Biology subjects

Berrettini, W. H.

Publications and source records attributed to Berrettini, W. H..

4 recordsLinked to original sources

bioRxiv2024

A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens

Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.

genetics↗

bioRxiv2020

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response

Bipolar disorder (BD) is a neuropsychiatric disorder with genetic risk factors defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. While lithium is an effective drug for BD, 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, rhythm abnormalities in BD have not been evaluated in neurons and it is unknown if neuronal rhythms differ between Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients and controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R. NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein expression was higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

neuroscience↗

bioRxiv2020

Single-nuclei transcriptomics of schizophrenia prefrontal cortex primarily implicates neuronal subtypes

Transcriptomic studies of bulk neural tissue homogenates from persons with schizophrenia and controls have identified differentially expressed genes in multiple brain regions. However, the brains heterogeneous nature prevents identification of relevant cell types. This study analyzed single-nuclei transcriptomics of ~275,000 nuclei from frozen human postmortem dorsolateral prefrontal cortex samples from males with schizophrenia (n = 12) and controls (n = 14). 4,766 differential expression events were identified in 2,994 unique genes in 16 of 20 transcriptomically-distinct cell populations. ~96% of differentially expressed genes occurred in five neuronal cell types, and differentially expressed genes were enriched for genes associated with schizophrenia and bipolar GWAS loci. Downstream analyses identified cluster-specific enriched gene ontologies, KEGG pathways, and canonical pathways. Additionally, microRNAs and transcription factors with overrepresented neuronal cell type-specific targets were identified. These results expand our knowledge of disrupted gene expression in specific cell types and permit new insight into the pathophysiology of schizophrenia.

neuroscience↗

bioRxiv2019

Restriction Enzyme Based Enriched L1Hs sequencing (REBELseq)

Long interspersed element-1 retrotransposons (LINE-1 or L1) are ~6 kb mobile DNA elements implicated in the origins of many Mendelian and complex diseases. The actively retrotransposing L1s are mostly limited to the L1 human specific Ta subfamily. In this manuscript, we present REBELseq as a method for the construction of differentially amplified next-generation sequencing libraries and bioinformatic identification of Ta subfamily long interspersed element-1 human specific elements. REBELseq was performed on DNA isolated from NeuN+ neuronal nuclei from postmortem brain samples of 177 individuals and empirically-driven bioinformatic and experimental cutoffs were established. REBELseq reliably identified both known and novel Ta subfamily L1 insertions distributed throughout the genome. Differences in the proportion of individuals possessing a given reference or non-reference retrotransposon insertion were identified. We conclude that REBELseq is an unbiased, whole genome approach to the amplification and detection of Ta subfamily L1 retrotransposons.

genetics↗