Biology subjects

Johns, T.

Publications and source records attributed to Johns, T..

2 recordsLinked to original sources

bioRxiv2020

Cortico-subthalamic projections send brief stop signals to halt visually-guided locomotion

Goal-directed locomotion requires control signals that propagate from higher-order areas to regulate spinal mechanisms. The cortico-subthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task where head-fixed mice run to a visual landmark then stop and wait to collect reward, and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our modeled behavioral strategy indicates a switching point in behavior or a sudden change from running to stopping, suggesting a critical neuronal control signal at stop locations. Optogenetic activation of M2 axons in STN leads the animal to stop prematurely. By imaging M2 neurons projecting to STN, we find neurons that are active at the onset of stops when executed at the landmark but not when executed spontaneously elsewhere. Our results suggest that the M2-STN pathway can be recruited during visually-guided locomotion to rapidly and precisely control the mesencephalic locomotor region (MLR) through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, MLR and STN, we find that the cortico-subthalamic projections potentially control MLR activity by differentiating an M2 error signal to ensure fast input-output dynamics.

neuroscience↗

bioRxiv2017

PI3K Activation In Neural Stem Cells Drives Tumorigenesis Which Can Be Suppressed By Targeting CREB

Hyperactivation of the PI3K signaling is common in human cancers, including gliomas, but the precise role of the pathway in glioma biology remains to be determined. Some limited understanding of PI3K signaling in brain cancer come from studies on neural stem/progenitor cells (NSPCs) where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate NSPC proliferation. To investigate the role for the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a Pik3caH1047A oncogenic mutation and simultaneous deletion of the PI3K negative regulator, Pten, in NSPCs. We show that the expression of a Pik3caH1047A was sufficient to initiate tumorigenesis but that simultaneous loss of Pten, was required for the development of invasive, high-grade glioma. Mutant NSPCs exhibited enhanced neurosphere forming capacity which correlated with increased Wnt signaling. We also show that loss of CREB in Pik3ca-PTEN tumors led to a longer symptom-free survival in mice. Taken together, our findings present a novel mouse model for high-grade glioma with which we demonstrate that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.

cancer biology↗