No abstract

The human chemosignal, Delta 4,16-androstadien-3-one modulates psychological state without being consciously discernible as an odor. This study demonstrates that Delta 4,16-androstadien-3-one (androstadienone) alters cerebral glucose utilization both in subcortical regions and in areas of the neocortex not exclusively associated with olfaction. These widely distributed changes are consistent with modulation of an integrated neural network for regulation of emotional and attentional states. This is the first study to demonstrate the effects of a sustained chemosignal on brain metabolism and to show that they are similar to those of long acting chemical substances that affect psychological states. Moreover, this provides the first evidence that a human chemosignal has distributed effects on cortical processes and brain metabolism even when it is not detected consciously.

Transcranial magnetic stimulation (TMS) has been applied to a growing number of psychiatric disorders as a noninvasive probe to study the underlying neurobiologic processes involved in psychiatric disorders and as a putative treatment. Transcranial magnetic stimulation is unparalleled in its ability to test the hypotheses generated by functional neuroimaging studies by modulating activity in selected neural circuits. As a focal intervention that may in some cases exert lasting effects, TMS offers the hope of targeting and ameliorating the circuitry underlying psychiatric disorders. The ultimate success of such an approach depends on our knowledge of the neural circuitry underlying these disorders, of how TMS exerts its effects, and of how to control the application of TMS to exert the desired effects. Although most clinical trials have focused on the treatment of major depression, increasing attention has been paid to schizophrenia and anxiety disorders. Many of these trials have supported a significant effect of TMS, but in some studies the effect is small and short lived. Current challenges in the field include determining how to enhance the efficacy of TMS in these disorders and how to identify patients for whom TMS may be efficacious.

In early mouse embryos, the major inducible heat shock gene, hsp68, is spontaneously and transiently activated at the two-cell stage and becomes heat-inducible around blastocyst stage. We have probed mouse embryo's ability to activate the promoter of this gene during preimplantation development by expression analysis of DNA constructs containing a reporter lacZ gene driven by hsp68 (hsp70A1) 5'-regulatory sequences of various length: (i) a full-length promoter (construct phsplacZ); (ii) a heat shock element (HSE)-deleted promoter (p delta 1hsplacZ); and (iii) a minimal, proximal promoter (p delta 2hsplac Z). When analyzed in transfected L-cells, phsplacZ was heat-inducible, while neither p delta 1hsplacZ nor p delta 2hsplacZ was. Developmental activity of the full-length construct was first analyzed after genome integration in transgenic embryos and found to follow endogenous hsp68 expression in terms of spontaneous activation at the 2-cell stage, down-regulation at the 4-cell stage, and acquisition of heat inducibility at the 16/32-cell stage. In transient expression experiments, injected phsplacZ, p delta 1hsplacZ, and p delta 2hsplacZ were expressed at similar levels by 2-cell embryos, independently of construct topology and injection stage. At the 4-cell stage, however, phsplacZ and p delta 1hsplacZ were expressed at similar levels, while p delta 2hsplacZ was inactive. Only phsplacZ became heat-inducible in late morulas. We conclude that in early mouse embryos, developmental activity of episomic hsp68 promoter depends on proximal sequences at the 2-cell stage and on putative enhancer sequences at the 4-cell stage, while HSEs appear dispensable during early cleavage.