Publications by authors named "Inga D Neumann"

158 Publications

Modelling sexual violence in male rats: the sexual aggression test (SxAT).

Transl Psychiatry 2022 May 18;12(1):207. Epub 2022 May 18.

Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93040, Regensburg, Germany.

Sexual assault and rape are crimes that impact victims worldwide. Although the psychosocial and eco-evolutionary factors associated with this antisocial behavior have repeatedly been studied, the underlying neurobiological mechanisms are still largely unknown. Here, we established a novel paradigm to provoke and subsequently assess sexual aggression (SxA) in adult male Wistar rats: the sexual aggression test (SxAT). Briefly, male Wistar rats are sexually aroused by a receptive female, which is exchanged by a non-receptive female immediately after the first intromission. This protocol elicits forced mounting and aggressive behavior toward the non-receptive female to different degrees, which can be scored. In a series of experiments we have shown that SxA behavior is a relatively stable trait in rats and correlates positively with sexual motivation. Rats with innate abnormal anxiety and aggressive behavior also show abnormal SxA behavior. In addition, central infusion of oxytocin moderately inhibits aggressive behavior, but increases forced mounting. Finally, we identified the agranular insular cortex to be specifically activated by SxA, however, inhibition of this region did not significantly alter behavior in the SxAT. Altogether, the SxAT is a paradigm that can be readily implemented in behavioral laboratories as a valuable tool to find answers regarding the biological mechanisms underlying SxA in humans, as well as social decision-making in general.
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http://dx.doi.org/10.1038/s41398-022-01973-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117203PMC
May 2022

Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?

Mol Psychiatry 2022 Apr 20. Epub 2022 Apr 20.

Department of Neurobiology and Animal Physiology, University Regensburg, 93040, Regensburg, Germany.

Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of ɣ-aminobutyric acid type A (GABA) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABA receptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.
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http://dx.doi.org/10.1038/s41380-022-01561-3DOI Listing
April 2022

Transcriptome and chromatin alterations in social fear indicate association of MEG3 with successful extinction of fear.

Mol Psychiatry 2022 Mar 25. Epub 2022 Mar 25.

Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, 93053, Germany.

Social anxiety disorder is characterized by a persistent fear and avoidance of social situations, but available treatment options are rather unspecific. Using an established mouse social fear conditioning (SFC) paradigm, we profiled gene expression and chromatin alterations after the acquisition and extinction of social fear within the septum, a brain region important for social fear and social behaviors. Here, we particularly focused on the successful versus unsuccessful outcome of social fear extinction training, which corresponds to treatment responsive versus resistant patients in the clinics. Validation of coding and non-coding RNAs revealed specific isoforms of the long non-coding RNA (lncRNA) Meg3 regulated, depending on the success of social fear extinction. Moreover, PI3K/AKT was differentially activated with extinction success in SFC-mice. In vivo knockdown of specific Meg3 isoforms increased baseline activity of PI3K/AKT signaling, and mildly delayed social fear extinction. Using ATAC-Seq and CUT&RUN, we found alterations in the chromatin structure of specific genes, which might be direct targets of lncRNA Meg3.
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http://dx.doi.org/10.1038/s41380-022-01481-2DOI Listing
March 2022

Neuropeptide Y, calcitonin gene-related peptide, and neurokinin A in brain regions of HAB rats correlate with anxiety-like behaviours.

Eur Neuropsychopharmacol 2022 04 7;57:1-14. Epub 2022 Jan 7.

Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.

Anxiety disorders are pervasive psychiatric disorders causing great suffering. The high (HAB) and low (LAB) anxiety-related behaviour rats were selectively bred to investigate neurobiological correlates of anxiety. We compared the level of neuropeptides relevant for anxiety- and depression-related behaviours in selected brain regions of HAB and LAB rats. Increased anxiety and depression-like behaviours of male and female HAB rats in the elevated plus-maze and forced swim tests were accompanied by elevated levels of neuropeptide Y (NPY) in the prefrontal (PFC), frontal (FC) and cingulate cortex (CCx), the striatum, and periaqueductal grey (PAG). Moreover, HAB rats displayed sex-dependent, elevated levels of calcitonin gene-related peptide (CGRP) in PFC, FC, CCx, hippocampus, and PAG. Higher neurokinin A (NKA) levels were detected in CCx, striatum, and PAG in HAB males and in CCx and hypothalamus in HAB females. Increased neurotensin was detected in CCx and PAG in HAB males and in hypothalamus in HAB females. Elevated corticotropin-releasing hormone (CRH) levels appeared in female HAB hypothalamus. Significant correlations were found between anxiety-like behaviour and NPY, CGRP, NKA, and neurotensin, particularly with NPY in CCx and striatum, CGRP in FC and hippocampus, and NKA in entorhinal cortex. This is the first report of NPY, CGRP, NKA, Neurotensin, and CRH measurements in brain regions of HAB and LAB rats, which showed widespread NPY and CGRP alterations in cortical regions, with NKA and neurotensin changes localised in sub-cortical areas. The results may contribute to elucidate pathophysiological mechanisms underlying anxiety and depression and should facilitate identifying novel therapeutic targets.
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http://dx.doi.org/10.1016/j.euroneuro.2021.12.011DOI Listing
April 2022

Structure-function relationships of the disease-linked A218T oxytocin receptor variant.

Mol Psychiatry 2022 Feb 4;27(2):907-917. Epub 2022 Jan 4.

Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany.

Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous SNP rs4686302 results in the OXTR variant A218T and has been linked to core characteristics of ASD, trait empathy and preterm birth. However, the molecular and intracellular mechanisms underlying those associations are still elusive. Here, we uncovered the molecular and intracellular consequences of this mutation that may affect the psychological or behavioral outcome of oxytocin (OXT)-treatment regimens in clinical studies, and provide a mechanistic explanation for an altered receptor function. We created two monoclonal HEK293 cell lines, stably expressing either the wild-type or A218T OXTR. We detected an increased OXTR protein stability, accompanied by a shift in Ca dynamics and reduced MAPK pathway activation in the A218T cells. Combined whole-genome and RNA sequencing analyses in OXT-treated cells revealed 7823 differentially regulated genes in A218T compared to wild-type cells, including 429 genes being associated with ASD. Furthermore, computational modeling provided a molecular basis for the observed change in OXTR stability suggesting that the OXTR mutation affects downstream events by altering receptor activation and signaling, in agreement with our in vitro results. In summary, our study provides the cellular mechanism that links the OXTR rs4686302 SNP with genetic dysregulations associated with aspects of ASD.
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http://dx.doi.org/10.1038/s41380-021-01241-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054668PMC
February 2022

Consequences of pandemic-associated social restrictions: Role of social support and the oxytocin system.

Psychoneuroendocrinology 2022 01 20;135:105601. Epub 2021 Nov 20.

Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. Electronic address:

During pandemics, governments take drastic actions to prevent the spreading of the disease, as seen during the present COVID-19 crisis. Sanctions of lockdown, social distancing and quarantine urge people to exclusively work and teach at home and to restrict social contacts to a minimum; lonely people get into further isolation, while families` nerves are strained to the extreme. Overall, this results in a dramatic and chronic increase in the level of psychosocial stress over several months mainly caused by i) social isolation and ii) psychosocial stress associated with overcrowding, social tension in families, and domestic violence. Moreover, pandemic-associated social restrictions are accompanied by loss of an essential stress buffer and important parameter for general mental and physical health: social support. Chronic psychosocial stress and, in particular, social isolation and lack of social support affect not only mental health, but also the brain oxytocin system and the immune system. Hence, pandemic-associated social restrictions are expected to increase the risk of developing psychopathologies, such as depression, anxiety-related and posttraumatic stress disorders, on the one hand, but also to induce a general inflammatory state and to impair the course of infectious disorders on the other. Due to its pro-social and stress-buffering effects, resulting in an anti-inflammatory state in case of disease, the role of the neuropeptide oxytocin will be discussed and critically considered as an emerging treatment option in cases of pandemic-induced psychosocial stress, viral infection and during recovery. In this review, we aim to critically focus on possible short- and long-term consequences of social restrictions on mental health and the immune system, while discussion oxytocin as a possible treatment option.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605825PMC
January 2022

Neurobiology of the lateral septum: regulation of social behavior.

Trends Neurosci 2022 01 19;45(1):27-40. Epub 2021 Nov 19.

Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. Electronic address:

Social interactions are essential for mammalian life and are regulated by evolutionary conserved neuronal mechanisms. An individual's internal state, experiences, and the nature of the social stimulus are critical for determining apt responses to social situations. The lateral septum (LS) - a structure of the basal forebrain - integrates abundant cortical and subcortical inputs, and projects to multiple downstream regions to generate appropriate behavioral responses. Although incoming cognitive information is indispensable for contextualizing a social stimulus, neuromodulatory information related to the internal state of the organism significantly influences the behavioral outcome as well. This review article provides an overview of the neuroanatomical properties of the LS, and examines its neurochemical (neuropeptidergic and hormonal) signaling, which provide the neuromodulatory information essential for fine-tuning social behavior across the lifespan.
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http://dx.doi.org/10.1016/j.tins.2021.10.010DOI Listing
January 2022

Co-Stimulation of Oxytocin and Arginine-Vasopressin Receptors Affect Hypothalamic Neurospheroid Size.

Int J Mol Sci 2021 Aug 6;22(16). Epub 2021 Aug 6.

Department of Molecular and Behavioural Neurobiology, Institute of Zoology, University of Regensburg, 93051 Regensburg, Germany.

Oxytocin (OXT) is a neuropeptide involved in a plethora of behavioral and physiological processes. However, there is a prominent lack of 3D cell culture models that investigate the effects of OXT on a cellular/molecular level. In this study, we established a hypothalamic neuronal spheroid model to investigate the cellular response in a more realistic 3D setting. Our data indicate that the formation of spheroids itself does not alter the basic characteristics of the cell line and that markers of cellular morphology and connectivity are stably expressed. We found that both OXT and arginine vasopressin (AVP) treatment increase spheroid size (surface area and volume), as well as individual nucleus size, which serves as an indicator for cellular proliferation. The cellular response to both OXT and AVP seems mainly to be mediated by the AVP receptor 1a (V1aR); however, the OXT receptor (OXTR) contributes significantly to the observed proliferative effect. When we blocked the OXTR pharmacologically or knocked down the OXTR by siRNA, the OXT- or AVP-induced cellular proliferation decreased. In summary, we established a 3D cell culture model of the neuronal response to OXT and AVP and found that spheroids react to the treatment via their respective receptors but also via cross-talk between the two receptor types.
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http://dx.doi.org/10.3390/ijms22168464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395152PMC
August 2021

Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety.

Mol Psychiatry 2021 May 25. Epub 2021 May 25.

Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.

The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.
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http://dx.doi.org/10.1038/s41380-021-01141-xDOI Listing
May 2021

Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats.

Nat Commun 2021 05 18;12(1):2900. Epub 2021 May 18.

Department of Neurobiology and Animal Physiology, Behavioural and Molecular Neurobiology, University of Regensburg, Universitaetstraße, Regensburg, Bavaria, Germany.

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal release of OXT and AVP differentially affects aggression in females by modulating the inhibitory tone within LS sub-networks.
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http://dx.doi.org/10.1038/s41467-021-23064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131389PMC
May 2021

Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons.

Nat Neurosci 2020 09 27;23(9):1125-1137. Epub 2020 Jul 27.

Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons.
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http://dx.doi.org/10.1038/s41593-020-0674-yDOI Listing
September 2020

Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors.

Neuron 2020 08 15;107(4):644-655.e7. Epub 2020 Jun 15.

Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany. Electronic address:

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.
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http://dx.doi.org/10.1016/j.neuron.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447984PMC
August 2020

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry.

Mol Psychiatry 2021 01 8;26(1):265-279. Epub 2020 Jun 8.

Department of Neurobiology and Animal Physiology, University of Regensburg, 93040, Regensburg, Germany.

The neuropeptide oxytocin has attracted great attention of the general public, basic neuroscience researchers, psychologists, and psychiatrists due to its profound pro-social, anxiolytic, and "anti-stress" behavioral and physiological effects, and its potential application for treatment of mental diseases associated with altered socio-emotional competence. During the last decade, substantial progress has been achieved in understanding the complex neurobiology of the oxytocin system, including oxytocinergic pathways, local release patterns, and oxytocin receptor distribution in the brain, as well as intraneuronal oxytocin receptor signaling. However, the picture of oxytocin actions remains far from being complete, and the central question remains: "How does a single neuropeptide exert such pleotropic actions?" Although this phenomenon, typical for many of about 100 identified neuropeptides, may emerge from the anatomical divergence of oxytocin neurons, their multiple central projections, distinct oxytocin-sensitive cell types in different brain regions, and multiple intraneuronal signaling pathways determining the specific cellular response, further basic studies are required. In conjunction, numerous reports on positive effects of intranasal application of oxytocin on human brain networks controlling socio-emotional behavior in health and disease require harmonic tandems of basic researchers and clinicians. During the COVID-19 crisis in 2020, oxytocin research seems central as question of social isolation-induced inactivation of the oxytocin system, and buffering effects of either activation of the endogenous system or intranasal application of synthetic oxytocin need to be thoroughly investigated.
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http://dx.doi.org/10.1038/s41380-020-0802-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278240PMC
January 2021

Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain.

Cells 2020 05 17;9(5). Epub 2020 May 17.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Changes in sphingolipid metabolism have been suggested to contribute to the pathophysiology of major depression. In this study, we investigated the activity of acid and neutral sphingomyelinases (ASM, NSM) and ceramidases (AC, NC), respectively, in twelve brain regions of female rats selectively bred for high (HAB) versus low (LAB) anxiety-like behavior. Concomitant with their highly anxious and depressive-like phenotype, HAB rats showed increased activity of ASM and NSM as well as of AC and NC in multiple brain regions associated with anxiety- and depressive-like behavior, including the lateral septum, hypothalamus, ventral hippocampus, ventral and dorsal mesencephalon. Strong correlations between anxiety-like behavior and ASM activity were found in female HAB rats in the amygdala, ventral hippocampus and dorsal mesencephalon, whereas NSM activity correlated with anxiety levels in the dorsal mesencephalon. These results provide novel information about the sphingolipid metabolism, especially about the sphingomyelinases and ceramidases, in major depression and comorbid anxiety.
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http://dx.doi.org/10.3390/cells9051239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290887PMC
May 2020

Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons.

Int J Mol Sci 2020 Mar 23;21(6). Epub 2020 Mar 23.

Department of Behavioral and Molecular Neurobiology, University of Regensburg, 93040 Regensburg, Germany.

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair bonding. However, when dysregulated, it is associated with adverse psychiatric traits, such as various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor myocyte enhancer factor 2A (MEF2A) as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A activity as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.
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http://dx.doi.org/10.3390/ijms21062200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139413PMC
March 2020

GDF15 promotes simultaneous astrocyte remodeling and tight junction strengthening at the blood-brain barrier.

J Neurosci Res 2020 07 13;98(7):1433-1456. Epub 2020 Mar 13.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.
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http://dx.doi.org/10.1002/jnr.24611DOI Listing
July 2020

Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner.

Transl Psychiatry 2019 09 13;9(1):223. Epub 2019 Sep 13.

University of Regensburg, Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, Regensburg, Germany.

Major depressive disorder is the main cause of disability worldwide with imperfect treatment options. However, novel therapeutic approaches are currently discussed, from augmentation strategies to novel treatments targeting the immune system or the microbiome-gut-brain axis. Therefore, we examined the potential beneficial effects of minocycline, a tetracycline antibiotic with pleiotropic, immunomodulatory action, alone or as augmentation of escitalopram on behavior, prefrontal microglial density, and the gut microbiome in rats selectively bred for high anxiety-like behavior (HAB). We show that concomitant with their high innate anxiety and depression, HABs have lower microglial numbers in the infralimbic and prelimbic prefrontal cortex and an altered gut microbiota composition compared with controls. Three weeks of minocycline treatment alleviated the depressive-like phenotype, further reduced microglial density, exclusively in male HAB rats, and reduced plasma concentrations of pro-inflammatory cytokines. However, coadministration of escitalopram, which had no effect alone, prevented these minocycline-induced effects. Moreover, minocycline led to a robust shift in cecal microbial composition in both HABs and rats non-selected for anxiety-like behavior. Minocycline markedly increased relative abundance of Lachnospiraceae and Clostridiales Family XIII, families known for their butyrate production, with a corresponding increase and positive correlation in plasma 3-OH-butyrate levels in a trait-dependent manner. Thus, our data suggest that the antidepressant effect of minocycline is sex- and trait-dependent, associated with a reduced microglial number in the prefrontal cortex, and with changes in microbial composition and their metabolites. These results further support the microbiome-gut-brain axis as potential target in the treatment of depression.
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http://dx.doi.org/10.1038/s41398-019-0556-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744405PMC
September 2019

Epigenetic Regulation of the Social Brain.

Trends Neurosci 2019 07 15;42(7):471-484. Epub 2019 May 15.

Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany. Electronic address:

Social behavior, a highly adaptive and crucial component of mammalian life, is regulated by particularly sensitive regulatory brain mechanisms. Substantial evidence implicates classical epigenetic mechanisms including histone modifications, DNA methylation, and nucleosome remodeling as well as nonclassical mechanisms mediated by noncoding RNA in the regulation of social behavior. These mechanisms collectively form the 'epigenetic network' that orchestrates genomic integration of salient and transient social experiences. Consequently, its dysregulation has been linked to behavioral deficits and psychopathologies. This review focuses on the role of the epigenetic network in regulating the enduring effects of social experiences during early-life, adolescence, and adulthood. We discuss research in animal models, primarily rodents, and associations between dysregulation of epigenetic mechanisms and human psychopathologies, specifically autism spectrum disorder (ASD) and schizophrenia.
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http://dx.doi.org/10.1016/j.tins.2019.04.001DOI Listing
July 2019

Chemogenetic activation of oxytocin neurons: Temporal dynamics, hormonal release, and behavioral consequences.

Psychoneuroendocrinology 2019 08 29;106:77-84. Epub 2019 Mar 29.

Division of Neuropeptides (V078), German Cancer Research Center and Central Institute of Mental Health, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address:

Chemogenetics provides cell type-specific remote control of neuronal activity. Here, we describe the application of chemogenetics used to specifically activate oxytocin (OT) neurons as representatives of a unique class of neuroendocrine cells. We injected recombinant adeno-associated vectors, driving the stimulatory subunit hM3Dq of a modified human muscarinic receptor into the rat hypothalamus to achieve cell type-specific expression in OT neurons. As chemogenetic activation of OT neurons has not been reported, we provide systematic analysis of the temporal dynamics of OT neuronal responses in vivo by monitoring calcium fluctuations in OT neurons, and intracerebral as well as peripheral release of OT. We further provide evidence for the efficiency of chemogenetic manipulation at behavioral levels, demonstrating that evoked activation of OT neurons leads to social motivation and anxiolysis. Altogether, our results will be profitable for researchers working on the physiology of neuroendocrine systems, peptidergic modulation of behaviors and translational psychiatry.
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http://dx.doi.org/10.1016/j.psyneuen.2019.03.019DOI Listing
August 2019

De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin.

Biol Psychiatry 2019 05 22;85(10):802-811. Epub 2019 Jan 22.

Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany. Electronic address:

Background: The neuropeptide oxytocin (OXT) mediates its actions, including anxiolysis, via its G protein-coupled OXT receptor. Within the paraventricular nucleus of the hypothalamus (PVN), OXT-induced anxiolysis is mediated, at least in part, via activation of the mitogen-activated protein kinase pathway following calcium influx through transient receptor potential cation channel subfamily V member 2 channels. In the periphery, OXT activates eukaryotic elongation factor 2 (eEF2), an essential mediator of protein synthesis.

Methods: In order to study whether OXT activates eEF2 also in neurons to exert its anxiolytic properties in the PVN, we performed in vivo and cell culture experiments.

Results: We demonstrate that OXT, in a protein kinase C-dependent manner, activates eEF2 both in a hypothalamic cell line and in vivo within the PVN. Next, we reveal that OXT stimulates de novo protein synthesis, while inhibition of protein synthesis within the PVN prevents the anxiolytic effect of OXT in male rats. Moreover, activation of eEF2 within the PVN conveyed an anxiolytic effect supporting a role of OXT-induced eEF2 activation and protein synthesis for its anxiolysis. Finally, we show that one of the proteins that is upregulated by OXT is the neuropeptide Y receptor 5. Infusion of a specific neuropeptide Y receptor 5 agonist into the PVN consequently led to decreased anxiety-related behavior, while pretreatment with a neuropeptide Y receptor 5 antagonist prevented the anxiolytic effect of OXT.

Conclusions: Taken together, these results show that OXT recruits several intracellular signaling cascades to induce protein synthesis, which mediates the anxiolytic effects of OXT within the PVN and suggests that eEF2 represents a novel target for anxiety-related disorders.
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http://dx.doi.org/10.1016/j.biopsych.2019.01.010DOI Listing
May 2019

Tracking oxytocin functions in the rodent brain during the last 30 years: From push-pull perfusion to chemogenetic silencing.

J Neuroendocrinol 2019 03 11;31(3):e12695. Epub 2019 Mar 11.

RIAgnosis, Sinzing, Germany.

A short overview is provided of the last 30 years of oxytocin (and vasopressin) research performed in our laboratories, starting with attempts to monitor the release of this nonapeptide in the rodent brain during physiological conditions such as suckling in the lactating animal. Using push-pull perfusion and microdialysis approaches, release patterns in hypothalamic and limbic brain regions could be characterised to occur from intact neuronal structures, to be independent of peripheral secretion into blood, and to respond differentially to various stimuli, particularly those related to reproduction and stress. Parallel efforts focused on the functional impact of central oxytocin release, including neuroendocrine and behavioural effects mediated by nonapeptide receptor interactions and subsequent intraneuronal signalling cascades. The use of a variety of sophisticated behavioural paradigms to manipulate central oxytocin release, along with pharmacological, genetic and pharmacogenetic approaches, revealed multiple consequences on social behaviours, particularly social fear.
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http://dx.doi.org/10.1111/jne.12695DOI Listing
March 2019

Post-weaning social isolation exacerbates aggression in both sexes and affects the vasopressin and oxytocin system in a sex-specific manner.

Neuropharmacology 2019 09 18;156:107504. Epub 2019 Jan 18.

Department of Behavioral and Molecular Neurobiology, University of Regensburg, Germany; Lifelines Biobank Noord-Nederland B.V. Groningen, Netherlands.

Post-weaning social isolation (PWSI) is known to induce exaggerated and abnormal aggression in male rats. Here we aimed to assess the effects of PWSI on aggressiveness and social behavior in both male and female rats. Furthermore, we evaluated how PWSI affects the central oxytocin (OXT) and vasopressin (AVP) systems in both sexes. Wistar rats were isolated (IS) or group housed (GH) in same-sex groups immediately after weaning. After seven weeks, rats underwent an intruder test to assess aggression. In one group, brains were immediately dissected afterwards for in situ hybridization and receptor autoradiography. The other group underwent additional anxiety-like and social behavior tests. PWSI induced increased (abnormal) aggression and impaired social memory in both sexes. Especially IS females exhibited abnormal aggression towards juveniles. Furthermore, PWSI increased OXT mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) and decreased OXTR binding in the anterior portion of the nucleus accumbens (NAcc), independent of the sex. V1a receptor binding was decreased in the lateral hypothalamus (LH) and dentate gyrus (DG) in IS rats, regardless of sex. However, V1a receptor binding in the anterior portion of the bed nucleus of stria terminalis (BNSTa) was decreased in IS females but increased in IS males. Taken together, our data support PWSI as a reliable model to exacerbate aggression not only in male but also in female rats. In addition, OXT receptors in the NAcca and V1a receptors in the LH, DG, and BNSTa may play a role in the link between PWSI and aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.01.019DOI Listing
September 2019

Adolescent oxytocin response to stress and its behavioral and endocrine correlates.

Horm Behav 2018 09 4;105:157-165. Epub 2018 Sep 4.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe University, Deutschordenstraße 50, 60528 Frankfurt am Main, Germany.

Oxytocin (OXT) shows anxiolytic and stress-reducing effects, but salivary OXT response to laboratory-induced stress has only been assessed in one study in healthy adults. The present study aimed at extending these findings by assessing salivary OXT stress reactivity in healthy adolescents (aged 11-18) compared to a control condition. A higher salivary OXT response to stress compared to the control condition was expected. In addition, the association between OXT, cortisol (CORT) and psychological reactivity patterns was explored. Psychosocial stress was induced using the Trier Social Stress Test (TSST; 13 males, 15 females), while the Control-TSST (14 males, 15 females) served as a non-stress control condition. Salivary OXT increased in response to the TSST with a peak at +1 and decline at +10 min after stress. Baseline OXT correlated negatively with experienced anxiety and insecurity, while both correlated positively with OXT reactivity. OXT and CORT increase as well as OXT increase and CORT recovery were positively correlated. Results indicate that salivary OXT in response to the TSST is a valid method to assess biological effects of laboratory-induced stress also in adolescents. Due to a rapid increase and decline, salivary OXT needs to be assessed directly after stress exposure. Given the interplay of OXT with affective symptoms and CORT response, the combined measure of salivary OXT and CORT reactivity adds to studying stress reactivity in typically developing and clinical samples.
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http://dx.doi.org/10.1016/j.yhbeh.2018.08.010DOI Listing
September 2018

Brain neuropeptide S: via GPCR activation to a powerful neuromodulator of socio-emotional behaviors.

Cell Tissue Res 2019 Jan 15;375(1):123-132. Epub 2018 Aug 15.

Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, 93040, Regensburg, Germany.

Neuropeptide S (NPS) has attracted the attention of the scientific community due to its potent anxiolytic-like and fear-attenuating effects studied in rodents. Therefore, NPS might represent a treatment option for neuropsychiatric disorders, such as anxiety disorders, even more so as single nucleotide polymorphisms in the human NPS receptor gene have been associated with increased anxiety traits that contribute to the pathogenesis of fear- and anxiety-related disorders. However, the signaling mechanisms underlying the behavioral effects of NPS and the interaction with other brain neuropeptides are still rather unknown. To illuminate how NPS modulates the expression of selected emotional and social behaviors, the present review focuses on neuroanatomical and electrophysiological studies, as well as intracellular signaling mechanisms following NPS receptor stimulation in rodents. We will also discuss interactions of the NPS system with two well-described neuropeptides, namely corticotropin-releasing factor and oxytocin, which may contribute to the fear- and anxiety-reducing effects.
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http://dx.doi.org/10.1007/s00441-018-2902-2DOI Listing
January 2019

The Oxytocin Receptor: From Intracellular Signaling to Behavior.

Physiol Rev 2018 07;98(3):1805-1908

Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg , Regensburg , Germany.

The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1 , as listed in PubMed), which revealed central roles for OXT and its receptor (OXTR) in reproduction, and social and emotional behaviors in animal and human studies focusing on mental and physical health and disease. In this review, we discuss the mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OXTR-coupled signaling cascades, and their involvement in behavioral outcomes to assemble a comprehensive picture of the central and peripheral OXT system. Traditionally known for its role in milk let-down and uterine contraction during labor, OXT also has implications in physiological, and also behavioral, aspects of reproduction, such as sexual and maternal behaviors and pair bonding, but also anxiety, trust, sociability, food intake, or even drug abuse. The many facets of OXT are, on a molecular basis, brought about by a single receptor. The OXTR, a 7-transmembrane G protein-coupled receptor capable of binding to either Gα or Gα proteins, activates a set of signaling cascades, such as the MAPK, PKC, PLC, or CaMK pathways, which converge on transcription factors like CREB or MEF-2. The cellular response to OXT includes regulation of neurite outgrowth, cellular viability, and increased survival. OXTergic projections in the brain represent anxiety and stress-regulating circuits connecting the paraventricular nucleus of the hypothalamus, amygdala, bed nucleus of the stria terminalis, or the medial prefrontal cortex. Which OXT-induced patterns finally alter the behavior of an animal or a human being is still poorly understood, and studying those OXTR-coupled signaling cascades is one initial step toward a better understanding of the molecular background of those behavioral effects.
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http://dx.doi.org/10.1152/physrev.00031.2017DOI Listing
July 2018

Animal models of social stress: the dark side of social interactions.

Stress 2018 09 10;21(5):417-432. Epub 2018 May 10.

a Department of Behavioral and Molecular Neurobiology , University of Regensburg , Regensburg , Germany.

Social stress occurs in all social species, including humans, and shape both mental health and future interactions with conspecifics. Animal models of social stress are used to unravel the precise role of the main stress system - the HPA axis - on the one hand, and the social behavior network on the other, as these are intricately interwoven. The present review aims to summarize the insights gained from three highly useful and clinically relevant animal models of psychosocial stress: the resident-intruder (RI) test, the chronic subordinate colony housing (CSC), and the social fear conditioning (SFC). Each model brings its own focus: the role of the HPA axis in shaping acute social confrontations (RI test), the physiological and behavioral impairments resulting from chronic exposure to negative social experiences (CSC), and the neurobiology underlying social fear and its effects on future social interactions (SFC). Moreover, these models are discussed with special attention to the HPA axis and the neuropeptides vasopressin and oxytocin, which are important messengers in the stress system, in emotion regulation, as well as in the social behavior network. It appears that both nonapeptides balance the relative strength of the stress response, and simultaneously predispose the animal to positive or negative social interactions.
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http://dx.doi.org/10.1080/10253890.2018.1462327DOI Listing
September 2018

Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation.

Curr Biol 2018 04 15;28(7):1066-1078.e6. Epub 2018 Mar 15.

Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany. Electronic address:

Oxytocin (OXT)-mediated behavioral responses to social and stressful cues have extensively been studied in male rodents. Here, we investigated the capacity of brain OXT receptor (OXTR) signaling in the lateral septum (LS) to prevent social fear expression in female mice using the social-fear-conditioning paradigm. Utilizing the activated OXT system during lactation, we show that lactating mice did not express fear 24 hr after social fear conditioning. Supporting the role of OXTR signaling in the LS in attenuation of social fear, synthetic OXT infusion or overexpression of OXTR in the LS diminished social fear expression, whereas constitutive OXTR knockout severely impaired social fear extinction in virgin mice. Subsequently, both pharmacological blockade of local OXTRs in the LS and chemogenetic silencing of supraoptic nucleus OXTergic afferents to the LS increased social fear expression in lactating mice. Hence, LS-projecting OXT neurons suppress social fear in female mice.
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http://dx.doi.org/10.1016/j.cub.2018.02.044DOI Listing
April 2018

Abandoned prairie vole mothers show normal maternal care but altered emotionality: Potential influence of the brain corticotropin-releasing factor system.

Behav Brain Res 2018 04 27;341:114-121. Epub 2017 Dec 27.

Center for Translational Social Neuroscience, Silvio O. Conte Center for Oxytocin and Social Cognition, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd., Atlanta, GA 30329, USA. Electronic address:

When fathers leave the family, mothers are at increased risk of developing depression and anxiety disorders. In biparental, socially monogamous prairie voles (Microtus ochrogaster), sudden bond disruption increases passive stress-coping, indicative of depressive-like behavior, and acts as chronic stressor in both males and females. However, the consequences of separation in lactating prairie vole mothers are unknown. In the present study, following 18 days of cohousing, half of the prairie vole pairs were separated by removing the male. In early lactation, maternal care was unaffected by separation, whereas anxiety-related behavior and passive stress-coping were significantly elevated in separated mothers. Separation significantly increased corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus under basal conditions, similar to levels of paired females after acute exposure to forced swim stress. A second cohort of lactating prairie voles was infused intracerebroventricularly with either vehicle or the CRF receptor antagonist D-Phe just prior to behavioral testing. The brief restraining during acute infusion significantly decreased arched back nursing in vehicle-treated paired and separated groups, whereas in the D-Phe-treated separated group the behavior was not impaired. Furthermore, in the latter, anxiety-related behavior and passive stress-coping were normalized to levels similar to vehicle-treated paired mothers. In conclusion, maternal investment is robust enough to withstand loss of the partner, whereas the mother's emotionality is affected, which may be - at least partly - mediated by a CRF-dependent mechanism. This animal model has potential for mechanistic studies of behavioral and physiological consequences of partner loss in single mothers.
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http://dx.doi.org/10.1016/j.bbr.2017.12.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800976PMC
April 2018

Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species.

Sci Signal 2017 Dec 5;10(508). Epub 2017 Dec 5.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.

Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein-coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging because of the difficulty in obtaining ligands that retain selectivity across rodents and humans for translational studies. We identified a selective and more stable oxytocin receptor (OTR) agonist by subtly modifying the pharmacophore framework of human oxytocin and vasopressin. [Se-Se]-oxytocin-OH displayed similar potency to oxytocin but improved selectivity for OTR, an effect that was retained in mice. Centrally infused [Se-Se]-oxytocin-OH potently reversed social fear in mice, confirming that this action was mediated by OTR and not by V1a or V1b vasopressin receptors. In addition, [Se-Se]-oxytocin-OH produced a more regular contraction pattern than did oxytocin in a preclinical labor induction and augmentation model using myometrial strips from cesarean sections. [Se-Se]-oxytocin-OH had no activity in human cardiomyocytes, indicating a potentially improved safety profile and therapeutic window compared to those of clinically used oxytocin. In conclusion, [Se-Se]-oxytocin-OH is a novel probe for validating OTR as a therapeutic target in various biological systems and is a promising new lead for therapeutic development. Our medicinal chemistry approach may also be applicable to other peptidergic signaling systems with similar selectivity issues.
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http://dx.doi.org/10.1126/scisignal.aan3398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892705PMC
December 2017

Rebalancing the Addicted Brain: Oxytocin Interference with the Neural Substrates of Addiction.

Trends Neurosci 2017 12 8;40(12):691-708. Epub 2017 Nov 8.

Regensburg Center of Neuroscience, Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. Electronic address:

Drugs that act on the brain oxytocin (OXT) system may provide a much-needed treatment breakthrough for substance-use disorders. Targeting the brain OXT system has the potential to treat addiction to all major classes of addictive substance and to intervene across all stages of the addiction cycle. Emerging evidence suggests that OXT is able to interfere with such a wide range of addictive behaviours for such a wide range of addictive substances by rebalancing core neural systems that become dysregulated over the course of addiction. By improving our understanding of these interactions between OXT and the neural substrates of addiction, we will not only improve our understanding of addiction, but also our ability to effectively treat these devastating disorders.
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http://dx.doi.org/10.1016/j.tins.2017.10.003DOI Listing
December 2017
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