Implications of Prefrontal Cortex Development for Adolescent Reward Seeking Behavior

点击翻译按钮获取中文摘要

PROJECT SUMMARY As we get older, we learn to modulate our behaviors to optimize reward outcomes. These adaptive choices are orchestrated by current sensory conditions, internal cognitive states, and future expectations. In adolescence, rewards circuits that link peripheral detection of sensory stimuli to central circuits involved in decision-making and motivational states continue to grow, remodeling the microcircuit connectivity within the medial prefrontal cortex (mPFC). This development may explain why adolescents demonstrate increased impulsivity and diminished behavioral flexibility, and fail to optimize reward outcomes. However, the developmental changes within the reward circuits that inform differences in reward learning during adolescence are poorly understood. The mPFC is a key area for emotional regulation, decision making, and reward-seeking. The reward- modulating properties of mPFC are derived from inputs from the ventral tegmental area (VTA). During adolescence, VTA inputs into mPFC are still developing, and the functional impact of these developmental changes is unknown. One influential theory suggests that increased dopaminergic (DA) signaling in adolescence drives heightened reward sensitivity. However, additional mechanisms such as changes in local mPFC connectivity and changes in reward information sent to the mPFC are likely at play. In this proposal, we use a combination of chemogenetics, optogenetics, anatomical, and neural calcium imaging, to test how the developing adolescent mPFC (Aim 1) and VTA projections to mPFC (Aim 2) contribute to adolescent reward behaviors and influence reward optimization strategies (Aim 3). This work reframes the role of neuronal subtypes, and probes if their role in a given behavior is shaped by the age of the microcircuit, asking the question, do cells carry the same information in adolescents as they do in adulthood? In addition to the value of this work from a basic science perspective, this study is likely to produce testable hypotheses that will tackle why certain psychiatric disorders such as impulse control and feeding disorders tend to emerge during adolescence. Training in calcium imaging, neuronal activity data analysis and advanced anatomical techniques will be provided by the mentor Dr. Conor Liston, with additional expertise in 2-photon imaging provided by the consultants Drs. Rajasethupathy and De Marco Garcia. Dr. Sullivan will serve as a consultant on developmental behavioral neuroscience, providing feedback on experimental design and outcomes. Dr. Bravo Rivera will provide an additional behavioral neuroscientific perspective and will be instrumental in providing additional career development training to the applicant. Together the mentor and the External Advisory Committee will facilitate the transition of Dr. Manzano Nieves into an independent research career focused on uncovering how postnatal development alters brain circuits to bias behavior and create psychiatric vulnerabilities.