Monitoring blood plasma leptin and lactogenic hormones in pregnant sows.

The mechanism of action of leptin in pregnant breeding sows, in which hyperphagia is managed through dietary strategies, is yet to be clarified. The aim of this study was to monitor leptin concentrations and their interactions with lactogenic hormones in Large White×Landrace breeding multiparous sows (n=15). All sows showed a normal body condition (mean body condition score: 2.96). Blood samples were collected the day after weaning the litters, at insemination, every 15 days up to day 45 of pregnancy and every 7 days from day 46 to farrowing. At delivery, the placenta was collected for the analysis of leptin and leptin receptor expressions. Plasma leptin levels increased from the end of mid gestation (day 72) and remained high until farrowing (P<0.05). As expected, plasma prolactin (PRL), low during most of pregnancy, increased during the 2 weeks before farrowing (P<0.05), whereas progesterone levels reached plateau at 30 days of gestation and decreased at farrowing (P<0.05). Cortisol levels peaked close to farrowing (P<0.05). Leptin was expressed in the placenta, where the receptor expression analysis showed the presence of the short form but not of the long form. A positive correlation was found between leptin and PRL concentrations during mid (r=0.430; P<0.001) and late (r=0.687; P<0.001) pregnancy, and with progesterone in early pregnancy (r=0.462; P<0.05). During late gestation, a positive correlation was observed between leptin and cortisol (r=0.585; P<0.001). Our results suggested that, in restrictively fed pregnant sows, the leptin levels increased from the end of mid pregnancy to delivery, confirming the presence of leptin resistance. We showed a correlation between leptin and lactogenic hormones during different stages of pregnancy in sows. Lactogenic hormones show pregnancy-specific changes in their secretion and all may become involved in modulating leptin signal

Sunday Driver/JIP3 binds kinesin heavy chain directly and enhances its motility

Neuronal development, function and repair critically depend on axonal transport of vesicles and protein complexes, which is mediated in part by the molecular motor kinesin‐1. Adaptor proteins recruit kinesin‐1 to vesicles via direct association with kinesin heavy chain (KHC), the force‐generating component, or via the accessory light chain (KLC). Binding of adaptors to the motor is believed to engage the motor for microtubule‐based transport. We report that the adaptor protein Sunday Driver (syd, also known as JIP3 or JSAP1) interacts directly with KHC, in addition to and independently of its known interaction with KLC. Using an in vitro motility assay, we show that syd activates KHC for transport and enhances its motility, increasing both KHC velocity and run length. syd binding to KHC is functional in neurons, as syd mutants that bind KHC but not KLC are transported to axons and dendrites similarly to wild‐type syd. This transport does not rely on syd oligomerization with itself or other JIP family members. These results establish syd as a positive regulator of kinesin activity and motility

Deletion of Tsc2 in nociceptors reduces target innervation, ion channel expression, and sensitivity to heat

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors in Tsc2-deleted mice. In addition to these changes in innervation and gene expression, Tsc2-deleted mice exhibited reduced noxious heat sensitivity and decreased injury-induced cold hypersensitivity, but normal baseline sensitivity to cold and mechanical stimuli. Together, these data show that excess mTORC1 activity in sensory neurons produces changes in gene expression, neuron morphology and sensory behavior.</jats:p

Sunday Driver links axonal transport to damage signaling

Neurons transmit long-range biochemical signals between cell bodies and distant axonal sites or termini. To test the hypothesis that signaling molecules are hitchhikers on axonal vesicles, we focused on the c-Jun NH2-terminal kinase (JNK) scaffolding protein Sunday Driver (syd), which has been proposed to link the molecular motor protein kinesin-1 to axonal vesicles. We found that syd and JNK3 are present on vesicular structures in axons, are transported in both the anterograde and retrograde axonal transport pathways, and interact with kinesin-I and the dynactin complex. Nerve injury induces local activation of JNK, primarily within axons, and activated JNK and syd are then transported primarily retrogradely. In axons, syd and activated JNK colocalize with p150Glued, a subunit of the dynactin complex, and with dynein. Finally, we found that injury induces an enhanced interaction between syd and dynactin. Thus, a mobile axonal JNK–syd complex may generate a transport-dependent axonal damage surveillance system

Voltage-independent SK-channel dysfunction causes neuronal hyperexcitability in the hippocampus of Fmr1 knock-out mice

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (

Hyperexcitability of sensory neurons in Fragile X mouse model

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability i