Decision letter for "Laminar distribution of cortical projection neurons to the pulvinar: A comparative study in cats and mice"

The cortical projection to the subcortical pathway underlying the optokinetic reflex was studied using antidromic electrical stimulation in the midbrain structures nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system (NOT-DTN) while simultaneously recording from cortical neurons in the superior temporal sulcus (STS) of macaque monkeys. Projection neurons were found in all subregions of the middle temporal area (MT) as well as in the medial superior temporal area (MST). Antidromic latencies ranged from 0.9 to 6 ms with a median of 1.8 ms. There was a strong bias in the population of cortical neurons projecting to the NOT-DTN for ipsiversive stimulus movement (towards the recording side), whereas in the population of cortical neurons not projecting to the NOT-DTN a more or less equal distribution of stimulus directions was evident. Our data indicate that there is no special area in the posterior STS coding for ipsiversive horizontal stimulus movement. Instead, a specific selection of cortical neurons from areas MT and MST forms the projection to the NOT-DTN and as a subpopulation has the same directional bias as their subcortical target neurons. These findings are discussed in relation to the functional grouping of cortical output as an organizational principle for specific motor responses.

Download Full-text

Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01088-0 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Yongchao Mou ◽

Yi Dong ◽

Zhenyu Chen ◽

Kyle R. Denton ◽

Michael O. Duff ◽

...

Keyword(s):

Axonal Transport ◽

Lipid Droplet ◽

Axonal Degeneration ◽

Cholesterol Homeostasis ◽

Projection Neurons ◽

Missense Mutations ◽

Cortical Projection ◽

Hereditary Spastic Paraplegias ◽

Cholesterol Levels ◽

Lipid Droplet Size

AbstractHereditary spastic paraplegias (HSPs) are caused by a length-dependent axonopathy of long corticospinal neurons, but how axons of these cortical projection neurons (PNs) degenerate remains elusive. We generated isogenic human pluripotent stem cell (hPSC) lines for two ATL1 missense mutations associated with SPG3A, the most common early-onset autosomal dominant HSP. In hPSC-derived cortical PNs, ATL1 mutations resulted in reduced axonal outgrowth, impaired axonal transport, and accumulated axonal swellings, recapitulating disease-specific phenotypes. Importantly, ATL1 mutations dysregulated proteolipid gene expression, reduced lipid droplet size in astrocytes, and unexpectedly disrupted cholesterol transfer from glia to neurons, leading to cholesterol deficiency in SPG3A cortical PNs. Applying cholesterol or conditioned medium from control astrocytes, a major source of cholesterol in the brain, rescued aberrant axonal transport and swellings in SPG3A cortical PNs. Furthermore, treatment with the NR1H2 agonist GW3965 corrected lipid droplet defects in SPG3A astrocytes and promoted cholesterol efflux from astrocytes, leading to restoration of cholesterol levels and rescue of axonal degeneration in SPG3A cortical PNs. These results reveal a non-cell autonomous mechanism underlying axonal degeneration of cortical PNs mediated by impaired cholesterol homeostasis in glia.

Download Full-text

Single-cell genomics identifies cell type–specific molecular changes in autism

Science ◽

10.1126/science.aav8130 ◽

2019 ◽

Vol 364 (6441) ◽

pp. 685-689 ◽

Cited By ~ 134

Author(s):

Dmitry Velmeshev ◽

Lucas Schirmer ◽

Diane Jung ◽

Maximilian Haeussler ◽

Yonatan Perez ◽

...

Keyword(s):

Cell Types ◽

Molecular State ◽

Clinical Severity ◽

Projection Neurons ◽

Specific Cell ◽

Cortical Projection ◽

Molecular Changes ◽

Single Nucleus ◽

Gene Expression Studies ◽

Transcriptomic Changes

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

Download Full-text

Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson’s disease

Human Molecular Genetics ◽

10.1093/hmg/ddaa039 ◽

2020 ◽

Vol 29 (7) ◽

pp. 1180-1191

Author(s):

Razvan-Marius Brazdis ◽

Julian E Alecu ◽

Daniel Marsch ◽

Annika Dahms ◽

Katrin Simmnacher ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Brain Region ◽

Neuronal Death ◽

Dopaminergic Neurons ◽

Control Individual ◽

Projection Neurons ◽

Cortical Projection ◽

Human Ipscs

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.

Download Full-text