Optically-controlled cns dysfunction

Patent metadata

Field	Value
Publication number	US-2016303192-A1
Application number	US-201615194379-A
Country	US
Kind code	A1
Filing date	Jun 27, 2016
Priority date	Nov 5, 2010
Publication date	Oct 20, 2016
Grant date	—

Abstract

Provided herein are animals expressing light-responsive opsin proteins in the basal lateral amygdala of the brain and methods for producing the same wherein illumination of the light-responsive opsin proteins causes anxiety in the animal. Also provided herein are methods for alleviating and inducing anxiety in an animal as well as methods for screening for a compound that alleviates anxiety in an animal.

First claim

What is claimed is:

1 . An animal comprising a light-responsive opsin expressed in glutamatergic pyramidal neurons of the BLA, wherein the opsin is an opsin which induces hyperpolarization by light, and wherein the selective illumination of the opsin in the BLA-CeL induces anxiety of the animal.

2 . The animal of claim 1 , wherein the opsin is selected from the group consisting of NpHR, BR, AR, and GtR3.

3 . The animal of claim 1 , further comprising a second light-responsive opsin expressed in glutamatergic pyramidal neurons of the BLA, wherein the second opsin is an opsin that induces depolarization by light, and wherein the selective illumination of the second opsin in the BLA-CeL reduces anxiety of the animal.

4 . The animal of claim 3 , wherein the second opsin is selected from the group consisting of ChR2, VChR1, and DChR.

5 . An animal comprising a light-responsive opsin expressed in the glutamatergic pyramidal neurons of the BLA, wherein the opsin is an opsin that induces depolarization by light, and wherein the selective illumination of the opsin in the BLA-CeL reduces anxiety of the animal.

6 . The animal of claim 5 , wherein the opsin is selected from the group consisting of ChR2, VChR1, and DChR.

7 . A vector for delivering a nucleic acid to glutamatergic pyramidal neurons of the BLA in an individual, wherein the vector comprises the nucleic acid encoding a light-responsive opsin and the nucleic acid is operably linked to a promoter that controls the specific expression of the opsin in the glutamatergic pyramidal neurons.

8 . The vector of claim 7 , wherein the nucleic acid encoding the opsin is operably linked to a CaMKIIα promoter.

9 . The vector of claim 7 , wherein the vector is an AAV vector.

10 . The vector of claim 7 , wherein the opsin is an opsin that induces depolarization by light, and wherein selective illumination of the opsin in the BLA-CeL alleviates anxiety.

11 . The vector of claim 10 , wherein the opsin is selected from the group consisting of ChR2, VChR1, and DChR.

12 . The vector of claim 7 , wherein the opsin is an opsin that induces hyperpolarization by light, and wherein selective illumination of the opsin in the BLA-CeL and induces anxiety.

13 . The vector of claim 12 , wherein the opsin is selected from the group consisting of NpHR, BR, AR, and GtR3.

14 . The vector of claim 7 , wherein the individual is a mouse or a rat.

15 . A method of delivering a nucleic acid to glutamatergic pyramidal neurons of the BLA in an individual, comprising administering to the individual an effective amount of a vector comprising a nucleic acid encoding a light-responsive opsin and the nucleic acid is operably linked to a promoter that controls the specific expression of the opsin in the glutamatergic pyramidal neurons.

16 . A coronal brain tissue slice comprising BLA, CeL, and CeM, wherein a light-responsive opsin is expressed in the glutamatergic pyramidal neurons of the BLA.

17 . A method for screening for a compound that alleviates anxiety, comprising
(a) administering a compound to an animal having anxiety induced by selectively illumination of an opsin expressed in the glutamatergic pyramidal neurons of the BLA, wherein the animal comprises a light-responsive opsin expressed in the glutamatergic pyramidal neurons of the BLA, wherein the opsin is an opsin that induces hyperpolarization by light; and (b) determining the anxiety level of the animal, wherein a reduction of the anxiety level indicates that the compound may be effective in treating anxiety.

18 . The method of claim 17 , wherein the opsin is selected from the group consisting of NpHR, BR, AR, and GtR3.

19 . A method for alleviating anxiety in an individual, comprising:
(a) administering to the individual an effective amount of a vector comprising a nucleic acid encoding a light-responsive opsin and the nucleic acid is operably linked to a promoter that controls the specific expression of the opsin in the glutamatergic pyramidal neurons of the BLA, wherein the opsin is expressed in the glutamatergic pyramidal neurons of the BLA, wherein the opsin is an opsin that induces depolarization by light; and (b) selectively illuminating the opsin in the glutamatergic pyramidal neurons in the BLA-CeL to alleviate anxiety.

20 . The method of claim 19 , wherein the opsin is selected from the group consisting of ChR2, VChR1, and DChR.

21 . A method for inducing anxiety in an individual, comprising:
(a) administering to the individual an effective amount of a vector comprising a nucleic acid encoding an opsin and the nucleic acid is operably linked to a promoter that controls the specific expression of the opsin in the glutamatergic pyramidal neurons of the BLA, wherein the opsin is expressed in the glutamatergic pyramidal neurons, wherein the opsin is an opsin that induces hyperpolarization by light; and (b) selectively illuminating the opsin in the glutamatergic pyramidal neurons in the BLA-CeL to induce anxiety.

22 . A device or method relating to: modifying activity of the BLA-CeM to treat or study anxiety.

23 . The device or method of claim 22 , wherein modifying activity includes selective stimulation of the BLA-CeL.

24 . The device or method of claim 22 , wherein modifying activity includes selective stimulation of the BLA-CeL by targeted expression of light-responsive opsins in glutamatergic pyramidal neurons.

25 . The device or method of claim 24 , wherein modifying activity further includes selective illumination of the CeA relative to illumination of the BLA somata.

26 . The device or method of claim 24 , further including implantation of a beveled guide cannula over the CeL to prevent light delivery to the BLA and to allow selective illumination of 20 the CeA.

27 . The device or method of claim 22 , further including screening for treatments including, but not limited to, one or more of pharmacological agents, electrical stimulus, magnetic stimulus, surgical procedures, or optogenetic stimulus.

28 . A device or method of any of the preceding claims, further directed toward providing treatments that target the BLA-CeM circuit including, but not limited to, one or more of pharmacological agents, electrical stimulus, magnetic stimulus, surgical procedures, or optogenetic stimulus.

29 . A device or method using the circuit model(s) of the present disclosure for studying and probing anxiety and/or related disorders.

30 . A device or method of any of the preceding claims further including one or more of identifying phenotypes, endophenotypes, and treatment targets.

31 . A device or method of any of embodiments of the present disclosure, including the embodiments described in the Examples.

Assignees

• Univ Leland Stanford Junior

Inventors

• Deisseroth Karl
• Tye Kay
• Fenno Lief

Classifications

• A61P25/22

  Anxiolytics · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A01K2227/105

  Murine · CPC title

• A61K48/0058

  Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct · CPC title

• A01K2267/0356

  Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy · CPC title