Projections and interconnections of genetically defined serotonin neurons in mice

Abstract

Brain serotonin neurons are heterogeneous and can be distinguished by several anatomical and physiological characteristics. Toward resolving this heterogeneity into classes of functional relevance, subtypes of mature serotonin neurons were previously identified based on gene expression differences initiated during development in different rhombomeric (r) segments of the hindbrain. This redefinition of mature serotonin neuron subtypes based on the criteria of genetic lineage, along with the enabling genetic fate mapping tools, now allows various functional properties, such as axonal projections, to be allocated onto these identified subtypes. Furthermore, our approach uniquely enables interconnections between the different serotonin neuron subtypes to be determined; this is especially relevant because serotonin neuron activity is regulated by several feedback mechanisms. We used intersectional and subtractive genetic fate mapping tools to generate three independent lines of mice in which serotonin neurons arising in different rhombomeric segments, either r1, r2 or both r3 and r5, were uniquely distinguished from all other serotonin neurons by their expression of enhanced green fluorescent protein. Each of these subgroups of serotonergic neurons had a unique combination of forebrain projection targets. Typically more than one subgroup innervated an individual target area. Unique patterns of interconnections between the different groups of serotonin neurons were also observed and these pathways could subserve feedback regulatory circuits. Overall, the current findings suggest that activation of subsets of serotonin neurons could result in topographic serotonin release in the forebrain coupled with feedback inhibition of serotonin neurons with alternative projection targets.

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

“…We directly tested this by measuring the electrophysiological properties of the serotonergic raphe neurons in both the lateral wings (lwDR) and ventromedial (vmDR) aspect of the dorsal raphe in WT and KD animals as adults. We examined both of these subfields, because we previously found differences in their cell parameters (Crawford et al, 2010) and because they are known to have different projections, with the vmDR sending axons to forebrain structures such as the amygdala, medial prefrontal cortex, and caudate-putamen (Bang et al, 2012;Lowry et al, 2008;Michelsen et al, 2008), whereas the lwDR projects to sympathomimetic nuclei (Hale and Lowry, 2011;Johnson et al, 2004). We found that post-natal knockdown of receptors led to long-lasting changes in several of the membrane characteristics of the neurons, the sum of which resulted in increased cell excitability ( Figure 5).…”

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

“…The largest population of relaxin-3 expressing neurons is located within the tegmental area known as the nucleus incertus (NI), and these neurons project broadly throughout the brain [15][16][17][18][19]. The neuroanatomy of the relaxin-3/RXFP3 system suggests a broad role as an ascending neuromodulatory network [20,21], akin to the monoamine systems including serotonin, and noradrenaline [22][23][24][25]. Anatomical and functional data [15][16][17][18] suggest that relaxin-3/RXFP3 systems may interact directly with monoamine [19,26] and other peptide systems [27][28][29], and/or act at shared downstream limbic and hypothalamic target areas to modulate 'anxiety' and other stress-related responses [30][31][32][33][34].…”

Expanding the power of recombinase-based labeling to uncover cellular diversity

“…Only those cells that have expressed both recombinases will express the marker encoded by the indicator allele. Additionally, some indicator alleles encode a second marker designed to label the subtractive population (Awatramani et al, 2003;Bang et al, 2012;Farago et al, 2006;Jensen et al, 2008;Yamamoto et al, 2009). The subtractive population consists of the balance of cells defined by one of the gene expression domains, minus the intersectional population (Farago et al, 2006).…”