Thursday, April 25, 2024
4/25/2024
Adolescence is a window of vulnerability for the development of schizophrenia and other mental disorders. In schizophrenia, imaging studies have found that thalamo-prefrontal resting state connectivity is reduced during adolescence prior to disease onset. This decrease in functional connectivity has been linked to cognitive symptoms and the etiology of the disorder. For many years, an altered maturation of the prefrontal cortex (PFC) has been implicated in the cognitive deficits of mental disorders yet the mechanisms that drive PFC maturation are largely unknown. Because thalamic input activity is important for circuit maturation in sensory cortices, we hypothesize here that thalamic input activity is also important for prefrontal circuit maturation. To address whether adolescence is a sensitive time-period during which thalamic activity regulates the maturation of PFC circuitry, we used mice and compared the effects of reducing activity in the thalamic nuclei projecting to the PFC during postnatal days P20-50 with that in adulthood (P90-120). We found that inhibiting the thalamus during adolescence leads to a long-lasting decrease in the density of thalamo-mPFC projections and a reduced excitatory drive to mPFC neurons. Adolescent thalamic inhibition further causes cognitive deficits in attentional set shifting during adulthood that are associated with disrupted correlated neuronal activity and task outcome encoding in the mPFC. In contrast, thalamic inhibition during adulthood has no long-lasting consequences on mPFC excitation, correlated activity, outcome encoding and behavior. Strikingly, exciting the thalamus in adulthood during the set shifting task rescues in vivo neuronal activity and cognitive deficits induced by adolescent inhibition. While these data point to adolescence as a sensitive time window for PFC circuit maturation the underlying mechanisms by which adolescent inhibition impairs mPFC maturation are still unclear. To address this, first, the development of mPFC circuitry needs to be characterized during adolescence. Second, it will be important to determine whether adolescent inhibition induces long-lasting changes in intrinsic mPFC circuitry, and which specific mPFC projections and interneurons are regulated by adolescent thalamic inhibition. Third, it will be important to know when such changes arise and how they relate to the changes in in vivo cross correlated activity and outcome encoding. Our data further suggest that boosting thalamic activity could provide a strategy for rescuing cognitive deficits in neurodevelopmental disorders. However, as presented, the beneficial effect only occurs while the thalamus is stimulated. Therefore, strategies will need to be identified that allow for a longer lasting rescue of the cognitive abilities. We will address these questions using three aims: Aim 1: To determine when and where adolescent thalamic activity regulates the development of mPFC circuit connectivity. Aim 2: To determine whether the impact of adolescent thalamic inhibition on cognition requires maturation of the mPFC. Aim 3. To determine whether thalamic excitation can lead to a long-lasting rescue of the cognitive deficit.
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