Activation of the supramammillary-dentate gyrus circuit enhances alertness and cognitive function in a rat model of ADHD

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, with growing evidence suggesting hypoalertness as a contributing factor to its associated cognitive impairments. Despite promising results from behavioral interventions employing external stimuli to improve cognitive function, the underlying neural mechanisms remain inadequately understood. Here, we identify the supramammillary nucleus (SuM) as a critical neural substrate involved in modulating alertness and cognitive deficits associated with ADHD. We show that hypoactivity of SuM neurons correlates with reduced alertness and impaired recognition using a rat ADHD model. We further demonstrate that SuM neurons influence recognition through projections to the dentate gyrus (DG), primarily by facilitating long-term depression (LTD) within this pathway. Importantly, chemogenetic and optogenetic activation of the SuM-DG circuit resulted in significant enhancement of alertness and restoration of cognitive performance in ADHD rats, aligning their cognitive function with that of control animals. These findings elucidate a pivotal role for the SuM-DG pathway in mediating cognitive deficits related to hypoalertness in ADHD, offering mechanistic insights into the efficacy of alertness-enhancing interventions and highlighting novel therapeutic targets for ADHD treatment.