Biology subjects

Sanders, T. H.

Publications and source records attributed to Sanders, T. H..

3 recordsLinked to original sources

bioRxiv2020

Evidence that an HDAC2-targeted ASO persistently upregulates cortical acetylcholine and dopamine signaling via a CREB | Gs positive feedback loop

Epigenetic modulation of neural circuits facilitates learning and memory. Here, we examined specific inhibition of histone deacetylase 2 (HDAC2) expression in rats receiving a single intracerebroventricular injection of HDAC2-targeted anti-sense oligonucleotides (ASOs) one month prior to cognitive testing. The HDAC2 ASO-injected rats displayed increased novelty preference, decreased cortical and hippocampal HDAC2 mRNA and protein, and upregulated gene expression that persisted 1-month post-injection. Cortical RNA-seq revealed strongly increased transcription of a subset of cyclic adenosine monophosphate (cAMP)-response element binding (CREB) genes known to influence synaptic plasticity, along with dopamine (DRD1, DRD2) and adenosine (ADORA2A) G-protein-coupled receptors (GPCRs). Our analysis identified evidence of a positive-feedback loop that amplified expression of CREB-regulated Gs GPCRs and genes in cAMP/Gs/Gi signaling pathways. Additionally, we found differential expression of enzymes that shift neurotransmitter biosynthesis away from norepinephrine and toward dopamine and acetylcholine (DBH, CHAT). We also observed increased expression of genes important for neurotransmitter packaging (SV2C, VMAT) and release (SYT9). The data indicate that persistent inhibition of HDAC2 expression enables long-lived enhancement of aspects of cognition through increased cortical transcription of a subset of CREB-regulated genes amplified by a positive-feedback mechanism that increases synaptic plasticity and shifts neurotransmitter balance toward increased dopaminergic and cholinergic signaling.

neuroscience↗

bioRxiv2019

Phase discontinuities underlie increased drowsiness and diminished sleep quality in older humans

Healthy humans switch seamlessly between activity states, wake up and fall asleep with regularity, and cycle through sleep stages necessary for restored homeostasis and memory consolidation each night. This study tested the hypothesis that such smooth behavioral transitions are accompanied by smooth transitions between stable neural states within the brain. A method for detecting phase discontinuities across a broad range of frequencies was created to quantify phase disruptions in the Fp-Cz EEG channel from 20 annotated sleep files. Phase discontinuities decreased with increasingly deep sleep, and increased phase discontinuity was associated with increased drowsiness, reduced deep sleep, and shorter REM sleep. A 10s phase discontinuity summary measure (the phase jump indicator) closely tracked the annotated sleep stages and enabled discrimination between short (< 10 min) and longer REM periods. Overall phase discontinuity correlated inversely with broadband EEG power, suggesting that reduced spurious signaling may facilitate increased synchronization. However, the correlation between phase discontinuity and power varied with sleep stage and age. Older individuals spent significantly more time in the Awake and Drowsy stages and less time in the deepest sleep stage and REM sleep. Interestingly, although EEG power was reduced in older individuals across all sleep stages, increased phase discontinuity only occurred in stages that showed impairment. In older patients the power vs. phase discontinuity correlation shifted to positive during drowsiness, suggesting potential deficits in cortical inhibition. These results provide evidence that phase discontinuity measures extend current capabilities for assessing sleep and may yield new insights into pathological brain states.\n\nSignificance statementEvidence continues to accumulate regarding the positive relationship between healthy sleep and brain function. Recent studies also show that more healthful sleep can be induced with timely application of non-invasive therapies. Accordingly, the ability to accurately assess sleep quality in real-time has become increasingly important. Here, a newly defined measure, referred to as phase discontinuity, enabled rapid identification of unhealthful neural patterns associated with increased drowsiness, reduced deep sleep, and early termination of REM sleep. Moreover, the measure was linked to underlying neuronal and circuit properties known to impact sleep quality. Thus, the phase discontinuity measure defined in this study provides new insight into sleep pathology and has potential implications for closed-loop therapeutic intervention.

neuroscience↗

bioRxiv2019

An antisense oligonucleotide leads to suppressed transcriptional elongation of Hdac2 and long-term memory enhancement

Repression of the memory suppressor gene histone deacetylase 2 (Hdac2) in mice elicits cognitive enhancement, and drugs that block HDAC2 catalytic activity are being investigated for treating disorders affecting memory. Currently available compounds that target HDAC2 are not specific to the HDAC2 isoform, and have short half-lives. Antisense oligonucleotides (ASOs) are a class of drugs that base pair with RNA targets and exhibit extremely long-lasting, specific inhibition relative to small molecule drugs. We utilized an ASO to reduce Hdac2 messenger RNA (mRNA) quantities, and explored its longevity, specificity, and mechanism of repression. A single injection of the Hdac2-targeted ASO in the central nervous system diminished Hdac2 mRNA levels for at least 4 months in the brain, and knockdown of this factor resulted in significant memory enhancement for 8 weeks in mice. RNA-seq analysis of brain tissues revealed that the ASO repression was specific to the Hdac2 isoform relative to other classical Hdac genes, and caused alterations in levels of other memory-associated mRNAs. In cultured neurons, we observed that the Hdac2-targeted ASO suppressed Hdac2 mRNA and an Hdac2 non-coding regulatory extra-coding RNA (ecRNA). The ASO not only triggered a reduction in mRNA levels, but also elicited direct transcriptional suppression of the Hdac2 gene through blocking RNA polymerase II elongation. These findings suggest transcriptional suppression of the target gene as a novel mechanism of action of ASOs, and opens up the possibility of using ASOs to achieve lasting gene silencing in the brain without altering the nucleotide sequence of a gene.

pharmacology and toxicology↗