Development of hypothalamic dopaminergic neurons and their role in anxiety-like behaviour in mice

Maja Zupančič (2019) Development of hypothalamic dopaminergic neurons and their role in anxiety-like behaviour in mice. MSc thesis.

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Abstract

Anxiety by itself serves as an adaptive and necessary response to threat. However, when it becomes disproportionate and persistent, it may lead to development of anxiety disorders. The lifetime prevalence of anxiety disorders is as high as 28% in adults, which makes them one of the most common psychiatric ailments. Anxiety disorders have both biological and environmental basis, however their complete pathology is so far still not explored. Due to the anatomical similarities and comparable behavioural responses, anxiety-like behaviour and its underlying mechanisms are often studied using animal models, most often rodents. Subcortical brain areas, including the hypothalamus and amygdala, as well as neurotransmitter systems involved in anxiety, are in mice and humans highly similar. Previous research done on transgenic animals and dopamine related diseases has linked dopaminergic signalling as one of the neurotransmitter systems implicated in anxiety-like behaviour. Single cell transcriptome data of the hypothalamic area in the juvenile mouse revealed a novel subgroup of dopaminergic neurons (“PeVNd” neurons), located in the periventricular nucleus of the hypothalamus. They are also present in the periventricular nucleus of the adult human brain. Their axonal projections terminate, among other regions, in the amygdala, thus their involvement in anxiety-like behaviour is considered. The aims of this thesis are to investigate the presence and location of hypothalamic “PeVNd” neurons in embryonic mouse and human fetal tissue, determine their birth place and furthermore explore their involvement in anxiety. Using in utero electroporation technique, performed on mouse embryos, we were able to fluorescently label a subpopulation of hypothalamic progenitors, lining the wall of the third ventricle. Due to methodological limitations the electroporation was limited to the dorsal part of the hypothalamus, thus we were at this point unable to confirm this hypothalamic neurogenic niche as the birth place of “PeVNd” neurons. We performed immunohistochemistry on mouse tissue of different developmental stages to investigate the presence and location of “PeVNd” neurons. By tracing their migratory routes from very early embryonic time-point to neonatal stages, we show that these neurons are in the mouse brain present already at embryonic day 9.5-10.5, and are by embryonic day 14.5 confined to the periventricular space of the hypothalamus. So far, with our initial experiments we were not able to confirm the presence of “PeVNd” neurons during human fetal development. We need to perform further experiment and, if possible, obtain additional samples. Due to the time limitations, we were so far not able to investigate the role of “PeVNd” neurons in relation to anxiety. We were only able to test a methodologically similar experimental design, of which we show our preliminary results. After establishing this technique, we will use it for future experiments involving in vivo manipulation of “PeVNd” neurons.

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