Ning Guo

The negative cell cycle regulator, Tob (transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory

Tob (transducer of ErbB2) is a negative cell cycle regulator with anti-proliferative activity in the periphery. Using a behavioral screening paradigm to look for novel gene functions in the brain, we identified Tob as a brain-expressed protein involved in learning and memory. Behavioral training of fear-conditioning triggered a transient elevation of Tob protein, which preceded the formation of long-term memory. Functional perturbation of Tob by intra-CA1 infusion of antisense oligonucleotides in rats impaired spatial learning and memory in the Morris water maze and long-term memory for contextual fear conditioning, two behavioral paradigms that require the hippocampus. Furthermore, long-term potentiation was suppressed by Tob antisense infusion into the CA1 region. Together, these results indicate that the negative cell cycle regulator Tob is a multifunctional protein involved in hippocampus-dependent learning and memory.

Role of SIP30 in the development and maintenance of peripheral nerve injury-induced neuropathic pain

ABSTRACT Using the chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord, and identified SIP30 as a gene whose expression was elevated after CCI. SIP30 was previously shown to interact with SNAP25, but whose function was otherwise unknown. We now show that in the spinal cord, SIP30 was present in the dorsal horn laminae where the peripheral nociceptive inputs first synapse, co‐localizing with nociception‐related neuropeptides CGRP and substance P. With the onset of neuropathic pain after CCI surgery, SIP30 mRNA and protein levels increased in the ipsilateral side of the spinal cord, suggesting a potential association between SIP30 and neuropathic pain. When CCI‐upregulated SIP30 was inhibited by intrathecal antisense oligonucleotide administration, neuropathic pain was attenuated. This neuropathic pain‐reducing effect was observed both during neuropathic pain onset following CCI, and after neuropathic pain was fully established, implicating SIP30 involvement in the development and maintenance phases of neuropathic pain. Using a secretion assay in PC12 cells, anti‐SIP30 siRNA decreased the total pool of synaptic vesicles available for exocytosis, pointing to a potential function for SIP30. These results suggest a role of SIP30 in the development and maintenance of peripheral nerve injury‐induced neuropathic pain.

rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells

Sac domain-containing proteins belong to a newly identified family of phosphoinositide phosphatases (the PIPPase family). Despite well-characterized enzymatic activity, the biological functions of this mammalian Sac domain PIPPase family remain largely unknown. We identified a novel Sac domain-containing protein, rat Sac3 (rSac3), which is widely expressed in various tissues and localized to the endoplasmic reticulum, Golgi complex and recycling endosomes. rSac3 displays PIPPase activity with PI(3)P, PI(4)P and PI(3,5)P2 as substrates in vitro, and a mutation in the catalytic core of the Sac domain abolishes its enzymatic activity. The expression of rSac3 is upregulated during nerve growth factor (NGF)-stimulated PC12 cell neuronal differentiation, and overexpression of this protein promotes neurite outgrowth in PC12 cells. Conversely, inhibition of rSac3 expression by antisense oligonucleotides reduces neurite outgrowth of NGF-stimulated PC12 cells, and the active site mutation of rSac3 eliminates its neurite-outgrowth-promoting activity. These results indicate that rSac3 promotes neurite outgrowth in differentiating neurons through its PIPPase activity, suggesting that Sac domain PIPPase proteins may participate in forward membrane trafficking from the endoplasmic reticulum and Golgi complex to the plasma membrane, and may function as regulators of this crucial process of neuronal cell growth and differentiation.

Magnetic reversal processes and critical thickness in FePt/α-Fe/FePt trilayers

Abstract Magnetic reversal processes of a FePt/α-Fe/FePt trilayer system with in-plane easy axes have been investigated within a micromagnetic approach. It is found that the magnetic reversal process consists of three steps: nucleation of a prototype of domain wall in the soft phase, the evolution as well as the motion of the domain wall from the soft to the hard phase and finally, the magnetic reversal of the hard phase. For small soft layer thickness Ls, the three steps are reduced to one single step, where the magnetizations in the two phases reverses simultaneously and the hysteresis loops are square with nucleation as the coercivity mechanism. As Ls increases, both nucleation and pinning fields decrease. In the meantime, the single-step reversal expands to a standard three-step one and the coercivity mechanism changes from nucleation to pinning. The critical thickness where the coercivity mechanism alters, could be derived analytically, which is found to be inversely proportional to the square root of the crystalline anisotropy of the hard phase. Such a scaling law might provide an easy way to test the present theory. Further increase of Ls leads to the change of the coercivity mechanism from pinning to nucleation.

RSEP1 is a novel gene with functional involvement in neuropathic pain behaviour

Neuropathic pain from nerve injury by trauma, disease or surgery often causes prolonged suffering. To explore the molecular mechanisms that underlie neuropathic pain, we used mRNA from the L4–5 segments of the lumbar spinal cord of rats with chronic constriction injury (CCI)‐induced neuropathic pain, and differentially screened a cDNA library from the rat brain. A novel gene, termed RSEP1 (Rat Spinal cord Expression Protein 1), was identified. Northern blots revealed that RSEP1 was expressed mainly in the central nervous system including the cerebral cortex, hippocampus, brainstem and spinal cord, as well as in the kidney and ovary. In situ hybridization showed a high level of RSEP1 expression in the CA1, CA3 and dentate gyrus regions of the hippocampus and the small sensory neurons in the dorsal horn, as well as the large neurons in the ventral horn of the spinal cord. Intrathecal injection of RSEP1 antisense oligonucleotide into the spinal cord lumbar enlargement attenuated neuropathic pain behaviours in CCI rats, suggesting a functional involvement of RSEP1 in neuropathic pain.

Sciatic Nerve Neuropathy in Cynomolgus Monkey Macaca Fascicularis: AlteredLeg Usage and Peripheral Nerve Firing

Sciatic nerve is susceptible to trauma and injuries. Animal models for sciatic nerve trauma are mostly in rodents, with limited information about injury-induced neuropathy in non-human primates. We constructed a model of sciatic nerve neuropathy (SNN) in the cynomolgus macaque monkey, Macaca fascicularis, with mild injury to, but without transection of, the sciatic nerve. Monkeys’ behavioral and physiological properties were characterized. SNN led to reduced leg usage as well as muscle atrophy. Sciatic nerve retained the ability of nerve signal transduction, and showed a flat-line type of firing rate profile, consistent with the hypothesis of injury-resulted hyper-sensitization. These data suggest that mild injury to sciatic nerve result in long-lasting malfunction and neuropathy in monkeys. This model may serve as a non-human primate model to study functional changes, as well as underlying pathological mechanisms, of traumatic injury to the sciatic nerve.

Maxillary nerve compression in cynomolgus monkey Macaca fascicularis: altered somatic sensation and peripheral nerve firing

BackgroundTrigeminal nerve is a major source of the sensory input of the face, and trigeminal neuropathology models have been reported in rodents with injury to branches of the maxillary or mandibular division of the trigeminal nerve. Non-human primates are neuroanatomically more closely related to human than rodents; however, nerve injury studies in non-human primates are limited.ResultsWe describe here a nerve injury model of maxillary nerve compression (MNC) in the cynomolgus macaque monkey, Macaca fascicularis, and the initial characterization of the consequences of damage to this trigeminal nerve branch. The nerve injury from the compression appeared to be mild, as we did not observe overt changes in home-cage behavior in the monkeys. When mechanical stimulation was applied to the facial area, monkeys with MNC displayed increased mechanical sensitivity, as the avoidance response scores were lower than those from the control animals. Such a change in mechanical sensitivity appeared to be somewhat bilateral, as the contralateral side also showed increased mechanical sensitivity, although the change on the ipsilateral side was more robust. Multiple-unit recording of the maxillary nerve showed a general pattern of increasing responsiveness to escalating force in mechanical stimulation on the contralateral side. Ipsilateral side of the maxillary nerve showed a lack of responsiveness to escalating force in mechanical stimulation, possibly reflecting a maximum stimulation threshold effect from sensitized nerve due to MNC injury.ConclusionsThese results suggest that MNC may produce increased sensitivity of the ipsilateral maxillary nerve, and that this model may serve as a non-human primate model to evaluate the effect of injury to trigeminal nerve branches.

Pattern of novel object exploration in cynomolgus monkey Macaca fascicularis

Primates exhibit substantial capacity for behavioral innovation, expanding the diversity of their behavioral repertoires, and benefiting both individual survival and species development in evolution. Novel object exploration is an integral part of behavioral innovation. Thus, qualitative and quantitative analysis of novel object exploration helps to better understand behavioral innovation.

Differential behavior patterns in cynomolgus monkey Macaca fascicularis in home cage in response to human gaze

Non‐human primates, when encountering human beings, show wariness and alertness. These behaviors differ when there is direct human gaze vs. when human averts his gaze.