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J N Crawley

Publications and source records attributed to J N Crawley.

At least 37 records · Page 2Linked to original sources
PubMed1999

Rat strain differences in response to galanin on the Morris water task.

Galanin acts as an inhibitory modulator of cholinergic transmission in the septohippocampal pathway of the rat. Centrally administered galanin induces performance deficits on rodent learning and memory tasks, including delayed non-matching to position, T-maze delayed alternation, passive avoidance, starbust radial maze acquisition, and the Morris water task. The present study investigates differences in responsiveness to intraventricularly administered galanin across three strains of laboratory rat on acquisition of spatial learning in the Morris water task. Sprague-Dawley rats showed normal performance during training, but lack of selective quadrant search on the probe trial in response to galanin treatment. Long-Evans rats showed no effects of galanin on performance during training or probe trial. Wistar rats showed longer latencies to reach the hidden platform during training, and lack of selective quadrant search on the probe trial in response to galanin. Performance on the visible platform task and on locomotor activity in the open field was normal in rats treated with galanin. These results are consistent with an interpretation of strain differences in sensitivity to the inhibitory actions of galanin on learning and memory.

Animals↗
PubMed1999

The role of galanin in feeding behavior.

Galanin inhibits food consumption in satiated rats. Discovered relatively recently, galanin is a 29-amino-acid neuropeptide, not homologous with any other known peptide. Three G-protein-linked galanin receptor subtypes have been cloned. This review summarizes the mechanisms by which exogenously administered galanin may stimulate ingestion, discusses pharmacological and genetic investigations of the role of endogenous galanin on feeding and body weight, and speculates on the therapeutic potential of non-peptide galanin receptor antagonists for the treatment of appetite disorders.

Animals↗
PubMed1999

A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder.

Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations.

Animals↗
PubMed1999

Behavioral effects of ivermectin in mice.

BACKGROUND AND PURPOSE: Ivermectin is a common anthelmintic drug, widely used in laboratory rodents for treatment of pinworm and mite infestations. We evaluated the action of ivermectin on sensitive behavioral tasks in mice during treatment for mites within a barrier facility. METHODS: A total of 21 (5 males, 16 females) mice (129/SvEv) were used for measuring body weight, open field locomotor activity, and rotarod motor coordination. For acoustic startle and prepulse inhibition, 20 C57BL/6J and 29 AKR/J mice were studied. For the Morris water task, the same 20 C57BL/6J mice were studied. Ivermectin (0.08% sheep drench) was administered in the drinking water of the home cage for 8 weeks. Control groups received normal tap water in identical bottles. RESULTS: Ivermectin did not affect general health, body weight, motor coordination, swimming behavior, or spatial learning in several inbred strains of mice. However, it induced a small but significant effect on some sensitive behaviors. CONCLUSIONS: A cautious approach to initiating ivermectin treatment in mice should be used for sensitive behavioral experiments.

Acoustic Stimulation↗
PubMed1998

Galanin inhibits performance on rodent memory tasks.

Central administration of galanin produces performance deficits on a variety of rodent learning and memory tasks. Galanin impairs acquisition and/or retention of the Morris water task, delayed nonmatching to position, T-maze delayed alternation, starburst radial maze, and passive avoidance in normal rats. A primary site of action is the ventral hippocampus, with an additional modulatory site in the medial septum-diagonal band. The behavioral actions of galanin at rat septohippocampal sites mediating cognitive processes are consistent with previous reports of inhibitory actions of galanin on acetylcholine release and cholinergically activated transduction at the M1 muscarinic receptor in rat hippocampus. The peptidergic galanin receptor antagonist M40 blocks the inhibitory actions of galanin on memory tasks. Treatment combinations of M40 with an M1 agonist, TZTP, improves performance on delayed nonmatching to position, in rats with 192IgG-saporin-induced cholinergic lesions of basal forebrain neurons. Nonpeptide, bioavailable, subtype-selective galanin receptor antagonists may provide tools to test the hypothesis that antagonism of endogenous galanin, which is overexpressed in the basal forebrain in Alzheimer's patients, can contribute to the alleviation of the cognitive deficits associated with Alzheimer's disease.

Animals↗
PubMed1998

Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein delta.

CCAAT/enhancer binding protein delta (C/EBPdelta) is a transcriptional regulator implicated in the hepatic acute phase response and in adipogenic and myeloid cell differentiation. We found that C/EBPdelta is widely expressed in the peripheral and central nervous systems, including neurons of the hippocampal formation, indicating a role in neural functions. To examine the role of C/EBPdelta in vivo, we generated mice with a targeted deletion of the C/EBPdelta gene. This mutation does not interfere with normal embryonic and postnatal development. Performance in a battery of behavioral tests indicates that basic neurological functions are normal. Furthermore, performance in a Morris water maze task suggests that C/EBPdelta mutant mice have normal spatial learning. However, in the contextual and auditory-cue-conditioned fear task, C/EBPdelta null mice displayed significantly more conditioned freezing to the test context than did wild-type controls, but equivalent conditioning to the auditory cue. These data demonstrate a selectively enhanced contextual fear response in mice carrying a targeted genomic mutation and implicate C/EBPdelta in the regulation of a specific type of learning and memory.

Animals↗
PubMed1998

Biochemical and morphometric analyses show that myelination in the insulin-like growth factor 1 null brain is proportionate to its neuronal composition.

To elucidate the role of insulin-like growth factor 1 (IGF1) in the normal development of brain myelination, we used behavioral, biochemical, and histological analyses to compare the myelination of brains from Igf1(-/-) and wild-type (WT) littermate mice. The studies were conducted at postnatal day 40, at which time the Igf1(-/-) mice weighed approximately 66% less than wild-type mice. However, the Igf1(-/-) brain weight was only reduced by approximately 34%. Formal neurological testing showed no sign of central or peripheral myelinopathy in Igf1(-/-) mice. Myelin composition was not significantly different, and myelin concentration, normalized to brain weight or protein, was equal in Igf1(-/-) and WT mice. Likewise, concentrations of myelin-specific proteins (MBP, myelin proteolipid protein, MAG, and 2',3'-cyclic nucleotide,3'-phosphodiesterase) were not significantly different in Igf1(-/-) and WT mice. The myelin-associated lipids galactocerebroside and sulfatide were modestly reduced in Igf1(-/-) brains. Regional oligodendrocyte populations and myelin staining patterns were comparable in Igf1(-/-) and WT brains, with the notable exception of the olfactory system. The Igf1(-/-) olfactory bulb was profoundly reduced in size and was depleted of mitral neurons and oligodendrocytes, and its efferent tracts were depleted of myelin. In summary, this study shows that myelination of the Igf1(-/-) brain is proportionate to its neuronal composition. Where projection neurons are preserved despite the deletion of IGF1, as in the cerebellar system, oligodendrocytes and myelination are indistinguishable from wild type. Where projection neurons are depleted, as in the olfactory bulb, oligodendrocytes are also depleted, and myelination is reduced in proportion to the reduced projection neuron mass. These data make a strong case for the primacy of axonal factors, not including IGF1, in determining oligodendrocyte survival and myelination.

Animals↗
PubMed1998

Coadministration of galanin antagonist M40 with a muscarinic M1 agonist improves delayed nonmatching to position choice accuracy in rats with cholinergic lesions.

The neuropeptide galanin is overexpressed in the basal forebrain in Alzheimer's disease (AD). In rats, galanin inhibits evoked hippocampal acetylcholine release and impairs performance on several memory tasks, including delayed nonmatching to position (DNMTP). Galanin(1-13)-Pro2-(Ala-Leu)2-Ala-NH2 (M40), a peptidergic galanin receptor ligand, has been shown to block galanin-induced impairment on DNMTP in rats. M40 injected alone, however, does not improve DNMTP choice accuracy deficits in rats with selective cholinergic immunotoxic lesions of the basal forebrain. The present experiments used a strategy of combining M40 with an M1 cholinergic agonist in rats lesioned with the cholinergic immunotoxin 192IgG-saporin. Coadministration of intraventricular M40 with intraperitoneal 3-(3-S-n-pentyl-1,2,5-thiadiazol-4-yl)-1,2,5, 6-tetrahydro-1-methylpyridine (TZTP), an M1 agonist, improved choice accuracy significantly more than a threshold dose of TZTP alone. These results suggest that a galanin antagonist may enhance the efficacy of cholinergic treatments for the cognitive deficits of AD.

Acetylcholine↗
PubMed1998

Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice.

The GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses.

Animals↗
PubMed1998

Mesolimbic dopaminergic mechanisms underlying individual differences in sugar consumption and amphetamine hyperlocomotion in Wistar rats.

Individual differences within strains of rats have been demonstrated for dopamine-mediated behaviours and responses to dopaminergic drugs. Differences in mesolimbic dopamine function may underlie individual differences in some of these behaviours, including sugar consumption and amphetamine hyperlocomotion. The present study addressed two potential mechanisms for these differences in dopamine-mediated behaviours. The possibility of functional differences in dopamine receptor subtypes was tested in LOW and HIGH sugar feeders. LOW and HIGH feeders did not differ in their response to the partial D1 agonist SKF-38393. The highest dose (2.5 mg/kg) of the D2 agonist quinpirole stimulated locomotor activity to a greater degree in a subset of HIGH sugar feeders as compared with LOW feeders. All doses of amphetamine induced a greater locomotor response in HIGH feeders as compared with LOW feeders, and HIGH feeders exhibited higher levels of extracellular dopamine in the nucleus accumbens than LOW feeders following exposure to sugar and treatment with amphetamine. These results support the interpretation that LOW and HIGH feeders exhibit differences in presynaptic nucleus accumbens dopamine function that account for the expression of individual differences in sugar consumption and response to amphetamine treatments. A subset of HIGH feeders may also exhibit greater D2 receptor function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1.

Mice completely deficient for Dvl1, one of three mouse homologs of the Drosophila segment polarity gene Dishevelled, were created by gene targeting. Dvl1-deficient mice are viable, fertile, and structurally normal. Surprisingly, these mice exhibited reduced social interaction, including differences in whisker trimming, deficits in nest-building, less huddling contact during home cage sleeping, and subordinate responses in a social dominance test. Sensorimotor gating was abnormal, as measured by deficits in prepulse inhibition of acoustic and tactile startle. Thus, Dvl1 mutants may provide a model for aspects of several human psychiatric disorders. These results are consistent with an interpretation that common genetic mechanisms underlie abnormal social behavior and sensorimotor gating deficits and implicate Dvl1 in processes underlying complex behaviors.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment.

The GM2 activator deficiency (also known as the AB variant), Tay-Sachs disease, and Sandhoff disease are the major forms of the GM2 gangliosidoses, disorders caused by defective degradation of GM2 ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of beta-hexosaminidase A. The GM2 activator deficiency is caused by mutations in the GM2A gene encoding the GM2 activator protein. For degradation of GM2 ganglioside by beta-hexosamindase A, the GM2 activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, GM2 ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the GM2 activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of GM2 with a low amount of GA2. The results demonstrate that the activator protein is required for GM2 degradation and also may indicate a role for the GM2 activator in GA2 degradation.

Animals↗
PubMed1997

A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice.

Behavioral phenotyping of transgenic and knockout mice requires rigorous, formal analyses. Well-characterized paradigms can be chosen from the established behavioral neuroscience literature. This review describes (1) a series of neurological and neuropsychological tests which are effectively used as a first screen for behavioral abnormalities in mutant mice, and (2) a series of specific behavioral paradigms, clustered by category. Included are multiple paradigms for each category, including learning and memory, feeding, analgesia, aggression, anxiety, depression, schizophrenia, and drug abuse models. Examples are given from the experiences of the authors, in applying these experimental designs to transgenic and knockout mice. Extensive references for each behavioral paradigm are provided, to allow new investigators to access the relevant literature on behavioral methodology.

Animals↗
PubMed1997

Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies.

Choosing the best genetic strains of mice for developing a new knockout or transgenic mouse requires extensive knowledge of the endogenous traits of inbred strains. Background genes from the parental strains may interact with the mutated gene, in a manner which could severely compromise the interpretation of the mutant phenotype. The present overview summarizes the literature on a wide variety of behavioral traits for the 129, C57BL/6, DBA/2, and many other inbred strains of mice. Strain distributions are described for open field activity, learning and memory tasks, aggression, sexual and parental behaviors, acoustic startle and prepulse inhibition, and the behavioral actions of ethanol, nicotine, cocaine, opiates, antipsychotics, and anxiolytics. Using the referenced information, molecular geneticists can choose optimal parental strains of mice, and perhaps develop new embryonic stem cell progenitors, for new knockouts and transgenics to investigate gene function, and to serve as animal models in the development of novel therapeutics for human genetic diseases.

Animals↗
PubMed1997

Inbred strain differences in prepulse inhibition of the mouse startle response.

Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating.

Acoustic Stimulation↗
PubMed1997

Opioidergic and dopaminergic gene expression in the caudate-putamen and accumbens of the mutant mouse, tottering (tg/tg).

Expression of preproenkephalin, dynorphin and D2 dopamine receptor mRNAs was examined in selected regions of the forebrain of homozygous and heterozygous tottering mice, using in situ hybridization histochemistry. Homozygous tottering mice carry an autosomal recessive mutation causing them to exhibit petit mal-like epilepsy. Preproenkephalin mRNA levels were significantly higher in the lateral caudate and the core of the nucleus accumbens of homozygous tottering mice compared to wild-type controls. No differences were observed in the expression of dynorphin and D2 receptor mRNA distribution in brain regions examined in the mutant mice as compared to wild-type controls.

Animals↗
PubMed1997

Mapping quantitative trait loci for open-field behavior in mice.

By performing a whole genome screen in an F2 intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial "response to novelty" ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit116; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, > 2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F2 population's phenotypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences.

Animals↗