## 5 Discussion
Together with innervations to the striatum from the hippocampus and amygdala [81; 82; 83; 84], the ventral striatum has been suggested to represent odor valence cues and instigate goal-directed behavior [78], facilitated by additional input from piriform cortex and prefrontal cortex [85; 86; 87]. Output from the ventral striatum proceeds to the pallidum and then the thalamus, which then closes the feedback loop with prefrontal cortex [88; 89]. An important structure in this loop is the orbitofrontal cortex, which plays an important role in maintaining changing odor representations but also more broadly in decision making and stimulus evaluation [90]. Integrated into these loops are other subcortical structures, including the cerebellum, which also has a significant role in movement and more recently emphasized role in cognition and language [91]. Through the thalamus and pons, the cerebellum indirectly projects to putamen, pallidum, and the subthalamic nucleus [92; 93]. These outputs may be topographically organized, converging on both the ventral striatum and frontal areas, with suggested involvement in appetitive reward [94] and strategic motor learning [95]. Disruption of this interconnected network is likely captured by BDS scores, which are then sensitive to striatally relevant neurodevelopmental outcomes. Higher BDS in the CHD cohort was correlated with known genetic abnormalities in the human infants, suggesting a genetic mechanism might also drive these subcortical dysplastic structural findings. Concordant with this, we also found a similar spectrum of paralimbic and subcortical abnormalities exists between human and _Ohia_ mutants, suggesting a common genetic mechanistic etiology. Within the _Ohia_ mouse model, the two main driver genes were _Sap130_ and _Pcdha9_, and while both genes were necessary to have cardiac phenotype, both genes were not required to have neuroanatomic abnormalities. Additionally, _Sap130_ mutations presented with a more severe brain phenotype compared to _Pcdha9_ mutations. This is interesting as knock-out mice for _Sap130_ are embryonically lethal whereas _Pcdha9_ knock-out mice are viable, suggesting that _Sap130_ may have a more upstream effect whereas _Pcdha9_ is more downstream [96]. _Sap130_ functions as a subunit of the histone deacetylase-dependent co-repressor complex, which has roles in transcriptional regulation and has been specifically mentioned to be required for recovery from hypoxia [97]. _Pcdha9_ is a member of the protocadherin alpha gene cluster, which are important plasma membrane proteins for cell-cell connections, neural projects, and synapse formation [98]. Interestingly, both genes show overlap in connectomes with chromatin and histone modification pathways [43]. Alterations in histone-modifying pathways have been linked to various forms of CHD [99; 100; 101]. It is likely that there are many other genes and gene pairings that could cause a similar neurodevelopmental phenotype as it is possible the main driver could be epigenetic dysregulation resulting in altered differential expression of genes required for signaling and migration. Incorrect timing for migrating neural cells might explain why preterm infants and CHD infants look phenotypically similar in regard to neurodevelopment and impact the BDS (particularly the olfactory bulb and hippocampus, which undergo early developmental neurogenesis). Looking at the genetics of the preclinical mouse model could not be conclusive as to the etiology of the human CHD neurodevelopmentalment issues; however, we demonstrate spectra of cardiac and brain anatomical abnormalities associated with the different genetic combinations of the _Ohia_ mouse, parallel to those seen in human subjects. CHD subjects have a documented risk of poor neurodevelopmentalment outcomes although the specific mechanism is unknown [102; 103; 104; 105; 106]. Additionally, neurodevelopmental impairments can continue to affect individuals well past infancy and into adolescence and early adulthood [107; 108; 109; 110; 111; 112].