Publications by authors named "Oliver J Bosch"

45 Publications

Dysfunctions of brain oxytocin signaling: Implications for poor mothering.

Neuropharmacology 2022 06 4;211:109049. Epub 2022 Apr 4.

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

Good mothering has profound impact on both the mother's and the young's well-being. Consequently, experiencing inadequate maternal care - or even neglect - in the first stages of life is a major risk factor for the development of psychiatric disorders, and even for poor parenting towards the future offspring. Thus, understanding the neurobiological basis of maternal neglect becomes crucial. Along with other neurotransmitters and neuropeptides, oxytocin (OXT) has long been known as one of the main modulators of maternal behavior. In rodents, disruptions of central OXT transmission have been associated with poor maternal responses, like impaired onset of nursing behaviors, and reduced care and defense of the pups. Importantly, such behavioral and molecular deficits can be transmitted through generations, creating a vicious circle of low-quality maternal behavior. Similarly, evidence from human studies shows that OXT signaling is defective in conditions of inadequate mothering and child neglect. On those premises, this review aims at providing a comprehensive overview of animal and human studies linking perturbed OXT transmission to poor maternal behavior. Considering the important fallouts of inadequate maternal responses, we believe that unraveling the alterations in OXT transmission might provide useful insights for a better understanding of maternal neglect and, ultimately, for future intervention approaches.
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http://dx.doi.org/10.1016/j.neuropharm.2022.109049DOI Listing
June 2022

The brain oxytocin and corticotropin-releasing factor systems in grieving mothers: What we know and what we need to learn.

Peptides 2021 09 6;143:170593. Epub 2021 Jun 6.

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

The bond between a mother and her child is the strongest bond in nature. Consequently, the loss of a child is one of the most stressful and traumatic life events that causes Prolonged Grief Disorder in up to 94 % of bereaved parents. While both parents are affected, mothers are of higher risk to develop mental health complications; yet, very little research has been done to understand the impact of the loss of a child, stillbirth and pregnancy loss on key neurobiological systems. The emotional impact of losing a child, e.g., Prolonged Grief Disorder, is likely accompanied by dysregulations in neural systems important for mental health. Among those are the neuropeptides contributing to attachment and stress processing. In this review, we present evidence for the involvement of the brain oxytocin (OXT) and corticotropin-releasing factor (CRF) systems, which both play a role in maternal behavior and the stress response, in the neurobiology of grief in mothers from a behavioral and molecular point of view. We will draw conclusions from reviewing relevant animal and human studies. However, the paucity of research on the tragic end to an integral bond in a female's life calls for the need and responsibility to conduct further studies on mothers experiencing the loss of a child both in the clinic and in appropriate animal models.
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http://dx.doi.org/10.1016/j.peptides.2021.170593DOI Listing
September 2021

Microglia react to partner loss in a sex- and brain site-specific manner in prairie voles.

Brain Behav Immun 2021 08 28;96:168-186. Epub 2021 May 28.

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

Positive social relationships are paramount for the survival of mammals and beneficial for mental and physical health, buffer against stressors, and even promote appropriate immune system functioning. By contrast, impaired social relationships, social isolation, or the loss of a bonded partner lead to aggravated physical and mental health. For example, in humans partner loss is detrimental for the functioning of the immune system and heightens the susceptibility for the development of post-traumatic stress disorders, anxiety disorders, and major depressive disorders. To understand potential underlying mechanisms, the monogamous prairie vole can provide important insights. In the present study, we separated pair bonded male and female prairie voles after five days of co-housing, subjected them to the forced swim test on the fourth day following separation, and studied their microglia morphology and activation in specific brain regions. Partner loss increased passive stress-coping in male, but not female, prairie voles. Moreover, partner loss was associated with microglial priming within the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) in male prairie voles, whereas in female prairie voles the morphological activation within the whole PVN and the prelimbic cortex (PrL) was decreased, marked by a shift towards ramified microglial morphology. Expression of the immediate early protein c-Fos following partner loss was changed within the PrL of male, but not female, prairie voles. However, the loss of a partner did not affect the investigated aspects of the peripheral immune response. These data suggest a potential sex-dependent mechanism for the regulation of microglial activity following the loss of a partner, which might contribute to the observed differences in passive stress-coping. This study furthers our understanding of the effects of partner loss and its short-term impact on the CNS as well as the CNS immune system and the peripheral innate immune system in both male and female prairie voles.
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http://dx.doi.org/10.1016/j.bbi.2021.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319132PMC
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

Metabotropic glutamate receptor subtype 7 controls maternal care, maternal motivation and maternal aggression in mice.

Genes Brain Behav 2020 01 14;19(1):e12627. Epub 2019 Dec 14.

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

The group III metabotropic glutamate receptor subtype 7 (mGlu7) is an important regulator of glutamatergic and GABAergic neurotransmission and known to mediate emotionality and male social behavior. However, a possible regulatory role in maternal behavior remains unknown to date. Adequate expression of maternal behavior is essential for successful rearing and healthy development of the young. By understanding genetic and neural mechanisms underlying this important prosocial behavior, we gain valuable insights into possible dysregulations. Using genetic ablation as well as pharmacological modulation, we studied various parameters of maternal behavior in two different mouse strains under the influence of mGlu7. We can clearly show a regulatory role of mGlu7 in maternal behavior. Naïve virgin female C57BL/6 mGlu7 knockout mice showed more often nursing postures and less spontaneous maternal aggression compared to their heterozygous and wildtype littermates. In lactating C57BL/6 wildtype mice, acute central activation of mGlu7 by the selective agonist AMN082 reduced arched back nursing and accelerated pup retrieval without affecting maternal aggression. In addition, in lactating CD1 wildtype mice the selective mGlu7 antagonist XAP044 increased both pup retrieval and maternal aggression. With respect to receptor expression levels, mGlu7 mRNA expression was higher in lactating vs virgin C57BL/6 mice in the prefrontal cortex, but not hypothalamus or hippocampus. In conclusion, these findings highlight a significant role of the mGlu7 receptor subtype in mediating maternal behavior in mice. Region-dependent studies are warranted to further extend our knowledge on the specific function of the brain glutamate system in maternal behavior.
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http://dx.doi.org/10.1111/gbb.12627DOI Listing
January 2020

Social creatures: Model animal systems for studying the neuroendocrine mechanisms of social behaviour.

J Neuroendocrinol 2019 12 28;31(12):e12807. Epub 2019 Nov 28.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

The interaction of animals with conspecifics, termed social behaviour, has a major impact on the survival of many vertebrate species. Neuropeptide hormones modulate the underlying physiology that governs social interactions, and many findings concerning the neuroendocrine mechanisms of social behaviours have been extrapolated from animal models to humans. Neurones expressing neuropeptides show similar distribution patterns within the hypothalamic nucleus, even when evolutionarily distant species are compared. During evolution, hypothalamic neuropeptides and releasing hormones have retained not only their structures, but also their biological functions, including their effects on behaviour. Here, we review the current understanding of the mechanisms of social behaviours in several classes of animals, such as worms, insects and fish, as well as laboratory, wild and domesticated mammals.
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http://dx.doi.org/10.1111/jne.12807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916380PMC
December 2019

Parental Brain Conference 2018.

J Neuroendocrinol 2019 09 15;31(9):e12789. Epub 2019 Sep 15.

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

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http://dx.doi.org/10.1111/jne.12789DOI Listing
September 2019

More than reproduction: Central gonadotropin-releasing hormone antagonism decreases maternal aggression in lactating rats.

J Neuroendocrinol 2019 09 4;31(9):e12709. Epub 2019 Apr 4.

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

Gonadotropin-releasing hormone (GnRH) is a major regulator and activator of the hypothalamic-pituitary-gonadal axis. Many studies have demonstrated the importance of GnRH in reproduction and sexual behaviour. However, to date, only a single study shows an involvement of GnRH in maternal behaviour where a 30% reduction of GnRH neurones abolishes a mother's motivation to retrieve pups. On this basis, we aimed to investigate the effects of acute central GnRH receptor blockade in lactating rats on maternal care under non-stress and stress conditions, maternal motivation in the pup retrieval test, maternal anxiety on the elevated plus maze, and maternal aggression in the maternal defence test. We found that acute central infusion of a GnRH antagonist ([d-Phe ,Pro ]-luteinising hormone-releasing hormone; 0.5 ng 5 μL ) impaired a mother's attack behaviour against a female intruder rat during the maternal defence test compared to vehicle controls. However, in contrast to the previous study on reduced GnRH neurones, acute central GnRH antagonism did not affect pup retrieval, nor any other parameter of maternal behaviour or maternal anxiety. Taken together, GnRH receptor activation is mandatory for protection of the offspring. These findings shed new light on GnRH as a neuropeptide acting not exclusively on the reproductive axis but, additionally, on maternal behaviour including pup retrieval and maternal aggression.
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http://dx.doi.org/10.1111/jne.12709DOI Listing
September 2019

Mom doesn't care: When increased brain CRF system activity leads to maternal neglect in rodents.

Front Neuroendocrinol 2019 04 23;53:100735. Epub 2019 Jan 23.

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

Mothers are the primary caregivers in mammals, ensuring their offspring's survival. This strongly depends on the adequate expression of maternal behavior, which is the result of a concerted action of "pro-maternal" versus "anti-maternal" neuromodulators such as the oxytocin and corticotropin-releasing factor (CRF) systems, respectively. When essential peripartum adaptations fail, the CRF system has negative physiological, emotional and behavioral consequences for both mother and offspring often resulting in maternal neglect. Here, we provide an elaborate and unprecedented review on the implications of the CRF system in the maternal brain. Studies in rodents have advanced our understanding of the specific roles of brain regions such as the limbic bed nucleus of the stria terminalis, medial preoptic area and lateral septum even in a CRF receptor subtype-specific manner. Furthermore, we discuss potential interactions of the CRF system with other neurotransmitters like oxytocin and noradrenaline, and present valuable translational aspects of the recent research.
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http://dx.doi.org/10.1016/j.yfrne.2019.01.001DOI Listing
April 2019

Brain vasopressin signaling modulates aspects of maternal behavior in lactating rats.

Genes Brain Behav 2019 01 11;18(1):e12517. Epub 2018 Oct 11.

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

The brain vasopressin system mediates various social behaviors as has been studied mostly in males. Only recently, advances in social neuroscience revealed that central vasopressin signaling via its V1a and V1b receptors also facilitates female social behavior, including maternal behavior. In this review, we show how maternal care, maternal motivation and maternal aggression of lactating rat mothers are modulated in a V1 receptor subtype- and brain region-specific manner. Measuring local release pattern of vasopressin via intracerebral microdialysis in the behaving rat mother as well as using pharmacological approaches to activate or block vasopressin receptors with subsequent behavioral observation provide detailed insight into the functional role of the vasopressin system in maternal behavior. In this context, the complementary rat animal model of high (HAB) and low anxiety-related behavior (LAB) is particularly helpful due to the genetically determined high activity of the vasopressin gene in HAB rats, which also underlies their high levels of maternal behavior. Furthermore, first studies in humans indicate that the vasopressin system in general and the V1a receptor in more particular might mediate mothering.
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http://dx.doi.org/10.1111/gbb.12517DOI Listing
January 2019

When mothers neglect their offspring: an activated CRF system in the BNST is detrimental for maternal behavior.

Arch Womens Ment Health 2019 06 4;22(3):409-415. Epub 2018 Aug 4.

Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany.

Becoming a mother is an intense experience that not only changes a woman's life but is also paralleled by multiple central adaptations. These changes evolve before parturition and continue to persist into lactation, thereby ensuring the full commitment of the mother to care for the newborns. Most of our knowledge on these adaptations that drive the peripartum brain come from rodent animal models. On one side, it is known that maternal behavior is initiated and maternal mood is stabilized by an upregulation of the pro-maternal neuropeptide systems' activity of oxytocin and arginine-vasopressin. On the other side, signaling of the rather anti-maternal corticotropin-releasing factor system triggers maternal neglect and increases maternal anxiety. Here, we discuss how the corticotropin-releasing factor system based in the limbic bed nucleus of the stria terminalis negatively affects maternal behavior and maternal mood. Moreover, we apply microdialysis and acute pharmacological interventions to demonstrate how the corticotropin-releasing factor system potentially interacts with the pro-maternal oxytocin system in the posterior bed nucleus of the stria terminalis to trigger certain aspects of maternal behavior.
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http://dx.doi.org/10.1007/s00737-018-0897-zDOI Listing
June 2019

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

Maternal stress and the MPOA: Activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats.

Neuropharmacology 2018 05 2;133:440-450. Epub 2018 Mar 2.

University of Regensburg, Regensburg, Germany. Electronic address:

Maternal behavior and anxiety are potently modulated by the brain corticotropin-releasing factor (CRF) system postpartum. Downregulation of CRF in limbic brain regions is essential for appropriate maternal behavior and an adaptive anxiety response. Here, we focus our attention on arguably the most important brain region for maternal behavior, the hypothalamic medial preoptic area (MPOA). Within the MPOA, mRNA for CRF receptor subtype 1 (protein: CRFR1, gene: Crhr1) was more abundantly expressed than for subtype 2 (protein: CRFR2, gene: Crhr2), however expression of Crhr1, Crhr2 and CRF-binding protein (protein: CRFBP, gene: Crhbp) mRNA was similar between virgin and lactating rats. Subtype-specific activation of CRFR, predominantly CRFR1, in the MPOA decreased arched back nursing and total nursing under non-stress conditions. Following acute stressor exposure, only CRFR1 inhibition rescued the stress-induced reduction in arched back nursing while CRFR1 activation prolonged the decline in nursing. Furthermore, inhibition of CRFR1 strongly increased maternal aggression in the maternal defense test. CRFR1 activation had anxiogenic actions and reduced locomotion on the elevated plus-maze, however neither CRFR1 nor R2 manipulation affected maternal motivation. In addition, activation of CRFR1, either centrally or locally in the MPOA, increased local oxytocin release. Finally, inhibition of CRFBP (a potent regulator of CRFR activity) in the MPOA did not affect any of the maternal parameters investigated. In conclusion, activity of CRFR in the MPOA, particularly of subtype 1, needs to be dampened during lactation to ensure appropriate maternal behavior. Furthermore, oxytocin release in the MPOA may provide a regulatory mechanism to counteract the negative impact of CRFR activation on maternal behavior.
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http://dx.doi.org/10.1016/j.neuropharm.2018.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869057PMC
May 2018

Lost connections: Oxytocin and the neural, physiological, and behavioral consequences of disrupted relationships.

Int J Psychophysiol 2019 02 9;136:54-63. Epub 2018 Jan 9.

Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, 93053 Regensburg, Germany. Electronic address:

In humans and rodent animal models, the brain oxytocin system is paramount for facilitating social bonds, from the formation and consequences of early-life parent-infant bonds to adult pair bond relationships. In social species, oxytocin also mediates the positive effects of healthy social bonds on the partners' well-being. However, new evidence suggests that the negative consequences of early neglect or partner loss may be mediated by disruptions in the oxytocin system as well. With a focus on oxytocin and its receptor, we review studies from humans and animal models, i.e. mainly from the biparental, socially monogamous prairie vole (Microtus ochrogaster), on the beneficial effects of positive social relationships both between offspring and parents and in adult partners. The abundance of social bonds and benevolent social relationships, in general, are associated with protective effects against psycho- and physiopathology not only in the developing infant, but also during adulthood. Furthermore, we discuss the negative effects on well-being, emotionality and behavior, when these bonds are diminished in quality or are disrupted, for example through parental neglect of the young or the loss of the partner in adulthood. Strikingly, in prairie voles, oxytocinergic signaling plays an important developmental role in the ability to form bonds later in life in the face of early-life neglect, while disruption of oxytocin signaling following partner loss results in the emergence of depressive-like behavior and physiology. This review demonstrates the translational value of animal models for investigating the oxytocinergic mechanisms that underlie the detrimental effects of developmental parental neglect and pair bond disruption, encouraging future translationally relevant studies on this topic that is so central to our daily lives.
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http://dx.doi.org/10.1016/j.ijpsycho.2017.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037618PMC
February 2019

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

Oxytocin and Social Relationships: From Attachment to Bond Disruption.

Curr Top Behav Neurosci 2018;35:97-117

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 School of Medicine, Atlanta, GA, 30329, USA.

Social relationships throughout life are vital for well-being and physical and mental health. A significant amount of research in animal models as well as in humans suggests that oxytocin (OT) plays an important role in the development of the capacity to form social bonds, the mediation of the positive aspects of early-life nurturing on adult bonding capacity, and the maintenance of social bonding. Here, we focus on the extensive research on a socially monogamous rodent model organism, the prairie vole (Microtus ochrogaster). OT facilitates mating-induced pair bonds in adults through interaction with the mesolimbic dopamine system. Variation in striatal OT receptor density predicts resilience and susceptibility to neonatal social neglect in female prairie voles. Finally, in adults, loss of a partner results in multiple disruptions in OT signaling, including decreased OT release in the striatum, which is caused by an activation of the brain corticotropin releasing factor (CRF) system. The dramatic behavioral consequence of partner loss is increased depressive-like behavior reminiscent of bereavement. Importantly, infusions of OT into the striatum of adults prevents the onset of depressive-like behavior following partner loss, and evoking endogenous OT release using melanocortin agonists during neonatal social isolation rescues impairments in social bonding in adulthood. This work has important translational implications relevant to the disruptions of social bonds in childhood and in adults.
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http://dx.doi.org/10.1007/7854_2017_10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815947PMC
October 2018

Look behind the eyes - vasopressin rules the day.

Authors:
Oliver J Bosch

J Physiol 2017 06 28;595(11):3245. Epub 2017 Apr 28.

Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, 93053, Regensburg, Germany.

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http://dx.doi.org/10.1113/JP274223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451701PMC
June 2017

Brain CRF-binding protein modulates aspects of maternal behavior under stressful conditions and supports a hypo-anxious state in lactating rats.

Horm Behav 2016 08 28;84:136-44. Epub 2016 Jun 28.

Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany. Electronic address:

Reduced corticotropin-releasing factor (CRF) receptor activation in the postpartum period is essential for adequate maternal behavior. One of the factors contributing to this hypo-activity might be the CRF-binding protein (CRF-BP), which likely reduces the availability of free extracellular CRF/urocortin 1. Here, we investigated behavioral effects of acute CRF-BP inhibition using 5μg of CRF(6-33) administered either centrally or locally within different parts of the bed nucleus of the stria terminalis (BNST) in lactating rats. Additionally, we assessed CRF-BP expression in the BNST comparing virgin and lactating rats. Central CRF-BP inhibition increased maternal aggression during maternal defense but did not affect maternal care or anxiety-related behavior. CRF-BP inhibition in the medial-posterior BNST had no effect on maternal care under non-stress conditions but impaired the reinstatement of maternal care following stressor exposure. Furthermore, maternal aggression, particularly threat behavior, and anxiety-related behavior were elevated by CRF-BP inhibition in the medial-posterior BNST. In the anterior-dorsal BNST, CRF-BP inhibition increased only non-maternal behaviors following stress. Finally, CRF-BP expression was higher in the anterior compared to the posterior BNST but was not different between virgin and lactating rats in either region. Our study demonstrates a key role of the CRF-BP, particularly within the BNST, in modulating CRF's impact on maternal behavior. The CRF-BP is important for the reinstatement of maternal care after stress, for modulating threat behavior during an aggressive encounter and for maintaining a hypo-anxious state during lactation. Thus, the CRF-BP likely contributes to the postpartum-associated down-regulation of the CRF system in a brain region-dependent manner.
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http://dx.doi.org/10.1016/j.yhbeh.2016.06.009DOI Listing
August 2016

Vasopressin and Oxytocin: Conductors of the Symphony of Physiology and Behaviour.

J Neuroendocrinol 2016 04;28(4)

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

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http://dx.doi.org/10.1111/jne.12386DOI Listing
April 2016

Vasopressin V1a, but not V1b, receptors within the PVN of lactating rats mediate maternal care and anxiety-related behaviour.

Behav Brain Res 2016 May 22;305:18-22. Epub 2016 Feb 22.

Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93053 Regensburg, Germany. Electronic address:

The brain neuropeptide arginine-vasopressin (AVP) mediates a wide range of social behaviours via its V1a (V1aR) but also its V1b receptor (V1bR). With respect to maternal behaviour, V1bR are still less investigated, whereas V1aR have been shown repeatedly to trigger maternal behaviour, depending on the brain region. Here, we aimed to study the role of both V1aR and V1bR within the hypothalamic paraventricular nucleus (PVN), a major source of AVP, in maternal care (lactation day (LD) 1), maternal motivation in the pup retrieval test (LD 3) and anxiety-related behaviour on the elevated plus maze (EPM; LD 5) by acute local infusion of receptor subtype-specific antagonists for V1aR (d(CH2)5Tyr(Me)(2)AVP) or V1bR (SSR149415). Furthermore, we compared V1bR expression in the PVN of virgin versus lactating rats (LD 4). Our results demonstrate that within the PVN neither V1bR mRNA (qPCR) nor protein (Western Blot) content differed between virgin and lactating rats. Regarding behaviour, acute antagonism of V1aR, but not of V1bR, decreased the occurrence of nursing as well as anxiety-related behaviour as reflected by higher percentage of time spent on and of entries into the open arms of the EPM. Maternal motivation was not affected by any treatment. In summary, we demonstrate subtype-specific involvement of V1 receptors within the PVN in mediating various maternal behaviours. The lack of effects after V1bR blockade reveals that AVP acts mainly via V1aR in the PVN, at least in lactating rats, to mediate maternal care and anxiety.
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http://dx.doi.org/10.1016/j.bbr.2016.02.020DOI Listing
May 2016

Antagonism of V1b receptors promotes maternal motivation to retrieve pups in the MPOA and impairs pup-directed behavior during maternal defense in the mpBNST of lactating rats.

Horm Behav 2016 Mar 30;79:18-27. Epub 2015 Dec 30.

Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93053 Regensburg, Germany. Electronic address:

Recent studies using V1b receptor (V1bR) knockout mice or central pharmacological manipulations in lactating rats highlighted the influence of this receptor for maternal behavior. However, its role in specific brain sites known to be important for maternal behavior has not been investigated to date. In the present study, we reveal that V1bR mRNA (qPCR) and protein levels (Western blot) within either the medial preoptic area (MPOA) or the medial-posterior part of the bed nucleus of the stria terminalis (mpBNST) did not differ between virgin and lactating rats. Furthermore, we characterized the effects of V1bR blockade via bilateral injections of the receptor subtype-specific antagonist SSR149415 within the MPOA or the mpBNST on maternal behavior (maternal care under non-stress and stress conditions, maternal motivation to retrieve pups in a novel environment, maternal aggression) and anxiety-related behavior in lactating rats. Blocking V1bR within the MPOA increased pup retrieval, whereas within the mpBNST it decreased pup-directed behavior, specifically licking/grooming the pups, during the maternal defense test. In addition, immediately after termination of the maternal defense test, V1bR antagonism in both brain regions reduced nursing, particularly arched back nursing. Anxiety-related behavior was not affected by V1bR antagonism in either brain region. In conclusion our data indicate that V1bR antagonism significantly modulates different aspects of maternal behavior in a brain region-dependent manner.
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http://dx.doi.org/10.1016/j.yhbeh.2015.12.003DOI Listing
March 2016

CRF-R1 activation in the anterior-dorsal BNST induces maternal neglect in lactating rats via an HPA axis-independent central mechanism.

Psychoneuroendocrinology 2016 Feb 26;64:89-98. Epub 2015 Nov 26.

Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93053 Regensburg, Germany. Electronic address:

Adequate maternal behavior in rats requires minimal corticotropin-releasing factor receptor (CRF-R) activation in the medial-posterior bed nucleus of the stria terminalis (mpBNST). Based on the architectural heterogeneity of the BNST and its distinct inter-neural connectivity, we tested whether CRF-R manipulation in another functional part, the anterior-dorsal BNST (adBNST), differentially modulates maternal behavior. We demonstrate that in the adBNST, activation of CRF-R1 reduced arched back nursing (ABN) and nursing, whereas activation of CRF-R2 resulted in an initial reduction in nursing but significantly increased the incidence of ABN 5h after the treatment. Following stressor exposure, which is detrimental to maternal care, ABN tended to be protected by CRF-R1 blockade. Maternal motivation, maternal aggression, and anxiety were unaffected by any manipulation. Furthermore, under basal and stress conditions, activation of adBNST CRF-R1 increased plasma ACTH and corticosterone concentrations, whereas stimulation of adBNST CRF-R2 increased basal plasma ACTH and corticosterone concentrations, but blocked the stress-induced increase in plasma corticosterone secretion. Moreover, both the CRF-R1 and -R2 antagonists prevented the stress-induced increase in plasma corticosterone secretion. Importantly, elevated levels of circulating corticosterone induced by intra-adBNST administration of CRF-R1 or -R2 agonist did not impact maternal care. Finally, Crf mRNA expression in the adBNST was increased during lactation; however, Crfr1 mRNA expression was similar between lactating and virgin rats. In conclusion, maternal care is impaired by adBNST CRF-R1 activation, and this appears to be the result of a central action, rather than an effect of elevated circulating levels of CORT. These data provide new insights into potential causes of disturbed maternal behavior postpartum.
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http://dx.doi.org/10.1016/j.psyneuen.2015.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712652PMC
February 2016

Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles.

Psychoneuroendocrinology 2016 Feb 23;64:66-78. Epub 2015 Nov 23.

Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA; Silvio O. Conte Center for Oxytocin and Social Cognition, Emory University, Atlanta, GA 30322, USA. Electronic address:

Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression.
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http://dx.doi.org/10.1016/j.psyneuen.2015.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698175PMC
February 2016

Salivary oxytocin concentrations in response to running, sexual self-stimulation, breastfeeding and the TSST: The Regensburg Oxytocin Challenge (ROC) study.

Psychoneuroendocrinology 2015 Dec 15;62:381-8. Epub 2015 Sep 15.

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

Intranasal oxytocin (OXT) application is emerging as a potential treatment for socio-emotional disorders associated with abnormalities in OXT system (re-) activity. The crucial identification of patients with such abnormalities could be streamlined by the assessment of basal and stimulus-induced OXT concentrations in saliva, using a simple, stress-free sampling procedure (i.e. an OXT challenge test). We therefore established the Regensburg Oxytocin Challenge (ROC) test to further validate salivary OXT concentrations as a practical, reliable and sensitive biomarker. OXT concentrations were quantified by radioimmunoassay in samples collected at home by healthy adult male and female volunteers before and after running ("Run") or sexual self-stimulation ("Sex"). In lactating women, salivary OXT concentrations were quantified before, during and after breastfeeding. Salivary OXT along with salivary cortisol and heart rate were monitored in healthy adult participants undergoing the Trier Social Stress Test (TSST). The home-based "Run" and "Sex" challenges as well as the laboratory-based TSST caused quantifiable, rapid, and consistent increases in salivary OXT (approximately 2.5-fold after 10-15min), which were similar for men and women. Breastfeeding did not result in measurably increased salivary OXT levels, probably because the short pulses of OXT release characteristic for lactation were missed. Taken together, ROC tests reliably assess the responsiveness of the OXT system (i.e., the increase in salivary OXT concentrations as compared to basal levels) to challenges such as "Run" and "Sex" at home or psychosocial stress (TSST) in the laboratory. Further studies with larger sample numbers are essentially needed in order to reveal individual differences in ROC test outcomes depending on, for example, genetic or environmental factors.
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http://dx.doi.org/10.1016/j.psyneuen.2015.08.027DOI Listing
December 2015

The 5th parental brain conference.

J Neuroendocrinol 2014 Oct;26(10):625-6

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

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http://dx.doi.org/10.1111/jne.12189DOI Listing
October 2014

Hypoactivation of CRF receptors, predominantly type 2, in the medial-posterior BNST is vital for adequate maternal behavior in lactating rats.

J Neurosci 2014 Jul;34(29):9665-76

Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93053 Regensburg, Germany, and

Maternal behavior ensures the proper development of the offspring. In lactating mammals, maternal behavior is impaired by stress, the physiological consequence of central corticotropin-releasing factor receptor (CRF-R) activation. However, which CRF-R subtype in which specific brain area(s) mediates this effect is unknown. Here we confirmed that an intracerebroventricularly injected nonselective CRF-R antagonist enhances, whereas an agonist impairs, maternal care. The agonist also prolonged the stress-induced decrease in nursing, reduced maternal aggression and increased anxiety-related behavior. Focusing on the bed nucleus of the stria terminalis (BNST), CRF-R1 and CRF-R2 mRNA expression did not differ in virgin versus lactating rats. However, CRF-R2 mRNA was more abundant in the posterior than in the medial BNST. Pharmacological manipulations within the medial-posterior BNST showed that both CRF-R1 and CRF-R2 agonists reduced arched back nursing (ABN) rapidly and after a delay, respectively. After stress, both antagonists prevented the stress-induced decrease in nursing, with the CRF-R2 antagonist actually increasing ABN. During the maternal defense test, maternal aggression was abolished by the CRF-R2, but not the CRF-R1, agonist. Anxiety-related behavior was increased by the CRF-R1 agonist and reduced by both antagonists. Both antagonists were also effective in virgin females but not in males, revealing a sexual dimorphism in the regulation of anxiety within the medial-posterior BNST. In conclusion, the detrimental effects of increased CRF-R activation on maternal behavior are mediated via CRF-R2 and, to a lesser extent, via CRF-R1 in the medial-posterior BNST in lactating rats. Moreover, both CRF-R1 and CRF-R2 regulate anxiety in females independently of their reproductive status.
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http://dx.doi.org/10.1523/JNEUROSCI.4220-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099544PMC
July 2014

Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence.

Authors:
Oliver J Bosch

Philos Trans R Soc Lond B Biol Sci 2013 28;368(1631):20130085. Epub 2013 Oct 28.

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

The most significant social behaviour of the lactating mother is maternal behaviour, which comprises maternal care and maternal aggression (MA). The latter is a protective behaviour of the mother serving to defend the offspring against a potentially dangerous intruder. The extent to which the mother shows aggressive behaviour depends on extrinsic and intrinsic factors, as we have learned from studies in laboratory rodents. Among the extrinsic factors are the pups' presence and age, as well as the intruders' sex and age. With respect to intrinsic factors, the mothers' innate anxiety and the prosocial brain neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) play important roles. While OXT is well known as a maternal neuropeptide, AVP has only recently been described in this context. The increased activities of these neuropeptides in lactation are the result of remarkable brain adaptations peripartum and are a prerequisite for the mother to become maternal. Consequently, OXT and AVP are significantly involved in mediating the fine-tuned regulation of MA depending on the brain regions. Importantly, both neuropeptides are also modulators of anxiety, which determines the extent of MA. This review provides a detailed overview of the role of OXT and AVP in MA and the link to anxiety.
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http://dx.doi.org/10.1098/rstb.2013.0085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826214PMC
June 2014

Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats.

Eur J Neurosci 2013 Sep 7;38(5):2742-50. Epub 2013 Jun 7.

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

The brain corticotropin-releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety-related behaviour or non-selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF-R) antagonist D-Phe to manipulate CRF-R1/2 non-specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation-specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D-Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D-Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF-R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour.
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http://dx.doi.org/10.1111/ejn.12274DOI Listing
September 2013

RGS2 mediates the anxiolytic effect of oxytocin.

Brain Res 2012 May 13;1453:26-33. Epub 2012 Mar 13.

Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

The neuropeptide oxytocin (OT) has been shown to exert multiple functions in both males and females, and to play a key role in the regulation of emotionality in the central nervous system (CNS). OT has an anxiolytic effect in the CNS of rodents and humans. However, the molecular mechanisms of this effect are unclear. Here we show that OT induced the expression of regulator of G-protein signaling 2 (RGS2), a regulatory factor for anxiety, in the central amygdala (CeA) of female mice. Bath application of OT increased RGS2 levels in slices of the amygdala of virgin mice. RGS2 levels in the CeA were higher in lactating mice than in virgin mice. In contrast, RGS2 levels in mice that had given birth did not increase when the pups were removed. Acute restraint stress for 4h induced RGS2 expression within the CeA, and local administration of an OT receptor antagonist inhibited this expression. Behavioral experiments revealed that transient restraint stress had an anxiolytic effect in wild-type females, and RGS2 levels in the CeA correlated with the anxiolytic behavior. By contrast, in the OT receptor-deficient mice, restraint stress neither increased RGS2 levels in the CeA nor had an anxiolytic effect. These results suggest that OT displays an anxiolytic effect through the induction of RGS2 expression in the CNS.
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http://dx.doi.org/10.1016/j.brainres.2012.03.012DOI Listing
May 2012
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