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Inhibition of miR-132 impairs extinction of social fear in mice: Possible involvement in oxytocin receptor signalling
S12
References
P.1.012 Inhibition of miR-132 impairs extinction of social fear in mice: Possible involvement in oxytocin receptor signalling
followed by Bonferroni post hoc analysis). Moreover, we observed a post-extinction increase in miR-132 (by trend; p= 0.067; two way ANOVA followed by Bonferroni post hoc analysis) and miR-124 (p =0.001; two way ANOVA followed by Bonferroni) expression levels in SFC- animals. However, in SFC + mice a significant increase of miR-124, but not miR132 (vs. SFC- mice without extinction training; p= 0.03; separate students t-test) was found. In line, pre-acquisition (48h) inhibition of miR-132 in the LS via a locked nucleic acid lead to impaired extinction of social fear in SFC+ compared to scrambled control infused SFC + mice (po0.05; two way ANOVA for repeated measures followed by LSD post hoc analysis). During recall of social fear extinction no significant differences between inhibitor and scrambled infusions of SFC- and SFC + mice, respectively were found (two way ANOVA for repeated measures). These data reveal a possible functional role of miR-124 in the regulation of social fear extinction that still needs further investigation. Moreover, our data implicate miR-132 to be functionally involved in the extinction of social fear, since its inhibition lead to impaired extinction of SFC induced social fear. Taken together, we conclude that miR-132 may underlie the social fear reversing effect of OXT. However, further investigation of expression patterns of possible miR132 target mRNAs and proteins in the LS have to be performed to decipher a molecular pathway of OXT induced reversal of social fear.
A. Bludaun,1, R. Menon1, G. Meister2, I.D. Neumann1
Disclosure statement
1
Department for Molecular and Behavioural Neuroscience, University of Regensburg, Regensburg, Germany
Supported by DFG (Ne465, GRK2174).
2
References
[1] Brown, A.S., Derkits, E.J., 2009. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167(3), 261-280. [2] Chang, H., Li, L., Li, M., Xiao, X., 2016. Rare and common variants at 16p11. 2 are associated with schizophrenia. Schizophrenia research. [3] Mondelli, V., Vernon, A.C., Turkheimer, F., Dazzan, P., Pariante, C.M., 2017. Brain microglia in psychiatric disorders. The Lancet Psychiatry. [4] Winchester, C.L., Ohzeki, H., Vouyiouklis, D.A., Thompson, R., Penninger, J.M., Yamagami, K., Norrie, J.D., Hunter, R., Pratt, J.A., Morris, B.J., 2012. Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. Human molecular genetics 21(22), 4910-4921. [5] Nagamoto-Combs, K., Kulas, J., Combs, C.K., 2014. A novel cell line from spontaneously immortalized murine microglia. Journal of neuroscience methods 233, 187-198. http://dx.doi.org/10.1016/j.euroneuro.2017.12.029
Department for Biochemistry I, University of Regensburg, Regensburg, Germany Neuronal microRNAs are important post-transcriptional regulators of gene expression. For example, miR-132 plays a major role in neuronal plasticity and development, suggesting its crucial function in the regulation of various genes associated with anxiety disorders. Another example is miR124, which is known to regulate social behaviour in mice and humans via AMPA receptor subunit expression [1]. Recently, we developed a social fear conditioning (SFC) paradigm, a mouse model that resembles social anxiety disorder in humans. Here, the prosocial neuropeptide oxytocin (OXT) has been shown to reverse social fear when administered intracerebroventricularly (icv) or local into the lateral septum (LS) of male mice. Additionally, OXT is released within the LS during extinction training in unconditioned mice [2]. Moreover, we showed recently that icv OXT leads to an increased miR-132 level within the paraventricular nucleus of the rat hypothalamus in a sex-independent manner, suggesting a possible involvement of this particular microRNA in OXT receptor (OXTR) signalling. Since the underlying molecular mechanisms of OXTR signalling in the context of its social fear reversing properties are not well studied, we examined the involvement of microRNAs in extinction of SFC induced social fear in male mice. 90 min after acquisition of SFC, miR-132 and miR-124 levels in the LS of conditioned (SFC +) mice are elevated compared to unconditioned (SFC-) mice (both po0.01; two way ANOVA
[1] Gascon, E., Lync,h K., Ruan, H., Almeida, S., Verheyden, J.M., Seeley, W.W., Dickson, D.W., Petrucelli, L., Sun, D., Jiao, J., Zhou, H., Jakovcevski, M., Akbarian, S., Yao, W., Gao, F., 2014. Alterations in microRNA-124 and AMPA receptors contribute to social behavioural deficits in frontotemporal dementia. Nature Medicine, 20(12), 1444-1451. [2] Zoicas, I., Slattery, D.A., Neumann, I.D., 2014. Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum. Neuropsychopharmacology, 39 (13), 3027-3035. http://dx.doi.org/10.1016/j.euroneuro.2017.12.030
P.1.013 Optical and pharmacological activation of TrkB receptors in parvalbumin interneurons induces plasticity in the adult visual cortex F. Winkeln, G. Didio, M. Pou Llach, A. Steinzeig, J. Umemori, E. Castrén Helsinki University, Neuroscience Center, Helsinki, Finland Brain network plasticity occurs principally during critical periods in early postnatal life [1]. Chronic treatment with the antidepressant fluoxetine, however, can induce critical
References
P.1.012 Inhibition of miR-132 impairs extinction of social fear in mice: Possible involvement in oxytocin receptor signalling
followed by Bonferroni post hoc analysis). Moreover, we observed a post-extinction increase in miR-132 (by trend; p= 0.067; two way ANOVA followed by Bonferroni post hoc analysis) and miR-124 (p =0.001; two way ANOVA followed by Bonferroni) expression levels in SFC- animals. However, in SFC + mice a significant increase of miR-124, but not miR132 (vs. SFC- mice without extinction training; p= 0.03; separate students t-test) was found. In line, pre-acquisition (48h) inhibition of miR-132 in the LS via a locked nucleic acid lead to impaired extinction of social fear in SFC+ compared to scrambled control infused SFC + mice (po0.05; two way ANOVA for repeated measures followed by LSD post hoc analysis). During recall of social fear extinction no significant differences between inhibitor and scrambled infusions of SFC- and SFC + mice, respectively were found (two way ANOVA for repeated measures). These data reveal a possible functional role of miR-124 in the regulation of social fear extinction that still needs further investigation. Moreover, our data implicate miR-132 to be functionally involved in the extinction of social fear, since its inhibition lead to impaired extinction of SFC induced social fear. Taken together, we conclude that miR-132 may underlie the social fear reversing effect of OXT. However, further investigation of expression patterns of possible miR132 target mRNAs and proteins in the LS have to be performed to decipher a molecular pathway of OXT induced reversal of social fear.
A. Bludaun,1, R. Menon1, G. Meister2, I.D. Neumann1
Disclosure statement
1
Department for Molecular and Behavioural Neuroscience, University of Regensburg, Regensburg, Germany
Supported by DFG (Ne465, GRK2174).
2
References
[1] Brown, A.S., Derkits, E.J., 2009. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167(3), 261-280. [2] Chang, H., Li, L., Li, M., Xiao, X., 2016. Rare and common variants at 16p11. 2 are associated with schizophrenia. Schizophrenia research. [3] Mondelli, V., Vernon, A.C., Turkheimer, F., Dazzan, P., Pariante, C.M., 2017. Brain microglia in psychiatric disorders. The Lancet Psychiatry. [4] Winchester, C.L., Ohzeki, H., Vouyiouklis, D.A., Thompson, R., Penninger, J.M., Yamagami, K., Norrie, J.D., Hunter, R., Pratt, J.A., Morris, B.J., 2012. Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. Human molecular genetics 21(22), 4910-4921. [5] Nagamoto-Combs, K., Kulas, J., Combs, C.K., 2014. A novel cell line from spontaneously immortalized murine microglia. Journal of neuroscience methods 233, 187-198. http://dx.doi.org/10.1016/j.euroneuro.2017.12.029
Department for Biochemistry I, University of Regensburg, Regensburg, Germany Neuronal microRNAs are important post-transcriptional regulators of gene expression. For example, miR-132 plays a major role in neuronal plasticity and development, suggesting its crucial function in the regulation of various genes associated with anxiety disorders. Another example is miR124, which is known to regulate social behaviour in mice and humans via AMPA receptor subunit expression [1]. Recently, we developed a social fear conditioning (SFC) paradigm, a mouse model that resembles social anxiety disorder in humans. Here, the prosocial neuropeptide oxytocin (OXT) has been shown to reverse social fear when administered intracerebroventricularly (icv) or local into the lateral septum (LS) of male mice. Additionally, OXT is released within the LS during extinction training in unconditioned mice [2]. Moreover, we showed recently that icv OXT leads to an increased miR-132 level within the paraventricular nucleus of the rat hypothalamus in a sex-independent manner, suggesting a possible involvement of this particular microRNA in OXT receptor (OXTR) signalling. Since the underlying molecular mechanisms of OXTR signalling in the context of its social fear reversing properties are not well studied, we examined the involvement of microRNAs in extinction of SFC induced social fear in male mice. 90 min after acquisition of SFC, miR-132 and miR-124 levels in the LS of conditioned (SFC +) mice are elevated compared to unconditioned (SFC-) mice (both po0.01; two way ANOVA
[1] Gascon, E., Lync,h K., Ruan, H., Almeida, S., Verheyden, J.M., Seeley, W.W., Dickson, D.W., Petrucelli, L., Sun, D., Jiao, J., Zhou, H., Jakovcevski, M., Akbarian, S., Yao, W., Gao, F., 2014. Alterations in microRNA-124 and AMPA receptors contribute to social behavioural deficits in frontotemporal dementia. Nature Medicine, 20(12), 1444-1451. [2] Zoicas, I., Slattery, D.A., Neumann, I.D., 2014. Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum. Neuropsychopharmacology, 39 (13), 3027-3035. http://dx.doi.org/10.1016/j.euroneuro.2017.12.030
P.1.013 Optical and pharmacological activation of TrkB receptors in parvalbumin interneurons induces plasticity in the adult visual cortex F. Winkeln, G. Didio, M. Pou Llach, A. Steinzeig, J. Umemori, E. Castrén Helsinki University, Neuroscience Center, Helsinki, Finland Brain network plasticity occurs principally during critical periods in early postnatal life [1]. Chronic treatment with the antidepressant fluoxetine, however, can induce critical