mTOR Attenuation with Rapamycin Reverses Neurovascular Uncoupling and Memory Deficits in Mice Modeling Alzheimer's Diseasea

• Published in: The Journal of neuroscience Vol. 41; no. 19; p. 4305
• Main Authors: Van Skike, Candice E, Hussong, Stacy A, Hernandez, Stephen F, Banh, Andy Q, DeRosa, Nicholas, Galvan, Veronica
• Format: Journal Article
• Language: English
• Published: Baltimore Society for Neuroscience 12.05.2021
• Subjects: Addictions; Alzheimer's disease; Attention deficit hyperactivity disorder; Attenuation; Bipolar disorder; Cognition; Cortex (temporal); Dopamine; Dopamine receptors; Impulsive behavior; Impulsivity; Innervation; Intertrial interval; Mental disorders; Neurodegenerative diseases; Nucleus accumbens; Prefrontal cortex; Rapamycin; Reaction time; Reaction time task; Schizophrenia; Stimulation; TOR protein; Ventral tegmentum
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2144-20.2021

Deficits in impulse control and attention are prominent in the symptomatology of mental disorders such as attention deficit hyperactivity disorder (ADHD), substance addiction, schizophrenia, and bipolar disorder, yet the underlying mechanisms are incompletely understood. Frontostriatal structures, such as the nucleus accumbens (NAcb), the medial prefrontal cortex (mPFC), and their dopaminergic innervation from the ventral tegmental area (VTA) have been implicated in impulse control and attention. What remains unclear is how the temporal pattern of activity of these VTA projections contributes to these processes. Here, we optogenetically stimulated VTA dopamine (DA) cells, as well as VTA projections to the NAcb core (NAcbC), NAcb shell (NAcbS), and the mPFC in male rats performing the 5-choice serial reaction time task (5-CSRTT). Our data show that stimulation of VTA DA neurons, and VTA projections to the NAcbC and the mPFC immediately before presentation of the stimulus cue, impaired attention but spared impulse control. Importantly, in addition to reducing attention, activation of VTA-NAcbS also increased impulsivity when tested under a longer intertrial interval (ITI), to provoke impulsive behavior. Optogenetic stimulation at the beginning of the ITI only partially replicated these effects. In sum, our data show how attention and impulsivity are modulated by neuronal activity in distinct ascending output pathways from the VTA in a temporally specific manner. These findings increase our understanding of the intricate mechanisms by which mesocorticolimbic circuits contribute to cognition.