The effect of combined chronic hypoxia and N-ethyl-N-nitrosourea on the carotid bodies of rats

Summary We measured the carotid body volume of rats treated with chronic hypoxia alone and chronic hypoxia together with a single neonatal injection of N-ethyl-N-nitrosourea (10 mg/kg). All the animals so treated showed enlargement of their carotid bodies, but no carotid body chemodectomas occurred.This work was supported by a grant from the North West Cancer Research Fund.     

Circadian rhythm genetics: from flies to mice to humans

A successful genetic dissection of the circadian regulation of behaviour has been achieved through phenotype-driven mutagenesis screens in flies and mice. Cloning and biochemical analysis of these evolutionarily conserved proteins has led to detailed molecular insight into the clock mechanism. Few behaviours enjoy the degree of understanding that exists for circadian rhythms at the genetic, cellular and anatomical levels. The circadian clock has so eagerly spilled her secrets that we may soon know the unbroken chain of events from gene to behaviour. It will likely be fruitful to wield this uncommon degree of knowledge to attack one of the most challenging problems in genetics: the basis of complex human behavioural disorders. We review here the genetic screens that provided the entreé into the heart of the circadian clock, the model of the clock mechanism that has resulted, and the prospects for using the homologues as candidate genes in studies of human circadian dysrhythmias.     

Amygdala circuitry mediating reversible and bidirectional control of anxiety

Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.     

A candidate spermatogenesis gene on the mouse Y chromosome is homologous to ubiquitin-activating enzyme E1.

The human X-linked gene A1S9 complements a temperature-sensitive cell-cycle mutation in mouse L cells, and encodes the ubiquitin-activating enzyme E1. The gene has been reported to escape X-chromosome inactivation, but there is some conflicting evidence. We have isolated part of the mouse A1s9 gene, mapped it to the proximal portion of the X chromosome and shown that it undergoes normal X-inactivation. We also detected two copies of the gene on the short arm of the mouse Y chromosome (A1s9Y-1 and A1s9Y-2). The functional A1s9Y gene (A1s9Y-1) is expressed in testis and is lost in the deletion mutant Sxrb. Therefore A1s9Y-1 is a candidate for the spermatogenesis gene, Spy, which maps to this region. A1s9X is similar to the Zfx gene in undergoing X-inactivation, yet having homologous sequences on the short arm of the Y chromosome, which are expressed in the testis. These Y-linked genes may form part of a coregulated group of genes which function during spermatogenesis.