Abnormalities in reward circuitry are characteristic of multiple neuropsychiatric disorders; however, elucidating the precise biological mechanisms underlying this dysfunction has proved challenging. 22q11.2 Deletion Syndrome (Velocardiofacial/DiGeorge Syndrome; 22qDS) presents a compelling model for investigating these mechanisms, as this neurogenetic disorder is associated with extremely high risk for multiple psychiatric disorders, particularly those associated with dopaminergic dysfunction, such as schizophrenia and attention deficit disorder. Several genes within the deletion region are implicated in brain development and prefrontal cortical (PFC) dopamine metabolism. As such, this disorder provides an ideal model in which to study the structure and function of brain regions known to be essential for frontally-mediated cognitive functions that rely on optimal dopamine levels. Our hypothesis is that a life-long biological vulnerability, resulting from haploinsufficiency for specific genes critical for dopamine regulation, leads to alterations in behavior and neuroanatomy related to the reward system in patients with 22qDS. Examining these endophenotypes can offer empirical support for how the function of these genes impacts the brain at a system-wide level, [and how these effects may change over the course of development (particularly during the vulnerable adolescent period)]. The purpose of the proposed project is to quantify behavioral and structural neuroanatomic alterations in patients with 22qDS, [both cross-sectionally and longitudinally], and to investigate the contribution of allelic variation in the intact chromosome to these neuroanatomic and behavioral alterations.
Aim 1 will first investigate an experimental measure of risk- taking and optimal decision-making in patients with 22qDS, [as well as a measure of real-world executive control], both of which we hypothesize to be impaired in this population.
Aim 2 will examine alterations in volume, thickness and surface area in brain regions critical for decision-making and reward expectation (e.g., orbitofrontal and dorsolateral prefrontal cortex), with the hypothesis that 22qDS patients will show baseline abnormalities in these structures relative to typically developing controls, as well as abnormal trajectories of prefrontal cortical maturation.
Aim 3 will employ genetic techniques to examine variation in specific genes relevant to dopaminergic and glutamatergic function (COMT and PRODH, respectively) that are hemizygously deleted in patients with 22qDS, in order to determine how allelic variation in the intact chromosome in 22qDS translates into differences in gene expression and, in turn, PFC structural variation and downstream effects on behavior. Together, the results of the experiments planned in pursuit of these aims will expand the current sphere of knowledge about the relationship between genetics and brain structure and function in the context of dopamine and reward circuitry. Investigation of this unique clinical population allows us to directly investigate links between genetic variation and brain dysfunction, thereby helping to elucidate the complex neurobiological mechanisms by which reward-related dysfunction and psychiatric illness may arise.
Dopaminergic dysregulation has been linked to many psychiatric illnesses, such as schizophrenia and attention deficit hyperactivity disorder. Given the complex and heterogeneous etiology of these disorders, it is difficult to pinpoint the specific role dopamine plays in the pathophysiology of these idiopathic conditions. Given that patients with 22qDS are hemizygous for genes contributing to dopamine metabolism, we can use this unique opportunity to study the structure and function of regions of the brain known to be essential for cognition and psychiatric variability that rely on optimal dopamine levels.
|Jonas, Rachel K; Jalbrzikowski, Maria; Montojo, Caroline A et al. (2015) Altered Brain Structure-Function Relationships Underlie Executive Dysfunction in 22q11.2 Deletion Syndrome. Mol Neuropsychiatry 1:235-46|