The Hcrtr2 (hypocretin (orexin) receptor 2; also called OX2R) gene plays a role in regulating arousal, REM sleep, and depression-like behavior.

In this conditional mutant OX2R TD strain, a loxP-flanked transcription-disrupter (TD) cassette was introduced to intron 1 of the gene to prevent expression of functional protein. Cre-mediated excision of the TD restores expression under the direction of the native promoter.

The impact of this mutation was first tested electrophysiologically using in vitro patch-clamp recordings of histaminergic neurons of the tuberomammillary nucleus (TMN), a type of neuron that expresses only OX2R but not OX1R. Orexin-A ligand depolarizes TMN neurons from wild type mice but has no effect on TMN neurons from homozygous OX2R TD mice.

Behaviorally, OX2R TD mice had normal amounts of wake, non-REM, and REM sleep, but their wake bouts are short during the dark period. Cataplexy (episodes of sudden muscle atonia during active wakefulness) is rare in these mice. OX2R TD mice have milder sleep/wake deficits than prepro-orexin null mice. This phenotype is quite similar to that seen in constitutive OX2R null mice. These electrophysiological and behavioral deficits are fully restored after crossing OX2R mice with Zp3-Cre mice, which express Cre recombinase in the female germline.

OX1/2R TD progeny from crosses with OX1R TD mice (see Stock No. 027706) have severely fragmented sleep/wake behavior, similar to that seen in prepro-orexin null mice.

OX2R TD mice are useful as OX2R null mice in their native state. More importantly, they can be used to study the effects of focal or global restoration of OX2R signaling, using methods that produce focal or germline expression of Cre recombinase, respectively. Focal OX2R restoration can be used to test whether OX2R signaling in a specific brain region is sufficient to rescue specific behaviors.