This report briefly describes our findings as mentioned in our objectives. Interesting MRI findings emerged related to the identification of a new intermediate phenotype and cortical circuitry. We tested whether altered dorso-lateral-prefrontal cortex (DLPFC) connectivity is heritable, independent of DLPFC activation, and is affected by a genetic variation in the ZNF804A gene. Siblings of patients with SZ showed increased DLPFC inefficiency vs. controls. Our connectivity analyses showed abnormal DLPFC functional coupling with the hippocampus formation (HF) and to a lesser degree the rest of the PFC, in patients and siblings but not controls. Correlation between PFC activation and connectivity in the siblings was not detected, concluding that these events may be independent. The ZNF804A gene affects distributed network-based neurointegrative deficits that reflect genetic risk mechanisms for SZ. These deficits are mildly present in siblings and normal controls with the risk-associated genotype. This suggests that altered PFC activation and coupling are independent intermediate phenotypes, one of which is modulated by susceptibility genes. A SNP in ZNF804A appears to modulate PFC-HF coupling but not PFC activation. DLPFC, which communicates with HF, inferior parietal lobules and ventrolateral PFC during working memory (WM), is probably susceptible to genetic modulation and our data suggest that genes related to increased SZ susceptibility effect in this modulation. Imaging Genetics has allowed us to expand our knowledge of genetic interactions that support biologic phenomena. We studied interactions between NRG1 and NMDA-glutamate pathway partners. NRG1 plays a role in brain development, neuronal function and is a SZ risk gene. We show an interaction between NRG1 and SZ which we validated using BOLD fMRI on WM in controls. Carriers of risk alleles showed inefficiency in processing in DLPFC. We showed epistasis between SNPs inNRG1 and ErbB4 and a 3-way interaction between NRG1 and SNPs in ErbB4 and AKT1. Each of these interactions (NRG1 x ErbB4 x AKT1) was validated using fMRI in controls carrying the risk SNPs and all were found to be inefficient in DLPFC processing. Our data suggest complex epistatic effects implicating a NRG1 molecular pathway in cognitive function and pathogenesis of SZ. Another study, explored the impact of an AKT1 functional variation on human medial temporal lobe (MTL) development and plasticity. We found another 3-way interaction of AKT1 with BDNF and COMT, adding to convergent evidence identifying effects of AKT1 variation in memory-dependent neuroplasticity and structural brain processes in development and SZ and epistatic interactions with neurotrophic and dopaminergic processes that modulate AKT1 effects. AKT1 modulation via pharmaceuticals effected cognition and PF-MTL brain structure in SZ. Therefore, AKT1 and related neuroplasticity and developmental pathways may influence cognition and risk for SZ through effects that may be pharmacologically modifiable. Other allelic variations we found in DAOA and COMT genes interact to increase risk for SZ and impaired DLPFC information processing. This again, demonstrated a functional yet statistically significant interaction between risk alleles in DAOA and COMT which may play a role in glutaminergic and dopaminergic dysregulation. Lastly a variant of the FGF20 gene, which modulates hippocampal biology, mRNA expression, verbal episodic memory, and morphology, was shown in T allele carriers to increase HP mRNA expression, had relatively larger HP volume, reduction in verbal episodic memory, and a sharp decline in HP volume with normal aging. From mRNA expression to brain morphology to cognition and interaction with aging, we confirm a role for the Parkinsons disease-associated FGF20 gene in brain structure and function during development and aging. Another study used healthy controls to explore the neural mechanism through which selective updating of information is stored in WM. A novel wm task was designed that parsed WM maintenance, overwriting, and selective updating. A functionally coupled network consisting of midbrain regions were selectively engaged during wm updating when compared to both overwriting and maintenance. In both behavioral and neurophysiological terms, we revealed that selective updating was clearly parsed from maintenance and nonselective updating of information. Analysis also showed differential midbrain-dorsolateral prefrontal interactions during selective updating between subjects rated as low and high-performers. The midbrain engaged the DLPFC during updating to a greater degree in low performers vs. high performers. These findings of meso-cortico-striatal network engagement during updating supports the notion of dopaminergic modulation of striatal gating of DLPFC during the selective updating of wm content, which was predicted in computational models of wm function. Future studies using genetic assays and pharmacological manipulations to investigate this network will be needed to further support these claims. The group also investigated neurophysiological correlates of altered brain function associated with aging. Our study analyzed age-related brain morphometric changes using cortical thickness, cortical gray matter volume, and surface area as morphological indices. It has been previously reported that there are global and regional changes in gray matter volume as we age. Using a surface-based automated reconstruction technique, we analyzed healthy subjects and found with age, there are global and regional changes in cortical volume, thickness and surface area. Age-related atrophy, in most cortical regions was indicated by a reduction in thickness however, most striking was that the prefrontal cortex showed a reduced thickness, surface area, in addition to volume which confirmed previously published reports. Interestingly, the average global surface area reduction was greater than in any one cortical region alone. The area that appeared preserved with age was the MTL, but this may have been due to limitations in our method. Future studies will be needed to assess brain histological changes that occur during normal aging as related to these morphometric measures. We will continue to explore the effect of aging on brain structures and systems, and the role of genetics on these changes. Finally, we explored changes in GABA levels in SZ in vivo and examined the genetic association with the ErbB4 gene. We found significant effects in A carriers as increased ErbB4 expression and higher cortical GABA levels. To our knowledge, this is the first study to measure GABA in living human brain. It is unclear whether this association reflects functional differences in enzyme activity or is a neuroanatomical decrease in the total number or distribution of interneurons or synapses. Another study examined a method to reproduce quantification of brain metabolites and parse gray/white matter differences that impact interpretation of imaging results in clinical populations. There have been inconsistencies in the reproducibility of MRS studies that quantify GABA levels in vivo, such as field strength, scanning techniques, acquisition and processing which resulted in varied measures. GABA is a major inhibitory neurotransmitter in human brain and its dysfunction has been implicated in many neuropsychiatric disorders. We used a J-edited, single voxel-based spectroscopy method to measure GABA + macromolecules in the anterior cingulate cortex and right frontal white matter. In fact, our method allowed us to quantify metabolite differences between gray and white matter. Reproducibility of estimations of brain metabolites may lead to a clearer interpretation of results where voxels have both gray and white matter and may be applied to studies of clinical population.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2011
Total Cost
$2,050,566
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Radulescu, Eugenia; Sambataro, Fabio; Mattay, Venkata S et al. (2013) Effect of Schizophrenia risk-associated alleles in SREB2 (GPR85) on functional MRI phenotypes in healthy volunteers. Neuropsychopharmacology 38:341-9
Thurin, K; Rasetti, R; Sambataro, F et al. (2013) Effects of ZNF804A on neurophysiologic measures of cognitive control. Mol Psychiatry 18:852-4
Tost, Heike; Alam, Tajvar; Geramita, Matthew et al. (2013) Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults. Neuropsychopharmacology 38:525-32
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Marenco, Stefano; Stein, Jason L; Savostyanova, Antonina A et al. (2012) Investigation of anatomical thalamo-cortical connectivity and FMRI activation in schizophrenia. Neuropsychopharmacology 37:499-507
Rasetti, Roberta; Weinberger, Daniel R (2011) Intermediate phenotypes in psychiatric disorders. Curr Opin Genet Dev 21:340-8

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