Aberrant brain development during critical periods of heightened vulnerability contributes to lifelong cognitive impairments underlying many psychiatric disorders. Mechanisms driving critical period circuit development are well described in sensory systems-but poorly characterized for complex cognitive behaviors. Identification of a critical period and underlying mechanisms for cognitive circuits and behavior would eventually improve diagnosis, prevention and treatment of psychiatric disorders. This study will test whether a mechanism critical for regulating the critical period for visual cortex development also modulates maturation of frontal cortex- dependent attentional functions. Lynx1 is an endogenous nicotinic acetylcholine receptor (nAchR) inhibitor and regulates the critical period of visual cortex plasticity by its increased expression across adolescence. In addition to its role in visual cortex, our preliminary data show that the Lynx1 knock-out mice with high nAChR signaling unexpectedly present with attention-deficits in adulthood. Strikingly, this deficit was prevented by transient suppression of nAChR signaling only during early adolescence but not acutely in adulthood. This study will test the overarching hypothesis that the excessive nAChR signaling during adolescence, normally limited by peri-adolescent increase in Lynx1 expression, causes long-lasting impairment in frontal cortical circuits and behaviors that support attention. Understanding how excess nAChR signaling disrupts normal circuit development could provide mechanistic insight into developmental neuropsychiatric disorders characterized by disrupted nAChR signaling, such as Autism, ADHD and schizophrenia.
In Aim1, we will test the hypothesis that Lynx1 expression in anterior cingulate cortex during peri-adolescence is required for normal attentional function in the adult. We will precisely define the critical period and key brain regions mediating the long-lasting impact of excess nAChR signaling on adult attentional function by combining pharmacological, viral and genetic gene manipulations in vivo with 5-choice serial reaction time task (5- CCRTT) employing a translational touchscreen system.
In Aim2, we will test the hypothesis that the fronto- posterior cortical circuits require nAChR signaling to be suppressed by Lynx1 during adolescence to establish attention in the adult. By introducing a novel viral system that allows circuit-specific labeling and gene manipulations at time points of interest, the impact of Lynx1 deletion to neurons projecting from anterior cingulate cortex to visual cortex, and the cell-autonomous contribution of Lynx1 in these circuits will be determined. At the completion of this study, we will have defined the developmental time window, anatomical region, and circuit that require optimal nAChR signaling for normal attentional function, which is identified by the NIMH Research Domain Criteria (RDoC) project as one major construct of cognitive systems impaired in a number of psychiatric conditions.
The goal of this study is to identify a developmental critical period and underlying mechanisms for establishing attentional circuits and behavior regulated by an endogenous inhibitor of nicotinic acetylcholine receptor called Lynx1. Such knowledge may represent a novel mechanism and therapeutic target for a cognitive function that is disturbed in developmental neuropsychiatric disorders including autism, ADHD, and schizophrenia.
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