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Published in final edited form as: Psychoneuroendocrinology. 2018 May 30;96:143–147. doi: 10.1016/j.psyneuen.2018.05.039

Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: A human post-mortem study

MR Lee a,*, MB Sheskier a, M Farokhnia a, N Feng b, S Marenco b, BK Lipska b, L Leggio a,c
PMCID: PMC12258498  NIHMSID: NIHMS2095719  PMID: 29940428

Abstract

There is growing interest in oxytocin as a putative treatment for various psychiatric disorders including major depressive disorder, bipolar disorder and schizophrenia/schizoaffective disorder. However, potential alterations in the endogenous brain oxytocin system in these disorders are poorly characterized. Brain expression of oxytocin and its receptor genes in patients with these psychiatric disorders has not been well studied outside the hypothalamus. We measured expression of mRNA for oxytocin and its receptor in the dorsolateral prefrontal cortex of postmortem brains using quantitative polymerase chain reaction in a total of 581 individuals. These individuals either were diagnosed with major depressive disorder (n = 135), bipolar disorder (n = 57), schizophrenia/schizoaffective disorder (n = 169), or were control subjects, defined as individuals with no lifetime history of any of these disorders (n = 220). Diagnoses of major depressive disorder and bipolar disorder were associated with significantly increased oxytocin receptor mRNA levels in the dorsolateral prefrontal cortex. This finding is discussed in light of the extant literature on the dysregulation of oxytocin signaling in individuals with major psychiatric disorders.

Keywords: Oxytocin, Oxytocin receptor, mRNA, Dorsolateral prefrontal cortex, Major depressive disorder, Bipolar disorder, Schizophrenia

1. Introduction

There is growing interest in investigating the role of the nine amino acid peptide oxytocin (OT) as a pharmacologic therapy for various psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BPD) and schizophrenia(SZ)/schizoaffective disorder (Macdonald and Macdonald, 2010). This interest in oxytocin as a treatment stems from preclinical and clinical studies demonstrating the role of exogenous and endogenous OT to promote social affiliation and cognition, to improve mood and to reduce anxiety (Meyer-Lindenberg et al., 2011). Therefore, it is important to shed light on whether the endogenous OT system (including both the peptide and the receptor) is altered in psychiatric disorders.

There are only a few human postmortem studies examining alterations in brain expression of OT and its receptor in psychiatric disorders. Most of these studies focused on the hypothalamus, which is the site of OT synthesis. OT was found to be upregulated in mood disorders: there were increased numbers of OT positive neurons in the paraventricular nucleus (PVN) in patients with MDD and BPD compared to controls (Purba et al., 1996). In a more recent case-control study, there was also significantly greater OT immunoreactivity in the PVN of patients with MDD or BPD compared to controls (Dai et al., 2017). Case-control studies in individuals with MDD found no difference in OT mRNA levels in the PVN (Wang et al., 2008). Among subjects with MDD, there was a higher level of PVN OT mRNA in the subgroup with melancholic depression compared to those with non-melancholic depression, however, neither group nor the combined group differed from controls (Meynen et al., 2007). In individuals with SZ, there was reduced OT receptor (OTR) mRNA expression in the temporal cortex and decreased receptor binding in the cerebellar vermis. There was also a trend for decreased OTR mRNA expression in the anterior prefrontal cortex and caudate nucleus (Uhrig et al., 2016).

The dorsolateral prefrontal cortex (DLPFC) has been implicated in structural and functional brain abnormalities in numerous psychiatric disorders including MDD (Fischer et al., 2016), BPD (Strakowski et al., 2005) and SZ (Berman et al., 1988). Reciprocal DLPFC cortical connections with the PVN mediate the stress response, which is altered in these psychiatric disorders (López et al., 1999). Therefore, examining the OT system in a critical brain region like the DLPFC that is involved in the pathophysiology of mood disorders and schizophrenia may be important. In this study, we measured expression of OT and OTR mRNA in the postmortem human DLPFC from a large group of individuals with MDD, BPD and SZ, compared to individuals with no lifetime history of any psychiatric disorders.

2. Materials and methods

2.1. Subjects and human postmortem brain tissue collection

Postmortem brain tissues (n = 581 subjects) were collected at the Human Brain Collection Core, National Institute of Mental Health (NIMH), with informed consent from the legal next of kin according to the National Institutes of Health Institutional Review Board and ethical guidelines under an NIMH protocol (90-M-0142). Clinical characterization, neuropathological screening, toxicological analyses, and dissection of the DLPFC were performed as previously described (Lipska et al., 2006).

Briefly, clinical information was obtained through postmortem family interviews including the Structured Clinical Interview for DSM-IV-clinician version (First et al., 1997) as well as psychiatric record reviews with the Diagnostic Evaluation after Death (Salzman et al., 1983). After these interviews and reviews, a case report was prepared summarizing the demographic, clinical, medical and death information. Each case was reviewed by two board-certified psychiatrists, who arrived at consensus DSM-IV Axis I lifetime diagnoses. All patients met criteria for a lifetime diagnosis of SZ (including those with schizoaffective disorder) (n = 169), BPD (n = 57), or MDD (n = 135) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) (First et al., 2002). The control group (n = 220) was defined as those with no history of psychiatric or substance use disorders as determined by telephone screening, medical examiner documentation and chart review, as well as negative toxicological analysis (except cotinine and alcohol) of blood and review of medical records when available. The lowest age of the comparison subject group was determined by the youngest age of any member of the three patient groups (i.e., 12 years). Information on manner of death (suicide, homicide, natural causes or accident) was available for all but 11 individuals.

2.2. Tissue retrieval, processing and neuropathology

From the DLPFC, gray matter tissue from the crown of the middle frontal gyrus was obtained from the coronal slab corresponding to the middle one-third immediately anterior to the genu of the corpus callosum. Grey matter was dissected out using a dental drill. Subcortical white matter was carefully trimmed from the area immediately below the middle frontal gyrus Neuropathological examination was performed in all cases by a board-certified neuropathologist. Brain sections through several cortical regions and the cerebellar vermis were examined microscopically, including the use of Bielschowsky’s silver stain. Cases with cerebrovascular disease (infarcts or hemorrhages), subdural hematoma, neuritic pathology, or other significant pathological features were excluded from further study. Cases with acute subarachnoid hemorrhages that were directly related to the immediate cause of death were not excluded (Lipska et al., 2006).

2.3. Antemortem drug exposure

Smoking status was determined by report that the subject was a smoker at the time of death (n = 255) and was available for > 99% of the individuals. This status was further confirmed by detectable levels of nicotine and cotinine in blood or cerebral tissue, available in > 85% of the samples. Postmortem toxicology screening was available for most samples to test for nicotine, alcohol, illicit drug use and prescription drug use at the time of death. Levels were measured using toxicology testing services of National Medical Services (Willow Grove, PA).

2.4. RNA extraction and real time qPCR analysis

Total RNA was extracted from ~ 100 mg of tissue from the DLPFC. The expression levels of OT and OTR mRNA were measured using quantitative real-time PCR on the ABI Prism 7900 sequence detection system with 384-well format (Applied Biosystems, Carlsbad, CA) by a standard curve method using Taqman assays (OT, Hs00792417_g1; OTR, Hs00168573_m1). The expression data were normalized to a geometric mean of three housekeeping genes (ACTB, Hs99999903_m1; B2M, Hs99999907_m1; GUSB, Hs99999908_m1). Amplification efficiencies for OT and OTR assays: 97% and 94%, respectively, and the correlation coefficients (R2) for the standard curves were > 0.997.

These samples were obtained as part of a larger cohort. Microarray RNA expression data on this cohort are currently publicly available (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000979.v1.p1).

2.5. Data analysis

Cycles to threshold (Ct), standard curves and amplification plots were assessed for all data. Ct were high for all OT gene mRNA (> 37) samples, therefore, it was concluded that there was no expression of OT gene mRNA in the DLPFC.

Ct for OTR gene mRNA were lower (28–32) and the standard curve was linear. Therefore, mRNA levels for OTR were examined for normality using the Shapiro-Wilk test. The data were not normally distributed; therefore, OTR mRNA levels were natural log (ln) transformed and this ln transformed value was the dependent variable in all further analyses. SPSS (version 23) was used for all statistical analyses.

Stepwise linear regression was conducted to determine whether psychiatric diagnosis (MDD, BPD, SZ or Control) was a significant predictor of ln-transformed OTR mRNA levels. The psychiatric diagnostic groups were first entered as the base model, then the following independent variables were added: age at death, race (African American or European American), sex, RNA integrity number (RIN), brain pH, postmortem interval (PMI), as well as positive toxicology for smoking (nicotine or cotinine) and alcohol at the time of death, as additional independent variables in stepwise fashion (p ≤ 0.050 to enter and p ≥ .100 to remove). If diagnostic group was a significant predictor in the final model, post-hoc one-way ANOVA was conducted with Bonferroni corrections for multiple comparisons between the 4 groups.

A second set of stepwise regressions was conducted on ln-transformed OTR mRNA expression levels for the SZ, MDD and BPD groups only (omitting the control group), and adding each of the following predictors (Table 1) to the aforementioned predictor variables in a separate regression model: manner of death (suicide, accident, homicide or natural causes; all homicides were in the control group), toxicology results for psychiatric medications (antipsychotics, antidepressants and mood stabilizers), toxicology results for substances of abuse (opiates, benzodiazepines, cocaine, cannabis) and history of alcohol dependence or illicit drug abuse.

Table 1.

Demographic Characteristics and Toxicology Results.

Diagnosis
Control MDD BPD SZ Total Missing Data Statistic
Number 220 135 57 169 581 0
Age at death (SD) 38.6(17.3) 44.7(14.3) 44.0(14.6) 49.8(14.9) 43.8(16.4)[n = 581] 0 < 0.001
Gender(M/F) (%F) 154/66(30) 78/57(42) 34/23(40) 106/63(37) 372/209(36) 0 0.10
Race(AA/Caucasian) (% Caucasian) 110/110(50) 14/121(90) 6/51(89) 73/96(57) 203/378(65) 0 < 0.001
Manner of Death Accident: 38 Accident: 16 Accident: 7 Accident: 21 Accident: 82 11 < 0.001a
Homicide: 30 Homicide: 0 Homicide: 0 Homicide: 0 Homicide: 30
Natural: 151 Natural: 32 Natural: 11 Natural: 110 Natural: 304
Suicide: 0 Suicide: 85 Suicide: 36 Suicide: 33 Suicide: 154
RNA integrity number (RIN) 8.64(0.56) 8.32(0.90) 8.07(0.94) 8.17(0.94) 8.37(0.83) 0 < 0.001
pH Mean (SD) 6.53(0.30) 6.35(0.28) 6.35(0.27) 6.41(0.25) 6.44(0.30)[n = 581] 0 < 0.001
PMI (hours) Mean(SD) 28.6(14.7) 38.1(25.5) 33.4(18.5) 38.7(23.8) 34.2(21.1)[n = 581] 0 < 0.001
Substance Abuse (N/Y) (%Y) 220/0(0) 78/57(42) 21/36(63) 98/71(42) 417/164(28) 0 0.014a
Alcohol Dependence (N/Y) (%Y) 220/0(0) 109/26(19) 44/13(23) 151/18(11) 524/57(10) 0 0.035a
Toxicology Results
Cotinine (−/+) 165/55 41/31 34/19 85/65 325/170[495] 86 0.001
   % positive 25% 43% 36% 43% 34%
ETOH (−/+) 209/11 62/23 44/9 156/12 471/55[526] 55 < 0.001
   % positive 5% 27% 17% 7% 10%
Antipsychotic (−/+) 153/0 73/7 37/16 61/106 324/129[453] 128 < 0.001a
   % positive 0% 9% 30% 63% 28%
Antidepressant (−/+) 154/0 36/44 24/29 123/43 337/116[453] 128 < 0.001a
   % positive 0% 55% 55% 26% 26%
Mood stabilizer (−/+) 133/0 72/8 36/17 137/30 378/55[433] 148 0.005a
   % positive 0% 10% 32% 18% 13%
Benzodiazepine (−/+) 214/0 68/12 37/16 156/11 475/39[514] 67 < 0.001a
   % positive 0% 15% 30% 7% 8%
THC (−/+) 211/0 57/4 52/1 153/2 473/7[480] 101 0.085a
   % positive 0% 7% 2% 1% 2%
Cocaine (−/+) 211/0 76/5 50/3 163/6 500/14[514] 67 0.603a
   % positive 0% 6% 6% 4% 3%
Opiate (−/+) 220/0 67/15 38/15 150/19 475/49[524] 57 0.014a
   % positive 0% 18% 28% 12% 9%
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AA = African Americans; MDD = Major Depressive Disorder; BPD = Bipolar Disorder.

a

Compared across the 3 patient groups only, controls excluded.

3. Results

Demographic characteristics of the study sample, manner of death, toxicology results and postmortem brain tissue characteristics are summarized in Table 1.

As stated above, the ln-transformed value for OTR mRNA level was the dependent variable in the linear regression analyses. There was no evidence of multi-collinearity, as shown by VIF < 3 for all independent variables.

The full model of diagnostic group (MDD, BPD or SZ), pH and RIN was statistically significant, R2 = 0.151, F (5,489) = 17.34, p < 0.001; Adjusted R2 = 0.142. A diagnosis of MDD and BPD significantly positively predicted normalized OTR mRNA levels (Table 2). On post-hoc testing, ln OTR mRNA levels were significantly higher for the MDD and BPD groups (p < 0.001, Bonferroni corrected) compared to the other 2 groups, whose levels did not significantly differ from each other (Fig. 1). Both pH and RIN were independent predictors of OTR mRNA levels (Table 2).

Table 2.

Summary of Multiple Regression Analysis for Oxytocin Receptor (OTR) mRNA: Stepwise linear regression with psychiatric diagnosis (MDD, BPD, SZ or Control) and additional independent variables, age at death, race, sex, RNA integrity number (RIN), brain pH, postmortem interval (PMI), positive toxicology for cotinine or alcohol at the time of death as predictors of OTR mRNA level. MDD = Major Depressive Disorder; BPD = Bipolar Disorder; Sz = Schizophrenia.

B SE Beta t p value
Constant 2.546 0.671 3.795  < 0.001
MDD 0.300 0.088 0.164 3.421 0.001
BPD 0.392 0.094 0.188 4.152  < 0.001
SZ  −0.038 0.066  −0.027  −0.577 0.564
RIN  −0.169 0.033  −0.223  −5.087  < 0.001
pH  −0.254 0.102  −0.115  −2.484 0.013
Age Death 0.011 0.239 0.811
Sex  −0.015  −0.348 0.728
Race  −0.033  −0.747 0.456
PMI  −0.005  −0.114 0.910
Alcohol 0.024 0.545 0.586
Cotinine 0.006 0.147 0.883
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Fig. 1.

Fig. 1.

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Mean (± 95% CI) Oxytocin Receptor (OTR) mRNA levels in three diagnostic groups. *p < 0.001, Bonferroni corrected (MDD = Major Depressive Disorder; BPD = Bipolar Disorder; SZ = Schizophrenia).

Next, regression analyses were conducted with SZ, MDD and BPD subjects only (Table 3). Additional covariates were added: toxicology results (Table 1) and manner of death (suicide, natural causes or accident, as homicides occurred only in control subjects), as well as history of alcohol dependence and illicit drug abuse. The full model of diagnostic group (MDD, BPD, SZ), pH, RIN, drug abuse, toxicology positive for mood stabilizers and antipsychotics was significant: R2 = .203, F(7,247) = 8.98, p < 0.001; Adjusted R2 = 0.180. MDD and BPD remained significant predictors of OTR mRNA levels as did pH and RIN (Table 2). The presence of mood stabilizers significantly predicted ln-transformed OTR mRNA levels such that mood stabilizers predicted a reduction of OTR mRNA levels (Table 2). Presence of antipsychotics also significantly predicted an increase in OTR mRNA (Table 2). Having a history of substance abuse was a significant positive predictor, such that ln-transformed OTR mRNA levels with a history of substance use predicted higher OTR mRNA levels (Table 2).

Table 3.

Summary of Multiple Regression Analyses for Oxytocin Receptor (OTR) mRNA for Patient Groups Only: Stepwise linear regression with additional independent variables: manner of death (suicide, accident, homicide or natural causes; all homicides were in the control group), toxicology results for psychiatric medications (antipsychotics, antidepressants and mood stabilizers), toxicology results for substances of abuse (opiates, benzodiazepines, cocaine, cannabis) and history of alcohol dependence or illicit drug abuse.

B SE Beta t p value
Constant 3.144 1.086 2.894 0.004
MDD 0.396 0.119 0.236 3.325 0.001
BPD 0.473 0.115 0.269 4.124  < 0.001
RIN  −0.174 0.046  −0.226  −3.803  < 0.001
pH  −0.403 0.174  −0.145  −2.323 0.021
Substance Abuse 0.198 0.085 0.138 2.327 0.021
Mood Stabilizer  −0.258 0.109  −0.140  −2.370 0.019
Antipsychotic 0.199 0.092 0.138 2.154 0.032
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Analyses were repeated removing subjects with positive toxicology at the time of death (for antipsychotics and mood stabilizers) leaving n = 66 MDD, n = 28 BPD and n = 53 SZ subjects. Diagnostic group remained a positive predictor of OTR mRNA level [MDD: Beta = 0.256, p = 0.01 and BPD: Beta = 0.295, p = 0.002]. When subjects with a history of substance abuse were removed, leaving n = 78 MDD, n = 21 BPD, and n = 97 SZ subjects, diagnostic group was also a positive significant predictor of OTR mRNA levels (MDD: Beta = 0.362, p < 0.001 and BPD: Beta = 0.215, p = 0.006.

4. Discussion

Compared to control subjects, we observed increased expression of OTR mRNA in the DLPFC in both MDD and BPD patients compared to patients with SZ and controls. Presence of either alcohol or cotinine in blood at the time of death, as well as sex, race, or history of alcohol dependence did not predict receptor mRNA levels, nor did they modify the effect of psychiatric diagnosis on receptor mRNA levels. The presence of antidepressants, THC, benzodiazepines, cocaine or opiates in the blood at death also did not predict OTR mRNA levels or modify the effect of psychiatric diagnosis on receptor mRNA levels. However, mood stabilizers predicted lower OTR mRNA levels, whereas antipsychotics higher expression of OTR mRNA.

The distribution of the OTR in primate species has not been well defined due to cross reactivity of the ligands with the vasopressin 1a receptor. A recently developed competitive binding method allows for determination of OTR location in the primate brain with more specificity and nonhuman primate studies using this method have not found appreciable expression of OTR in the PFC (Freeman et al., 2014a, b). While a recent human study using the same competitive binding method, found OTR in the human brainstem, particularly in the trigeminal nucleus (Freeman et al., 2017), there have been no human studies analyzing the PFC to date with this competitive binding method. A recent analysis of OTR mRNA expression in the human adult brain from the Allen Brain Atlas (Allen Institute for Brain Science, 2010) reported that OTR mRNA expression in the DLPFC was equivalent to the average across the brain(Quintana et al., 2017).

The PFC plays a role in the regulation of emotion (Gray et al., 2002), cognition (Frith and Dolan, 1996) and stress reactivity (Diorio et al., 1993). In depression, there are structural changes in the PFC such as cell loss and atrophy in the dorsolateral and orbitofrontal cortex (Rajkowska, 2000). There are also functional alterations in the PFC in depression, such as frontal hypometabolism (George et al., 1993) and glucocorticoid receptor dysregulation (Webster et al., 2002). The PFC is functionally and structurally linked to the hypothalamus (Spencer et al., 2005) where an increased number of hypothalamic OT, vasopressin and corticotropin releasing factor cells in mood disorders has been reported (Purba et al., 1996; Raadsheer et al., 1994). The PFC acts to inhibit the upregulation of the HPA axis and the hypercortisolism that occurs in depression. Conversely, upregulation of the HPA axis inhibits the PFC, perhaps creating an amplification of impaired PFC function (Swaab et al., 2000).

The majority of postmortem studies measuring OT gene expression have focused on the hypothalamus. Purba and colleagues reported increased numbers of OT immunoreactive neurons in the PVN of the hypothalamus in eight depressed patients, including patients with BPD, when compared to healthy controls (Purba et al., 1996). In another small study, OT mRNA levels were increased in the PVN of patients with melancholic compared to non-melancholic (Meynen et al., 2007). In animal models of depression, where a first stressor in early postnatal life is administered followed by a second stressor in adulthood, the OTR was upregulated in the hippocampus (the only region studied) (Lesse et al., 2016).

If there is an upregulation of OT synthesis in individuals with mood disorders, we might expect a down regulation of the receptor, as was found in a recent whole-transcriptome profiling (RNA-seq) study of the DLPFC. In this study by Pantazatos and colleagues, there was a lower level of OTR mRNA expression in 30 individuals with MDD compared to 29 controls (Pantazatos et al., 2017). The discrepancy between those results and the ones reported here may be due to cohort differences as the cohort in the study by Pantazatos et al. (2017) had no substance use comorbidity and negative toxicology for psychotropic medications and illicit drugs. In addition, the qPCR (used here) assesses only a single transcript, while counts derived from RNA-seq constitute an average across multiple transcripts at the whole gene level. We found that the presence of a mood stabilizer on toxicology at death significantly predicted a lower OTR mRNA level, therefore, the negative relationship may represent a down-regulation of the OTR in the setting of mood stabilizers.

We found no difference in the level of OTR mRNA in patients with SZ compared to controls. Similarly, a previous postmortem study in individuals with SZ reported no significant changes in OTR mRNA in the anterior PFC of SZ patients when compared to controls (Uhrig et al., 2016). Almost 30% of the individuals in the present study (largely in the SZ group) had positive toxicology for antipsychotics. This percentage may suggest that a diagnostic difference is blunted by antipsychotic medication. However, removing the patients with positive toxicology for antipsychotics at the time of death did not change the effect of diagnostic group on OTR mRNA levels. Lastly, a history of substance abuse was positively associated with mRNA levels for the OTR and this correlation is consistent with preclinical, as well as clinical, studies that report overall upregulation of OTR after chronic exposure to drugs of abuse, such as psychostimulants and opiates [for review, see: (Lee et al., 2016)]. However, removing subjects from the analysis with a history of illicit drug use disorder did not alter the results of significantly elevated OTR mRNA in individuals with mood disorders.

Despite the large postmortem sample size, there are several limitations that warrant consideration. First, this study was limited to one brain area, the DLPFC. We did not study OT expression in the hypothalamus, the critical area where OT is produced. Second, the extensive degree of comorbidity and presence of a positive toxicology in the patient groups, as well as significant differences among the 4 groups in age at death, and race, PMI, pH and RIN, may not have been fully corrected by statistical covariation. In addition, it is not clear whether our findings extend to the levels of protein expression for OTR in the DLPFC.

Despite these limitations, the present study relies on a large sample and, to our knowledge, is one of the largest studies examining OTR mRNA in postmortem samples from psychiatric patients. Further studies should be conducted to characterize gene expression for OT and OTR in multiple brain regions including the hypothalamus where OT is synthesized. In summary, we report elevated OTR mRNA expression in individuals with MDD and BPD, compared to individuals with SZ or control subjects. Our findings add to the literature on alterations in the endogenous brain OT system in psychiatric disorders, and may inform research toward targeting the OTR as a pharmacological approach for treating psychiatric disorders.

Acknowledgements

We acknowledge the families who donated the brains of their loved ones to HBCC and the Medical Examiner’s offices of the District of Columbia and Northern Virginia, who collected the brain tissue. The authors would like to thank Ms. Holly Thompson from the NIH Library for bibliographic assistance.

Funding and disclosure

This work was supported by National Institutes of Health (NIH) intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research and the National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP). The Human Brain Collection Core (ZIC MH002903-11) is funded by the NIMH IRP.

Footnotes

Conflict of interest

The authors declare that they have no conflict of interest.

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