Shades of gray in human white matter

Abstract

Anatomists have long expressed interest in neurons of the white matter, which is by definition supposed to be free of neurons. Hypotheses regarding their biochemical signature and physiological function are mainly derived from animal models. Here, we investigated 15 whole‐brain human postmortem specimens, including cognitively normal cases and those with pathologic Alzheimer's disease (AD). Quantitative and qualitative methods were used to investigate differences in neuronal size and density, and the relationship between neuronal processes and vasculature. Double staining was used to evaluate colocalization of neurochemicals. Two topographically distinct populations of neurons emerged: one appearing to arise from developmental subplate neurons and the other embedded within deep, subcortical white matter. Both populations appeared to be neurochemically heterogeneous, showing positive reactivity to acetylcholinesterase (AChE) [but not choline acetyltransferase (ChAT)], neuronal nuclei (NeuN), nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPH‐d), microtubule‐associated protein 2 (MAP–2), somatostatin (SOM), nonphosphorylated neurofilament protein (SMI‐32), and calcium‐binding proteins calbindin‐D28K (CB), calretinin (CRT), and parvalbumin (PV). PV was more richly expressed in superficial as opposed to deep white matter neurons (WMNs); subplate neurons were also significantly larger than their deeper counterparts. NADPH‐d, a surrogate for nitric oxide synthase, allowed for the striking morphological visualization of subcortical WMNs. NADPH‐d‐positive subcortical neurons tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. The presence of AChE positivity in these neurons, but not ChAT, suggests that they are cholinoceptive but noncholinergic. WMNs were also significantly smaller in AD compared to control cases. These observations provide a landscape for future systematic investigations.

Neuropeptide FF (NPFF)-positive nerve cells of the human cerebral cortex and white matter in controls, selected neurodegenerative diseases, and schizophrenia

“…3 ). Nonetheless, apart from the fact that approximately 68% of the NPFF cells were somatostatin-positive and displayed the same morphologies as cortical interneurons (bipolar, multipolar), they were, in contrast to the findings reported by others for WMIC in non-human primates and humans, calretinin- as well as calbindin- and parvalbumin-negative [ 20 , 24 , 75 – 78 , 83 , 94 ]. Thus, based on their morphology and topographical distribution, we conclude that the NPFF-positive neurons are neither classical short-axoned interneurons nor long-axoned projection neurons.…”

“…In conclusion, we can now add the neuropeptide NPFF to the pool of markers available for studying the distribution, morphology, and neurochemistry of WMIC, which are characterized by enormous neurochemical heterogeneity: glutamatergic, but mostly GABAergic predominate, but there are also subpopulations displaying acetylcholinesterase, nicotinamide-adenine dinucleotide phosphate diaphorase (NADPH), MAP2, somatostatin, calbindin-D28K, calretinin, and parvalbumin [ 13 , 21 , 24 , 33 , 41 , 42 , 45 , 47 , 54 , 75 , 94 ]. The observed density and the partial overlap between somatostatin-positive and nNOS-positive WMIC (but not between calretinin-positive or calbindin-positive WMIC) and wNPFF cells suggests that NPFF-positive neurons could overlap with previously identified WMIC subpopulations.…”

“…However, reports also indicate that superficial WMIC and their late-myelinating axons may be implicated in the pathophysiology and pathogenesis of neurological, neurodevelopmental, and neuropsychiatric disorders, such as Alzheimer’s disease, Huntington’s disease, schizophrenia, bipolar disease, autism spectrum disorder, and epilepsy [ 1 – 4 , 16 , 17 , 22 , 23 , 32 , 37 , 43 , 45 , 47 , 56 , 65 , 66 , 70 , 85 , 89 ]. Up to now, both their neurochemical heterogeneity [ 94 ] and the lack of a reliable marker with high staining efficiency in human autopsy tissue have made it difficult to obtain a more comprehensive understanding of WMIC morphology, distribution, and involvement across the spectrum of neurodegenerative diseases.…”