The Corticotropin-Releasing Factor system in lactating rats: implications in the regulation of maternal behavior with special focus on the BNST

Item type:	Thesis of the University of Regensburg (PhD)
Open Access Type:	Primary Publication
Date:	26 February 2015
Referee:	PD Dr. Oliver Bosch
Date of exam:	12 February 2015
Institutions:	Biology, Preclinical Medicine > Institut für Zoologie > Tierphysiologie/Neurobiologie (Prof. Dr. Inga Neumann)
Keywords:	maternal behavior, CRF, Urocortin, BNST, lactation, rat
Dewey Decimal Classification:	500 Science > 590 Zoological sciences
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	31369

Abstract (English)

The survival of the offspring strongly depends on the adequate expression of maternal behavior. Any dysregulations during the peripartum period can easily result in behavioral or physiological maladaptations that are detrimental to the offspring as well as to the mother herself. One factor, potentially contributing to dysregulations peripartum, is the corticotropin-releasing factor (CRF) system, ...

Abstract (English)

The survival of the offspring strongly depends on the adequate expression of maternal behavior. Any dysregulations during the peripartum period can easily result in behavioral or physiological maladaptations that are detrimental to the offspring as well as to the mother herself. One factor, potentially contributing to dysregulations peripartum, is the corticotropin-releasing factor (CRF) system, which triggers nearly every behavioral and physiological response to stress. Given that the behavioral role of the CRF system during lactation is still under-investigated I aimed to characterize its implications in the regulation of maternal behavior in lactating rats. Therefore, I used a variety of methods including in situ hybridization, ELISA, repeated intravenous blood sampling, and central or local acute pharmacological manipulation of CRF receptors (CRF-R) or the CRF binding protein (CRF-BP) followed by various behavioral tests. For local manipulation, I focused on the bed nucleus of the stria terminalis (BNST) given its role in maternal behavior and its abundant expression of most members of the CRF family.
In the present thesis, I showed that the CRF system needs to be down-regulated postpartum given that central and local activation of CRF-R in the BNST impaired maternal care and maternal aggression, increased anxiety-related behavior but had no effect on maternal motivation. Importantly, the effects of CRF-R activation differed specifically in the various subdivisions of the BNST depending on the CRF-R subtype. In the mpBNST, predominantly CRF-R2 activation reduced maternal care and maternal aggression while both CRF-R1 and CRF-R2 mediated anxiety-related behavior. In the adBNST, CRF-R manipulation solely affected maternal care; CRF-R1 activation reduced maternal care while CRF-R2 stimulation reduced nursing but increased arched back nursing in a time-dependent manner. These behavioral changes following specific CRF-R manipulation in the adBNST might be indirectly mediated via activation of the hypothalamo-pituitary-adrenal axis. Interestingly, I could demonstrate that the CRF-BP, which appears to sequester extracellular CRF / urocortin 1 and inhibit their binding to the CRF-R, has emerged as potent regulator of the required down-regulation of CRF-R activity as well as of maternal aggression, especially in the mpBNST.
In conclusion, both central and local activation of CRF-R in the BNST are detrimental to the appearance of maternal behavior in lactating rats. Therefore, CRF-R activation needs to be down-regulated postpartum, which is partly achieved and supported by altered expression patterns of CRF-R and its ligands as well as by the CRF-BP. This well balanced interplay of the CRF family members is essential to enable the mother showing adequate maternal behavior and, thus, to increase her fitness.

Translation of the abstract (German)

Eine erfolgreiche Reproduktion hängt sehr von der adäquaten Expression mütterlichen Verhaltens ab. Jegliche Art von Dysregulationen in der peripartalen Phase kann schwerwiegende Folgen für Mutter und Nachkommen haben. Ein wichtiger Faktor, der in eine solche Dysregulation involviert sein könnte, ist das Corticotropin-Releasing Factor (CRF) System, welches der Hauptregulator der Stressantwort ist. ...

Translation of the abstract (German)

Eine erfolgreiche Reproduktion hängt sehr von der adäquaten Expression mütterlichen Verhaltens ab. Jegliche Art von Dysregulationen in der peripartalen Phase kann schwerwiegende Folgen für Mutter und Nachkommen haben. Ein wichtiger Faktor, der in eine solche Dysregulation involviert sein könnte, ist das Corticotropin-Releasing Factor (CRF) System, welches der Hauptregulator der Stressantwort ist. In meiner Dissertation habe ich die bisher wenig untersuchte Rolle des CRF Systems in der Regulation mütterlichen Verhaltens in laktierenden Ratten untersucht. Hierbei habe ich mich hauptsächlich auf den Bed Nucleus der Stria Terminalis (BNST) konzentriert.
Ich konnte zeigen, dass das CRF System sowohl zentral als auch im BNST während der Laktation stark herunter reguliert sein muss, um adäquates mütterliches Verhalten zu gewährleisten. Im anterior-dorsalen Teil des BNST wurden CRF-R1 und im medial-posterioren Teil des BNST CRF-R2 als maßgebliche Rezeptoren in der Regulation mütterlichen Verhaltens charakterisiert. Um eine Hypo-Aktivierung dieser Rezeptoren zu garantieren, spielt das CRF Bindeprotein eine wichtige Rolle.
Zusammenfassend konnte ich zeigen, dass sowohl eine zentrale als auch lokale Aktivierung der CRF Rezeptoren im BNST schlecht für das adäquate Auftreten mütterlichen Verhaltens in laktierenden Ratten ist, weswegen eine reduzierte Aktivierung der Rezeptoren während der Laktation unabdingbar ist. Solche eine Hypo-Aktivierung kann teilweise durch unterschiedliche Expressionsmuster der CRF Familienmitglieder oder auch durch das CRF Bindeprotein erreicht werden. Dieses gut balancierte Zwischenspiel der CRF Familienmitglieder ist essentiell für das Wohlergehen von Mutter und Kind in der peripartalen Phase.

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