Dataset Information

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

ABSTRACT:

Introduction

Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs).

Methods

We analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation.

Results

NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations.

Discussion

Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

SUBMITTER: Shulman D

PROVIDER: S-EPMC9934682 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

Shulman Dana D Dubnov Serafima S Zorbaz Tamara T Madrer Nimrod N Paldor Iddo I Bennett David A DA Seshadri Sudha S Mufson Elliott J EJ Greenberg David S DS Loewenstein Yonatan Y Soreq Hermona H

bioRxiv : the preprint server for biology 20230220

<h4>Introduction</h4>Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs).<h4>Methods</h4>We analyzed small RNA-sequencing data from the <i>nucleus accumbens</i> (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic ...[more]

PMID: 36798311

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Project description:The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study demonstrates that spontaneous dopamine release is (1) dependent of the activation of nicotinic receptors, (2) independent on the spontaneous activity of cholinergic interneurons, and (3) that cocaine increased the detection of dopamine transients by prolonging the presence and increasing the diffusion of dopamine in the extracellular space. The release of acetylcholine is therefore responsible for spontaneous dopamine transients, and cocaine augments dopamine tone without altering activity of cholinergic interneurons.

Dataset Information

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

Similar Datasets

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