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  1. Free, publicly-accessible full text available July 1, 2023
  2. About one in 3,500 people have a genetic disorder called neurofibromatosis type 1, often shortened to NF1, making it one of the most common inherited diseases. People with NF1 may have benign and cancerous tumors throughout the body, learning disabilities, developmental delays, curvature of the spine and bone abnormalities. Children with NF1 often experience difficulties with attention, hyperactivity, speech and language delays and impulsivity. They may also have autism spectrum disorder, or display symptoms associated with this condition. Studies in mice with a genetic mutation that mimics NF1 suggest that abnormal development in cells in the middle of the brain may cause the cognitive symptoms. These midbrain neurons produce a chemical called dopamine and send it throughout the brain. Dopamine is essential for concentration and it is involved in how the brain processes pleasurable experiences. Now, Robinson et al. show that, at rest, the NF1 model mice release dopamine less often than typical mice. This happens because, when there are no stimuli to respond to, neighboring cells slow down the activity of dopamine-producing neurons in NF1 model mice. In the experiments, both NF1 model mice and typical mice were taught to associate environmental cues with rewards or punishments. Robinson etmore »al. then measured the release of dopamine in the mice using a sensor called dLight1, which produces different intensities of fluorescent light depending on the amount of dopamine present. This revealed that the NF1 model mice produced more dopamine in response to visual cues and had enhanced behavioral responses to these stimuli. For example, when a looming disc that mimics predators approached them from above, the NF1 model mice tried to hide in an exaggerated way compared to the typical mice. Previously, it had been shown that this type of behavior is due to the activity of the dopamine-producing neurons' neighboring cells, which Robinson et al. found is greater in NF1 model mice. Next, Robinson et al. stopped neighboring cells from interfering with the dopamine-producing neurons in NF1 model mice. This restored dopamine release to normal levels at rest, and stopped the mice from overreacting to the looming disc. The experiments help explain how the NF1 model mice process visual information. Further study of the role dopamine plays in cognitive symptoms in people with NF1 may help scientists develop treatments for the condition.« less
  3. The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopamine receptor (D2R) modulation. Inhibiting the ISR inverted the sign of D2R modulation of CIN firing and evoked dopamine release and altered skill learning. Thus, a noncanonical, steady-state mode of ISR activation is found in CINs, revealing a neuromodulatory role for the ISR in learning.