Adolescence is a vulnerable period for the onset of several psychiatric disorders where the prefrontal cortex (PFC) is involved, yet, our mechanistic understanding of this susceptibility remains incipient due to insufficient knowledge of the normative changes occurring during this developmental stage. Thus, the long-term goal of this proposal is to identify key cell- and circuit-level processes underlying the normal development of the PFC in order to understand the adolescent vulnerability to the onset of psychiatric disorders where the PFC is compromised. Studies from our previous funding period reveal that the PFC undergoes massive functional remodeling in both glutamatergic and GABAergic transmission during adolescence. Nonetheless, it is the local GABAergic system that appears to render the PFC labile during adolescence to the extent that any insult occurring during this developmental period will prevent the normal functional acquisition of inhibitory control in the PFC through a gain of local GABAergic function. Interestingly, our data indicate this GABAergic facilitation is contemporaneous with two other developmentally-regulated PFC events occurring during adolescence: 1) a functional strengthening of the ventral hippocampus-to-PFC pathway, and 2) increased glutamatergic activity onto a subset of PFC GABAergic interneurons, suggesting these events are interrelated. Thus, the objective of this application is to determine whether there is a causal relationship between specific excitatory afferents and the acquisition of PFC inhibitory control through their effect in specific GABAergic populations. The central hypothesis is that the functional maturation of GABAergic transmission in the PFC is dependent upon the activation of specific prefrontal interneurons by specific afferents that drive PFC activity during adolescence, such as those from the ventral hippocampus and basolateral amygdala. We will test this hypothesis through the pursuit of 3 Specific Aims. We will first determine the contribution of input-specific afferent drive (Aim 1) and the role of specific prefrontal interneurons (Aim 2) in enabling the gain of GABAergic function in the PFC during adolescence.
Aim 3 will test if impaired GABAergic maturation in the PFC during adolescence can elicit enduring deficits in PFC-dependent behaviors as adults. All in all, the proposed research plan is innovative in our opinion because it will incorporate knowledge of the events occurring during adolescence to explain the acquisition of adult PFC faculties and development of PFC deficits, especially from the perspective of how prefrontal GABAergic maturation is regulated by afferent structures widely involved in normal and pathological neural responses. The proposed studies are significant because they will uncover key neurodevelopmental mechanisms that contribute to the acquisition of mature cognitive abilities in adults. Such knowledge is expected to have a positive impact in the development of age-specific interventions aimed at decreasing the incidence or ameliorating the symptoms of mental disorders within the adolescent/young adult population.
The proposed research is directly relevant to public health because it will uncover key neurodevelopmentally-regulated synaptic mechanisms that enable the normal maturation of the prefrontal cortex during adolescence and the neurobiology that renders this developmental period susceptible for the onset of psychiatric disorders. This goal is directly aligned with the NIMH agenda by establishing a developmental framework in which mental disorders can be understood, specifically those arising during the adolescent to adult transition period. This knowledge is expected to fully serve NIH mission by devising the proper timing of intervention strategies to prevent or ameliorate the onset of mental disorders during critical periods.
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