Optogenetic control of inputs to the ventral tegmental area

Patent metadata

Field	Value
Publication number	US-9636380-B2
Application number	US-201414209004-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 15, 2013
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The present disclosure provides a method of inducing or modulating reward- or aversive-related behaviors in animals using light-responsive opsins. The present disclosure provides methods of identifying or screening compounds that may be used to treating mental disorders, or are relevant to disrupt or improve reward- or aversive related behaviors.

First claim

What is claimed is:

1. A method of modulating a reward- or aversive-related behavior in a mammal, the method comprising:
a) expressing in one or both of a laterodorsal tegmentum (LDT) neuron and a lateral habenula (LHb) neuron projecting to the ventral tegmental area (VTA):
i) a depolarizing light-responsive opsin polypeptide that comprises an amino acid sequence having at least about 90% amino acid sequence identity to an amino acid sequence selected from SEQ ID NOs:5-11; or
ii) a hyperpolarizing light-responsive opsin that comprises an amino acid sequence having at least about 90% amino acid sequence identity to an amino acid sequence selected from SEQ ID NOs:1, 4, 12, 14, and 15; and

b) exposing the LDT neuron and/or the LHb neuron to light,
wherein said exposing activates the light-responsive opsin polypeptide, thereby hyperpolarizing or depolarizing the neuron, and wherein said hyperpolarizing or depolarizing modulates a reward- or aversive-related behavior in the mammal.

2. The method of claim 1 , wherein said hyperpolarizing light-responsive opsin polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to an amino acid sequence selected from SEQ ID NOs: 1, 4, 12, 14, and 15, and wherein said depolarizing comprises an amino acid sequence having at least about 90% amino acid sequence identity to an amino acid sequence selected from SEQ ID NOs:5-11.

3. The method of claim 1 , wherein said light-responsive opsin polypeptide comprises an amino acid sequence having at least about 90% amino acid sequence identity to an amino acid sequence selected from SEQ ID NOs:5-11, wherein the method comprises exposing the LDT to light of a wavelength that activates the light-responsive polypeptide, thereby increasing the reward-related behavior.

4. The method of claim 3 , wherein said light-responsive opsin polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to an amino acid sequence selected from SEQ ID NOs:5-11.

5. The method of claim 3 , wherein said expressing comprises directly delivering into the LDT neuron a nucleic acid comprising a nucleotide sequence encoding the light-responsive opsin polypeptide.

6. The method of claim 5 , wherein the nucleic acid is a recombinant viral expression vector.

7. The method of claim 6 , wherein the recombinant viral expression vector is a lentiviral vector or an adeno-associated viral vector.

8. The method of claim 5 , wherein the nucleotide sequence is operably linked to a promoter.

9. The method of claim 8 , wherein the promoter is an EF1α promoter, a cytomegalovirus promoter, a CAG promoter, a synapsin-I promoter, a synuclein 1 promoter, a CAMKIIα promoter.

10. The method of claim 1 , wherein the light is provided by an implantable light source.

11. The method of claim 10 , wherein the light source comprises a light-emitting diode.

12. The method of claim 3 , wherein the light-responsive opsin polypeptide comprises a membrane trafficking signal comprising the amino acid sequence KSRITSEGEYIPLDQIDINV (SEQ ID NO:16).

13. The method of claim 3 , wherein the light-responsive opsin polypeptide comprises an endoplasmic reticulum export signal comprising the amino acid sequence FCYENEV (SEQ ID NO: 17).

14. The method of claim 1 , wherein the reward-related behavior is addiction.

Assignees

• Univ Leland Stanford Junior

Inventors

• Lammel Stephan
• Lim Byungkook
• Malenka Robert C

Classifications

• A01K2267/03

  Animal model, e.g. for test or diseases · CPC title

• A61N2005/0663

  Coloured light · CPC title

• A61K49/0008

  Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure · CPC title

• A61K38/1709 Primary

  from mammals · CPC title

• A61N2005/0612

  using probes penetrating tissue; interstitial probes · CPC title