The cerebral cortex performs its computations with many six-layered fundamental units, collectively spreading along the cortical sheet. What is the local network structure and the operating dynamics of such a fundamental unit? Previous investigations of primary sensory areas revealed a classic “canonical” circuit model, leading to an expectation of similar circuit organization and dynamics throughout the cortex. This review clarifies the different circuit dynamics at play in the higher association cortex of primates that implements computation for high-level cognition such as memory and attention. Instead of feedforward processing of response selectivity through Layers 4 to 2/3 that the classic canonical circuit stipulates, memory recall in primates occurs in Layer 5/6 with local backward projection to Layer 2/3, after which the retrieved information is sent back from Layer 6 to lower-level cortical areas for further retrieval of nested associations of target attributes. In this review, a novel “dynamic multimode module (D3M)” in the primate association cortex is proposed, as a new “canonical” circuit model performing this operation.
The RET proto-oncogene encodes a receptor tyrosine kinase whose alterations are responsible for various human cancers and developmental disorders, including thyroid cancer, non-small cell lung cancer, multiple endocrine neoplasia type 2, and Hirschsprung’s disease. RET receptors are physiologically activated by glial cell line-derived neurotrophic factor (GDNF) family ligands that bind to the coreceptor GDNF family receptor α (GFRα). Signaling via the GDNF/GFRα1/RET ternary complex plays crucial roles in the development of the enteric nervous system, kidneys, and urinary tract, as well as in the self-renewal of spermatogonial stem cells. In addition, another ligand, growth differentiation factor-15 (GDF15), has been shown to bind to GFRα-like and activate RET, regulating body weight. GDF15 is a stress response cytokine, and its elevated serum levels affect metabolism and anorexia-cachexia syndrome. Moreover, recent development of RET-specific kinase inhibitors contributed significantly to progress in the treatment of patients with RET-altered cancer. This review focuses on the broad roles of RET in development, metabolic diseases, and cancer.
Many organisms can survive and proliferate in changing environmental temperatures. Here, we introduce a molecular physiological mechanism for cold tolerance and acclimation of the nematode Caenorhabditis elegans on the basis of previous reports and a new result. Three types of thermosensory neurons located in the head, ASJ, ASG, and ADL, regulate cold tolerance and acclimation. In ASJ, components of the light-signaling pathway are involved in thermosensation. In ASG, mechanoreceptor DEG-1 acts as thermoreceptor. In ADL, transient receptor potential channels are thermoreceptors; however, the presence of an additional unidentified thermoreceptor is also speculated. ADL thermoresponsivity is modulated by oxygen sensory signaling from URX oxygen sensory neurons via hub interneurons. ASJ releases insulin and steroid hormones that are received by the intestine, which results in lipid composition changing with cold tolerance. Additionally, the intestinal transcriptional alteration affects sperm functions, which in turn affects the thermosensitivity of ASJ; thus, the neuron–intestine–sperm–neuron tissue circuit is essential for cold tolerance.