A dense cluster of D1 + cells in the mouse nucleus accumbens.

The striatum is known to be largely composed of intermingled medium-sized projection neurons expressing either the D1 or the D2 dopamine receptors. In the present study, we took advantage of the double BAC Drd1a-TdTomato/Drd2-GFP (D1 /D2 ) transgenic mice to reveal the presence of a peculiar cluster of densely-packed D1 + cells located in the shell compartment of the nucleus accumbens. This spherical cluster has a diameter of 110 µm and is exclusively composed by D1 + cells, which are all immunoreactive for the neuronal nuclear marker (NeuN). However, in contrast to other D1 + or D2 + striatal cells, those that form the accumbens cluster are devoid of calbindin (CB) and DARPP-32, two faithful markers for striatal projection neurons. Using GAD-GFP transgenic mice, we confirm the GABAergic nature of the D1 + clustered neurons. Intracellular injections from fixed brain slices indicate that these neurons are endowed with distinctive morphological features, including a small (5-6 µm), round cell body giving rise to a single primary dendrite that branches into two secondary processes. Single-neuronal injections combined to electron microscopy reveal the existence of GAP junctions linking these D1 + cells. Based on their location, morphological characteristics and neurochemical phenotype, we conclude that the D1 + accumbens cluster form a highly compact group of small neurons distinct from the larger and more diffusely distributed D1 + or D2 + striatal projection neurons that surround it. This remarkable nucleus might play a crucial role in the limbic function of the murine striatum.

The number of striatal cholinergic interneurons expressing calretinin is increased in parkinsonian monkeys.

The most abundant interneurons in the primate striatum are those expressing the calcium-binding protein calretinin (CR). The present immunohistochemical study provides detailed assessments of their morphological traits, number, and topographical distribution in normal monkeys (Macaca fascicularis) and in monkeys rendered parkinsonian (PD) by MPTP intoxication. In primates, the CR+ striatal interneurons comprise small (8-12µm), medium (12-20µm) and large-sized (20-45µm) neurons, each with distinctive morphologies. The small CR+ neurons were 2-3 times more abundant than the medium-sized CR+ neurons, which were 20-40 times more numerous than the large CR+ neurons. In normal and PD monkeys, the density of small and medium-sized CR+ neurons was twice as high in the caudate nucleus than in the putamen, whereas the inverse occurred for the large CR+ neurons. Double immunostaining experiments revealed that only the large-sized CR+ neurons expressed choline acetyltransferase (ChAT). The number of large CR+ neurons was found to increase markedly (4-12 times) along the entire anteroposterior extent of both the caudate nucleus and putamen of PD monkeys compared to controls. Comparison of the number of large CR-/ChAT+ and CR+/ChAT+ neurons together with experiments involving the use of bromo-deoxyuridine (BrdU) as a marker of newly generated cells showed that it is the expression of CR by the large ChAT+ striatal interneurons, and not their absolute number, that is increased in the dopamine-depleted striatum. These findings reveal the modulatory role of dopamine in the phenotypic expression of the large cholinergic striatal neurons, which are known to play a crucial role in PD pathophysiology.

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease.

Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.

Distribution and morphological characteristics of striatal interneurons expressing calretinin in mice: a comparison with human and nonhuman primates.

Striatal interneurons display a morphological and chemical heterogeneity that has been particularly well characterized in rats, monkeys and humans. By comparison much less is known of striatal interneurons in mice, although these animals are now widely used as transgenic models of various neurodegenerative diseases. The present immunohistochemical study aimed at characterizing striatal interneurons expressing calretinin (CR) in mice compared to those in squirrel monkeys and humans. The mouse striatum contains both small (9-12 µm) and medium-sized (15-20 µm) CR+ cells. The small cells are intensely stained with a single, slightly varicose and moderately arborized process. They occur throughout the striatum (77±9 cells/mm(3)), but prevail in the area of the subventricular zone and subcallosal streak, with statistically significant anteroposterior and dorsoventral decreasing gradients. The medium-sized cells are less intensely immunoreactive and possess 2-3 long, slightly varicose and poorly branched dendrites. They are rather uniformly scattered throughout the striatum and three times more numerous (224±31 cells/mm(3)) than the smaller CR+ cells. Double immunostaining experiments with choline acetyltransferase (ChAT) as a cholinergic marker in normal and Drd1a-tdTomato/Drd2-EGFP double transgenic mice reveal that none of the small or medium-sized CR+ cells express ChAT or D1 and D2 dopamine receptors. In contrast, the striatum in human and nonhuman primates harbors small and medium-sized CR+/ChAT- cells, as well as large CR+/ChAT+ interneurons that are absent in mice. Such a difference between rodents and primates must be taken into consideration if one hopes to better understand the striatal function in normal and pathological conditions.