Abstract
Calcium-binding proteins are widely used to distinguish neuronal subsets in the brain. This study focuses on secretagogin, an EF-hand calcium sensor, to identify distinct neuronal populations in the brainstem of several vertebrate species. By using neural tube whole mounts of mouse embryos, we show that secretagogin is already expressed during the early ontogeny of brainstem noradrenaline cells. In adults, secretagogin-expressing neurons typically populate relay centres of special senses and vegetative regulatory centres of the medulla oblongata, pons and midbrain. Notably, secretagogin expression overlapped with the brainstem column of noradrenergic cell bodies, including the locus coeruleus (A6) and the A1, A5 and A7 fields. Secretagogin expression in avian, mouse, rat and human samples showed quasi-equivalent patterns, suggesting conservation throughout vertebrate phylogeny. We found reduced secretagogin expression in locus coeruleus from subjects with Alzheimer’s disease, and this reduction paralleled the loss of tyrosine hydroxylase, the enzyme rate limiting noradrenaline synthesis. Residual secretagogin immunoreactivity was confined to small submembrane domains associated with initial aberrant tau phosphorylation. In conclusion, we provide evidence that secretagogin is a useful marker to distinguish neuronal subsets in the brainstem, conserved throughout several species, and its altered expression may reflect cellular dysfunction of locus coeruleus neurons in Alzheimer’s disease.
Highlights
Our brainstem harbours a wealth of distinctly or ambiguously demarcated cell groups with various functions serving basic physiological needs
We suggest that altered secretagogin expression in locus coeruleus neurons is a clinicopathological sign of Alzheimer’s disease paralleling or even preceding tyrosine hydroxylase (TH) loss
The distribution pattern of immunoreactive cells was largely similar to what we found in rats: secretagogin+ neurons typically occurred in the microcellular tegmental nucleus (Fig. 6a–a1’’, d, d 1), nucleus of the solitary tract (6b, b1), the dorsal nucleus of vagus (Fig. 6c, c1), the noradrenergic fields, especially locus coeruleus (Fig. 6e), and the superior colliculus (Fig. 6f, f1)
Summary
Our brainstem harbours a wealth of distinctly or ambiguously demarcated cell groups with various functions serving basic physiological needs. Pathways of special senses have relay centres in the cranial brainstem: the superior colliculus. Cranial nerve nuclei of different modalities are arranged in logical mediolateral and craniocaudal orders, reaching from the caudal medulla oblongata to the cranial midbrain. These include stations of specific sensory pathways, like the cochlear and vestibular nuclei in the caudal pons, or complex vegetative centres, like the solitary tract nucleus in the medulla oblongata. Like the periaqueductal grey involved in behavioural responses to threatening stimuli (Faull et al 2019) and opioid modulation of pain (Martins and Tavares 2017), or the parabrachial nuclear complex controlling fluid and food homoeostasis, cardiovascular functions (Davern 2014) and body temperature (Morrison and Nakamura 2011) appear as independent nuclei in the brainstem. The nuclei and centres of these different systems (Fig. 1) are intertwined and may in the brainstem even overlap, which has made their identification and separation an ongoing challenge
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