Melanopsin has been proposed as an important photoreceptive molecule for the mammalian circadian system. Its importance in this role was tested in melanopsin knockout mice. These mice entrained to a light/dark cycle, phase-shifted after a light pulse, and increased circadian period when light intensity increased. Induction of the immediate-early gene c-fos was observed after a nighttime light pulse in both wild-type and knockout mice. However, the magnitude of these behavioral responses in knockout mice was 40% lower than in wild-type mice. Although melanopsin is not essential for the circadian clock to receive photic input, it contributes significantly to the magnitude of photic responses.

The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT 1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT 1A receptormutant mice. These animals lack functional 5-HT 1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT 1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT 1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs. The brain serotonin (5-hydroxytryptamine; 5-HT) system has been strongly implicated in the neural regulation of mood and anxiety state. Accordingly, many commonly used antidepressant and antianxiety medications target this system (1). The complex physiological actions of serotonin are mediated by a heterogeneous family of at least 14 distinct receptor subtypes (2). Although the relative contributions of individual receptor subtypes to the serotonergic regulation of mood are incompletely understood, particular attention has focused on the 5-HT 1A receptor subtype. Partial agonists at this receptor, such as buspirone, are in clinical use as anxiolytics (3), and 5-HT 1A receptor antagonists are reported to accelerate the therapeutic effects of antidepressant medications (4).These compounds produce complex effects on brain function through interactions with functionally distinct populations of 5-HT 1A receptors. 5-HT 1A receptors located on serotonergic neuronal cell bodies and dendrites are the predominant somatodendritic autoreceptors of these neurons; their activation suppresses serotonergic neuronal activity (5, 6). In addition, postsynaptic 5-HT 1A receptors are expressed in numerous serotonergic projection sites such as the cerebral cortex, septal nuclei, hippocampus, and amygdala (7). The relatively selective 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and antagonist WAY 100635 (8) have been used as pharmacological probes of 5-HT 1A receptor function. Systemic administration of 8-OH-DPAT produces hyperphagia, hypothermia, and an anxiolytic-like effect in rodents (9-12). The behavioral and physiological effects of 8-OH-DPAT are blocked by pretreatment with WAY 100635 (12-14).To complement pharmacological approaches to the study of 5-HT 1A receptor function, we have used a gene-targeting strategy to generate a line of m...

A B S T R A C T A sensitive and specific radioimmunoassay for plasma arginine vasopressin (AVP) has been used to study the effects of blood osmolality and volume in regulating AVP secretion in unanesthetized rats. Under basal conditions, plasma AVP and osmolality were relatively constant, averaging 2.3+0.9 (SD) pg/ml and 294±+1.4 mosmol/kg, respectively. Fluid restriction, which increased osmolality and decreased volume, resulted in a progressive rise in plasma AVP to about 10 times basal levels after 96 h. A 2-3-fold increase in plasma AVP occurred as early as 12 h, when osmolality and volume had each changed by less than 2%. Intraperitoneal injections of hypertonic saline, which had no effect on blood volume, also produced a rise in plasma AVP that was linearly correlated with the rise in osmolality (r > 0.9) and quantitatively similar to that found during fluid restriction (plasma AVP increased 2-4-fold with each 1% increase in osmolality). Intraperitoneal injection of polyethylene glycol, which decreased blood volume without altering osmolality, also increased plasma AVP but this response followed an exponential pattern and did not become significant until volume had decreased by 8% or more. At these levels of hypovolemia, the osmoregulatory system continued to function but showed a lower threshold and increase sensitivity to osmotic stimula-A 'preliminary report of this work was published in abstract form in Clin. Res. 21: 329. 1973.

LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis. We show here that LRH-1 induces cell proliferation through the concomitant induction of cyclin D1 and E1, an effect that is potentiated by its interaction with beta-catenin. Whereas beta-catenin coactivates LRH-1 on the cyclin E1 promoter, LRH-1 acts as a potent tissue-restricted coactivator of beta-catenin on the cyclin D1 promoter. The implication of LRH-1 in cell proliferation highlights an unanticipated crosstalk between LRH-1 and the beta-catenin/Tcf4 signaling pathway, which is relevant for the renewal of intestinal crypt cells.