear extinction learning in a longlasting manner. In other words, it could work on neuronal plasticity in the fear-related neural networks.…”

Section: Oxytocin Treatment: Mode Of Actionmentioning

confidence: 99%

See 2 more Smart Citations

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

Río¹,

Burg²,

Stoop³

et al. 2018

Psychopharmacology

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The extinction of conditioned fear responses entrains the formation of safe new memories to decrease those behavioral responses. The knowledge in neuronal mechanisms of extinction is fundamental in the treatment of anxiety and fear disorders. Interestingly, the use of pharmacological compounds that reduce anxiety and fear has been shown as a potent co-adjuvant in extinction therapy. However, the efficiency and mechanisms by which pharmacological compounds promote extinction of fear memories remains still largely unknown and would benefit from a validation based on functional neuronal circuits, and the neurotransmitters that modulate them. From this perspective, oxytocin receptor signaling, which has been shown in cortical and limbic areas to modulate numerous functions (Eliava et al. Neuron 89(6):1291-1304, 2016), among them fear and anxiety circuits, and to enhance the salience of social stimuli (Stoop Neuron 76(1):142-59, 2012), may offer an interesting perspective. Experiments in animals and humans suggest that oxytocin could be a promising pharmacological agent at adjusting memory consolidation to boost fear extinction. Additionally, it is possible that long-term changes in endogenous oxytocin signaling can also play a role in reducing expression of fear at different brain targets. In this review, we summarize the effects reported for oxytocin in corticolimbic circuits and on fear behavior that are of relevance for the modulation and potential extinction of fear memories.

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Section: Modulation Of Fear Circuits By Oxytocin In Preclinical Animamentioning

confidence: 95%

Section: Modulation Of Fear Circuits By Oxytocin In Preclinical Animamentioning

confidence: 99%

Section: Oxytocin Treatment: Mode Of Actionmentioning

confidence: 99%

See 1 more Smart Citation

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

Río¹,

Burg²,

Stoop³

et al. 2018

Psychopharmacology

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show abstract

“…DA is involved in the experience of pleasure and has been implicated in multiple trauma-related pathologies such as depression [31] and substance use [32]. OT is known for its role in social bonding [78] but has been further implicated in depression [79], anxiety [80], and more recently in stress and related disorders [81, 82], marking its relevance for trauma-related psychopathology. Further studies have uncovered sex-related heterogeneity in the relationship of both OT and DA to trauma-related psychopathology.…”

Section: Direct Evidence Of Sex Differences In Trauma-related Psychopmentioning

confidence: 99%

Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014–2017)

Helpman

Zhu

Suarez‐Jimenez

et al. 2017

Curr Psychiatry Rep

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Purpose of Review Sex differences in the epidemiology and clinical presentation of trauma-related psychopathology have long been documented. Multiple underlying mechanisms have been examined, both psychosocial and biological. Among the most promising biological mechanisms are neural substrates of trauma-related psychopathology that have been uncovered in recent years. Recent Findings Neuroimaging studies of sex-related heterogeneity published over the past 3 years (2014–2017) demonstrate an interaction between sex and type, timing, and load of trauma exposure. These studies suggest that, for males, early trauma exposure may involve a loss of gray matter in the limbic system, including the prefrontal cortex (PFC), amygdala, and hippocampus, and an over-activity and increased connectivity of salience hubs, and particularly dorsal anterior cingulate cortex (dACC). For females, however, early trauma exposure may involve overactive and possibly an enlarged amygdala, as well as decreased connectivity of salience hubs such as the dACC. Underlying mechanisms may include interaction with several endocrine systems and result in differential neural response to naturally occurring and added endocrine ligands, as well as sex-specific genetic and epigenetic risk and resilience factors. This complex interaction between multiple biological systems may be associated with sex-specific behavioral patterns, in turn associated with trauma-related psychopathology. Summary While substantial number of published studies present preliminary evidence for neural mechanisms of sex-specific posttraumatic responses, there is a paucity of research directly designed to examine sex as a biological factor in trauma-related psychopathology. Specific foci for future studies aiming to bridge current gaps in the literature are discussed.

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“…If social interaction preferentially recruits IL-BLA projecting neurons, this could explain how activation of these cells regulates fear expression. Additionally, oxytocin is required for social buffering, and oxytocin signaling in the prelimbic cortex reduces anxiety [10,14,22,69,70]. One intriguing possibility is that oxytocin signaling directly or via connections from the mPFC recruits the subset of cells in the IL-PFC that are active during social interaction.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic reactivation of prefrontal social memory trace mimics social buffering of fear

Ahuna

Santos

et al. 2019

Preprint

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Social buffering occurs when the presence of a companion attenuates the physiological and/or behavioral effects of a stressful or fear-provoking event. It represents a way in which social interactions can immediately and potently modulate behavior. As such, social buffering is one mechanism by which strong social support increases resilience to mental illness. While the behavioral and neuroendocrine impacts of social buffering are well studied in multiple species, including humans, the neuronal bases of this behavioral phenomenon remain largely unexplored. Previous work has shown that the infralimbic prefrontal cortex (IL-PFC) is important for processing social information and, in separate studies, for modulating fear and anxiety. Thus, we hypothesized that socially-active cells within the IL-PFC may integrate social information to modulate fear responsivity. To test this hypothesis, we employed social buffering paradigms in male and female mice. Similar to prior studies in rats, we found that the presence of a cagemate reduced freezing in fear and anxiety-provoking contexts. In accordance with previous work, we demonstrated that interaction with a novel or familiar conspecific induces activity in the IL-PFC as evidenced by increased immediate early gene (IEG) expression. We then utilized an activity-dependent tagging murine line, the ArcCreER T2 mice, to express channelrhodopsin (ChR2) in neurons active during the social encoding of a new cagemate. We found that optogenetic reactivation of these sociallyactive neuronal ensembles phenocopied the effects of cagemate presence in male and female mice in learned and innate fear contexts without being inherently rewarding or altering locomotion. These data suggest that a social neuronal ensemble within the IL-PFC may contribute to social buffering of fear. These neurons may represent a novel therapeutic target for fear and anxiety disorders.

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Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

Cited by 66 publications

References 120 publications

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014–2017)

Optogenetic reactivation of prefrontal social memory trace mimics social buffering of fear

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