Emerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain

doi:10.1016/j.pbb.2018.04.008

Pharmacology Biochemistry and Behavior

Volume 174, November 2018, Pages 2-8

https://doi.org/10.1016/j.pbb.2018.04.008 Get rights and content

Highlights

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Viral vectors have become critical tools for circuit-specific studies in the brain.
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We review the general classes of viral vectors used for study of the brain.
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We review the suitability of various viral tools for circuit-specific studies.
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We cover in detail a new long-lasting, retrograde expressing form of herpes simplex virus.

Abstract

Over the past half century, novel tools have allowed the characterization of myriad molecular underpinnings of neural phenomena including synaptic function, neurogenesis and neurodegeneration, membrane excitability, and neurogenetics/epigenetics. More recently, transgenic mice have made possible cell type-specific explorations of these phenomena and have provided critical models of many neurological and psychiatric diseases. However, it has become clear that many critical areas of study require tools allowing the study and manipulation of individual neural circuits within the brain, and viral vectors have come to the forefront in driving these circuit-specific studies. Here, we present a surface-level review of the general classes of viral vectors used for study of the brain, along with their suitability for circuit-specific studies. We then cover in detail a new long-lasting, retrograde expressing form of herpes simplex virus termed LT-HSV that has become highly useful in circuit-based studies. We detail some of its current uses and propose a variety of future uses for this critical new tool, including circuit-based transgene overexpression, gene editing, and gene expression profiling.

Section snippets

General introduction to viral vectors

Engineered viral vectors provide transport for a genetic payload and their utility derives from the great diversity of potential cargo and cellular targets. Because viral vectors enable or enhance the function of many other technologies, they have become indispensable in modern neuroscience research. In combination with Cre-recombinase driver lines, they allow cell-type specific manipulation of gene expression, while viral delivery of genetic calcium indicators or optogenetic and

Cell type-specific viral tools

As understanding of the specific contributions of various neuronal and non-neuronal cell types to brain function has increased, the need has arisen for tools that allow modification of gene expression and function of specific cell types in the brain. The most prominent strategy for achieving this end has been the advent of transgenic mouse lines expressing recombinases under the control of promoters derived from genes that are enriched in specific cell types. For instance, tyrosine hydroxylase

Current and potential circuit-specific viral manipulations

To assess the role of individual circuits in animal behavior or the circuit-specific contribution of individual genes to cell function or behavior, novel retrograde viral vector approaches will be critical. For instance, a combinatorial strategy using LT-HSV technology has made possible the manipulation of not only a specific projection, but specific cell types within that projection. Targeting dopaminergic cells of the ventral tegmental area (VTA) projecting to nucleus accumbens (NAc) requires

Conclusions

A variety of tools and techniques have emerged in recent years to revolutionize the study of the brain, from light-sensitive ion channels to genetically encoded calcium indicators to transgenic animal models. Of the many findings stemming from this ongoing technological wave, the prominence of circuit-specific drives on brain function and animal behavior has been universal. Although lesions and pharmacology have allowed a blunt interrogation of circuit function for many decades, there is a

Acknowledgements

We thank Dr. Michelle Mazei-Robison for her helpful suggestions and editing of the manuscript. This work was supported by the National Institute of Mental Health (R01 MH111604).

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ReviewEmerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain

Highlights

Abstract

Section snippets

General introduction to viral vectors

Cell type-specific viral tools

Current and potential circuit-specific viral manipulations

Conclusions

Acknowledgements

Mol. Ther.

Mol. Ther. Nucleic Acids

Cell

Cell

Biol. Psychiatry

Neuron

Cell

J. Physiol. Paris

Curr. Opin. Pharmacol.

Neuron

Brain Res.

Mol. Ther.

Mol. Ther.

Neuron

Brain Res.

Neuron

Neuron

Neuroscience

Prog. Brain Res.

Neuron

Neuron

Cell Rep.

Neuron

Adenovirus-associated defective virus particles

Science

Studies on the pathogenesis of fixed rabies virus in rats

Bull. World Health Organ.

Genetically timed, activity-sensor and rainbow transsynaptic viral tools

Nat. Methods

The use of chemogenetic approaches to study the physiological roles of muscarinic acetylcholine receptors in the central nervous system

Neuropharmacology

Improved tools for the Brainbow toolbox

Nat. Methods

Threonine 149 phosphorylation enhances DeltaFosB transcriptional activity to control psychomotor responses to cocaine

J. Neurosci.

Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems

Nat. Neurosci.

Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons

Nature

Lentiviral vectors: a powerful tool to target astrocytes in vivo

Curr. Drug Targets

Differences in transductional tropism of adenoviral and lentiviral vectors in the rat brainstem

Exp. Physiol.

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Activity-Dependent Transcriptional Regulation of Hippocampal Projections in Fear/Anxiety and Cocaine Reward

Lentivirus-mediated alpha-melanocyte-stimulating hormone overexpression in the hypothalamus decreases diet induced obesity in mice

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Review
Emerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain