This is the second renewal on a line of inquiry characterizing the neural basis of cognitive maturation through the adolescent period, a time of critical vulnerability to the emergence of major psychopathology (e.g., schizo- phrenia, mood disorders). Building on the findings from the first two grants using functional Magnetic Resonance Imaging, Diffusion Tensor Imaging, and Magnetoencephalography, indicating important specialization in cogni- tive brain systems during adolescence, we now propose to probe these underlying mechanisms.
We aim to characterize changes in key neurotransmitters (NT): gamma-Aminobutyric acid (GABA), glutamate (Glu), and dopamine (DA), which animal and postmortem models show underlie circuit plasticity and undergo unique changes during the adolescent period. Specifically, changes in Glu/GABA processing, modulated by adolescent increases in DA, affect the excitatory/inhibitory (E/I) balance of cognitive brain systems, driving increases in the cortical signal-to-noise ratio (SNR) into adulthood supporting cognitive maturation. Our Central Hypothesis is that the relative changes of these NTs will increase the SNR of neural activity supporting the transition to adult level cognition.
In Aim 1, we will use Magnetic Resonance Spectroscopy (MRS) at 7 Tesla to obtain measures of GABA and Glu as well as R2? indirect measures of dopamine (DA) longitudinally in vivo in 12-30 year olds. 7Tesla MRS provides critically greater sensitivity than 3Tesla affording significant increases in the accuracy of measures of GABA and Glu necessary for probing changes through adolescence, which have yet to be done. We hypothesize that we will observe decreases in measures of Glu and DA and increases in GABA resulting in decreases in the ratio of DA*Glu/GABA in prefrontal and subcortical regions.
In Aim 2, we will inves- tigate the association between relative NT changes and systems level effects on known developmental changes in brain connectivity using resting state connectivity and measures of white matter integrity. We propose that NT systems changes will be associated with greater network integration and changes in the strength of corticosub- cortical connectivity through adolescence. Lastly, in Aim 3 we propose to characterize changes in SNR in the context of developmental improvements in higher-order executive function using a task that probes learning and working memory, functions that are known to show important improvements through adolescence. Together, these findings have relevance in elucidating the relative contributions of different NT systems to brain matura- tional processes providing novel insight into the neurobiological basis of normative neurocognitive development that is critical for identifying vulnerabilities for abnormal development that can lead to psychopathology.
There are unique neurochemical changes during adolescence that reflect plasticity in brain systems that support the transition from adolescence to adult level cognitive abilities. Understanding normative plasticity in neurocognitive systems is critical for discerning what goes awry in psychopathology. We propose to extend the investigations on the development of brain systems underlying cognitive maturation from the earlier grants, by probing the neurobiological mechanisms underlying plasticity in the adolescent transition to adult level cognition using innovative methods. Together, these measures will provide an unprecedented integrated characterization of how the brain specializes during normative development that can better clarify the specific developmental processes that may underlie abnormal brain maturation.
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