First identified as a factor that controls pigmentation in fish, melanocortin receptors also serve to control hair color in mammals. In the brain, the best-studied function is regulation of food intake and metabolism. The results from Lim et al. (2012) also implicate melanocortins in a tightly regulated stress response where they adversely affect reward and hedonic state that is relevant to depression. We know that depression presents itself in many ways, with patients suffering from different symptoms. The parsing of anhedonia and helplessness is therefore critical, and the present work gives specific mechanisms and potentially distinct targets for future therapies. “
“The success of biological systems depends upon their capacity

to adapt to the environment. Over half a century ago, Conrad Waddington proposed that organismal development and reaction to the environment are governed by an “epigenetic system” that sculpts R428 cell line the pathway of embryogenesis

(Waddington, 1942, 1959). Waddington’s elegant metaphor of the “epigenetic landscape” illustrated the alternative pathways that a cell might traverse depending on extrinsic influences and adaptive responses, the topology of this landscape Depsipeptide being defined by a web of underlying gene networks (Waddington, 1957). Although modern usage of the term epigenetics invokes a rather specific set of chromosomal mechanisms that regulate gene expression, Waddington pondered the Isotretinoin relationships between genotype and phenotype before the molecular machinery

could be defined. In fact, Waddington described a genetically encoded adaptive mechanism as “a gun which is not only set on a hair trigger but which is aimed to hit the target when it goes off” (Waddington, 1959), anticipating the structure of cellular signaling to regulate downstream target genes (Figure 1A). We now appreciate that cells possess an extensive arsenal of adaptive signaling mechanisms suitable for responses to a wide range of temporal domains and environmental conditions or cellular interactions (Figure 1B). While rapid and local state changes are effectively triggered by conformational, catalytic, and posttranslational modification of molecules already available in the cell, sustained adaptive state changes can persist beyond the lifetime of individual molecules, such as the memories stored in neural networks. Mechanisms that link adaptive responses to expression of the genome not only provide the renewable resource of RNA and protein, but also can alter the “program” of the cell via qualitative changes in expression (reviewed by Flavell and Greenberg, 2008). Although transcriptional mechanisms can produce very long-lived state change, they offer limited spatial acuity and thus depend on posttranscriptional processes for regulated delivery of the expressed genome. Spatial constraint is particularly important in the nervous system, where extremely complex cell architecture is essential for circuit structure and function.