The role of midbrain mTOR signaling in hyperactivity and impulsivity

The mechanistic target of rapamycin (mTOR) is a serine/threonine-protein kinase that regulates cell growth, proliferation, and synaptic plasticity. Dysfunction in mTOR signaling has been implicated in several neurological disorders, including seizures, autism, and attention deficit hyperactivity disorder. However, there is limited understanding of how abnormal mTOR signaling in specific cell types leads to neuropsychiatric and behavioral disorders. The mTOR controls protein synthesis by sensing nutrient and energy levels. Midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) have large somata and widespread axonal arborizations rich in mitochondria. Their high energy demands make dopamine neurons highly sensitive to the status of mTOR signaling. To investigate the role of mTOR signaling in midbrain dopamine neurons, we generated dopamine neuron-specific mTOR conditional knockout (mTOR-cKO) mice by crossing mTOR-floxed mice with DAT-Cre mice. We made the serendipitous discovery that mTOR-cKO mice exhibited a pronounced increase in basal locomotor activity in an open field compared with that of wild-type mice, and a low dose of the stimulant amphetamine increased locomotor activity in wildtype mice but produced a paradoxical calming effect on locomotor activity in mTOR-cKO mice. In addition, mTOR-cKO mice exhibited impulsive behavior and attention deficits. Although mTOR-cKO mice share a striking resemblance to the distinct behavioral endophenotypes of hyperactivity, impulsivity, and inattention, this proposal does not seek to create a mouse model of a human neurodevelopmental illness. Instead, the long-term goal of this application is to investigate cellular and circuit mechanisms underlying the hyperactive and impulsive behavioral phenotypes. Three Specific Aims are proposed. In Aim I, we will examine how mTOR-cKO alters dopamine neuron physiology. In Aim II, we will investigate the mechanisms that underlie differential locomotor responses to amphetamine between the two genotypes. In Aim III, we will investigate the molecular and circuit mechanisms underlying impulsive behavior and attention deficits in mTOR-cKO mice. Together, these studies will elucidate mechanisms that govern hyperactive and impulsive behavior and provide novel insight into the role of mTOR signaling in regulating the function of dopamine neurons. Project Number: 1R01MH140483-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Qing-song Liu (+1 co-PI) | Institution: MEDICAL COLLEGE OF WISCONSIN, MILWAUKEE, WI | Award Amount: $521,266 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 ICN-L (94)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11319259