Abstract
Central noradrenergic neurons, collectively defined by synthesis of the neurotransmitter norepinephrine, are a diverse collection of cells in the hindbrain, differing in their anatomy, physiological and behavioral functions, and susceptibility to disease and environmental insult. To investigate the developmental basis of this heterogeneity, we have used an intersectional genetic fate mapping strategy in mice to study the dorsoventral origins of the En1-derived locus coeruleus (LC) complex which encompasses virtually all of the anatomically defined LC proper, as well as a portion of the A7 and subcoeruleus (SubC) noradrenergic nuclei. We show that the noradrenergic neurons of the LC complex originate in two different territories of the En1 expression domain in the embryonic hindbrain. Consistent with prior studies, we confirm that the majority of the LC proper arises from the alar plate, the dorsal domain of the neural tube, as defined by expression of Pax7Cre. In addition, our analysis shows that a large proportion of the En1-derived A7 and SubC nuclei also originate in the Pax7Cre-defined alar plate. Surprisingly, however, we identify a smaller subpopulation of the LC complex that arises from outside the Pax7Cre expression domain. We characterize the distribution of these neurons within the LC complex, their cell morphology, and their axonal projection pattern. Compared to the broader LC complex, the newly identified Pax7Cre-negative noradrenergic subpopulation has very sparse projections to thalamic nuclei, suggestive of distinct functions. This developmental genetic analysis opens new avenues of investigation into the functional diversity of the LC complex.
Highlights
Defined by their synthesis of the neurotransmitter norepinephrine, central noradrenergic neurons are heterogeneous
Using intersectional genetic fate-mapping, we have previously shown that noradrenergic neurons derived from the En1 expression domain of the embryonic hindbrain populate 99.8% of the locus coeruleus (LC) and a portion of the dorsal subcoeruleus and A7 nuclei (Robertson et al, 2013) according to an adult mouse brain atlas (Paxinos and Franklin, 2013)
To determine if all noradrenergic neurons of the LC complex originate from the alar plate, we employed a recombinase-based intersectional and subtractive genetic fate mapping strategy that allows labeled neurons to be mapped into the adult brain (Jensen and Dymecki, 2014)
Summary
Defined by their synthesis of the neurotransmitter norepinephrine, central noradrenergic neurons are heterogeneous. The organization of central noradrenergic neurons was initially defined over fifty years ago by their rostrocaudal position in the adult brainstem (Dahlström and Fuxe, 1964) This mature anatomical organization is still the primary means by which the noradrenergic system is studied, but evidence of heterogeneity within anatomically defined noradrenergic nuclei indicates that other approaches will be required to fully explain functional diversity. An alternative strategy for understanding this heterogeneity is the study of genetic neuroanatomy, correlating gene expression with brain structure and function (Joyner and Sudarov, 2012) To this end, we have recently used a recombinase-mediated intersectional genetic fate mapping approach to subdivide the mature noradrenergic system based on gene expression differences along the anteroposterior axis of the embryonic hindbrain (Robertson et al, 2013, 2016). A dorsal subpopulation is derived from the Fgf8Cre expression domain encompassing r0, and by inference, the remaining ventral subpopulation is derived from r1
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