posttraumatic stress disorder ( ptsd ) is a complex mental disorder that can develop in response 
     to a traumatic event such as a motor vehicle accident , rape , combat exposure or natural 
     disaster .
the national vietnam veterans readjustment study estimated that 53.4% of us male 
     veterans of the vietnam war developed full or partial ptsd and 15.2% still suffered from the 
     disorder in 1990 1 . the application of conservative 
     procedures for analysis led dohrenwend et al to document that 18.7% of male veterans developed 
     war - related ptsd during their life time and 9.1% were still suffering from ptsd 11 to 12 years 
     after the war 2 . in the general population , the estimated 
     lifetime prevalence of ptsd is 7.8% in adult americans , with women having a 2.3-fold higher 
     prevalence than men 3 .
ptsd symptoms include intrusive 
     thoughts , hyperarousal , nightmares , flashbacks , emotional detachment or numbing of feelings , 
     insomnia , fear , avoidance of reminders , distress when exposed to reminders , irritability , 
     hypervigilance , and heightened startle response 4 .
several lines of evidence support neurochemical , functional and structural alterations in the 
     neuroendocrine system in patients with ptsd .
the neurochemical alterations range from adrenergic 
     hyperresponsiveness , increased thyroid activity , increased levels of corticotrophin - releasing 
     factor , to low cortisol levels and increased negative feedback sensitivity of the 
     hypothalamo - pituitary - adrenal - axis after the administration of low - dosage dexamethasone 5 . functional brain imaging studies in patients with ptsd 
    
demonstrate increased function in the amygdala and decreased activity in the hippocampus and 
     prefrontal cortex ( pfc ) 6;7 .
these functional alterations are consistent with the structural findings in animal 
     models of ptsd that neurons in the hippocampus and pfc display atrophy while those in amygdala 
     show growth in response to repeated stress 8 .
dlpfc including ba46 is one of the three regions of pfc , which regulates working memory and 
     execution of fear responses 9 .
this brain region has been 
     correlated with structural and functional alterations , and with the treatment response of 
     patients with ptsd . in children with ptsd symptoms , decreased volume of gray matter in the dlpfc 
     is correlated with increased functional impairment 10 . 
    
adult patients with ptsd core symptoms ( i.e. re - experiencing , avoidance ) were markedly improved 
     by treatment with 10-hz repetitive transcranial magnetic stimulation over the right dlpfc 11 .
furthermore , the indicator of neuronal viability , 
     n - acetylaspartate , in dlpfc was correlated positively in healthy people with verbal intelligence 
      12 , and negatively in patients with a generalized 
     anxiety disorder following a previous traumatic event 13 . although the prefrontal cortex , amygdala and hippocampus are the brain regions considered to 
     be related to ptsd 6;7 , the underlying molecular mechanisms are unknown .
one of the possibilities is that 
     functional and structural changes in the brain may result from mitochondria - centered responses 
     to repeated or chronic harmful stresses 14;15 .
mitochondria provide the cell with energy in the form of 
     atp and play fundamental roles in many metabolic pathways , such as -oxidation , the 
     tricarboxylic acid cycle and urea cycle , the synthesis of steroid hormones and heme , and calcium 
     signaling .
in addition , mitochondrial biochemical and molecular pathways are a natural central 
     target of diverse pharmacological agents 16 . however , 
     reactive oxygen species ( ros ) , an inevitable by - product of mitochondrial oxidative 
     phosphorylation , can impair molecules , contributing to various diseases including 
     neurodegeneration 17 .
thus , homeostasis of these 
     mitochondrial functions is critical in human brain because of its high energy demand .
mitochondrial dysfunctions are increasingly recognized as key components in stress related 
     mental disorders 14;15 .
although long or repetitive exposure to stress can induce a neurological change 
     resulting in ptsd , the molecular pathology involving in such a neuronal damage remain elusive . 
    
overexpression of antioxidant enzymes ( glyoxalase and 
     glutathione reductase 1 ) in mouse brain was also associated with increase in anxious behavior 
      19 .
in addition , chronic stress of rats inhibits the 
     activities of mitochondrial respiratory complexes ( inhibition of 69% in complex i - iii and of 67% 
     in complex ii - iii ) 20 .
cortisol has widespread functions 
     including activation of glucocorticoid receptor which bind directly to mitochondrial membrane 
     and regulate apoptosis 15 .
the steroidogenic acute 
     regulatory protein is one of the outer mitochondrial membrane protein required for stress 
     responses 21 .
although all these studies indicate 
     mitochondrial dysfunction , they are all focusing on a specific candidate gene(s ) .
the lack of a 
     holistic study of all the mitochondria - related genes hinders the progress of the ptsd research . to date , methods employing a systems biology approach to identify the mitochondria - focused 
     genes underlying the pathogenesis in ptsd - related brain regions have not been documented , 
     probably due to the lack of human postmortem brain tissue from ptsd patients .
the expression 
     signatures in blood cells have been associated with changes in peripheral lymphocytes of 
     subjects with ptsd 22;23 , but provide no information for molecular abnormalities in brain tissues . here
we 
     report the identification of expression signatures , canonical pathways , molecular networks and 
     drug targets of dysregulated neuropsychiatric disease - related genes in ba46 of postmortem brain 
     tissue from patients with ptsd using a human mitochondria - focused cdna microarray ( hmitchip3 ) 
      24 .
our results indicate mitochondrial dysfunction in 
     the dlpfc ba46 and may prove useful for developing methods for diagnosis and treatment of 
    ptsd .
postmortem brain tissue : postmortem brain tissues were collected by the traumatic 
     stress brain study group who diagnosed , collated , planned , coordinated , made decisions on 
     inclusion and exclusion , established procedures of diagnosis and interrogated reliability , and 
     obtained normal brains for controls as well .
medical records were meticulously reviewed and 
     clinical diagnoses were confirmed using dsm - iv criteria 4 . 
    
table 1 lists all available brain tissues employed for 
     this study , with some clinical data including patient 's gender and age ( 4-year 
     difference ) , brain ph ( 0.65 difference ) and reasons of death .
eight subjects died 
     from myocardial infarction / heart attack , two from suicide by overdose , one from alcoholism 
     complications and another from pulmonary embolism .
tissue ( 0.4 - 0.8 g ) was thawed and homogenized in 10 times the 
     tissue volume of deionized distilled h2o and the homogenate ph was measured with the 
     perphect ph 370 model meter with a compatible perphect sure - flow type probe ( ati orion , boston , 
     ma , usa ) . the ph electrode was washed thoroughly in deionized distilled h2o after 
     each sample and recalibrated at the standard 3 points of ph ( 4 , 7 , and 10 ) . rna preparation :
dlpfc ba46 tissues were dissected from postmortem brains and the 
     samples contained primarily gray matter with small but random amount of white matter because the 
     dissections were done from frozen tissue blocks but not from cryostat sections .
carlsbad , ca , usa ) and then purified with rneasy 
     kit ( qiagen , valencia , ca ) , following the manufacture 's instructions .
gene chip and microarray data analysis : a third - generation human 
     mitochondria - focused cdna microarray ( hmitchip3 ) containing 37 mitochondrial dna - encoded genes , 
     1,098 nuclear dna - encoded and mitochondria - related genes and 225 controls was printed as 
     described previously 24 .
a total of 1135 
     mitochondria - related genes include 946 genes associated with 645 molecular functions , 930 genes 
     with 612 biological processes , 476 genes with biological chemistry pathways , 227 genes with 23 
     reactome events , 237 genes with 320 genetic disorders , and 55 genes with 87 drugs targets24 . for examples ,
89 genes are related to oxidative 
     phosphorylation , 20 genes to apoptosis , and 14 genes to neurotransmitter ( tyrosine , l - dopa and 
     dopamine ) metabolism .
five g of rna per sample were used for microarray labeling and 
     hybridization as previously described 24 .
slides were 
     scanned using the scanarray express microarray scanner ( perkinelmer , boston , ma , usa ) as 
     described previously 24 .
microarray database 
     construction , data filtering and normalization were performed as described previously 24;25 .
the normalized 
     data were used to cluster and visualize expression levels of genes in these brain tissue 
     specimens by using eisen 's cluster software 26 .
heat map 
     was visualized by using eisen 's maple tree software ( http://rana.lbl.gov/eisensoftware.htm ) .
gene information analysis : gene i d , symbols and names were derived from human 
     unigene build 204 ( ftp://ftp.ncbi.nih.gov/repository/unigene/ ) based on human cdna i.m.a.g.e .
ontology , pathways and 
     phenotypes of genes were compiled from entrez ( ftp://ftp.ncbi.nlm.nih.gov/gene ) and david bioinformatics resources 2008 ( http://david.abcc.ncifcrf.gov/ ) . 
    
ingenuity pathway analysis software ipa version 6.0 ( ingenuity systems inc . , redwood city , ca , 
     usa ) was used to map canonical pathways , diseases , disorders , molecular networks and drug 
     targets and to calculate the percentages and p - values ( fisher exact test ) .
quantitative rt - pcr ( qrt - pcr ) : two g of total rna was 
     reverse - transcribed into cdna by using superscript first - strand synthesis system 
     ( invitrogen ) .
30 ng cdna was used for qpcr reactions with the universal pcr master mix ( no 
     amperase ung ) on an applied biosystems 7300 real time pcr system ( foster city , ca , usa ) , 
     following the manufacturer 's instructions . after 40 cycles ,
taqman probes and primers for qpcr were 
     purchased from applied biosystems and include those of glyceraldehyde-3-phosphate dehydrogenase 
     ( gapdh , 4352934e ) , dnaj ( hsp40 ) homolog subfamily c member 19 ( dnajc19 , hs00829488_s1 ) , solute 
     carrier family 1 ( high affinity aspartate / glutamate transporter ) member 6 ( slc1a6 , 
     hs00192604_m1 ) , solute carrier family 9 ( sodium / hydrogen exchanger ) member 6 ( slc9a6 , 
     hs00234723_m1 ) , amyloid beta ( a4 ) precursor protein ( app , hs00169098_m1 ) , and estrogen receptor 
     2 ( er beta ) ( esr2 , hs00230957_m1 ) .
statistics : statistical calculations were performed on triplicate array 
     experiments using xlstat 2006 ( xlstat , new york , ny , usa ) .
differentially expressed genes were 
     identified arbitrarily by 1.25-fold change in the average expression of the 
     background - subtracted mean intensity ratios of a gene between ptsd and control , with 
     p - value < 0.05 .
student t - test was used to calculate 
     p - values for gene expression , while fisher exact test in ingenuity pathway 
     analysis software was used to calculate p - values for pathways and diseases .
the 
     level of statistical significance was set at a p - value < 0.05 .
total rna samples were extracted from gray matter that was 
     dissected from postmortem brain dlpfc ba46 of ptsd brains ( n=6 ) and unaffected controls ( n=6 ) 
     and labeled for triplicate microarray experiments using our recently developed third generation 
     human mitochondria - focused cdna microarray hmitchip3 . because use of 3 replicates in cdna 
     microarrays analysis of even a single specimen greatly reduces misclassification rates 29 , the hmitchip3 genes were all measured 9 times ( 3 identical 
     probes per microarray and 3 microarray experiments per specimen ) , which generated reliable 
     expression data for further analysis .
the microarray data of 4,080 spots across all 36 gene 
     chips used for 12 rna samples were filtered by uniform statistic and bioinformatic criteria as 
     described previously 24;30 , which generated 800 genes with informative expression profiles .
the supplemental 
     table 1 reports the expression data of the selected 800 genes in each of the triplicate 
     experiments before and after normalization as the raw and processed data , respectively ; while 
     figure 1 shows the box plots of mrna levels of 800 genes 
     before and after the data normalization .
the resultant dendrograms for all of these 800 genes and 
     12 brain dlpfc ba46 specimens classified p1 , p2 , p3 , p5 , p6 and n2 in one group and n1 , n3 , n4 
     n5 , n6 and p4 in another ( fig . 2a and supplemental figure 
     1 ) ; these analysis separated the ptsd brain from the control except for n2 and p4 ( opposite from 
     their clinical diagnosis ) . based on the unsupervised cluster results , we calculated an average expression level of each 
     gene in the ptsd group ( p1 , p2 , p3 , p5 , p6 and n2 ) and in the non - ptsd control group ( n1 , n3 ,
n4 
     n5 , n6 and p4 ) . the ratios and p - values ( t - test )
were calculated between the 
     ptsd and control specimens , resulting in the identification of 119 genes 
     ( p<0.05 , 1.25 ) and 42 genes 
     ( p<0.05 , 1.60 ) whose expression were dysregulated 
     in the ptsd dlpfc ba46 as compared to the controls ( supplemental table 2 ) .
clustering analysis 
     of these 119 and 42 genes across all 12 brain samples generated double dendrograms and heat maps 
     that clearly distinguish the ptsd dlpfc ba46 specimens from the controls ( fig .
the 
     identification of these dysregulated genes provides candidates with biological clues for 
     validation of mrna expression and future functional studies .
qrt - pcr confirmation of microarray results . to validate the microarray results , 
     we conducted qrt - pcr analysis on 5 genes including app , dnajc19 , esr2 , slc1a6 and slc9a6 because 
     of the highest ( slc9a6 ) and lowest ( danjc19 ) expression levels in ptsd ba46 or because of their 
     known relevance to neuropsychiatric disorders ( app , est2 and slc1a6 ) .
the results showed that 
     the relative mrna levels of these genes measured by qrt - pcr were essentially in agreement with 
     the data detected by microarray experiments ( fig .
3 ) . 
     specifically , 11 of 12 ( 92% ) of expression changes were consistent between these two methods for 
     app , 9 of 12 ( 75% ) for slc9a6 , and 8 of 12 ( 67% ) for dnajc19 , slc1a6 and esr2 .
the discrepant 
     data were randomly distributed among the genes and samples tested ( fig .
thus , we 
     subjected all the 119 dysregulated genes to analysis of a systems biology including the pathway , 
     ontology and network .
the mitochondrial dysfunction and oxidative phosphorylation pathways contained the 
      highest number of dysregulated genes . to see functional relationships
the results showed that out of 94 
     canonical pathways , 16 ( 17.0% ) contained a significant number of dysregulated genes per pathway , 
     of which 10 were listed in figure 4a .
the mitochondrial 
     dysfunction pathway contained 8 ( 4.8% ) dysregulated genes 
     ( p=6.61x10 ) including upregulated app , cat , ndufa10 and ucp2 and 
     downregulated cox8a , ndufb5 , ndufs2 and pdha1 .
the oxidative phosphorylation pathway had 6 
     ( 3.8% ) dysregulated genes ( p=9.04x10 ) including upregulated atp5c1 
     and ndufa10 and downregulated atp5e , cox8a , ndufb5 and ndufs2 .
the citrate cycle pathway had 3 
     ( 5.1% ) dysregulated genes ( p=1.71x10 ) including upregulated idh3b 
     and downregulated cs and suclg1 .
the methane metabolism pathway contained 2 ( 3.1% ) dysregulated 
     genes ( p=5.38x10 ) including upregulated cat and downregulated mpo . 
    
the ubiquinone biosynthesis pathway had 3 ( 2.9% ) dysregulated genes 
      ( p=1.11x10 ) including upregulated ndufa10 and downregulated 
     ndufb5 and ndufs2 . the erk / mark signaling pathway included upregulated h3f3a , ppp2r1b , prkcd and 
     tln2 , and downregulated prkar2b ( n=5 [ 2.8% ] , p=1.18x10 ) .
the 
     propanoate metabolism pathway had upregulated acad8 and acadl and downregulated suclg1 ( n=3 
     [ 2.4% ] , p=1.21x10 ) .
the xenobiotic metabolism pathway contained 
     upregulated cat , hsp90ab1 , ppp2r1b and prkcd and downregulated aldh18a1 and mgst1 ( n=6 [ 2.4% ] , 
      p=1.28x10 ) .
the valine , leucine and isoleucine degradation 
     pathway contained upregulated acad8 , acadl and hmgcl ( n=3 [ 2.8% ] , 
      p=1.38x10 ) .
the pyruvate metabolism pathway had downregulated 
     akr1b1 , hagh and pdha1 ( n=3 [ 2.1% ] , p=2.05x10 ) ( fig .
46 dysregulated genes were mapped to neurological diseases and other systemic 
     disorders . to see phenotypes involved , we performed mapping of all 119 dysregulated genes 
     to known human diseases and disorders .
the results revealed that 35 dysregulated genes had known 
     roles in a variety of neurological diseases ( 28 genes ) and other systematic disorders including 
     endocrine ( 14 genes ) , genetics ( 11 genes ) , metabolism ( 12 genes ) and psychology ( 6 genes ) .
the 
     number of these dysregulated genes were all statistically significant 
     ( p<0.05 ) .
in addition , 17 ( 61% ) of the 28 genes that were mapped to 
     neurological diseases were known to play a role in survival and apoptosis of a cell . moreover
, a 
     total of 30 dysregulated genes were mapped to the cell survival - apoptosis category ( fig .
many of these genes are involved in multiple abnormalities , 
     suggesting that ptsd is a neurological and systemic disorder .
table 2 lists 30 ptsd - dysregulated genes that have been 
     described to play a pathogenic role in various neurological diseases and psychiatric disorders . 
    
upregulated app induces changes in nitric oxide production and mitochondrial activity , leading 
     to apoptosis 31 , which have been implicated in 
     amyloidosis 32;33 , 
     neurodegeneration 34 , alzheimer 's disease 35;36 and down syndrome 
      37 .
considering the role of myeloperoxidase ( mpo ) in 
     modulating vascular inflammatory responses and transporting molecules as well as its 
     incapability of clearing up amyloid when mutated 38 - 40 , mpo downregulation may lead to regional accumulation of 
     amyloid , resulting in mitochondrial dysfunction and cell death .
peptidylprolyl isomerase d 
     ( ppid ) suppresses apoptosis via a mitochondrial hexokinase ii - dependent mechanism and its 
     decreased expression has been associated with corticobasal degeneration characterized by nerve 
     cell loss and atrophy 41 .
dysregulation of genes with 
     known functions as neurotransmitters in synaptic vesicles ( slc1a6 and vamp1 ) and cell adhesion 
     ( pecam1 , cdh13 and spg7 ) are related to diseases in the central nervous system .
dysregulation of 
     these genes might reduce synaptic communication , and jeopardize cell - to - cell interactions and/or 
     cell - to - matrix adhesion .
these are but a few examples ( table 2 ) . networks of 54 dysregulated genes involved in neuron function and survival and 7 protein 
      targets for neuropsychiatric drugs : to reveal complex interactions among dysregulated 
     genes and to identify gene targets for the central nervous system drugs , we mapped 54 
     dysregulated genes to molecular networks .
these genes were selected for analysis because of 
     their obvious relevance to neurological diseases , psychological disorders , psychiatric 
     disorders , and stress response in the central nervous system .
the results revealed interactive 
     networks with a total of 75 molecular elements that maintain neuronal function and survival . 
     within these networks ,
27 ( 36% ) genes were upregulated ; 27 ( 36% ) genes were downregulated ; and 
     21 ( 28% ) elements appear to be unchanged ( fig .
these 
     data strongly suggest molecular and cellular abnormalities in neuronal function and survival in 
     ptsd dlpfc ba46 .
importantly , 7 gene products within the neuronal function - survival networks were identified as 
     known targets of drugs that are used for neurological diseases , psychological and/or behavioral 
     disorders , including app as a target for bapineuzumab ( aab-001 ) , vamp1 for dysport , slc1a6 for 
     riluzole , esr2 for 17-estradiol ( agonist ) and tamoxifen ( antagonist ) , prkcd for 
     tamoxifen and rottlerin , pp2a for okadaic acid and fostriecin , and ucp2 for mptp 
     ( 1,2,3,6-methyl - phenyl - tetrahydropyridine ) .
human brain dlpfc including ba46 is involved in regulation of working memory and preparation 
     and selection of fear responses and has been correlated with structural and functional 
     alterations and treatment response of patients with ptsd 9 - 13 .
however , the underlying cellular and 
     molecular mechanisms are unknown . in this study , we applied human mitochondria - focused cdna 
     microarrays ( hmitchip3 ) to ptsd brain samples and have successfully identified expression 
     signatures , canonical pathways , molecular networks and drug targets of neurological disease- and 
     psychological / psychiatric disorder - related genes that are dysregulated in the dlpfc ba46 .
our 
     results indicate mitochondrial dysfunction involved in neuronal function and survival in the 
     dlpfc ba46 and may prove useful for development of methods for diagnosis , prevention and 
     treatment of ptsd .
unsupervised clusters of 12 dlpfc ba46 rna samples based solely on expression similarities of 
     informative 800 mitochondria - focused genes clearly distinguish the ptsd brains from the 
     controls .
the identification of 119 ( p<0.05 , 1.25 ) 
     and 42 ( p<0.05 , 1.60 ) dysregulated genes provides 
     candidates for qrt - pcr validation and for subsequent functional studies .
the clustering 
     signatures of these genes may facilitate further development of methods and tools for forensic 
     diagnosis of ptsd .
our approach has generated informative results partially because of our 
     accurate dissection of brain dlpfc ba46 gray matter , and partially because of the utilization of 
     our hypothesis - driven mitochondria - focused cdna microarrays .
however , we can not explain why the 
     samples p4 and n2 had expression profiles different from their clinical classification . due to a 
     small sample size , p4 and
n2 were kept in the groups based on their gene expression rather than 
     a clinical diagnosis because the former might be more objective than the latter .
we would like 
     to repeat the study when more ptsd and control specimens become available in order to improve 
     the molecular classification of ptsd .
the subsequent experiments should examine both mrna and 
     protein levels in the dlpfc ba46 , as well as other ptsd - related brain regions such as medial and 
     ventral pfc , hippocampus , and amygdala 6;7;42 .
the mitochondria - mediated cellular and molecular response to stress in the central nervous 
     system of patients with ptsd is the key part of our hypothesis because mitochondria are at the 
     center of a cellular response to stress 14;15 .
study of mitochondrial function is inevitable and our 
     application of the mitochondria - focused cdna microarrays to ptsd is just the beginning . 
    
mitochondrial function in the brain is of particular importance because of its high energy 
     demand .
although human brain represents only 2% of body weight , it receives 15% of the body 's 
     cardiac output , and uses 20% of total body oxygen .
these high level oxygen and energy 
     requirements are continuous and imply that even brief periods of oxygen or glucose deprivation 
     may impair neuron function and even result in neuron death .
our demonstration that a highly 
     significant number of oxidative phosphorylation genes were dysregulated in the ptsd brain ba46 
     strongly suggests the presence of at least energy deficiency in this brain region .
our findings 
     support the postulation that mitochondria - focused and stress - responsive genes may play a key 
     role in the pathogenesis of ptsd , although the specific impact of these dysregulated genes and 
     pathways on brain function remains to be determined .
the identification and validation of the dysregulated genes enhances our understanding of the 
     cellular and molecular mechanisms underlying the pathophysiology of ptsd .
the genes listed in 
     table 2 are critical to the ba46 neuronal functions 
     including survival and apoptosis , carbohydrate and lipid metabolism , atp and ros production , 
     synthesis and transport of neurotransmitter , mitochondrial and nuclear dna expression , and 
     protein phosphorylation and dephosphorylation as well as folding and degradation .
because 
     homeostasis of these mitochondrial functions is vital for neuronal function and survival , the 
     presence of a hundred consistently dysregulated genes in the ptsd dlpfc ba46 implies a 
     pathological role .
in addition , more genes were downregulated than those upregulated ( 63 vs. 56 
     in supplemental table 1 and 18 vs. 12 in table 2 ) . 
     moreover
, some upregulated genes play a degradative or negative role such as proapoptosis ( e.g. , 
     app ) , reduction of atp synthesis ( e.g. , ucp2 ) and protein breakdown ( e.g. , hspa1a ) . taken 
     together , functional impairment and atrophy in the ptsd dlpfc ba46 might be a consequence of 
     these dysregulated genes .
thus , the neurons in the ptsd dlpfc ba46 may be unable to regulate 
     working memory and preparation and selection of healthy responses to fear or may even send 
     abnormal signals to their downstream executive neurons such as those in the hippocampus and/or 
     amygdala .
our molecular insight in the ptsd dlpfc ba46 pathogenesis is reminiscent of the 
     neurocircuitry model by bremner 43 and rauch et al 42 that the fear extinction abnormalities in ptsd are 
     characterized by exaggerated amygdala responses and deficiency in ventral / medial pfc and 
     hippocampus .
therefore , our systems biology results appear not only to extend the neurocircuitry 
     model to brain dlpfc ba46 , but they also provide genes and proteins that should be further 
     investigated for better understanding of the molecular pathogenesis of ptsd .
seven protein targets for neuropsychiatric drugs are present in the neuronal function - survival 
     networks in human brain dlpfc ba46 .
in addition of dysregulation of 72% ( 54/75 ) genes in these 
     networks , many dysregulated genes are associated with multiple neuropsychiatric conditions such 
     as alzheimer 's disease , parkinson 's disease , schizophrenia , and major depressive disorder ( mdd ) , 
     down syndrome , attention disorders and mood disorders ( table 2 ) . obviously , modulations of these genes with drugs would affect neuropsychiatric 
     functions of the neurons in human dlpfc ba46 .
for example , the app is a target for the 
     immunotherapeutic drug bapineuzumab that is currently used for the phase 3 clinical trials for 
     the treatment of patients with alzheimer 's disease 44 . 
    
the esr2 is a target for 17-estradiol ( agonist ) and tamoxifen ( antagonist ) . beside the 
     treatment of estrogen - receptor positive breast cancer ,
tamoxifen is used to treat mania in 
     patients with bipolar disorder , probably by blocking prkcd 45 .
the prkcd is also a target for rottlerin used in preclinical study of parkinson 's 
     disease 46 .
the ucp2 is a target 
     for protection of dopaminergic neurons from oxidative stress caused by 
     1,2,3,6-methyl - phenyl - tetrahydropyridine ( mptp ) toxicity 48 .
however , whether these drugs and related targets might be useful for prevention and 
     treatment of ptsd is interesting and deserves further studies .
supplemental table 1a : microarray mean data before normalization click here for additional data file .
supplemental table 1b : microarray mean data after normalization click here for additional data file . click here for additional data file .
traumatic stress brain study group includes david benedek and harry holloway , dept of 
      psychiatry & center for the study of traumatic stress , usuhs , school of medicine ; maree 
      j. webster , stanley medical research institute ; christopher j. hough , fda ; ronald duman , 
      abraham ribicoff research facilities laboratory of molecular psychiatry , yale university school 
      of medicine ; matthew friedman , national center for ptsd , us dept of veterans affairs & 
      dartmouth medical school ; john krystal , clinical neuroscience division , va national center for 
      ptsd , va connecticut healthcare system , west haven , ct & dept of psychiatry , yale 
      university school of medicine ; gregory leskin , national center for ptsd , va palo alto health 
      care system ; james meyerhoff , georgetown university school of medicine & division of 
      psychiatry & neurosciences , walter reed army institute of research ; elizabeth osuch , 
      dept of psychiatry , university of western ontario , schulich school of medicine and 
     dentistry .
 posttraumatic stress disorder ( ptsd ) is associated with decreased activity in the 
      dorsolateral prefrontal cortex ( dlpfc ) , the brain region that regulates working memory and 
      preparation and selection of fear responses . 
 we investigated gene expression profiles in dlpfc 
      brodmann area ( ba ) 46 of postmortem patients with ( n=6 ) and without ptsd ( n=6 ) using human 
      mitochondria - focused cdna microarrays . 
 our study revealed ptsd - specific expression fingerprints 
      of 800 informative mitochondria - focused genes across all of these 12 ba46 samples , and 119 
      ( >1.25 , p<0.05 ) and 42 ( >1.60 , 
       p<0.05 ) dysregulated genes between the ptsd and control samples . 
      
 quantitative rt - pcr validated the microarray results . 
 these fingerprints can essentially 
      distinguish the ptsd dlpfc ba46 brains from controls . 
 of the 119 dysregulated genes 
      ( 125% , p<0.05 ) , the highest percentages were 
      associated with mitochondrial dysfunction ( 4.8% , p=6.61x10 - 6 ) , 
      oxidative phosphorylation ( 3.8% , p=9.04x10 - 4 ) , cell 
      survival - apoptosis ( 25.2% , p<0.05 ) and neurological diseases ( 23.5% , 
       p<0.05 ) . 
 fifty ( 50 ) dysregulated genes were present in the molecular 
      networks that are known to be involved in neuronal function - survival and contain 7 targets for 
      neuropsychiatric drugs . 
 thirty ( 30 ) of the dysregulated genes are associated with a number of 
      neuropsychiatric disorders . 
 our results indicate mitochondrial dysfunction in the ptsd dlpfc 
      ba46 and provide the expression fingerprints that may ultimately serve as biomarkers for ptsd 
      diagnosis and the drugs and molecular targets that may prove useful for development of remedies 
      for prevention and treatment of ptsd . 