Genetic Control of a Central Pattern Generator: Rhythmic Oromotor Movement in Mice Is Controlled by a Major Locus near Atp1a2

Fluid licking in mice is a rhythmic behavior that is controlled by a central pattern generator (CPG) located in a complex of brainstem nuclei. C57BL/6J (B6) and DBA/2J (D2) strains differ significantly in water-restricted licking, with a highly heritable difference in rates (h2≥0.62) and a corresponding 20% difference in interlick interval (mean ± SEM = 116.3±1 vs 95.4±1.1 ms). We systematically quantified motor output in these strains, their F1 hybrids, and a set of 64 BXD progeny strains. The mean primary interlick interval (MPI) varied continuously among progeny strains. We detected a significant quantitative trait locus (QTL) for a CPG controlling lick rate on Chr 1 (Lick1), and a suggestive locus on Chr 10 (Lick10). Linkage was verified by testing of B6.D2-1D congenic stock in which a segment of Chr 1 of the D2 strain was introgressed onto the B6 parent. The Lick1 interval on distal Chr 1 contains several strong candidate genes. One of these is a sodium/potassium pump subunit (Atp1a2) with widespread expression in astrocytes, as well as in a restricted population of neurons. Both this subunit and the entire Na+/K+-ATPase molecule have been implicated in rhythmogenesis for respiration and locomotion. Sequence variants in or near Apt1a2 strongly modulate expression of the cognate mRNA in multiple brain regions. This gene region has recently been sequenced exhaustively and we have cataloged over 300 non-coding and synonymous mutations segregating among BXD strains, one or more of which is likely to contribute to differences in central pattern generator tempo

Sex-specific enhancement of palatability-driven feeding in adolescent rats

<div><p>It has been hypothesized that brain development during adolescence perturbs reward processing in a way that may ultimately contribute to the risky decision making associated with this stage of life, particularly in young males. To investigate potential reward dysfunction during adolescence, Experiment 1 examined palatable fluid intake in rats as a function of age and sex. During a series of twice-weekly test sessions, non-food-deprived rats were given the opportunity to voluntarily consume a highly palatable sweetened condensed milk (SCM) solution. We found that adolescent male, but not female, rats exhibited a pronounced, transient increase in SCM intake (normalized by body weight) that was centered around puberty. Additionally, adult females consumed more SCM than adult males and adolescent females. Using a well-established analytical framework to parse the influences of reward palatability and satiety on the temporal structure of feeding behavior, we found that palatability-driven intake at the outset of the meal was significantly elevated in adolescent males, relative to the other groups. Furthermore, although we found that there were some group differences in the onset of satiety, they were unlikely to contribute to differences in intake. Experiment 2 confirmed that adolescent male rats exhibit elevated palatable fluid consumption, relative to adult males, even when a non-caloric saccharin solution was used as the taste stimulus, demonstrating that these results were unlikely to be related to age-related differences in metabolic need. These findings suggest that elevated palatable food intake during adolescence is sex specific and driven by a fundamental change in reward processing. As adolescent risk taking has been hypothesized as a potential result of hypersensitivity to and overvaluation of appetitive stimuli, individual differences in reward palatability may factor into individual differences in adolescent risky decision making.</p></div

Paraneoplastic syndromes in pancreatic cancer.

Paraneoplastic syndromes are defined as signs and symptoms which presentdistant to the site of primary cancer or metastases. However, they are closelyassociated with the malignant disease and comprise metabolic, dystrophic, and/ordegenerative symptoms, which are consequences of humoral or hormonal factors. The clinical symptoms vary widely and include systemic and organ-specificmanifestations. In some cases, these can become the major clinical problems determining survival. Systemic manifestations include frequent symptoms ofpancreatic cancer patients such as fever and cachexia. Organ-specific symptomsmay represent as cutaneous, neurological, hematological, or endocrine symptoms. A special focus of this chapter is on diabetes mellitus associated withpancreatic tumors. The best-understood syndromes result from tumor productionof biologically active substances or, to a lesser extent, from autoimmune phenomena. Biological active agents may promote the growth of the tumor directly. In turn, growth-promoting agents of this type may become the focus of newapproaches to anticancer treatment. After successful treatment of the underlyingmalignant disease, paraneoplastic symptoms may resolve completely. Thus, earlyrecognition of paraneoplastic syndromes is very important in the management ofpatients with pancreatic cancer. In the following chapter, the most commonparaneoplastic syndromes are described in detail