A hierarchical hormonal cascade along the hypothalamic‐pituitary‐adrenal axis orchestrates bodily responses to stress. Although corticotropin‐releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single‐cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH‐releasing neuron population reliant on secretagogin9s Ca²⁺ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin9s loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness. Synopsis Bodily responses to acute stress are orchestrated by the hierarchical release of stress hormones along the hypothalamic‐pituitary‐adrenal axis. Corticotropin‐releasing hormone (CRH)‐secreting neurons in the paraventricular nucleus of the hypothalamus are first order neurons in this axis, priming subsequent hormonal cascades upon CRH release into the portal circulation at the median eminence. Secretagogin is identified as the first neuronal Ca²⁺ sensor localized to parvocellular systems. The transcriptome landscape of a novel hypothalamic neuron subtype, which contains secretagogin as Ca²⁺ sensor, is shown. Secretagogin9s Ca²⁺‐dependent protein interactome minimally required for regulated CRH release is defined. Secretagogin is recognized to rate‐limit CRH release, thus limiting hormonal responses to stress.

The dense neuropil of the central nervous system leaves only limited space for extracellular substances free. The advent of immunohistochemistry, soon followed by advanced diagnostic tools, enabled us to explore the biochemical heterogeneity and compartmentalization of the brain extracellular matrix in exploratory and clinical research alike. The composition of the extracellular matrix is critical to shape neuronal function; changes in its assembly trigger or reflect brain/spinal cord malfunction. In this study, we focus on extracellular matrix changes in neurodegenerative disorders. We summarize its phenotypic appearance and biochemical characteristics, as well as the major enzymes which regulate and remodel matrix establishment in disease. The specifically built basement membrane of the central nervous system, perineuronal nets and perisynaptic axonal coats can protect neurons from toxic agents, and biochemical analysis revealed how the individual glycosaminoglycan and proteoglycan components interact with these molecules. Depending on the site, type and progress of the disease, select matrix components can either proactively trigger the formation of disease-specific harmful products, or reactively accumulate, likely to reduce tissue breakdown and neuronal loss. We review the diagnostic use and the increasing importance of medical screening of extracellular matrix components, especially enzymes, which informs us about disease status and, better yet, allows us to forecast illness.

Stress‐induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin‐releasing hormone‐releasing neurons innervate ependymal cells of the 3 ^rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal‐regulated kinase 1 and tyrosine hydroxylase with the Ca ²⁺ ‐sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress‐induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate‐limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long‐lasting cortical excitability following acute stress.

The rostral migratory stream (RMS) is viewed as a glia-enriched conduit of forward-migrating neuroblasts in which chemorepulsive signals control the pace of forward migration. Here we demonstrate the existence of a scaffold of neurons that receive synaptic inputs within the rat, mouse, and human fetal RMS equivalents. These neurons express secretagogin, a Ca²⁺-sensor protein, to execute an annexin V-dependent externalization of matrix metalloprotease-2 (MMP-2) for reconfiguring the extracellular matrix locally. Mouse genetics combined with pharmacological probing in vivo and in vitro demonstrate that MMP-2 externalization occurs on demand and that its loss slows neuroblast migration. Loss of function is particularly remarkable upon injury to the olfactory bulb. Cumulatively, we identify a signaling cascade that provokes structural remodeling of the RMS through recruitment of MMP-2 by a previously unrecognized neuronal constituent. Given the life-long presence of secretagogin-containing neurons in human, this mechanism might be exploited for therapeutic benefit in rescue strategies. Significance Persisting proliferative capacity and regeneration in the adult brain are confined to a minority of regions. In the murine brain, the olfactory system is supplied by thousands of newly born neuroblasts daily to support sensory plasticity. Here, we reveal a neuronal scaffold that resides within and alongside this migratory route [termed the “rostral migratory stream” (RMS)] to guide forward migration of newly born neuroblasts. These neurons can externalize the enzyme matrix metalloprotease-2 to loosen the extracellular matrix, thus producing permissive corridors for migrating neuroblasts. This mechanism is likely phylogenetically conserved because it exists in the RMS equivalent in human fetal brains. This inducible mechanism might be pharmacologically targeted for therapeutic benefit.

Composition of the brain extracellular matrix changes in time as maturation proceeds. Chondroitin sulfate proteoglycan 5 (CSPG-5), also known as neuroglycan C, has been previously associated to differentiation since it shapes neurite growth and synapse forming. Here, we show that this proteoglycan persists in the postnatal rat brain, and its expression is higher in cortical regions with plastic properties, including hippocampus and the medial prefrontal cortex at the end of the second postnatal week. Progressively accumulating after birth, CSPG-5 typically concentrates around glutamatergic and GABAergic terminals in twelve-week old rat hippocampus. CSPG-5-containing perisynaptic matrix rings often appear at the peripheral margin of perineuronal nets. Electron microscopy and analysis of synaptosomal fraction showed that CSPG-5 accumulates around, and is associated to synapses, respectively. In vitro analyses suggest that neurons, but less so astrocytes, express CSPG-5 in rat primary neocortical cultures, and CSPG-5 produced by transfected neuroblastoma cells appear at endings and contact points of neurites. In human subjects, CSPG-5 expression shifts in brain areas of the default mode network of suicide victims, which may reflect an impact in the pathogenesis of psychiatric diseases or support diagnostic power.

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.