Stabilized step function opsin proteins and methods of using the same

Abstract

Provided herein are compositions comprising non-human animals comprising neurons expressing stabilized step function opsin proteins on neural plasma membranes and methods of using the same to selectively depolarize neurons residing in microcircuits of the pre-frontal cortex to affect one or more social behaviors, communications, and / or conditioned behaviors in the non-human animal.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application No. 61 / 410,704 filed on Nov. 5, 2010, U.S. Provisional Patent Application No. 61 / 410,711 filed on Nov. 5, 2010, and U.S. Provisional Patent Application No. 61 / 511,905 filed on Jul. 26, 2011, the disclosures of each of which are incorporated by reference herein in their entireties.TECHNICAL FIELD[0002]This application pertains to compositions comprising non-human animal cells expressing stabilized step function opsin (SSFO) proteins on their plasma membranes and methods of using the same to selectively depolarize neurons residing in microcircuits of the pre-frontal cortex to affect one or more social behaviors, communications, and / or conditioned behaviors in the non-human animal.BACKGROUND[0003]Optogenetics is the combination of genetic and optical methods used to control specific events in targeted cells of living tissue, even within freely moving mammals and other an...

AI Technical Summary

Benefits of technology

The patent describes a method for modifying a balance of excitation and inhibition in a specific part of the brain called the prefrontal cortex. This balance is changed to cause temporary symptoms of a disorder while monitoring the behavior of an animal or a model of a disorder. The method can be used either to recapitulate symptoms in a healthy animal or to alleviate symptoms in an animal with a disorder. The technique can also be used to assess the efficacy of a stimulus in treating the disorder.

Problems solved by technology

However, in spite of these advances, the neurophysiological substrates of most psychiatric disorders remain poorly understood, despite rapidly emerging information on genetic factors that are associated with complex behavioral phenotypes such as those observed in autism and schizophrenia (Cichon et al., The American Journal of Psychiatry 166(5):540 (2009); O'Donovan et al., Human Genetics 126(1): 3 (2009)).

However, it has not been clear if such an imbalance (to be relevant to disease symptoms) would be operative on the chronic (e.g. during development) or the acute timescale.

Furthermore, this hypothesis is by no means universally accepted, in part because it has not yet been susceptible to direct testing.

Pharmacological and electrical interventions lack the necessary specificity to selectively favor activity (in a manner fundamentally distinct from receptor modulation) of neocortical excitatory cells over inhibitory cells, whether in the clinical setting or in freely behaving experimental mammals during social and cognitive tasks.

It is perhaps related to challenges such as this that the social and cognitive deficits of autism and schizophrenia have proven largely unresponsive to conventional psychopharmacology treatments in the clinic.

Existing optogenetic methods are also inadequate for this purpose; driving coordinated spikes selectively in excitatory or inhibitory cells with a channelrhodopsin is feasible, but not well suited to the sparse coding and asynchronous firing patterns of neocortical pyramidal cells.

Moreover, the continuous presence of an optical fiber and other hardware poses challenges for prolonged behavioral tests with fast and spatially complex movements typical of social behavior and cognitive measures (for example in contextual conditioning).

However, the known SFOs (C128A,S,T and D156A) are not stable enough to produce constant photocurrent after a single light flash over the many minutes required for complex behavioral testing.

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