Biomedical subjects

Xiaoxi Zhuang

Publications and source records attributed to Xiaoxi Zhuang.

12 recordsLinked to original sources

PubMed2006

Dopamine scales performance in the absence of new learning.

Learning and motivation are integral in shaping an organism's adaptive behavior. The dopamine system has been implicated in both processes; however, dissociating the two, both experimentally and conceptually, has posed significant challenges. We have developed an animal model that dissociates expression or scaling of a learned behavior from learning itself. An inducible dopamine transporter (DAT) knockdown mouse line has been generated, which exhibits significantly slower reuptake of released dopamine and increased tonic firing of dopamine neurons without altering phasic burst firing. Mice were trained in experimental tasks prior to inducing a hyperdopaminergic tone and then retested. Elevated dopamine enhanced performance in goal-directed operant responses. These data demonstrate that alterations in dopaminergic tone can scale the performance of a previously learned behavior in the absence of new learning.

Action Potentials↗

PubMed2006

Low amplitude entrainment of mice and the impact of circadian phase on behavior tests.

A tremendous increase in the use of genetically engineered mice as experimental animals has led to increased scrutiny of mouse models generally and mouse behavioral paradigms specifically. Although mice are nocturnal, for practical reasons, most experimental procedures, including behavioral studies, are conducted during their inactive, sleep phase. Accumulating evidence indicates that myriad behavioral, cellular and biochemical processes fluctuate with circadian rhythmicity; however, time of day at which experiments are conducted is rarely controlled. The impact of circadian phase on the reliability of experimental results has received little attention and the present data are conflicting. This study addressed two questions. First, will laboratory mice in a typical animal care facility entrain to a low amplitude light cycle using bright/dim rather than light/dark cycles? A positive answer will make reversing photocycle easy to implement in any facility as dim light suitable for animal husbandry and behavioral testing can substitute for darkness during work hours. By monitoring home cage wheel running, we examined the effectiveness of a dim/bright photocycle as a zeitgeiber. We found that mice subjected to dim/bright photocycles effectively entrained such that their subjective night and activity onset coincided with the beginning of the dim light period, suggesting a potential strategy for standardization and management of circadian phase in nocturnal animals. In a second experiment, we asked what effect circadian phase has on behavioral performance in commonly used mouse behavioral tests. We found no main effect of circadian phase on outcome in open field activity, elevated plus maze emotionality, water maze spatial memory, novel object exploration and hyperactivity in response to amphetamine; however, we observed occasional interactions between circadian phase and both strain and sex that were neither consistent nor systematic. These data suggest that the tests examined here are relatively impervious to circadian phase. In general, testing mice during their active phase is more suitable for behavioral studies; a reversed dim/bright photocycle potentially offers one practical strategy for managing rodents' circadian cycles.

Animals↗

PubMed2006

Instrumental learning in hyperdopaminergic mice.

In two experiments we investigated the effects of elevated dopaminergic tone on instrumental learning and performance using dopamine transporter knockdown (DAT KD) mice. In Experiment 1, we showed that both DAT KD mice and wild-type controls were similarly sensitive to outcome devaluation induced by sensory specific satiety, indicating normal action-outcome learning in both groups. In Experiment 2, we used a Pavlovian-to-instrumental transfer procedure to assess the potentiation of instrumental responding by Pavlovian conditional stimuli (CS). Although during the Pavlovian training phase the DAT KD mice entered the food magazine more frequently in the absence of the CS, when tested later both groups showed outcome-selective PIT. These results suggest that the elevated dopaminergic tone reduced the selectivity of stimulus control over conditioned behavior, but did not affect instrumental learning.

Animals↗

PubMed2005

Mice with chronically elevated dopamine exhibit enhanced motivation, but not learning, for a food reward.

Dopamine has been critically implicated in learning and motivation, although its precise role remains to be determined. In order to investigate the involvement of dopamine in learning and motivation for a food reward, we used dopamine transporter knockdown mice (DAT KD) that have chronically elevated levels of extracellular dopamine. The present study demonstrates that chronically elevated dopamine enhances tendency to work for a food reward without apparent effects on Pavlovian and operant learning for this reward. The increase in dopamine is associated with elevated levels of dynorphin and Fos B expression in the dorsal caudate-putamen and the core but not the shell subregion of the nucleus accumbens. These data suggest that motivation to work, but not learning, for a food reward appears to be under the critical influence of tonic dopaminergic activity in discrete brain areas relevant for a reward-directed behavior.

Animals↗

PubMed2005

Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice.

Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and task-dependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month- and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.

Age Factors↗

PubMed2005

Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's.

BACKGROUND: Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels. RESULTS: We found that the serial pattern of this instinctive behavioral sequence becomes strengthened as an entire entity in hyper-dopaminergic mutants, and more resistant to interruption. Hyper-dopaminergic mutant mice have stronger and more rigid syntactic grooming chain patterns than wild-type control mice. Mutants showed sequential super-stereotypy in the sense of having more stereotyped and predictable syntactic grooming sequences, and were also more likely to resist disruption of the pattern en route, by returning after a disruption to complete the pattern from the appropriate point in the sequence. By contrast, wild-type mice exhibited weaker forms of the fixed action pattern, and often failed to complete the full sequence. CONCLUSIONS: Sequential super-stereotypy occurs in the complex fixed action patterns of hyper-dopaminergic mutant mice. Elucidation of the basis for sequential super-stereotypy of instinctive behavior in DAT knockdown mutant mice may offer insights into neural mechanisms of overly-rigid sequences of action or thought in human patients with disorders such as Tourette's or OCD.

Animals↗

PubMed2004

Targeted gene expression in dopamine and serotonin neurons of the mouse brain.

We used a knock-in strategy to generate two lines of mice expressing Cre recombinase under the transcriptional control of the dopamine transporter promoter (DAT-cre mice) or the serotonin transporter promoter (SERT-cre mice). In DAT-cre mice, immunocytochemical staining of adult brains for the dopamine-synthetic enzyme tyrosine hydroxylase and for Cre recombinase revealed that virtually all dopaminergic neurons in the ventral midbrain expressed Cre. Crossing DAT-cre mice with ROSA26-stop-lacZ or ROSA26-stop-YFP reporter mice revealed a near perfect correlation between staining for tyrosine hydroxylase and beta-galactosidase or YFP. YFP-labeled fluorescent dopaminergic neurons could be readily identified in live slices. Crossing SERT-cre mice with the ROSA26-stop-lacZ or ROSA26-stop-YFP reporter mice similarly revealed a near perfect correlation between staining for serotonin-synthetic enzyme tryptophan hydroxylase and beta-galactosidase or YFP. Additional Cre expression in the thalamus and cortex was observed, reflecting the known pattern of transient SERT expression during early postnatal development. These findings suggest a general strategy of using neurotransmitter transporter promoters to drive selective Cre expression and thus control mutations in specific neurotransmitter systems. Crossed with fluorescent-gene reporters, this strategy tags neurons by neurotransmitter status, providing new tools for electrophysiology and imaging.

Animals↗

PubMed2004

Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses.

Dopamine neurons are thought to convey a fast, incentive salience signal, faster than can be mediated by dopamine. A resolution of this paradox may be that midbrain dopamine neurons exert fast excitatory actions. Using transgenic mice with fluorescent dopamine neurons, in which the axonal projections of the neurons are visible, we made horizontal brain slices encompassing the mesoaccumbens dopamine projection. Focal extracellular stimulation of dopamine neurons in the ventral tegmental area evoked dopamine release and early monosynaptic and late polysynaptic excitatory responses in postsynaptic nucleus accumbens neurons. Local superfusion of the ventral tegmental area with glutamate, which should activate dopamine neurons selectively, produced an increase in excitatory synaptic events. Local superfusion of the ventral tegmental area with the D2 agonist quinpirole, which should increase the threshold for dopamine neuron activation, inhibited the early response. So dopamine neurons make glutamatergic synaptic connections to accumbens neurons. We propose that dopamine neuron glutamatergic transmission may be the initial component of the incentive salience signal.

Animals↗

PubMed2003

Hyperdopaminergic mutant mice have higher "wanting" but not "liking" for sweet rewards.

What is the role of dopamine in natural rewards? A genetic mutant approach was taken to examine the consequences of elevated synaptic dopamine on (1) spontaneous food and water intake, (2) incentive motivation and learning to obtain a palatable sweet reward in a runway task, and (3) affective "liking" reactions elicited by the taste of sucrose. A dopamine transporter (DAT) knockdown mutation that preserves only 10% of normal DAT, and therefore causes mutant mice to have 70% elevated levels of synaptic dopamine, was used to identify dopamine effects on food intake and reward. We found that hyperdopaminergic DAT knockdown mutant mice have higher food and water intake. In a runway task, they demonstrated enhanced acquisition and greater incentive performance for a sweet reward. Hyperdopaminergic mutant mice leave the start box more quickly than wild-type mice, require fewer trials to learn, pause less often in the runway, resist distractions better, and proceed more directly to the goal. Those observations suggest that hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice in an affective taste reactivity test. These results indicate that chronically elevated extracellular dopamine facilitates "wanting" and learning of an incentive motivation task for a sweet reward, but elevated dopamine does not increase "liking" reactions to the hedonic impact of sweet tastes.

Animals↗

PubMed2003

Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system.

BACKGROUND: Dopamine transporter (DAT) knockdown (KD) mice, with approximately 90% loss of expression of the DAT, allow for the examination of the behavioral consequences of a chronically dysregulated dopamine system. The DAT KD mice have hyperdopaminergic tone, are hyperactive, and show impaired response inhibition in a number of paradigms. We hypothesized that the DAT KD mice would also display deficits in prepulse inhibition (PPI) and would be perseverative in their locomotor behavior. METHODS: Basal levels of PPI and patterns of locomotor behavior were measured in two cohorts of DAT KD mice. In addition, measurements of locomotor behavior were recorded after pretreatment with 100 mg/kg valproate in both DAT KD and wildtype mice. RESULTS: The DAT KD mice were hyperactive and displayed perseverative motor behavior but had normal levels of PPI. The clinically effective antimania drug valproate significantly attenuated the hyperactivity and perseverative locomotor behavior in the DAT KD mice and had no effect in control mice. CONCLUSIONS: The DAT KD mice appear to provide a model of some aspects of manic behavior. With limited models of bipolar disorder, the DAT KD mice might provide a vehicle to screen for new psychiatric therapies to treat mania and its related symptoms.

Animals↗

PubMed2003

Transgenic mouse models of dopamine deficiency.

The dopamine system is implicated in several neurological and psychiatric disorders. Genetic mutations or variations that affect dopamine system functions either directly cause or contribute to these disorders, even though other genetic and environmental factors may contribute significantly to some of these disorders as well. Transgenic mice increasingly become important tools in revealing functions of genes that are essential components of the dopamine system as well as in modeling human genetic disorders. We have reviewed a comprehensive list of those genes and compared genetic mutations/variations in humans and transgenic mouse models. The significance and limitations of these animal models as well as future directions are discussed.

Animals↗

PubMed2002

Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.

Serotonin is implicated in mood regulation, and drugs acting via the serotonergic system are effective in treating anxiety and depression. Specifically, agonists of the serotonin1A receptor have anxiolytic properties, and knockout mice lacking this receptor show increased anxiety-like behaviour. Here we use a tissue-specific, conditional rescue strategy to show that expression of the serotonin1A receptor primarily in the hippocampus and cortex, but not in the raphe nuclei, is sufficient to rescue the behavioural phenotype of the knockout mice. Furthermore, using the conditional nature of these transgenic mice, we suggest that receptor expression during the early postnatal period, but not in the adult, is necessary for this behavioural rescue. These findings show that postnatal developmental processes help to establish adult anxiety-like behaviour. In addition, the normal role of the serotonin1A receptor during development may be different from its function when this receptor is activated by therapeutic intervention in adulthood.

Aging↗