Are biochemical markers of neuroendocrine tumors coreleased with insulin following local calcium stimulation in patients with insulinomas?

The objective was to test whether chromogranin A (CgA), neuron-specific enolase (NSE), and pancreatic polypeptide (PP) are released from the pancreas during the selective arterial calcium stimulation and hepatic venous sampling test (ASVS) in patients with insulinomas.

Occurrence of gustducin-immunoreactive cells in von Ebner's glands of guinea pigs

An immunohistochemical examination of guinea-pig taste buds in vallate papillae revealed gustducin-immunoreactive cells in the area of von Ebner’s glands, minor salivary glands. Since there have been no reports describing those cells in these locations for other species, we investigated these glands in order both to localize the cells and compare their immunoreactive characteristics with corresponding cells in the vallate taste buds. The gustducin-immunoreactive cells coincided with cells containing no secretory granules in the end portion of the glands, which was supported by the electron-microscopic immunocytochemistry. Double immunofluorescence microscopy confirmed these cells to be entirely immunopositive to type III inositol 1,4,5-triphosphate receptor (IP3R-3), phospholipase Cβ2 (PLCβ2), and villin and also partly immunopositive to neuron-specific enolase (NSE) and calbindin D-28K. The gustducin-immunoreactive cells in the vallate taste buds exhibited completely the same immunoreactivities for these five molecules. Accordingly, the present results give credence to a consideration that the gustducin-immunnoreactive cells in both locations are identical in function(s) e.g., chemo-reception.

Sensory innervation of the dorsal longitudinal ligament and the meninges in the lumbar spine of the dog

Although intervertebral disc herniation is a well-known disease in dogs, pain management for this condition has remained a challenge. The goal of the present study is to address the lack of information regarding the innervation of anatomical structures within the canine vertebral canal. Immunolabeling was performed with antibodies against protein gene product 9.5, Tuj-1 (neuron-specific class III β-tubulin), calcitonin gene-related peptide, and neuropeptide Y in combination with the lectin from Lycopersicon esculentum as a marker for blood vessels. Staining was indicative of both sensory and sympathetic fibers. Innervation density was the highest in lateral areas, intermediate in dorsal areas, and the lowest in ventral areas. In the dorsal longitudinal ligament (DLL), the highest innervation density was observed in the lateral regions. Innervation was lower at mid-vertebral levels than at intervertebral levels. The presence of sensory and sympathetic fibers in the canine dura and DLL suggests that pain may originate from both these structures. Due to these regional differences in sensory innervation patterns, trauma to intervertebral DLL and lateral dura is expected to be particularly painful. The results ought to provide a better basis for the assessment of medicinal and surgical procedures.

The time window for generation of dendritic spikes by coincidence of action potentials and EPSPs is layer specific in somatosensory cortex

The precise timing of events in the brain has consequences for intracellular processes, synaptic plasticity, integration and network behaviour. Pyramidal neurons, the most widespread excitatory neuron of the neocortex have multiple spike initiation zones, which interact via dendritic and somatic spikes actively propagating in all directions within the dendritic tree. For these neurons, therefore, both the location and timing of synaptic inputs are critical. The time window for which the backpropagating action potential can influence dendritic spike generation has been extensively studied in layer 5 neocortical pyramidal neurons of rat somatosensory cortex. Here, we re-examine this coincidence detection window for pyramidal cell types across the rat somatosensory cortex in layers 2/3, 5 and 6. We find that the time-window for optimal interaction is widest and shifted in layer 5 pyramidal neurons relative to cells in layers 6 and 2/3. Inputs arriving at the same time and locations will therefore differentially affect spike-timing dependent processes in the different classes of pyramidal neurons.

Code-specific learning rules improve action selection by populations of spiking neurons

Population coding is widely regarded as a key mechanism for achieving reliable behavioral decisions. We previously introduced reinforcement learning for population-based decision making by spiking neurons. Here we generalize population reinforcement learning to spike-based plasticity rules that take account of the postsynaptic neural code. We consider spike/no-spike, spike count and spike latency codes. The multi-valued and continuous-valued features in the postsynaptic code allow for a generalization of binary decision making to multi-valued decision making and continuous-valued action selection. We show that code-specific learning rules speed up learning both for the discrete classification and the continuous regression tasks. The suggested learning rules also speed up with increasing population size as opposed to standard reinforcement learning rules. Continuous action selection is further shown to explain realistic learning speeds in the Morris water maze. Finally, we introduce the concept of action perturbation as opposed to the classical weight- or node-perturbation as an exploration mechanism underlying reinforcement learning. Exploration in the action space greatly increases the speed of learning as compared to exploration in the neuron or weight space.

Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.

Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SIL1, mutated in Marinesco-Sjögren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress-prone fast-fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sil1 allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus-mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival.

Aberrant association of misfolded SOD1 with Na+/K+ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS.

Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na+/K+ATPase-α3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na+/K+ATPase-α3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na+/K+ATPase-α3 onto a 10 amino acid stretch that is unique to Na+/K+ATPase-α3 but not found in the closely related Na+/K+ATPase-α1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na+/K+ATPase-α3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na+/K+ATPase-α3 restored Na+/K+ATPase-α3 activity in the spinal cord, delayed pathological alterations and prolonged survival of SOD1G93A mice. Additionally, altered Na+/K+ATPase-α3 expression was observed in the spinal cord of individuals with sporadic and familial ALS. A fraction of sporadic ALS cases also presented B8H10 positive misfSOD1 immunoreactivity, suggesting that similar mechanism might contribute to the pathology.