Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function

Abstract Impaired cortical maturation is a postulated mechanism in the etiology of neurodevelopmental disorders, including schizophrenia. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. Whether thalamic activity also shapes prefrontal cortical maturation is unknown. Here, we show that inhibiting the midline thalamus during adolescence leads to a long-lasting decrease in thalamo-prefrontal projection density and cortical excitation. Adolescent thalamic inhibition also causes prefrontal-dependent cognitive deficits during adulthood that are associated with disrupted prefrontal cross-correlations and task outcome encoding. In contrast, thalamic inhibition during adulthood has no long-lasting consequences. Strikingly, exciting the thalamus in adulthood during a cognitive task rescues prefrontal cross-correlations, task outcome encoding, and cognitive deficits. These data point to adolescence as a sensitive window of thalamo-cortical circuit maturation. Furthermore, by supporting prefrontal network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders.