New Research: The Molecular Biology of the Human Brain
Investigators at Pitt Psychiatry have recently published studies in Proceedings of the National Academy of Sciences of the United States of America (PNAS) and Translational Psychiatry on the molecular biology of the human brain.
Proceedings of the National Academy of Sciences of the United States of America (PNAS): Diurnal rhythms across the human dorsal and ventral striatum
In a paper recently published in Proceedings of the National Academy of Sciences of the United States of America (PNAS), University of Pittsburgh investigators identified molecular rhythms across the human caudate, putamen, and nucleus accumbens, aiming to better understand the normal function of diurnal rhythms in the striatum and how disruption to these rhythms could lead to pathology.
“Previous work from our group identified diurnal rhythms in gene expression in human cortical regions that are impacted by aging and schizophrenia. Transcriptome-wide studies in other regions, such as the striatum, have been limited by profiling of a single striatal region or profiling all subjects regardless of time of death. In this study, we aimed to characterize gene expression rhythms across the human dorsal and ventral striatum, regions critical for motor control, cognitive processing, reward, and motivation,” said postdoctoral scholar Kyle Ketchesin, PhD, the study’s lead author.
Using a time of death approach, departmental investigators including Dr. Ketchesin; Marianne Seney, PhD; postdoctoral scholars Madeline Scott, PhD, and Vaishnavi G. Shankar, PhD; Jill Glausier, PhD; David Lewis, MD; and Colleen McClung, PhD, analyzed rhythmic gene expression on caudate, putamen, and nucleus accumbens tissue samples from 59 individuals without any histories of lifetime psychiatric disorders. Findings revealed that core circadian clock genes are rhythmic across all three regions and showed strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the caudate and the nucleus accumbens.
The scientists additionally found many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in the nucleus accumbens (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs. Further, although the nucleus accumbens and putamen are generally in phase with regard to timing of expression rhythms, the nucleus accumbens and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts.
“Better understanding of how human striatal regions are regulated over the 24-hour cycle will help us identify deviations from this normal cycle that could contribute to psychiatric and neurological disorders,” said Dr. McClung, the study’s senior author.
Diurnal rhythms across the human dorsal and ventral striatum
Ketchesin KD, Zong W, Hildebrand MA, Seney ML, Cahill KM, Scott MR, Shankar VG, Glausier JR, Lewis DA, Tseng, GC, McClung CA.
PNAS January 12, 2021 118 (2) e2016150118; https://doi.org/10.1073/pnas.2016150118
Translational Psychiatry: Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder
Research has shown that dysfunction in the orbitofrontal cortex and striatum brain regions, including dysfunctional connectivity between the two, is associated with obsessive-compulsive disorder (OCD). A recent Translational Psychiatry study examines potential transcriptional changes in the orbitofrontal cortex and two striatal regions—the caudate nucleus and nucleus accumbens—to better understand the role of these regions in the etiology of OCD.
First author Sean Piantadosi, PhD, departmental collaborators Lora McClain, PhD, Bernie Devlin, PhD, David Lewis, MD, and the study’s senior author, Susanne Ahmari, MD, PhD, sequenced and analyzed gene transcripts from the medial and lateral orbitofrontal cortex, the caudate nucleus, and the nucleus accumbens in OCD post-mortem brain tissue.
The scientists found that 904 transcripts were differentially expressed between seven OCD samples versus eight unaffected comparison subject samples. Pathway analyses of the differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects.
“We are excited about these findings because they indicate consistent striatal molecular abnormalities in OCD, helping to solidify the foundation of the new field of OCD human post-mortem research,” said Dr. Ahmari. “Through our collaboration with Dr. Devlin, as well as with Dr. Wang in the Department of Biostatistics, we were also able to hone in on particular cell-types that may be impacted. These results could ultimately pave the way for the development of improved therapeutics for this severe mental illness.”
Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder
Piantadosi SC, McClain LL, Klei L, Wang J, Chamberlain BL, Spring SA, Lewis DA, Devlin B, Ahmari SE.
Translational Psychiatry 11, 171 (2021). https://doi.org/10.1038/s41398-021-01290-1
Translational Psychiatry: Involvement of the nuclear factor-κB transcriptional complex in prefrontal cortex immune activation in bipolar disorder
Pitt Psychiatry investigators Kaitlyn Roman, BS (first author of the current study), Department collaborators Aaron Jenkins, MD (postdoctoral scholar), and David Lewis, MD, and senior author David Volk, MD, PhD, studied whether higher activity of nuclear factor-κB (NF-κB) is present in the prefrontal cortex in bipolar disorder in a manner similar to that present in schizophrenia.
“Because schizophrenia and bipolar disorder share clinical features and immune-related genetic risk factors, we hypothesized that the elevated levels of NF-kB activity that we previously reported in schizophrenia would also be present in bipolar disorder,” said Dr. Volk, the study’s senior author.
The scientists hypothesized that in the prefrontal cortex of subjects with bipolar disorder, transcript levels are higher for NF-κB family members and activation receptors; higher for immune markers that are regulated by NF-κB activity; and lower for an NF-κB inhibitor. They quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative polymerase chain reaction (PCR).
In the study recently published in Translational Psychiatry, the team reported findings that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other.
“These findings suggest that cortical immune activation is a shared pathophysiological feature between schizophrenia and bipolar disorder,” said Dr. Volk.
Involvement of the nuclear factor-κB transcriptional complex in prefrontal cortex immune activation in bipolar disorder
Roman KM, Jenkins AK, Lewis DA, Volk DW.
Translational Psychiatry 11, 40 (2021). https://doi.org/10.1038/s41398-020-01092-x