Cell proliferation in the striatum during postnatal development: preferential distribution in subregions of the ventral striatum

Abstract

Cortico-ventral basal ganglia circuitry is associated with a variety of mental health disorders including obsessive-compulsive disorder and drug addiction, disorders that emerge during childhood through young adulthood, a period in which the cortex and striatum continue to development. Moreover, cell proliferation, which is associated with development and plasticity, also continues in the cortex and striatum through adulthood. Given the implication of cortico-basal ganglia circuitry in diseases emerging during postnatal development, we studied cell proliferation at different ages in striatal regions associated with specific frontal cortical areas. The results show cell proliferation throughout the striatum at all postnatal ages. The majority of the new cells were immunoreactive for NG2 chondroitin sulfate, a marker for specific progenitor cells, but not for NeuN, a neuronal marker. Although neurogenesis was not observed, approximately 30% of the new cells appeared to be paired with a neuron. There was a significantly higher degree of cell proliferation during the first postnatal year compared to other striatal regions. Finally, throughout the juvenile years, the ventral striatal areas receiving input from the ventral, medial prefrontal cortex and orbital prefrontal cortex have significantly more new cells compared to other striatal regions. Integrity of the ventral striatum is critical for the development of goal-directed behaviors. The high number of new cells in the ventral striatum during postnatal development may be particularly important for the refinement of the cortico-striatal network, and in the formation of neural ensembles fundamental to learning during behavioral development.

Figure 1

Schematic chartings and microphotographs of BrdU⁺ cells found to be in doublets and co-localized with NG2 in the striatum. a, b Distribution of BrdU⁺ cells found to be in doublets in an animal sacrificed 5 weeks (a) and 1 day (b) after BrdU injection in each of the four functionally defined striatal regions. Red=inputs from the vmPFC; orange=inputs from the OFC; yellow=inputs from the dorsal PFC; green=inputs from rostral motor control areas. Black dots indicate doublet pairs of BrdU⁺ cells. c. A series of microphotographs showing BrdU⁺ cells in double pairs. Scale bar, 25μm. d. Cell double labeled with BrdU and NG2 shown at successive z levels. Scale bar, 5.35 μm.

Figure 2

Photomicrographs of double-labeled immunofluorescence. a-c. BrdU⁺ cell associated with a neuron marked with NeuN. Scale bar, 10.064 μm. d. BrdU⁺ cell associated with a CaBP⁺ neuron. e. BrdU⁺ cell associated with a CR⁺ interneuron..

Figure 3

Schematic chartings and graphs demonstrating the change in total number of BrdU⁺ cells across development. a Mean total number of BrdU⁺ cells in animals for all age groups. Error bars indicate the SEM, n= 4 for 5 months, 1 year, 2 years, and 3 years age groups, n= 2 for the 12 years and 18 years age groups. b,c Chartings of BrdU⁺ cells in the striatum of a 5 months old animal (b) and a 2-year-old animal (c). d. Mean total number of BrdU⁺ cells in animals of the older age groups. Error bars indicate the SEM.

Figure 4

Functional distribution of total BrdU⁺ cells and BrdU⁺ cell density for animals in each age group. a. Mean percentage of total BrdU⁺ cells found in each of the four functionally defined striatal regions. Red=inputs from the vmPFC; orange=inputs from the OFC; yellow=inputs from the dorsal PFC; green=inputs from rostral motor control areas. Error bars indicate the SEM. b,c. 3-D models of BrdU⁺ cell density for a 5 month old (b) and a 2 years old animal (c). d. Mean BrdU⁺ cell density in each functional region of the striatum. Error bars indicate the SEM.