Biology subjects

Akil, H.

Publications and source records attributed to Akil, H..

31 records · Page 2Linked to original sources

bioRxiv2023

Patterns of Neural Activation During an Initial Social Stress Encounter are Predictive of Future Susceptibility or Resilience: A FosTRAP2 Study

Repeated social stress is a significant factor in triggering depression in vulnerable individuals, and genetic and environmental factors interact to contribute to this vulnerability. Interestingly, the role of experience in shaping vulnerability is not well studied. To what extent does an individuals initial reaction to a given stressor influence their response to similar stressors in the future? And how is this initial response encoded at the neural level to bias towards future susceptibility or resilience? The Chronic Social Defeat Stress (CSDS) mouse model offers an ideal opportunity to address these questions. Following 10 days of repeated social defeat, mice diverge into two distinct populations of social reactivity: resilient (interactive) and susceptible (avoidant). It is notable that the CSDS paradigm traditionally uses genetically inbred mice, indicating that this divergence is not genetically determined. Furthermore, the emergence of the two phenotypes only occurs following several days of exposure to stress, suggesting that the repeated experience of social defeat influences future susceptibility or resilience. In this study, we asked whether specific patterns of neural activation during the initial exposure to the social defeat stress can predict whether an individual will eventually emerge as resilient or susceptible. To address this question, we used Fos-TRAP2 mouse technology to capture brain-wide neural activation patterns elicited during the initial stress exposure, while allowing the mice to go on to experience the full course of CSDS and diverge into resilient and susceptible populations. Using a high-throughput brain-wide cell counting approach, we identified the bed nucleus of the stria terminalis and lateral septal nucleus as key hubs for encoding social defeat. We also identified the basomedial amygdala as a hub for encoding future susceptibility, and the hippocampal CA1 area and medial habenula for encoding future resilience. Our findings demonstrate that the initial experience with social stress induces a distinct brain-wide pattern of neural activation associated with defeat, as well as unique activation patterns that appear to set the stage for future resilience or susceptibility. This highly orchestrated response to defeat is seen especially in animals that emerge as resilient compared to susceptible. Overall, our work represents a critical starting place for elucidating mechanisms whereby early experiences can shape vulnerability to affective disorders.

neuroscience↗

bioRxiv2022

Effect of selective lesions of nucleus accumbens μ-opioid receptor-expressing cells on heroin self-administration in male and female rats: a study with novel Oprm1-Cre knock-in rats

The brain {micro}-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell-type specific genetic access to MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the role of nucleus accumbens (NAc) MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and fluorescence in situ hybridization chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum (DS), and dorsal hippocampus, or MOR receptor density (except DS) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly co-expressed with Oprm1 (95-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells and report sex-specific effects: the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an Oprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study with these rats suggests a sex-specific role of NAc MOR-expressing cells in heroin self-administration. Significance statementThe brain {micro}-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell-type specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to show a potential sex-specific role of nucleus accumbens MOR-expressing cells in heroin self-administration. The new Oprm1-Cre rats can be used to study both the general and sex-specific role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

neuroscience↗

bioRxiv2022

Transcriptional Profiling of the Hippocampus in an F2 Cross of a Genetic Rat Model of Internalizing vs. Externalizing Behavior and Addiction Liability

Selectively-bred High Responder (bHR) and Low Responder (bLR) rats model the extreme externalizing and internalizing behavior accompanying many psychiatric disorders. To elucidate gene expression underlying these heritable behavioral differences, bHRs and bLRs (generation 37) were used to produce a F0-F1-F2 cross. We measured exploratory locomotion, anxiety-like behavior, and reward cue sensitivity (Pavlovian Conditioned Approach), and performed hippocampal RNA-Seq in male and female F0s (n=24) and F2s (n=250). Behaviors that diverged during selective breeding remained correlated in F2s, implying a shared genetic basis. F0 bHR/bLR differential expression was robust, surpassing differences associated with sex, and predicted expression patterns associated with F2 behavior. With bHR-like behavior, gene sets related to growth/proliferation were upregulated, whereas with bLR-like behavior, gene sets related to mitochondrial function, oxidative stress, and microglial activation were upregulated. This differential expression could be successfully predicted based on F0 genotype using cis-expression quantitative trait loci (cis-eQTLs) identified in the F2s. Colocalization of these cis-eQTLs with behavioral Quantitative Trait Loci pinpointed 16 differentially expressed genes that were strong candidates for mediating the influence of genetic variation on behavioral temperament. Our findings implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, modulating vulnerability to psychiatric disorders.

neuroscience↗

bioRxiv2022

Cocaine during adolescence differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes

While early life drug use reliably predicts addiction liability in adulthood, the molecular mechanism by which this occurs, and the degree genetic predisposition is involved is not known. We used a unique genetic rat model of temperament to determine the impact of adolescent cocaine experience on adult psychomotor sensitization and epigenetic profiles in the striatum. Relative to adult bred low-responder (bLR) rats, bred high-responders (bHR) are more sensitive to the psychomotor-activating effects of cocaine and reinstate drug-seeking behavior more readily following prolonged cocaine exposure and a period of abstinence. We found that a 7-day sensitizing cocaine regimen (15 mg/kg/day) during either adolescence or adulthood produced psychomotor sensitization in bHRs only, while a dual cocaine exposure prevents further sensitization, suggesting limits on neuroplasticity. By contrast, adolescent cocaine in bLRs shifted their resilient phenotype, rendering them more responsive to cocaine in adulthood when initially challenged with cocaine We then assessed two functionally opposite epigenetic chromatin modifications, previously implicated in addiction liability, permissive acetylation (ac) and repressive tri-methylation (me3), on histone 3 lysine 9 (H3K9) in four sub-regions of the striatum. In bHRs, decreased repressive histone, H3K9me3, and increased permissive histone, acH3K9, in nucleus accumbens core associated with cocaine sensitization. However, there were limits on these epigenetic changes that paralleled the behavioral limits on further sensitization. In bLRs, the combination of cocaine exposure in adolescence and adulthood, which lead to an increase in their responsiveness to a cocaine challenge, also increased acH3K9 expression in the core. Thus, adolescent cocaine experience interacts with genetic background to elicit different behavioral profiles relevant to addiction in adulthood, with concurrent modifications in the epigenetic histone profiles in the nucleus accumbens that associate with cocaine sensitization and with metaplasticity. SIGNIFICANCE STATEMENTAdolescence is a critical period when brain developmental trajectories continue to be established and when most illicit drug use is initiated in humans. Notably, however, only a minority of adolescent drug users go on to develop substance use disorders in adulthood. We hypothesize that individual differences in genetic vulnerability, temperamental phenotype and adolescent drug history intersect to modify life-long drug abuse liability, with epigenetic modification playing an important role in this interplay. We tested this hypothesis in a genetic animal model of temperament. Our results show that adolescent cocaine experience induces psychomotor sensitization in vulnerable individuals, and that a dual exposure to cocaine (both in adolescence and adulthood) limits further sensitization in these individuals, an example of metaplasticity. By contrast, individuals who are typically resilient become more responsive to cocaine when exposed to this drug during adolescence and are then re-exposed as adults. Differences in behavioral response to cocaine were associated with unique epigenetic changes in the nucleus accumbens core. These findings shed light on the interplay of genes, environment and adolescent exposure to drugs in susceptibility to substance use disorders.

neuroscience↗

bioRxiv2022

Genome-Wide Association Study in a Rat Model of Temperament Identifies Multiple Loci for Exploratory Locomotion and Anxiety-Like Traits

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2 cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.

genetics↗

bioRxiv2022

High emotional reactivity is associated with activation of a molecularly distinct hippocampal-amygdala circuit modulated by the glucocorticoid receptor

Emotions are characterized not only by their valence but also by whether they are stable or labile. Yet, we do not understand the molecular or circuit mechanisms that control the dynamic nature of emotionality. We have shown that glucocorticoid receptor overexpression in the forebrain (GRov) leads to a highly reactive mouse with increased anxiety behavior coupled with greater swings in emotional responses. This phenotype is established early in development and persists into adulthood. However, the neural circuitry mediating this lifelong emotional lability remains unknown. In the present study, optogenetic stimulation in ventral dentate gyrus (vDG) of GRov mice led to a greater range and a prolonged duration of anxiety behavior. cFos expression showed that the amplified behavioral response to vDG activation in GRov mice is coupled to increased neuronal activity in specific brain regions. Relative to wild type mice, GRov mice displayed glutamatergic/GABAergic activation imbalance in ventral CA1 (vCA1) and selectively increased glutamatergic activation in the basal posterior amygdaloid complex. Fluorescence in situ hybridization chain reaction studies showed that forebrain GR overexpression led to increased activation of molecularly distinct subpopulations of neurons within the hippocampus and the posterior basolateral amygdala (pBLA). Increased cFos labeling was observed in the Calbindin 1 (Calbn1+) glutamatergic neurons in vCA1 and in the DARPP-32/Ppp1r1b+ glutamatergic neurons in pBLA. We propose that a molecularly distinct hippocampal-amygdala circuit is shaped by stress early in life and tunes the dynamics of emotional responses.

neuroscience↗

bioRxiv2022

Forebrain glucocorticoid receptor overexpression alters behavioral encoding of hippocampal CA1 pyramidal cells in mice

Stress hormone signaling via the glucocorticoid receptor (GR) modulates vulnerability to stress-related disorders, but whether GR influences how the brain encodes contextual experience is unknown. Mice with lifelong GR overexpression in forebrain glutamatergic neurons (GRov) show increased sensitivity to environmental stimuli. This phenotype is developmentally programmed and associated with profound changes in hippocampal gene expression. We hypothesized that GR overexpression influences hippocampal encoding of experiences. To test our hypothesis, we performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female WT and GRov mice during exploration of a novel open field. We compared calcium amplitude and event rate as well as sensitivity to center location and mobility between genotypes. GRov neurons exhibited higher average calcium activity than WT neurons in the novel open field. While most neurons showed sensitivity to center location and/or mobility, GRov neurons were more likely to be sensitive to center location and less likely to be sensitive to mobility, as compared to WT neurons. More than one-third of behavior-selective GRov neurons were uniquely sensitive to location without mobility sensitivity; these uniquely center-sensitive neurons were rare in WT. We conclude that dorsal CA1 pyramidal cells in GRov mice show increased activity in a novel environment and preferentially encode emotionally salient behavior. This heightened sensitivity to a novel environment and preferential encoding of emotionally salient elements of experience could underlie differential stress vulnerability in humans with increased glucocorticoid sensitivity. Significance Statement (120 words maximum)Endogenous stress hormones, glucocorticoids, are known to alter vulnerability to stress-related disorders. Here, we find that increased sensitivity to glucocorticoid via lifelong overexpression of glucocorticoid receptor in forebrain neurons (GRov) alters the encoding of environmental experiences in the hippocampus. GRov mice showed increased activity of dorsal CA1 hippocampal pyramidal cells during exploration of a novel environment and more sensitivity to emotionally relevant behaviors. These changes in how hippocampal neurons encode environmental experiences could underlie the differences in stress vulnerability in humans with genetic and epigenetic differences in glucocorticoid receptor signaling.

neuroscience↗

bioRxiv2021

Characterizing the Behavioral and Neuroendocrine Features of Susceptibility and Resilience to Social Stress

Evaluating and coping with stressful social events as they unfold is a critical strategy in overcoming them without long-lasting detrimental effects. Individuals display a wide range of responses to stress, which can manifest in a variety of outcomes for the brain as well as subsequent behavior. Chronic Social Defeat Stress (CSDS) in mice has been widely used to model individual variation following a social stressor. Following a course of repeated intermittent psychological and physical stress, mice diverge into separate populations of social reactivity: resilient (socially interactive) and susceptible (socially avoidant) animals. A rich body of work reveals distinct neurobiological and behavioral consequences of this experience that map onto the resilient and susceptible groups. However, the range of factors that emerge over the course of defeat have not been fully described. Therefore, in the current study, we focused on characterizing behavioral, physiological, and neuroendocrine profiles of mice in three separate phases: before, during, and following CSDS. We found that following CSDS, traditional read-outs of anxiety-like and depression-like behaviors do not map on to the resilient and susceptible groups. By contrast, behavioral coping strategies used during the initial social stress encounter better predict which mice will eventually become resilient or susceptible. In particular, mice that will emerge as susceptible display greater escape behavior on Day 1 of social defeat than those that will emerge as resilient, indicating early differences in coping mechanisms used between the two groups. We further show that the social avoidance phenotype in susceptible mice is specific to the aggressor strain and does not generalize to conspecifics or other strains, indicating that there may be features of threat discrimination that are specific to the susceptible mice. Our findings suggest that there are costs and benefits to both the resilient and susceptible outcomes, reflected in their ability to cope and adapt to the social stressor.

neuroscience↗

bioRxiv2021

Genomic Modules and Intramodular Network Convergency of Susceptibility and Resilience in Multimodeled Stress in Male Mice

The multifactorial etiology of stress-related disorders is a challenge in developing synchronized medical standards for treatment and diagnosis. It is largely unknown whether there exists molecular convergence in preclinical models of stress generated using disparate construct validity. Using RNA-sequencing (RNA-seq), we investigated the genomic signatures in the ventral hippocampus, which mostly regulates affective behavior, in mouse models that recapitulate the hallmarks of anxiety and depression. Chronic oral corticosterone (CORT), a model that causes a blunted endocrine response to stress, induced anxiety- and depression-like behavior in wildtype mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor (BDNF) Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of mice, chronic social defeat stress led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, standard housing or enriched environment. A rank-rank-hypergeometric (RRHO) analysis of the RNA-seq data set across models demonstrated that in mice treated with CORT and susceptible mice raised in standard housing differentially expressed genes (DEGs) converged toward gene networks involved in similar biological functions. Weighted gene co-expression analysis generated 54 unique modules of interconnected gene hubs, two of which included a combination of all experimental groups and were significantly enriched in DEGs, whose function was consistent with that predicted in the RRHO GO analysis. This multimodel approach showed transcriptional synchrony between models of stress with hormonal, environmental or genetic construct validity shedding light on common genomic drivers that embody the multifaceted nature of stress-related disorders.

neuroscience↗

bioRxiv2021

Differences in microglia morphological profiles reflect divergent emotional temperaments: Insights from a selective breeding model

Microglia are known to play critical roles in healthy brain development and function, as well as the neuropathology underlying a range of brain diseases. Despite the growing evidence for a role for microglia in affective regulation and mood disorders, relatively little is known regarding how variation in microglia status relates to individual differences in emotionality. Using a selective breeding model based on locomotor response to novelty, we have generated rat lines with unique temperamental phenotypes that reflect broad emotional traits: low responder rats (bLRs) are novelty-averse and model a passive coping style, whereas high responder rats (bHRs) are highly exploratory and model an active coping style. To identify a possible functional role of microglia in these phenotypes, we administered minocycline, an antibiotic with potent microglia inhibiting properties. We found changes in emotional and social behaviors in bLRs, with no discernable effects in bHRs. Using detailed anatomical analyses, we went on to explore the nature of baseline differences in hippocampal microglia populations associated with the divergent temperaments. Interestingly, we found that although bHRs and bLRs had comparable total numbers of hippocampal microglia, selective breeding was associated with a shift in the morphological features of these cells. Specifically, microglia from bLRs were characterized by a hyper-ramified morphology, with longer processes and more complicated branching patterns than microglia from bHRs. This morphology is thought to reflect an early stage of microglia activation and suggests that microglia from bLRs may be in a reactive state even when animals are not overtly stressed or challenged. Taken together, our results provide novel evidence linking variation in inborn temperament with differences in the baseline morphological status of microglia cells and highlight the importance of considering the role of microglia not only in acute responses to stress but also in shaping enduring characteristics of emotionality.

neuroscience↗

bioRxiv2021

Early acquisition of threat conditioning in a selectively-bred anxiety-like rat phenotype: regulation by maternal presence and FGF2

Temperament is an innate, stable predisposition towards particular emotional and behavioral responses. In humans, certain temperaments are associated with a heightened risk of developing anxiety later in life. Non-human animals, including rodents, also exhibit innate, stable dispositions; these are referred to as behavioral phenotypes. The interaction between behavioral phenotype and early life adverse events is critical for the development of maladaptive anxiety. Rodent studies of typically developing animals have identified a number of mechanisms that protect against aversive experiences in early life. One such mechanism is an early life quiescence of threat learning, which protects against the effects of stress and facilitates safety and attachment learning. However, little is known about the factors that alleviate the effects of early life aversive events on phenotypes vulnerable to pathological anxiety. Here, we examined threat learning and the stress response in selectively-bred infant rats that show an anxiety-like phenotype relative to typically developing animals. We investigated the potential roles of maternal presence and the anxiolytic neurotrophic factor fibroblast growth factor 2 (FGF2) in regulating threat learning and the stress response in infant anxiety-like phenotype animals. We observed that rats selectively-bred for anxiety-like behaviors could acquire conditioned freezing earlier in life than typically developing animals. FGF2 administration on postnatal day 1 (PND 1) and maternal presence during threat conditioning were both capable of suppressing this early emergence of conditioned freezing. However, neither FGF2 nor maternal presence during threat conditioning were associated with reduced corticosterone levels during threat conditioning. Our results suggest that although an anxiety-like phenotype may be associated with early threat learning, environmental factors (such as maternal presence) and pharmacological intervention (such as modulation of the FGF2 system) may be capable of counteracting that early aversive learning. Interventions in vulnerable infants may thus decrease the impact of aversive events.

neuroscience↗

bioRxiv2019

A Meta-Analysis of Hippocampal Transcriptional Profiling Studies in a Selectively-Bred Rat Model Provides Converging Evidence with Genetic Sequencing to Implicate Specific Candidate Genes and Pathways in the Liability for Internalizing and Externalizing Psychiatric Disorders

BackgroundFor over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These "bred High Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders. MethodsOur study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype. ResultsGenetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8. ConclusionThese candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.

neuroscience↗

bioRxiv2016

INFERENCE OF CELL TYPE COMPOSITION FROM HUMAN BRAIN TRANSCRIPTOMIC DATASETS ILLUMINATES THE EFFECTS OF AGE, MANNER OF DEATH, DISSECTION, AND PSYCHIATRIC DIAGNOSIS

Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type composition for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released: https://github.com/hagenaue/BrainInABlender). Using this method, we found that the principal components of variation in the datasets strongly correlated with the neuron to glia ratio of the samples.\n\nThis variability was not simply due to dissection - the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.

bioinformatics↗