Neuronal precursor cells with dopaminergic commitment in the rostral migratory stream of the mouse

Neuroblasts born in the subventricular zone of adult mammals migrate via the rostral migratory stream into the granular cell layer or periglomerular layer of the olfactory bulb to differentiate into interneurons. To analyze if new neurons in the granular cell layer or periglomerular layer have different origins, we inserted a physical barrier into the rostral migratory stream, depleted cell proliferation with cytarabine infusions, labeled newborn cells with bromodeoxyuridine, and sacrificed mice after short-term (0, 2, or 14 days) or long-term (55 or 105 days) intervals. After short-term survival, the subventricular zone and rostral migratory stream rapidly repopulated with bromodeoxyuridine+ cells after cytarabine-induced depletion. Nestin, glial fibrillary acidic protein and the PAX6 were expressed in bromodeoxyuridine+ cells within the rostral migratory stream downstream of the physical barrier. After long-term survival after physical barrier implantation, bromodeoxyuridine+ neurons were significantly reduced in the granular cell layer, but bromodeoxyuridine+ and dopaminergic neurons in the periglomerular layer remained unaffected by the physical barrier. Thus, newborn neurons for the granular cell layer are mainly recruited from neural stem cells located in the subventricular zone, but new neurons for the periglomerular layer with dopaminergic predisposition can rise as well from neuronal stem or precursor cells in the rostral migratory stream.

The Effects of Vascular Cognitive Impairment on the Thickness of the Granular Cell Layer of the Dentate Gyrus within the Hippocampus in a Mouse Model

Vascular Cognitive Impairment (VCI) is a form of dementia, most prevalent after Alzheimer’s Disease. However, VCI remains the second leading cause for dementia because it restricts blood flow to the brain and there are currently no treatments. There has been a positive correlation between VCI and hippocampal atrophy reported. Diet such as deficiencies in folic acid, is a modifiable risk factor for neurodegeneration. In the present study, a mouse model of VCI was combined with a deficiency in folic acid to assess hippocampal morphology. Animals were split into 4 experimental groups where they were placed into a control diet (CD) or folic acid deficient diet (FADD), and later these animals either had microcoils implanted around their common carotid arteries to model VCI or a sham, control surgery. For hippocampal morphological analysis, the thickness of the granular cell layer of the dentate gyrus within the hippocampus was measured. It was hypothesized that a mouse model of VCI with microcoil treatment and reduced levels of folic acid would reduce blood flow, and increase cell death resulting in a reduced thickness of the granular cell layer within the dentate gyrus of the hippocampus. Our results show that thickness had an increasing trend in the in the FADD microcoil group. These data suggest that there may be an additional factor coming into play such as compensation by neural stem cells that needs to be further researched.

Distinct Pattern of Microgliosis in the Olfactory Bulb of Neurodegenerative Proteinopathies

The olfactory bulb (OB) shows early neuropathological hallmarks in numerous neurodegenerative diseases, for example, in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The glomerular and granular cell layer of the OB is characterized by preserved cellular plasticity in the adult brain. In turn, alterations of this cellular plasticity are related to neuroinflammation such as microglia activation, implicated in the pathogenesis of AD and PD, as well as frontotemporal lobe degeneration (FTLD). To determine microglia proliferation and activation we analyzed ionized calcium binding adaptor molecule 1 (Iba1) expressing microglia in the glomerular and granular cell layer, and the olfactory tract of the OB from patients with AD, PD dementia/dementia with Lewy bodies (PDD/DLB), and FTLD compared to age-matched controls. The number of Iba1 and CD68 positive microglia associated with enlarged amoeboid microglia was increased particularly in AD, to a lesser extent in FTLD and PDD/DLB as well, while the proportion of proliferating microglia was not altered. In addition, cells expressing the immature neuronal marker polysialylated neural cell adhesion molecule (PSA-NCAM) were increased in the glomerular layer of PDD/DLB and FTLD cases only. These findings provide novel and detailed insights into differential levels of microglia activation in the OB of neurodegenerative diseases.

Characterization of NADPH Diaphorase- and Doublecortin-Positive Neurons in the Lizard Hippocampal Formation

The lizard cortex has remarkable similarities with the mammalian hippocampus. Both regions process memories, have similar cytoarchitectural properties, and are important neurogenic foci in adults. Lizards show striking levels of widespread neurogenesis in adulthood and can regenerate entire cortical areas after injury. Nitric oxide (NO) is an important regulatory factor of mammalian neurogenesis and hippocampal function. However, little is known about its role in nonmammalian neurogenesis. Here, we analyzed the distribution, morphology, and dendritic complexity (Neurolucida reconstructions) of NO-producing neurons through NADPH diaphorase (NADPHd) activity, and how they compare with the distribution of doublecortin-positive (DCX+) neurons in the hippocampal formation of the neotropical lizard Tropidurus hispidus. NADPHd-positive (NADPHd+) neurons in the dorsomedial cortex (DMC; putatively homologous to mammalian CA3) were more numerous and complex than the ones in the medial cortex (MC; putatively homologous to the dentate gyrus). We found that NADPHd+ DMC neurons send long projections into the MC. Interestingly, in the MC, NADPHd+ neurons existed in 2 patterns: small somata with low intensity of staining in the outer layer and large somata with high intensity of staining in the deep layer, a pattern similar to the mammalian cortex. Additionally, NADPHd+ neurons were absent in the granular cell layer of the MC. In contrast, DCX+ neurons were scarce in the DMC but highly numerous in the MC, particularly in the granular cell layer. We hypothesize that NO-producing neurons in the DMC provide important input to proliferating/migrating neurons in the highly neurogenic MC.

Immunohistochemical Analysis of GDNF and Its Cognate Receptor GFRα-1 Protein Expression in Vitiliginous Skin Lesions

Background: Vitiligo is an idiopathic skin disease, characterized by circumscribed white macules or patches on the skin due to loss of the functional melanocytes. Glial cell line–derived neurotrophic factor (GDNF) and its cognate receptor (GFRα-1) are distal members of the transforming growth factor-β superfamily. GDNF, produced by the basal cell keratinocytes, is involved in the migration and differentiation of the melanocytes from the neural crest to the epidermis. This study examines the hypothesis that expression of GDNF protein and its cognate receptor GFRα-1 protein is altered in vitiliginous skin. Patients and Methods: To test our hypothesis, we examined the expression patterns of these proteins in vitiliginous and corresponding healthy (control) skin biopsies (20 specimens each) using immunoperoxidase staining techniques. Results: We found variations between the vitiliginous skin and healthy skin. In healthy skin, the expression of GDNF and GFRα-1 proteins was strong (basal cell keratinocytes and melanocytes), moderate (spinous layer), and weak (granular cell layer). In contrast, weak expression of GDNF protein was observed in all epidermal layers of vitiliginous skin. GFRα-1 protein expression was strong (basal cell keratinocytes and melanocytes), moderate (spinous layer), and weak (granular cell layer). In both healthy skin and vitiliginous skin, the expression of GDNF and GFRα-1 proteins was strong in the adnexal structures. Conclusions: We report, for the first time, decreased expression of GDNF proteins in the epidermal keratinocytes of vitiliginous skin. Our findings suggest possible pathogenetic roles for these proteins in the development of vitiligo. The clinical ramifications of these observations mandate further investigations.