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Background 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. Methods To study the pattern of novel object exploration, two different sized balls were sequentially introduced to singly caged cynomolgus monkeys. Two aspects of monkeys' behaviors were analyzed: the types of motor activities in toy playing and whether there is an orderly sequence of such motor activities during novelty exploration. Results Four types of behavioral activities (oral contact, gross and fine forelimb motor, and hind limb motor) followed a pattern: first forelimb gross motor and oral contact, followed by forelimb fine motor and hind limb activities. Oral contact appeared to be an important behavior in monkeys' repertoire of novelty exploratory behaviors, both as an early appearing activity, and showing a consistent pattern of high cumulative time for two different novel objects. Conclusions These results provide a profile of novel object exploratory behaviors in cynomolgus monkeys, contributing to a better understanding of this aspect of behavioral innovation.

Background 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. Methods We observed cynomolgus monkey in their home cage and studied their behaviors in response to human gaze. Four behaviors were analyzed: opening mouth, staring at observer, agitated activity, and approaching observer. Results Three behaviors appeared to be sensitive to human gaze between when the human observer gazed at the monkey and when the human observer looked away. Individual animals also displayed subpatterns of responses to human gaze. Conclusions These results indicate that, even in their home cage, monkeys display a heightened level of awareness when gazed upon by a human observer, suggesting that human gaze may elicit emotional reactions. Further, under the human gaze, distinct behavioral subpatterns were apparent within the monkey cohort in our study, indicative of subgroups within the cohort.

Differences in exploratory, rearing and locomotion activity of ICR, BALB/c and C57BL/6 strain were investigated by a 16-hole board task and an open field with an automated infrared detecting system. ICR mice had the highest response rate while C57BL/6 mice had the lowest. It took less time for ICR mice to get used to a new environment and its performance in memory testing was also superior to C57BL/6 mice. The results confirmed the feasibility of using a hole-board test to assess memory. Comparisons between the trend of rearing and hole-poking activity demonstrated that the rearing behavior of mice, to a certain degree, reflected its exploratory and cognitive ability. Our results provided firm support for the notion that selection of a mouse strain is essential when conducting studies on higher cognitive behavior in mice.

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)P(2) 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.

To examine the effect of GNTI [5'-guanidinyl-17-(cyclopropylmethyl)-6,7- dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan], a selective antagonist for the kappa opioid receptor, in the MK-801 (dizocilpine maleate)-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia.Two doses of MK-801 (0.3 mg/kg and 0.6 mg/kg) were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis.GNTI inhibited MK-801-induced hyperlocomotion and stereotypy. In particular, GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg vs 0.6 mg/kg MK-801.Antagonism of kappa opioid receptors attenuates MK-801-induced behavior, suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia. GNTI appears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.

Tob (transducer of ErbB-2) is a negative cell cycle regulator with anti-proliferative activity in peripheral tissues. Our previous study identified Tob as a protein involved in hippocampus-dependent memory consolidation (M.L. Jin, X.M. Wang, Y.Y. Tu, X.H. Zhang, X. Gao, N. Guo, Z.Q. Xie, G.P. Zhao, N.H. Jing, B.M. Li, Y.Yu, The negative cell cycle regulator, Tob (Transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory, Neuroscience 131 (2005) 647-659). Here, we provide evidence that Tob in the central nervous system is engaged in acquisition of motor skill. Tob has a relatively high expression in the cerebellum. Tob expression is up-regulated in the cerebellum after rats receive training on a rotarod-running task. Rats infused with Tob antisense oligonucleotides into the 4th ventricle exhibit a severe deficit in running on a rotating rod or walking across a horizontally elevated beam.

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.

We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice. Lens opacity appears 11 days after birth. Slit lamp examination reveals that the opacity mainly localizes to the nuclear region of the lens. Histological analysis shows a severe degeneration of the epithelial cells underneath the anterior lens capsule, whereas those cells in the equatorial region display an excessive proliferation and migration. Within the cortical area underneath the posterior lens capsule, both vacuoles and morgagnian-like bodies are seen. Blue-stained spherical bodies are observed in the embryonic nucleus, forming a Y-like pattern. We mapped the disease locus and found a homozygous G to A nucleotide conversion at position 489 of Crygs in mutant mice, leading to a truncated gene product (Trp163Stop). This finding suggests that CRYGS is not only a lens structural protein, but is also likely to be involved in epithelial cell proliferation, apoptosis, and migration.

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.

Knowledge of genes influencing longitudinal patterns may offer information about predicting disease progression. We developed a systematic procedure for testing association between SNP genotypes and longitudinal phenotypes. We evaluated false positive rates and statistical power to localize genes for disease progression. We used genome-wide SNP data from the Framingham Heart Study. With longitudinal data from two real studies unrelated to Framingham, we estimated three trajectory curves from each study. We performed simulations by randomly selecting 500 individuals. In each simulation replicate, we assigned each individual to one of the three trajectory groups based on the underlying hypothesis (null or alternative), and generated corresponding longitudinal data. Individual Bayesian posterior probabilities (BPPs) for belonging to a specific trajectory curve were estimated. These BPPs were treated as a quantitative trait and tested (using the Wald test) for genome-wide association. Empirical false positive rates and power were calculated. Our method maintained the expected false positive rate for all simulation models. Also, our method achieved high empirical power for most simulations. Our work presents a method for disease progression gene mapping. This method is potentially clinically significant as it may allow doctors to predict disease progression based on genotype and determine treatment accordingly.

Summary Paramecium duboscqui Chatton and Brachon 1933 were collected during cold times of the year in Harbin, China. Cell growth and conjugation processes of this species were studied under various temperatures, and compared with those of P. caudatum. P. duboscqui can divide once every three days even at 5°C, whereas P. caudatum stops cell division at temperatures less than 10°C. Conjugating pair formation takes place from 5 to 20°C but not at 30°C in P. duboscqui. On the other hand, in P. caudatum, pairing is blocked at temperatures less than 10°C, but occurs at 30°C. Nuclear processes during conjugation of P. duboscqui were studied using protargol stained preparations. Changes in the micronuclei, such as 3 pregamic divisions, pronuclear exchange, synkaryon formation, and three postgamic divisions took place as were observed in other Paramecium species. After the third postgamic division, four macronuclear anlagen and four micronuclei were differentiated. Each of the four macronuclear anlagen were segregated into four daughter cells through successive two cell divisions. On the other hand, the four micronuclei divided mitotically at each cell division. The old macronucleus divided once amitotically at the time of the third postgamic division and then disappeared mostly before the first cell division.

Experimentation with alcohol is common during adolescence. However the long-term consequences from moderate alcohol use during adolescence development are not clear. Using a two-bottle free-choice paradigm in the home-cage setting, we studied adolescent mice (4 weeks old) across a 6-week time span of the adolescence-to-adulthood development period. Adolescent mice readily reached a steady level of alcohol consumption and maintained this level throughout the 6-week period. Chronic alcohol consumption resulted in reduced growth in adolescent mice, as well as accelerated acclimation to a novel environment. During a social interaction test, similar levels of initial social investigation and subsequent habituation were observed in both the chronic alcohol and the water-only control groups. However, chronic alcohol self-administration resulted in impaired social recognition and decreased social play/fight behavior. Taken together, these results indicated that chronic alcohol consumption across adolescence development negatively impacted both physical growth and social behavior in mice, highlighting the detrimental consequences from prolonged alcohol drinking in adolescence.

To characterize MK-801's effect on social behavior in mice, we examined adult male ICR mice for interaction with companion mice (juvenile male). Test mice were injected with either saline or MK-801 (0.1 mg/kg), and were tested 30 min later for their social behavior during a 5-min session. A second encounter took place 30 min later, with either a familiar companion mouse (the same as in the initial encounter) or a novel mouse. In saline controls, second encounter with a familiar companion mouse showed reduced social investigative behaviors (anogenital sniffing and staying together), indicating habituation toward a familiar mouse. Second encounter with a novel companion mouse did not show habituation in social investigative behaviors. Pretreatment with MK-801 reduced anogenital sniffing during the first encounter. At the second encounter, these mice displayed non-discriminative habituation of social investigative behaviors, with reduced anogenital sniffing and staying together, regardless of whether the companion mouse was a familiar or a novel one. These results indicate that MK-801 affected exploratory activities of mice, resulting in both reduced social investigative behaviors during first encounter with a companion mouse, and diminished discriminative capacities for a familiar vs. a novel companion mouse during subsequent encounter.

Psychomotor effects elicited by systemic administration of the noncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 (dizocilpine maleate) represent perturbation of glutamatergic pathways, providing an animal model for psychotic symptoms of schizophrenia. Hyperlocomotion and stereotypy are the two main psychomotor behaviors induced by MK-801. This study compared MK-801-induced hyperlocomotion and stereotypy in young (1-month old) and aged mice (12-month old), in order to determine how the aging process may influence these behaviors. The tested MK-801 doses ranged from 0.015 to 1 mg/kg. The data indicated that MK-801 impacted the aged mice more pronouncedly than the young mice, as both hyperlocomotion and stereotypy were increased significantly more in the aged mice relative to the young mice. These results suggest an age-related increase in MK-801 sensitivity in mice.

SNAP-25 is a synaptosomal protein of 25 kDa, a key component of synaptic vesicle-docking/fusion machinery, and plays a critical role in exocytosis and neurotransmitter release. We previously reported that SNAP-25 in the hippocampal CA1 region is involved in consolidation of contextual fear memory and water-maze spatial memory (Hou et al. European J Neuroscience, 20: 1593-1603, 2004). SNAP-25 is expressed not only in the CA1 region, but also in the CA3 region, and the SNAP-25 mRNA level in the CA3 region is higher than in the CA1 region. Here, we provide evidence that SNAP-25 in the CA3 region is also involved in learning/memory. Intra-CA3 infusion of SNAP-25 antisense oligonucleotide impaired both long-term contextual fear memory and water-maze spatial memory, with short-term memory intact. Furthermore, the SNAP-25 antisense oligonucleotide suppressed the long-term potentiation (LTP) of field excitatory post-synaptic potential (fEPSP) in the mossy-fiber pathway (DG-CA3 pathway), with no effect on paired-pulse facilitation of the fEPSP. These results are consistent with the notion that SNAP-25 in the hippocampal CA3 region is required for long-term memory formation.

Systemic injection of the noncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 (dizocilpine maleate) is known to cause increased locomotion and various stereotypic behaviors in rodents. However, the MK-801 dose ranges commonly examined usually begin at tenth of mg/kg and going higher, with the implicit assumption of lower doses being ineffective. We report here that very low dose MK-801, well below the commonly studied doses, exert distinct effects on rodent behaviors. In C57BL/6 mice, very low dose MK-801 (0.02 mg/kg) has strikingly different effects than higher doses commonly reported in the literature. Locomotion, rearing, grooming, and other behaviors are strongly inhibited, replaced by periods of immobility. This is in contrast to the mobility-enhancing effect of MK-801 at commonly reported dose ranges. The effects of very low dose MK-801 are qualitatively similar to those observed with moderate doses (0.1-0.2 mg/kg) of the typical antipsychotic haloperidol. These results highlight the complexity of the dose-response relation for MK-801-induced behaviors.

Memory formation, maintenance, and retrieval are a dynamic process, reflecting a combined outcome of new memory formation on one hand, and older memory suppression/clearance on the other. Although much knowledge has been gained regarding new memory formation, less is known about the molecular components and processes that serve the function of memory suppression/clearance. Here, we report the identification of a novel protein, termed hippyragranin (HGN), that is expressed in the rat hippocampus and its expression is reduced by hippocampal denervation. Inhibition of HGN by antisense oligonucleotide in area CA1 results in enhanced performance in Morris water maze, as well as elevated long-term potentiation. These results suggest that HGN is involved in negative memory regulation.

Neuronal differentiation and aging are known to involve many genes, which may also be differentially expressed during these developmental processes. From primary cultured cerebral cortical neurons, we have previously identified various differentially expressed gene transcripts from cultured cortical neurons using the technique of arbitrarily primed PCR (RAP-PCR). Among these transcripts, clone 0–2 was found to have high homology to rat and human synaptic glycoprotein. By in silico analysis using an EST database and the FACTURA software, the full-length sequence of 0–2 was assembled and the clone was named as mouse synaptic glycoprotein homolog 2 (mSC2). DNA sequencing revealed transcript size of mSC2 being smaller than the human and rat homologs. RT-PCR indicated that mSC2 was expressed differentially at various culture days. The mSC2 gene was located in various tissues with higher expression in brain, lung, and liver. Functions of mSC2 in neurons and other tissues remain elusive and will require more investigation.

As a synaptosomal protein, SNAP-25 plays a role in a number of neuronal functions including axonal growth, dendrite formation, fusion of synaptic vesicles with membrane and the expression of long-term potentiation (LTP) in the hippocampus. Using a learning/memory behavior screening, we identified SNAP-25 as one of the differentially expressed genes in the hippocampus upon behavioral training. The inhibition of SNAP-25 with intracerebroventricular antisense oligonucleotide caused a deficit in long- but not short-term memory for step-down inhibitory avoidance. Intra-CA1 infusion of the SNAP-25 antisense oligonucleotide impaired long-term contextual fear memory and spatial memory and interfered with the LTP of synaptic transmission in the CA1 region. The inhibitory effect on LTP was not mediated by a pre-synaptic mechanism because paired pulse facilitation of synaptic transmission was not affected after administration of the antisense oligonucleotide. Together, the results suggest that SNAP-25 in the CA1 region is involved in memory consolidation.

Systemic injection of the non-competitive NMDA (N-methyl-d-aspartate) receptor antagonist MK-801 (dizocilpine maleate) causes both increased locomotion in rodents and various stereotypic behaviors that are proposed to model certain aspects of schizophrenic symptoms in humans. This study presents a comprehensive characterization of the bimodal effects of MK-801 on locomotion and stereotypy in the C57BL/6 mouse strain, a strain commonly used for genetically modified mice. We found that it is important to analyze both locomotion and stereotypy in parallel, as MK-801-induced stereotypy results in abnormal movements that are recorded as locomotion by automated beam detection systems. Furthermore, it is important to analyze the bimodal effects of MK-801 over an extended time span, rather than the commonly used narrower time window, as at higher doses (e.g., above 0.3 mg/kg) the hyperlocomotion phase develops only after the stereotypic phase subsides. We also observed that the apparent dose–response curve is very sensitive to the particular time window chosen for analysis because MK-801 affects both the time course and maximum value of stimulated locomotion. We show that analyzing the absolute peak value of locomotion induced for each animal, rather than group-averaged time courses, provides a measure that is sensitive over a wider range of MK-801 doses. Interestingly, MK-801 even at a very low dose of 0.02 mg/kg suppressed rather than enhanced rearing behavior, differing in this regard from amphetamine. The non-competitive NMDA receptor antagonist MK-801 induces a complex pattern of behavioral modification in mice with respect to both the time course and the dose–response relationship of behavioral changes. The results of this study provide a foundation and frame of reference for the growing interest in studying MK-801-induced behavior in mice.

Ordered differential display (ODD) was developed recently and has been applied to systematic comparison of expression profiles of genes. It was further improved with the specific complexing property between biotin and streptavidin by the authors. First, random primer and biotinylated oligo (dT) primer were used to make pools of double strand cDNA. Second, streptavidin-coated PCR tube is used to absorb 3'ESTs specifically to avoid the negative effect of other DNA fragments. In the case of 3'ESTs comparison patterns between embryonic brain and body of SD rat, more than forty differentially expressed genes were cloned and identified. The function of rZIC gene, one of the genes identified and cloned, was studied through ethological experiments. The result showed that rZIC gene was associated with locomotion activity of adult mice.

Background Trigeminal 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. Results We 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. Conclusions These 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.

Background Adolescence is a developmental stage vulnerable to alcohol drinking-related problems and the onset of alcoholism. Hypothalamus is a key brain region for food and water intake regulation, and is one of the alcohol-sensitive brain regions. However, it is not known what would be the alcohol effect on hypothalamus following adolescent alcohol intake, chronically over the adolescent development, at moderate levels. Results We employed a paradigm of chronic moderate alcohol intake from adolescence-to-adulthood in mice, and analyzed the alcohol effect on both behavioral and hypothalamic gene expression changes. A total of 751 genes were found and subjected to pathway analysis. The dilated cardiomyopathy (DCM) pathway was identified. The changes of ten genes under this pathway were further verified using RT-PCR. Chronic alcohol consumption during adolescence, even at moderate levels, led to a decrease of motor activity in mice, and also a concerted down regulation of signaling pathway initiating factor (SPIF) genes in the DCM signaling pathway, including β1-adrenergic receptor (Adrb1), Gs protein (Gnas), adenylyl cyclase 1 (Adcy1), and dihydropyridine receptor/L-type calcium channel (Cacna1d). Conclusions These findings suggest that adolescent alcohol intake may trigger gene expression changes in the CNS that parallel those found in the dilated cardiomyopathy signaling pathway. If such effects also take place in humans, our findings would serve as a warning against alcohol intake in youth, such as by teens and/or college students.

Background Vitamin A and its derivatives (retinoids) are crucial for the development, maintenance and morphogenesis of the central nervous system (CNS). Although motor impairment has been reported in postnatal vitamin A depletion rodents, the effect of vitamin A depletion on homeostasis maintaining capability in response to external interference is not clear. Methods In the current study, we measured the effect of vitamin A depletion on motor ability and pain sensitivity under two different conditions: 1. prior to any injection and 2. after the injection of an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801). Results Vitamin A depletion mice showed decreased body weight, enhanced locomotor activity, increased rearing and less tail flick latency. Vitamin A depletion also induced hypersensitivity of stereotypy, ataxia, rearing, and tail flick latency to MK-801, but hyposensitivity of locomotion to MK-801. Conclusions These findings suggest that vitamin A depletion affect broad basal behavior and disrupt homeostasis maintaining capability in response to glutamate perturbation. We provide a useful animal model for assessing the role of vitamin A depletion in regulating animal behavior, and for detecting how neurotransmitter pathways might be involved in vitamin A depletion related behavioral abnormalities.