Molecular and functional neuroanatomy of mood disorder circuits

Sammanfattning: The ability to interpret and react to external stimuli is essential for survival. An organism has to be able to predict a favorable outcome, and, more importantly, a non-favorable one that could mean danger for life. The mammalian brain has developed a number of strategies to interpret external stimuli, to learn the value of a stimulus and to make decisions that promote wellbeing. The underlying neuronal networks are intricate and require numerous interactions in order to provide adequate flow of information. Consequently, slight imbalances in these networks can have disastrous results. In humans, for example, imbalances in monoaminergic neurotransmission can lead to the development of affective disorders like depression and anxiety or brain disorders like schizophrenia, Parkinson’s disease or addiction. The neurons involved in these mechanisms are being researched extensively, using a plethora of state of the art methods that examine neuronal activity, connectivity and precise action during behavior, just to name a few. The above-mentioned diseases are fairly common in the global population, a fact that shows how crucial it is to understand the underlying mechanisms and to develop adequate treatment. The aim of this thesis is to describe the molecular and neuroanatomical properties of neural circuits involved in reward and punishment prediction and decisionmaking. In chapter 1, I will describe the monoaminergic systems in the mouse brain, mainly focusing on the serotonergic and dopaminergic systems and their involvement in behavior and mood disorders. Chapter 2 reviews classical and current literature on the neural circuits that regulate reward and aversion, with the main focus on the basal ganglia, the habenular complex and the lateral hypothalamic area. Chapter 3 will describe the methodology used to research these circuits on which this thesis is based. More specifically, I will focus on the emergence of big scale single-cell (and single-nuclei) RNA sequencing and in situ hybridization techniques and data analysis. In paper 1, we examined the role of the lateral habenula in aversive behavior and the underlying network connections. A main focus lies on the glutamatergic projections from the lateral hypothalamic area that regulate lateral-habenula activity in fear and avoidance behavior. Molecular distinctions between glutamatergic neurons from neighboring Globus pallidus interna and lateral hypothalamus facilitate the identification of input to the LHb in aversive behavioral tasks. In paper 2, we identified spatial, striosomal and cell-type specific molecular properties of the mouse striatum. We were able to show molecular distinctions between patch, exopatch and matrix SPNs in the striatum. In addition, we reveal a new spatial map of the striatum and identified a unique SPN type that is independent of this aforementioned spatial code, direct or indirect pathway, or patch/exopatch/matrix characterizations. In paper 3, we show a molecular map of the entire span of the mouse brain with specific emphasis on the spatial distribution of gene expression. This map combines RNA-sequencing with spatial information using spatial transcriptomics. In paper 4, we used a novel two-virus retrograde tracing approach that enabled us to tag the nuclei of neurons sending monosynaptic projections. This allowed us to show the molecular composition of habenula and lateral hypothalamus neurons that directly target serotonergic neurons in the dorsal raphe nucleus and dopaminergic neurons in the ventral tegmental area. To conclude, genetic targeting of specific neurons is a valuable tool to unravel the exact function of a network. The studies included in this thesis provide new insight into the molecular and neuroanatomical properties of brain circuits involved in behavior. This allows for the identification of possible new genetic targets for behavioral research and ultimately, better understanding of underlying mechanisms.