Abstract
Motor learning depends on synaptic plasticity between corticostriatal projections and striatal medium spiny neurons. Retrograde tracing from the dorsolateral striatum reveals that both layer II/III and V neurons in the motor cortex express BDNF as a potential regulator of plasticity in corticostriatal projections in male and female mice. The number of these BDNF-expressing cortical neurons and levels of BDNF protein are highest in juvenile mice when adult motor patterns are shaped, while BDNF levels in the adult are low. When mice are trained by physical exercise in the adult, BDNF expression in motor cortex is reinduced, especially in layer II/III projection neurons. Reduced expression of cortical BDNF in 3-month-old mice results in impaired motor learning while space memory is preserved. These findings suggest that activity regulates BDNF expression differentially in layers II/III and V striatal afferents from motor cortex and that cortical BDNF is essential for motor learning.
SIGNIFICANCE STATEMENT Motor learning in mice depends on corticostriatal BDNF supply, and regulation of BDNF expression during motor learning is highest in corticostriatal projection neurons in cortical layer II/III.
Figure 7.
BDNF is enriched in glutamatergic corticostriatal presynaptic terminals. A, Confocal (top) and SIM (bottom) microscopic images showing BDNF-IR in the same section in glutamatergic (left) versus dopaminergic terminals (right) in the dorsal striatum. B, BDNF-IR is present in VGluT1-positive terminals (magenta arrows). Single BDNF-IR signals overlap with TH (white arrows). VGluT1- and TH-positive terminals reside in direct regional proximity but do not overlap. C, Quantification of BDNF signals in VGluT1-positive terminals and TH-positive terminals. True colocalization between BDNF/VGluT1 was confirmed by Costes p value (Costes p > 0.95) but not between BDNF/TH (Costes p ≪ 0.95). D, Representative Western blots showing recombinant BDNF (lanes 1, 2) versus endogenous BDNF derived from anterior cortex or striatum of P21 NFL-Cre BDNFfl/ko mice (lane 3), P21 sedentary mice (lanes 4, 5), and P21 runners after 72 h voluntary running-wheel exercise (lanes 6, 7); 30 µg of protein lysate was loaded for each sample. BDNF levels were normalized to cytochrome C. Band intensities were determined from extracts of 9 independent mice and presented in % of P21 sedentary mice. Statistical analysis reveals significant increase in BDNF protein levels in both brain areas after running-wheel exercise. Statistical analysis: unpaired t test (anterior CTX: t = 5,312, p < 0.0001; striatum: t = 2,784, p = 0.0133). E, SIM images showing BDNF-IR in VGluT1-positive terminals in the dorsal striatum in sedentary mice (top row) and after 72 h of voluntary running-wheel exercise (bottom row). Data are presented as box and whiskers (Tukey). +, Mean. Vertical line indicates median. Black dots indicate outliers. n, number indicated below. Raw data are provided in Extended Data Figure 7-1 and Table 2. Scale bars: A, 2.5 µm; B, 1.5 µm; E, Overview, 2 µm; Detail, 1 µm. *p < 0.05; ****p < 0.0001.
