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Neuropeptides

Dr. Valery Grinevich

Dr. Valery Grinevich

German Cancer Research Center

Central Institute of Mental Health

Im Neuenheimer Feld 581

69120 Heidelberg, Germany

Email: v.grinevich@dkfz-heidelberg.de

 

We aim to study mechanisms of neuropeptide actions in the mammalian brain. 

 

During the last decade oxytocin (OXT) became arguably the most popular neuropeptide, as it orchestrates social behavior in animals and humans via enhancing trust and attenuating fear and stress response. Importantly, besides the fact that OXT is a “great facilitator of social life”, OXT is presently considered as an important factor of pathogenesis of human disorders, such as depression, schizophrenia and autism. Taking advantage of virus-based targeting of OXT neurons (Knobloch et al., Neuron, 2012), we presently addressing two critical open questions in the field: “ How do different subsets of OXT neurons synchronize OXT release in various brain regions?” and “How does OXT release within distinct brain regions affect behavior?”

Anatomical connectivity of OXT neurons

It is tempting to propose that there is anatomical and functional heterogeneity among the ~9000 OXT neurons in the rodent hypothalamus. Although OXT fibers were detected in all major parts of the forebrain, it is difficult to imagine that a single OXT neuron projects simultaneously to all. To reveal anatomical heterogeneity of the OXT neurons population we use viral-based antero- and retrograde tracing of their projections in the forebrain.           

Detecting “fear-sensitive” OXT neurons

In order to target activated OXT neurons we employ the genetic activity induced tagging of cell, operating by virally-delivered c-fos promoter, driving Cre recombinase in conjunction with Cre-dependent viral vectors expressing genes of interest (such as fluorescent markers and light-sensitive channels) under the OXT promoter (a collaboration with Dr. Mazahir T. Hasan, MPImF, Heidelberg).

Monitoring axonal OXT release within the forebrain

The selective expression of light-sensitive channels, such as the channelrhodopsin 2 (ChR2) in those OXT neurons, which “historically” expressed c-fos upon fear, is now allow us to perform an in vivo functional study by optogenetic means. We presently focus on axonal OXT release from “fear-sensitive” OXT cells in the brain of awake animals, subjected to Pavlovian fear conditioning (a collaboration with Drs. Alexander Charlet and Ron Stoop, Lausanne University). In conjunction with the behavioral study we combine optogenetics with fMRI to monitor the activity of brain circuits after local OXT release (a collaboration with Prof. Dr. Andreas Meyer-Lindenberg, ZI, Mannheim). Furthermore, ongoing co-application of optogenetics and microdialysis technique (a collaboration with Prof. Inga Neumann, Regensburg University) would allow us to probe an actual light-evoked axonal release of OXT in various brain regions.

Other genetically accessed types of hypothalamic neurons

Although our studying of the OXT system is dominating in our laboratory, we also exploring projects related to other hypothalamic neuropeptides and factors controlling the activity and neurogenesis of hypothalamic neurons.

First of all we presently work on the anatomy and function of the hypothalamic vasopressin (VP) system, which has a similar origin and morphological organization as the OXT system. Despite this similarity, VP exerts behavioral effects opposite to OXT (i.e., VP enhances anxiety and aggression). Virus-based specific targeting of VP neurons has opened the possibility for studies on effects of endogenous OXT and VP release in various behavioral paradigms.

We also achieved virus-based targeting of neurons expressing corticotropin-releasing hormone (CRH), which represent the central limb of the hypothalamic-pituitary-adrenal axis. The virus-mediated genetic access to CRH neurons allow us to manipulate – by virus mediated expression of shRNA – the genes, essential for the initiation and maintenance of CRH gene transcription and, hence, controlling the onset and decline of stress response (a collaboration with Dr. Greti Aguilera, NICHD, NIH).

In parallel, we conduct research on the central mechanisms of reproduction, employing new mouse line, conditionally expressing Cre recombinase in gonadotropin-releasing hormone (GnRH) neurons. GnRH neurons control the activity of the hypothalamic-pituitary-gonadal axis, which is potently inhibited by stress. Using our Cre-expressing transgenic mice, we now selectively and conditionally delete the genes of likely candidates in GnRH neurons to dissect molecular pathways of stress-induced suppression of the reproductive axis (a collaboration with Dr. Jan Deussing, MPIP, Munich, Germany).

And last but not least, we pursue the dissection of the role of hypothalamic miRNAs in the regulation of metabolic functions and the development of obesity (a collaboration with Prof. Günther Schütz, DKFZ, Heidelberg) as well as the contribution of select genes in adult hypothalamic neurogenesis (a collaboration with Dr. Haikun Liu, DKFZ, Heidelberg).

In conclusion, our research should primarily advance the basic knowledge on different aspects of neuropeptide action in the brain and the regulation of hypothalamic functions. Moreover, our results should lead to a better understanding of pathogenetic mechanisms of emotional, endocrine, metabolic and reproductive alterations in human patients.