Publications by authors named "Dansha He"

10 Publications

  • Page 1 of 1

Mouse model systems of autism spectrum disorder: Replicability and informatics signature.

Genes Brain Behav 2020 09 2;19(7):e12676. Epub 2020 Jul 2.

PsychoGenics, Inc., Paramus, New Jersey, USA.

Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability, particularly in behavioral domains such as social and cognitive function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies of five genetic mouse model systems of ASD. To assess the intra-laboratory robustness of previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to assess commonalities and differences. Our results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle but pivotal differences in testing conditions, housing enrichment, or background strains and less so on the variability of the behavioral phenotypes. The overall informatics analysis suggests that in our behavioral assays we can separate the set of tested mouse model system into two main classes that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.
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http://dx.doi.org/10.1111/gbb.12676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540461PMC
September 2020

Cognitive Training at a Young Age Attenuates Deficits in the zQ175 Mouse Model of HD.

Front Behav Neurosci 2015 11;9:361. Epub 2016 Jan 11.

Psychogenics Inc.Tarrytown, NY, USA; Department of Psychiatry, New York State Psychiatric Institute, Columbia UniversityNew York, NY, USA.

Huntington's Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits. We found pronounced deficits in response rates and task engagement in naïve adult zQ175 mice (32-33 weeks age), while deficits in zQ175 mice trained from 6-7 weeks age were either absent or less severe. When those mice were re-tested as adults, FR/PR performance deficits were absent or otherwise less severe than deficits observed in naïve adult zQ175 relative to wild type (WT) mice. In Experiment 2, we used a Go/No-go operant task to assess the effects of early cognitive testing on response inhibition deficits in zQ175 mice. We found that zQ175 mice that began testing at 7-8 weeks did not exhibit deficits in Go/No-go testing, but when re-tested at 28-29 weeks age exhibited an initial impairment that diminished with training. These transient deficits were nonetheless mild relative to deficits observed among adult zQ175 mice without prior testing experience. In Experiment 3 we trained mice in a two-choice visual discrimination test to evaluate cognitive flexibility. As in prior experiments, we found performance deficits were mild or absent in mice that started training at 6-9 weeks of age, while deficits in naive mice exposed to training at 28-29 weeks were severe. Re-testing mice at 28-29 weeks age, were previously trained starting at 6-9 weeks, revealed that deficits in learning and cognitive flexibility were absent or reduced relative to effects observed in naive adults. In Experiment 4, we tested working memory deficits with a delayed non-match to position (DNMTP) test. Mice with prior experience exhibited mild working memory deficits, with males zQ175 exhibiting no deficits, and females performing significantly worse than WT mice at a single delay interval, whereas naive zQ175 exhibited severe delay-dependent deficits at all intervals exceeding 1 s. In sum, these experiments indicate that CAG-dependent impairments in motivation, motor control, cognitive flexibility, and working memory are sensitive to the environmental enrichment and experience. These findings are of clinical relevance, as HD carrier status can potentially be detected at an early age.
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http://dx.doi.org/10.3389/fnbeh.2015.00361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707270PMC
January 2016

Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

PLoS One 2015 14;10(8):e0134572. Epub 2015 Aug 14.

Roche, Basel, Switzerland.

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134572PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537259PMC
May 2016

Cognitive deficits in transgenic and knock-in HTT mice parallel those in Huntington's disease.

J Huntingtons Dis 2014 ;3(2):145-58

PsychoGenics Inc., Tarrytown, NY, USA Department of Psychiatry, Columbia University, NYSPI, NY, USA.

Background: Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline.

Objective: The BACHD and zQ175 mouse models present a more slowly progressing disease phenotype in both motor and cognitive domains, and might therefore offer a better opportunity to measure cognitive decline over a longer timeframe; such models could be useful in screening therapeutic compounds. In order to better define the cognitive impairments evident in BACHD and zQ175 HD mice, both were tested in an instrumental touchscreen visual discrimination assay designed to assess discrimination learning and cognitive flexibility.

Methods: BACHD and zQ175 mice, as well as their WT controls were tested for their ability to discriminate two complex visual stimuli. Following this discrimination phase, the reinforcement contingencies were reversed and the previously incorrect stimulus became the correct stimulus. In a final, third phase of testing, two novel stimuli were introduced and mice were required to undergo a second round of discrimination testing with these stimuli.

Results: Our results show that learning during the discrimination phase was similar between the WT and BACHD mice. In contrast, the zQ175 at 26 weeks of age showed decreased accuracy over the last 10 days of discrimination, compared to WT controls. During subsequent reversal and novel stimuli phases, both BACHD and zQ175 mice exhibited significant deficits compared to WT controls.

Conclusions: Our results suggest that the BACHD, and for the first time, zQ175 HD models exhibit cognitive inflexibility and psychomotor slowing, a phenotype that is consistent with cognitive symptoms described in HD patients.
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http://dx.doi.org/10.3233/JHD-130061DOI Listing
September 2014

Genetic deletion of transglutaminase 2 does not rescue the phenotypic deficits observed in R6/2 and zQ175 mouse models of Huntington's disease.

PLoS One 2014 23;9(6):e99520. Epub 2014 Jun 23.

CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines. To further evaluate the validity of this target for the treatment of HD, we examined the effects of TG2 deletion in two genetic mouse models of HD: R6/2 CAG 240 and zQ175 knock in (KI). Contrary to previous reports, under rigorous experimental conditions we found that TG2 ablation had no effect on either motor or cognitive deficits, or on the weight loss. In addition, under optimal husbandry conditions, TG2 ablation did not extend R6/2 lifespan. Moreover, TG2 deletion did not change the huntingtin aggregate load in cortex or striatum and did not decrease the brain atrophy observed in either mouse line. Finally, no amelioration of the dysregulation of striatal and cortical gene markers was detected. We conclude that TG2 is not a valid therapeutic target for the treatment of HD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099520PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067284PMC
October 2015

Acute changes in systemic hemodynamics and serum vasopressin after complete cervical spinal cord injury in piglets.

Neurocrit Care 2010 Aug;13(1):132-40

Saint Louis University School of Medicine, Saint Louis, MO, USA.

Background: Spinal cord injury (SCI) produces acute hemodynamic alterations through disruption of sympathetic output of the autonomic nervous system and places individuals with SCI at high risk of secondary ischemic insult to the spinal cord as well as to other organs. The purpose of this study was to examine hemodynamics and serum vasopressin concentration in the acute period following complete cervical SCI in piglets.

Methods: We developed a new model of traumatic complete cervical SCI in piglets and measured acute hemodynamic variables and serum arginine vasopressin (AVP) concentrations at baseline and for 4 h after SCI under fentanyl anesthesia.

Results: Complete cervical SCI caused an immediate tachycardia which lasted for approximately 1 h, immediate hypotension which was sustained for the 4-h duration of the study, decreases in both systemic and pulmonary vascular resistance, and a compensatory increase in cardiac output, which resulted initially from an increase in heart rate (HR) but was later sustained after resolution of tachycardia by an increase in cardiac stroke volume. Serum AVP concentration increased significantly after SCI and did not change in the control group. Neurogenic shock did not occur due to the robust increase in cardiac output and cardiac stroke volume.

Conclusions: Complete cervical SCI produces hemodynamic alterations consistent with the withdrawal of sympathetic tone. Although mean arterial pressure (MAP) decreased significantly after SCI, the increase in serum vasopressin may have played a role in maintaining blood pressure and preventing circulatory collapse, a complication which is encountered frequently in patients with cervical and upper thoracic SCI.
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http://dx.doi.org/10.1007/s12028-010-9364-zDOI Listing
August 2010

Pediatric spinal cord injury in infant piglets: description of a new large animal model and review of the literature.

J Spinal Cord Med 2010 ;33(1):43-57

Pediatric Critical Care (R-131), University of Miami School of Medicine, 1611 NW 12th Avenue, Miami, FL 33136, USA.

Objective: To develop a new, clinically relevant large animal model of pediatric spinal cord injury (SCI) and compare the clinical and experimental features of pediatric SCI.

Methods: Infant piglets (3-5 weeks old) underwent contusive SCI by controlled cortical impactor at T7. Severe complete SCI was induced in 6 piglets, defined as SCI with no spontaneous return of sensorimotor function. Eight piglets received incomplete SCI, which was followed by partial recovery. Somatosensory evoked potentials, magnetic resonance imaging, neurobehavioral function, and histopathology were measured during a 28-day survival period.

Results: Mean SCI volume (defined as volume of necrotic tissue) was larger after complete compared with incomplete SCI (387 +/- 29 vs 77 +/- 38 mm3, respectively, P < 0.001). No functional recovery occurred after complete SCI. After incomplete SCI, piglets initially had an absence of lower extremity sensorimotor function, urinary and stool retention, and little to no rectal tone. Sensory responses recovered first (1-2 days after injury), followed by spontaneous voiding, lower extremity motor responses, regular bowel movements, and repetitive flexion-extension of the lower extremities when crawling. No piglet recovered spontaneous walking, although 4 of 8 animals with incomplete injuries were able to bear weight by 28 days. In vivo magnetic resonance imaging was performed safely, yielded high-resolution images of tissue injury, and correlated closely with injury volume seen on histopathology, which included intramedullary hemorrhage, cellular inflammation, necrosis, and apoptosis.

Conclusion: Piglets performed well as a reproducible model of traumatic pediatric SCI in a large animal with chronic survival and utilizing multiple outcome measures, including evoked potentials, magnetic resonance imaging, functional outcome scores, and histopathology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853328PMC
http://dx.doi.org/10.1080/10790268.2010.11689673DOI Listing
May 2010

Traumatic injury activates MAP kinases in astrocytes: mechanisms of hypothermia and hyperthermia.

J Neurotrauma 2009 Sep;26(9):1535-45

Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, Florida, USA.

Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (308 degree C), normothermia (378 degree C), or hyperthermia (398 degree C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase ( JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120 min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24 h after injury. Our findings showed that only JNK activation at 15 min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.
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http://dx.doi.org/10.1089/neu.2008.0743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468954PMC
September 2009

Neuron-like differentiation of adipose-derived stem cells from infant piglets in vitro.

J Spinal Cord Med 2007 ;30 Suppl 1:S35-40

University of Miami School of Medicine, Miami, Florida, USA.

Background/objective: Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) that can be extracted from adipose tissue and obtained by a less invasive method and in larger quantities compared with bone marrow-derived MSCs. The objective of this study was to harvest ADSCs from piglets and to explore their neuronal differentiation potential.

Methods: Adipose tissue from piglet facial or abdominal fat was digested with collagenase type XI, followed by filter and centrifugation; the isolated adipose stromal cells were cultured in dishes. MSC markers were measured by flow cytometry; 2 to 5 passage cells were used for in vitro differentiation. Adipogenic, chondrogenic, osteogenic, and neuronal differentiation was induced by incubation of the ADSCs with different induction media.

Results: ADSCs were easily expanded to beyond 15 passages, maintaining the undifferentiated state and exhibiting MSC characteristics and markers CD29, CD44, and CD90. ADSCs differentiated into other mesodermal cells including adipocytes, chondrocytes, and osteocytes. These cells were induced to differentiate into neuron-like cells as evidenced by neuronal morphology and the presence of neuronal markers including microtubule-associated protein 2, neuronal nuclear antigen, and beta-tubulin III.

Conclusions: ADSCs can be readily obtained from a small amount fat tissue and expanded in culture. Adipose tissue may be an alternative source of stem cell therapy for nervous system injury.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2031970PMC
http://dx.doi.org/10.1080/10790268.2007.11753967DOI Listing
October 2007

New pediatric model of ischemic stroke in infant piglets by photothrombosis: acute changes in cerebral blood flow, microvasculature, and early histopathology.

Stroke 2007 Jun 26;38(6):1932-7. Epub 2007 Apr 26.

Department of Pediatrics, University of Miami School of Medicine, Miami, Florida, USA.

Background And Purpose: The etiology and pathophysiology of acute ischemic stroke in children differ greatly from those in adults. The purpose of this study was to establish a new pediatric model of ischemic stroke in infant piglets for use in future studies of the response of the developing brain to focal ischemic injury.

Methods: Ischemic stroke was produced in male infant piglets (2 to 4 weeks old) by photothrombotic occlusion of the middle cerebral artery. Regional cerebral blood flow was measured with radiolabeled microspheres up to 4 hours after occlusion. Early histopathology, including caspase-3 immunohistochemistry for apoptosis, was examined 4 hours after ischemia. The nature of the thrombus and its interaction with vascular endothelium were assessed by electron microscopy.

Results: Severe ischemia (0 to 15 mL/100 g per min) occurred rapidly in 1.4+/-0.2 g of tissue at 15 minutes and increased to 2.4+/-0.7 g at 4 hours. Similarly, moderate ischemia (16 to 30 mL/100 g per min) was measured in 1.2+/-0.3 g of tissue at 15 minutes and increased to 2.0+/-0.6 g at 4 hours. These regional cerebral blood flow values represent ischemic levels of blood flow in 20% to 25% of the volume of the ischemic hemisphere at 4 hours after ischemia. Ischemic infarction occurred in both gray and white matter, and cerebral microvessels in the ischemic hemisphere contained large numbers of inflammatory leukocytes. Caspase-3-positive cells were few in number and were found in the periphery of the infarct; cell death appeared to occur primarily by necrosis rather than apoptosis at 4 hours. Electron microscopy revealed a pure platelet thrombus firmly attached to the vascular endothelium, which in some areas appeared to be detached from the basement membrane.

Conclusions: Ischemic stroke can be produced in infant piglets by middle cerebral artery photothrombosis. The stroke involved both gray and white matter and exhibited a robust inflammatory component. The mean infarct volume determined histopathologically amounted to 9.6+/-2.4% of the affected (ipsilateral) hemisphere, which was correlated well with the mass equivalent of tissue (12.0+/-3.5%), in which severe declines in regional cerebral blood flow were observed at 4 hours.
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http://dx.doi.org/10.1161/STROKEAHA.106.475244DOI Listing
June 2007