Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus.
Ontology highlight
ABSTRACT:
SUBMITTER: Perzel Mandell KA
PROVIDER: S-EPMC9133054 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
Publications
Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus.
Perzel Mandell Kira A KA Eagles Nicholas J NJ Deep-Soboslay Amy A Tao Ran R Han Shizhong S Wilton Richard R Szalay Alexander S AS Hyde Thomas M TM Kleinman Joel E JE Jaffe Andrew E AE Weinberger Daniel R DR
Molecular psychiatry 20220302 4
Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abund ...[more]
Similar Datasets
Project description:ObjectiveThe object of this study was to define caudate nucleus locations responsive to intraoperative direct electrical stimulation for tinnitus loudness modulation and relate those locations to functional connectivity maps between caudate nucleus subdivisions and auditory cortex.MethodsSix awake study participants who underwent bilateral deep brain stimulation (DBS) electrode placement in the caudate nucleus as part of a phase I clinical trial were analyzed for tinnitus modulation in response to acute stimulation at 20 locations. Resting-state 3-T functional MRI (fMRI) was used to compare connectivity strength between centroids of tinnitus loudness-reducing or loudness-nonreducing caudate locations and the auditory cortex in the 6 DBS phase I trial participants and 14 other neuroimaging participants with a Tinnitus Functional Index > 50.ResultsAcute tinnitus loudness reduction was observed at 5 caudate locations, 4 positioned at the body and 1 at the head of the caudate nucleus in normalized Montreal Neurological Institute space. The remaining 15 electrical stimulation interrogations of the caudate head failed to reduce tinnitus loudness. Compared to the caudate head, the body subdivision had stronger functional connectivity to the auditory cortex on fMRI (p < 0.05).ConclusionsAcute tinnitus loudness reduction was more readily achieved by electrical stimulation of the caudate nucleus body. Compared to the caudate head, the caudate body has stronger functional connectivity to the auditory cortex. These first-in-human findings provide insight into the functional anatomy of caudate nucleus subdivisions and may inform future target selection in a basal ganglia-centric neuromodulation approach to treat medically refractory tinnitus.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).
| S-EPMC6687562 | biostudies-literature
Project description:Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.
| S-EPMC3593870 | biostudies-other
Project description:Although obesity is recognized as a global health epidemic, insufficient research has been directed to understanding the rising prevalence of obesity in the fastest growing segment of the population, older adults. Late-life obesity has been linked to declines in physical health and cognitive function, with implications not only for the individual, but also for society. We investigated the hypothesis that altered brain responses to food reward is associated with obesity, using fMRI of response to pleasant and aversive taste stimuli in young and older adults performing a hedonic evaluation task. Correlations between higher levels of abdominal fat/body mass index and reduced fMRI activation to sucrose in dopamine-related brain regions (caudate, nucleus accumbens) were large in older adults. Significant associations between a hypofunctioning reward response and obesity suggest the hypothesis that decreased dopamine functioning may be a plausible mechanism for weight gain in older adults.
| S-EPMC3086067 | biostudies-literature
Project description:Participants of the annual World Memory Championships regularly demonstrate extraordinary memory feats, such as memorising the order of 52 playing cards in 20 s or 1000 binary digits in 5 min. On a cognitive level, memory athletes use well-known mnemonic strategies, such as the method of loci. However, whether these feats are enabled solely through the use of mnemonic strategies or whether they benefit additionally from optimised neural circuits is still not fully clarified. Investigating 23 leading memory athletes, we found volumes of their right hippocampus and caudate nucleus were stronger correlated with each other compared to matched controls; both these volumes positively correlated with their position in the memory sports world ranking. Furthermore, we observed larger volumes of the right anterior hippocampus in athletes. Complementing these structural findings, on a functional level, fMRI resting state connectivity of the anterior hippocampus to both the posterior hippocampus and caudate nucleus predicted the athletes rank. While a competitive interaction between hippocampus and caudate nucleus is often observed in normal memory function, our findings suggest that a hippocampal-caudate nucleus cooperation may enable exceptional memory performance. We speculate that this cooperation reflects an integration of the two memory systems at issue-enabling optimal combination of stimulus-response learning and map-based learning when using mnemonic strategies as for example the method of loci.
| S-EPMC5869896 | biostudies-literature
Project description:BackgroundEnlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia.MethodsWe obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse.ResultsWe found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia.LimitationsThis study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small.ConclusionReductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.
| S-EPMC2834791 | biostudies-literature
Project description:The most common lethal accidents in General Aviation are caused by improperly executed landing approaches in which a pilot descends below the minimum safe altitude without proper visual references. To understand how expertise might reduce such erroneous decision-making, we examined relevant neural processes in pilots performing a simulated landing approach inside a functional MRI scanner. Pilots (aged 20-66) were asked to "fly" a series of simulated "cockpit view" instrument landing scenarios in an MRI scanner. The scenarios were either high risk (heavy fog-legally unsafe to land) or low risk (medium fog-legally safe to land). Pilots with one of two levels of expertise participated: Moderate Expertise (Instrument Flight Rules pilots, n = 8) or High Expertise (Certified Instrument Flight Instructors or Air-Transport Pilots, n = 12). High Expertise pilots were more accurate than Moderate Expertise pilots in making a "land" versus "do not land" decision (CFII: d' = 3.62 ± 2.52; IFR: d' = 0.98 ± 1.04; p<.01). Brain activity in bilateral caudate nucleus was examined for main effects of expertise during a "land" versus "do not land" decision with the no-decision control condition modeled as baseline. In making landing decisions, High Expertise pilots showed lower activation in the bilateral caudate nucleus (0.97 ± 0.80) compared to Moderate Expertise pilots (1.91 ± 1.16) (p<.05). These findings provide evidence for increased "neural efficiency" in High Expertise pilots relative to Moderate Expertise pilots. During an instrument approach the pilot is engaged in detailed examination of flight instruments while monitoring certain visual references for making landing decisions. The caudate nucleus regulates saccade eye control of gaze, the brain area where the "expertise" effect was observed. These data provide evidence that performing "real world" aviation tasks in an fMRI provide objective data regarding the relative expertise of pilots and brain regions involved in it.
| S-EPMC4245093 | biostudies-literature
Project description:BACKGROUND:The mechanisms underlying neurodegeneration in the striatum of Huntingon's Disease (HD) brain are currently unknown. While the striatum is massively degenerated in symptomatic individuals, which makes cellular characterization difficult, it is largely intact in asymptomatic HD gene positive (HD+) individuals. Unfortunately, as striatal tissue samples from HD+ individuals are exceedingly rare, recent focus has been on the Brodmann Area 9 (BA9), a relatively unaffected region, as a surrogate tissue. In this study, we analyze gene expression in caudate nucleus (CAU) from two HD+ individuals and compare the results with healthy and symptomatic HD brains. METHODS:High-throughput mRNA sequencing (mRNA-Seq) datasets were generated from post-mortem CAU of 2 asymptomatic HD+ individuals and compared with 26 HD and 56 neurologically normal controls. Datasets were analyzed using a custom bioinformatic analysis pipeline to identify and interpret differentially expressed (DE) genes. Results were compared to publicly available brain mRNA-Seq datasets from the Genotype-Tissue Expression (GTEx) project. The analysis employed current state of the art bioinformatics tools and tailored statistical and machine learning methods. RESULTS:The transcriptional profiles in HD+ CAU and HD BA9 samples are highly similar. Differentially expressed (DE) genes related to the heat shock response, particularly HSPA6 and HSPA1A, are common between regions. The most perturbed pathways show extensive agreement when comparing disease with control. A random forest classifier predicts that the two HD+ CAU samples strongly resemble HD BA9 and not control BA9. Nonetheless, when genes were prioritized by their specificity to HD+ CAU, pathways spanning many biological processes emerge. Comparison of HD+ BA9 with HD BA9 identified NPAS4 and REST1/2 as potential early responders to disease and reflect the active disease process. CONCLUSIONS:The caudate nucleus in HD brain is dramatically affected prior to symptom onset. Gene expression patterns observed in the HD BA9 are also present in the CAU, suggesting a common response to disease. Substantial caudate-specific differences implicate many different biological pathways including metabolism, protein folding, inflammation, and neurogenic processes. While these results are at best trends due to small sample sizes, these results nonetheless provide the most detailed insight to date into the primary HD disease process.
| S-EPMC6796419 | biostudies-literature
Project description:The caudate nucleus (CN) and the putamen (PUT) as parts of the human striatum are distinguished by a marked heterogeneity in functional, anatomical, and neurochemical patterns. Our study aimed to document in detail the regional diversity in the distribution of dopamine (DA), serotonin, γ-aminobuturic acid, and choline acetyltransferase within the CN and PUT. For this purpose we dissected the CN as well as the PUT of 12 post-mortem brains of human subjects with no evidence of neurological and psychiatric disorders (38-81 years old) into about 80 tissue parts. We then investigated rostro-caudal, dorso-ventral, and medio-lateral gradients of these neurotransmitter markers. All parameters revealed higher levels, turnover rates, or activities in the PUT than in the CN. Within the PUT, DA levels increased continuously from rostral to caudal. In contrast, the lowest molar ratio of homovanillic acid to DA, a marker of DA turnover, coincided with highest DA levels in the caudal PUT, the part of the striatum with the highest loss of DA in Parkinson's disease (N. Engl. J. Med., 318, 1988, 876). Highest DA concentrations were found in the most central areas both in the PUT and CN. We observed an age-dependent loss of DA in the PUT and CN that did not correspond to the loss described for Parkinson's disease indicating different mechanisms inducing the deficit of DA. Our data demonstrate a marked heterogeneity in the anatomical distribution of neurotransmitter markers in the human dorsal striatum indicating anatomical and functional diversity within this brain structure.
| S-EPMC7078952 | biostudies-literature
Project description:Welding has been associated with neurobehavioral disorders. Welding fumes contain several metals including copper (Cu), manganese (Mn), and iron (Fe) that may interact to influence welding-related neurotoxicity. Although welding-related airborne Fe levels are about 10-fold higher than Mn, previous studies have focused on Mn and its accumulation in the basal ganglia. This study examined differences in the apparent transverse relaxation rates [R2* (1/T2*), estimate of Fe accumulation] in the basal ganglia (caudate nucleus, putamen, and globus pallidus) between welders and controls, and the dose-response relationship between estimated Fe exposure and R2* values. Occupational questionnaires estimated recent and lifetime Fe exposure, and blood Fe levels and brain magnetic resonance imaging (MRI) were obtained. Complete exposure and MRI R2* and R1 (1/T1: measure to estimate Mn accumulation) data from 42 subjects with welding exposure and 29 controls were analyzed. Welders had significantly greater exposure metrics and higher whole-blood Fe levels compared with controls. R2* in the caudate nucleus was significantly higher in welders after controlling for age, body mass index, respirator use, caudate R1, and blood metals of Cu and Mn, whereas there was no difference in R1 values in the basal ganglia between groups. The R2* in the caudate nucleus was positively correlated with whole-blood Fe concentration. This study provides the first evidence of higher R2* in the caudate nucleus of welders, which is suggestive of increased Fe accumulation in this area. Further studies are needed to replicate the findings and determine the neurobehavioral relevance.
| S-EPMC4857156 | biostudies-literature
Project description:Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk antipsychotics and preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naïve samples provide the greatest power for mechanistic studies; (ii) weight and metabolic effects can be discordant, pointing to overlapping and distinct mechanisms; (iii) antipsychotics affect satiety and energy homeostasis signaling; (iv) the specific peptides mediating these effects are unknown but probably overlap with those involved in idiopathic obesity; and (v) single nucleotide polymorphisms in genes encoding known neurotransmitter receptors and metabolic proteins are promising pharmacogenomic targets for countering adverse affects. However, sophisticated molecular studies and genome-wide association studies, ideally in antipsychotic-naïve/first episode samples, are needed to further advance the field.
| S-EPMC3053585 | biostudies-literature