Publications by authors named "Owen Y Chao"

21 Publications

  • Page 1 of 1

Acute intranasal dopamine application counteracts the reversal learning deficit of spontaneously hypertensive rats in an attentional set-shifting task.

Psychopharmacology (Berl) 2021 May 12. Epub 2021 May 12.

M et P Pharma AG Emmetten Switzerland and Oceanographic Center, Nova Southeastern University, Fort Lauderdale, FL, USA.

Rationale: Studies on the attention-deficit/hyperactivity disorder (ADHD) have concluded that the disorder might be caused by a deficit in the inhibitory control of executive functions because of dopamine hypofunction. Recently, the intranasal route has emerged as an effective alternative means for sending dopamine directly to the brain. However, whether the treatment can ameliorate the deficits of inhibitory control in ADHD remains unknown.

Objectives: Investigating the effects of acute intranasal dopamine (IN-DA) on the inhibitory control of executive functions of an ADHD rodent model.

Methods: We trained an animal model of ADHD, the spontaneously hypertensive rat (SHR), and Wistar rats as controls, in an attentional set-shifting task (ASST) in which dopamine (0.15 mg/kg, 0.3 mg/kg, or vehicle) was intranasally administered before the final test.

Results: IN-DA application dose-dependently improved the performance and reduced errors of SHR in the initial reversal learning. The effect size was comparable to that of a peripheral injection of 0.6 mg/kg methylphenidate. In control Wistar rats, the highest dose of intranasal dopamine (0.3 mg/kg) induced deficits in the reversal learning of extradimensional discriminations.

Conclusions: The findings suggest that the IN-DA treatment has potential for use in the treatment of ADHD; however, caution must be exercised when determining the dosage to be administered, because too much dopamine may have negative effects.
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http://dx.doi.org/10.1007/s00213-021-05863-2DOI Listing
May 2021

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum.

Cerebellum 2021 Mar 4. Epub 2021 Mar 4.

Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA.

Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its "motor" and "non-motor" functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals' social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices, and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive, and social functions.
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http://dx.doi.org/10.1007/s12311-021-01246-7DOI Listing
March 2021

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism.

Mol Brain 2020 08 10;13(1):111. Epub 2020 Aug 10.

Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA.

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury TItpr3/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher "complexity" and lower "texture". Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.
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http://dx.doi.org/10.1186/s13041-020-00649-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418402PMC
August 2020

The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties.

Neurosci Biobehav Rev 2020 06 13;113:373-407. Epub 2020 Apr 13.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University, Düsseldorf, Germany. Electronic address:

Rats and mice have been demonstrated to show episodic-like memory, a prototype of episodic memory, as defined by an integrated memory of the experience of an object or event, in a particular place and time. Such memory can be assessed via the use of spontaneous object exploration paradigms, variably designed to measure memory for object, place, temporal order and object-location inter-relationships. We review the methodological properties of these tests, the neurobiology about time and discuss the evidence for the involvement of the medial prefrontal cortex (mPFC), entorhinal cortex (EC) and hippocampus, with respect to their anatomy, neurotransmitter systems and functional circuits. The systematic analysis suggests that a specific circuit between the mPFC, lateral EC and hippocampus encodes the information for event, place and time of occurrence into the complex episodic-like memory, as a top-down regulation from the mPFC onto the hippocampus. This circuit can be distinguished from the neuronal component memory systems for processing the individual information of object, time and place.
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http://dx.doi.org/10.1016/j.neubiorev.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302494PMC
June 2020

Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism.

Neuropsychopharmacology 2020 06 16;45(7):1159-1170. Epub 2020 Mar 16.

Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA.

Autism spectrum disorder (ASD) encompasses wide-ranging neuropsychiatric symptoms with unclear etiology. Although the cerebellum is a key region implicated in ASD, it remains elusive how the cerebellar circuitry is altered and whether the cerebellum can serve as a therapeutic target to rectify the phenotype of idiopathic ASD with polygenic abnormalities. Using a syndromic ASD model, e.g., Black and Tan BRachyury TItpr3/J (BTBR) mice, we revealed that increased excitability of presynaptic interneurons (INs) and decreased intrinsic excitability of postsynaptic Purkinje neurons (PNs) resulted in low PN firing rates in the cerebellum. Knowing that downregulation of Kv1.2 potassium channel in the IN nerve terminals likely augmented their excitability and GABA release, we applied a positive Kv1.2 modulator to mitigate the presynaptic over-inhibition and social impairment of BTBR mice. Selective restoration of the PN activity by a new chemogenetic approach alleviated core ASD-like behaviors of the BTBR strain. These findings highlight complex mechanisms converging onto the cerebellar dysfunction in the phenotypic model and provide effective strategies for potential therapies of ASD.
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http://dx.doi.org/10.1038/s41386-020-0656-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234983PMC
June 2020

Timing constraints of action potential evoked Ca current and transmitter release at a central nerve terminal.

Sci Rep 2019 03 14;9(1):4448. Epub 2019 Mar 14.

Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA.

The waveform of presynaptic action potentials (APs) regulates the magnitude of Ca currents (I) and neurotransmitter release. However, how APs control the timing of synaptic transmission remains unclear. Using the calyx of Held synapse, we find that Na and K channels affect the timing by changing the AP waveform. Specifically, the onset of I depends on the repolarization but not depolarization rate of APs, being near the end of repolarization phase for narrow APs and advancing to the early repolarization phase for wide APs. Increasing AP amplitude has little effect on the activation but delays the peak time of I. Raising extracellular Ca concentration increases the amplitude of I yet does not alter their onset timing. Developmental shortening of APs ensures I as a tail current and faithful synaptic delay, which is particularly important at the physiological temperature (35 °C) as I evoked by broad pseudo-APs can occur in the depolarization phase. The early onset of I is more prominent at 35 °C than at 22 °C, likely resulting from a temperature-dependent shift in the activation threshold and accelerated gating kinetics of Ca channels. These results suggest that the timing of Ca influx depends on the AP waveform dictated by voltage-gated channels and temperature.
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http://dx.doi.org/10.1038/s41598-019-41120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418091PMC
March 2019

Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene.

Pharmacol Biochem Behav 2019 04 16;179:73-79. Epub 2019 Feb 16.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Electronic address:

In humans, mutations in the Disrupted-in-schizophrenia 1 (DISC1) gene have been related to psychiatric disorders, including symptoms of abnormal cognitive and emotional behaviors. In our previous studies, overexpression of the human DISC1 gene in rats resulted in schizophrenia-like phenotypes showing deficits in motor learning, impaired cognitive function and dysfunctions of the dopamine system. Here we asked, whether the DISC1 overexpression affects locomotor activity in the open field (OF), anxiety in the elevated plus-maze (EPM), depression-related behavior in the forced swim test (FST), and attention-like/short-term working-memory in the spontaneous alternation behavior (SAB) in the T-maze in transgenic DISC1 (tgDISC1) rats and littermate controls (WT). TgDISC1 rats showed enhanced anxiety behavior in the EPM and an impairment in attention-like/short-term working-memory in the SAB. However, tgDISC1 animals showed no locomotor impairments or depression-like behavior in the OF and FST. These results suggest that DISC1 overexpression leads to higher anxiety level and an attention-like/working-memory deficit. These findings may expand the causal role of DISC1 in its contribution to multiple symptom dimensions of psychiatric disorders.
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http://dx.doi.org/10.1016/j.pbb.2019.02.005DOI Listing
April 2019

Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the Fragile X brain.

Mol Psychiatry 2020 09 17;25(9):2017-2035. Epub 2018 Sep 17.

Program in Neurosciences & Mental Health, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada.

Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.
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http://dx.doi.org/10.1038/s41380-018-0240-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473840PMC
September 2020

Corrigendum to "Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: implications for an animal model of psychiatric comorbidity in autism" [Behav. Brain Res. 347 (2018) 140-147].

Behav Brain Res 2019 01 6;356:516. Epub 2018 Sep 6.

Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bbr.2018.08.026DOI Listing
January 2019

Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

Neurobiol Aging 2018 09 17;69:1-9. Epub 2018 Apr 17.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.005DOI Listing
September 2018

Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: Implications for an animal model of psychiatric comorbidity in autism.

Behav Brain Res 2018 07 13;347:140-147. Epub 2018 Mar 13.

Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA. Electronic address:

Autism spectrum disorders (ASD) are diagnosed based on the behavioral criteria of impaired social interaction, defective communication and repetitive behaviors. Psychiatric comorbidities, such as anxiety and intellectual disability, are commonly present in ASD. The BTBR T+ Itpr3tf/J (BTBR) mice display a range of autistic phenotypes, yet whether this mouse model is appropriate to study psychiatric comorbidity in ASD remains unclear. We addressed this issue by subjecting the BTBR animals to three-chambered apparatus, open field, object attention test and elevated open platform. Compared to C57BL/6J control mice, the BTBR mice displayed hyperactivity in most of the tests. In the three-chamber assessment, they exhibited deficits in sociability. In the open field, more grooming and thigmotaxis and less rearing behaviors were observed. They also showed impaired object-based attention. On the elevated open platform, the BTBR animals stayed more to the edges than in the center of the platform. To further examine the properties of this test, naïve C57BL/6J mice were randomly administrated with saline or an anxiogenic substance, caffeine. The caffeine group demonstrated a similar behavioral pattern as the BTBR mice. When the saline group was re-exposed to the same platform, the time they stayed in the center substantially increased, likely due to reduced anxiety by habituation. These results indicate that the BTBR were more anxious than control mice on the open platform. Taken together, the BTBR strain exhibit emotional and cognitive impairments in addition to autistic behaviors, suggesting that they can be a valid model for ASD with psychiatric comorbidity.
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http://dx.doi.org/10.1016/j.bbr.2018.03.014DOI Listing
July 2018

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

Neurobiol Learn Mem 2017 Dec 28;146:12-20. Epub 2017 Oct 28.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany. Electronic address:

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention.

Results: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala.

Conclusions: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.
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http://dx.doi.org/10.1016/j.nlm.2017.10.015DOI Listing
December 2017

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

Neurobiol Learn Mem 2017 May 3;141:72-77. Epub 2017 Apr 3.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl--aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component.
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http://dx.doi.org/10.1016/j.nlm.2017.03.019DOI Listing
May 2017

Promnestic effects of intranasally applied pregnenolone in rats.

Neurobiol Learn Mem 2016 09 14;133:185-195. Epub 2016 Jul 14.

Oceanographic Center, Nova Southeastern University, Fort Lauderdale, FL 33314, USA; M et P Pharma AG, 6376 Emmetten, Switzerland. Electronic address:

The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration.
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http://dx.doi.org/10.1016/j.nlm.2016.07.012DOI Listing
September 2016

Concurrent assessment of memory for object and place: Evidence for different preferential importance of perirhinal cortex and hippocampus and for promnestic effect of a neurokinin-3 R agonist.

Neurobiol Learn Mem 2016 Apr 17;130:149-58. Epub 2016 Feb 17.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

We here explore the utility of a paradigm that allows the simultaneous assessment of memory for object (what) and object location (where) and their comparative predominance. Two identical objects are presented during a familiarity trial; during the test trial one of these is displaced, and a new object is presented in a familiar location. When tested 5 or 80min later, rats explored both the novel and the displaced objects more than two familiar stationary objects, indicating intact memory for both, object and place. When tested 24h later rats explored the novel object more than the displaced familiar one, suggesting that forgetting differently influenced object and place memory, with memory for object being more robust than memory for place. Animals that received post-trial administration of the neurokinin-3 receptor agonist senktide and were tested 24h later, now explored the novel and displaced objects equally, suggesting that the treatment prevented the selective decay of memory for location. Next, animals received NMDA lesions in either the perirhinal cortex or the hippocampus, which are hypothesized to be preferentially involved in memory for objects and memory for place, respectively. When tested 5 or 80min later, the perirhinal cortex lesion group explored the displaced object more, indicating relatively deficient object memory, while the hippocampal lesion led to the opposite pattern, demonstrating comparatively deficient place memory. These results suggest different preferential engagement of the perirhinal cortex and hippocampus in their processing of memory for object and place. This preference test lends itself to application in the comparison of selective lesions of neural sites and projection systems as well as to the assessment of possible preferential action of pharmacological agents on neurochemical processes that subserve object vs place learning.
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http://dx.doi.org/10.1016/j.nlm.2016.02.007DOI Listing
April 2016

The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition.

Hippocampus 2016 May 5;26(5):633-45. Epub 2015 Nov 5.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, Düsseldorf, 40225, Germany.

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item-associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic-like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic-like (what-where-when) and object-recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic-like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic-like and associative object-recognition memory.
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http://dx.doi.org/10.1002/hipo.22547DOI Listing
May 2016

Relationship between L-DOPA-induced reduction in motor and exploratory activity and degree of DAT binding in the rat.

Front Behav Neurosci 2014 17;8:431. Epub 2014 Dec 17.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) transporter (DAT) binding in relation to motor and exploratory behaviors in the rat.

Methods: Rats received injections of 5 mg/kg L-DOPA, 10 mg/kg L-DOPA or vehicle. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. Dopamine transporter binding was measured with small animal single-photon emission computed tomography (SPECT) 2 h after radioligand administration for 60 min.

Results: Both L-DOPA doses significantly reduced DAT binding and led to significantly less head-shoulder motility and more sitting relative to vehicle. Moreover, 10 mg/kg L-DOPA induced less distance traveled and ambulation than 5 mg/kg L-DOPA. Analysis of time-behavior (t-b) curves showed that L-DOPA-treated animals relative to vehicle exhibited (1) a faster rate of increase in duration of sitting; (2) a slower rate of increase in duration of head-shoulder motility; and (3) a slower rate of decrease in frequency of head-shoulder motility.

Conclusions: The reductions of striatal DAT binding after L-DOPA challenges reflected elevated concentrations of synaptic DA. L-DOPA-treated animals showed less head-shoulder motility and more sitting than vehicle-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster increase of sitting duration to a higher final level and the slower increase of head-shoulder motility to a lower final level relative to controls may be interpreted in terms on behavioral habituation to a novel environment.
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http://dx.doi.org/10.3389/fnbeh.2014.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269131PMC
January 2015

The neurokinin-3 receptor agonist senktide facilitates the integration of memories for object, place and temporal order into episodic memory.

Neurobiol Learn Mem 2014 Oct 24;114:178-85. Epub 2014 Jun 24.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in adult and aged rodents and to facilitate episodic-like memory (ELM) in mice when administrated before the learning trial. In the present study we assessed the effects of senktide on memory consolidation by administering it post-trial (after the learning trial) in adult rats. We applied an ELM test, based on the integrated memory for object, place and temporal order, which we developed (Kart-Teke, de Souza Silva, Huston, & Dere, 2006). This test involves two learning trials and one test trial. We examined intervals of 1h and 23 h between the learning and test trials (experiment 1) in untreated animals and found that they exhibited intact ELM after a delay of 1 h, but not 23 h. In another test for ELM performed 7 days later, vehicle or senktide (0.2 mg/kg, s.c.) was applied immediately after the second learning trial and the test was conducted 23 h later (experiment 2). Senktide treatment recovered components of ELM (memory for place and object) compared with vehicle-treated animals. After one more week, vehicle or senktide (0.2 mg/kg, s.c.) was applied post-trial and the test conducted 6h later (experiment 3). The senktide-treated group exhibited intact ELM, unlike the vehicle-treated group. Finally, animals received post-trial treatment with either vehicle or SR142801, a selective NK3-R antagonist (6 mg/kg, i.p.), 1 min before senktide injection (0.2 mg/kg, s.c.) in the ELM paradigm and were tested 6h later (experiment 4). The vehicle+senktide group showed intact ELM, while the SR142801+senktide group did not. The results indicate that senktide facilitated the consolidation or the expression of ELM and that the senktide effect was NK3-R dependent.
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http://dx.doi.org/10.1016/j.nlm.2014.06.009DOI Listing
October 2014

NK₃ receptor agonism reinstates temporal order memory in the hemiparkinsonian rat.

Behav Brain Res 2015 May 11;285:208-12. Epub 2014 Jun 11.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Animals treated with unilateral 6-hydroxydopamine (6-ODHA) injections, an animal model of Parkinson's disease, exhibit deficits in memory for temporal order, but show intact novel object recognition. Since senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in the aged rat and to alleviate scopolamine-induced impairment, the present study aimed to assess possible promnestic effects of senktide in the hemiparkinsonian rat model. Animals received unilateral 6-ODHA microinjections into the medial forebrain bundle. Two weeks later, they were randomly assigned to treatment with vehicle, 0.2, or 0.4 mg/kg senktide. Temporal order memory and place recognition tests were conducted, locomotor activity and turning behavior were assessed in the open field and anxiety-related behavior was measured in the light-dark box. Treatments were administered 30 min prior to behavioral testing with an interval of seven days between tests. The animals treated with 0.2 mg/kg senktide exhibited temporal order memory, unlike the vehicle-treated group. No significant treatment effects were found in the open field and light-dark box. Administration of 0.2 mg/kg senktide may influence the prefrontal cortex and hippocampus, leading to compensations for deficits in memory for temporal order.
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http://dx.doi.org/10.1016/j.bbr.2014.06.006DOI Listing
May 2015

Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury.

Exp Neurol 2012 Sep 19;237(1):170-9. Epub 2012 Jun 19.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury.
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http://dx.doi.org/10.1016/j.expneurol.2012.06.006DOI Listing
September 2012

Intranasally applied L-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions.

Brain Res Bull 2012 Feb 15;87(2-3):340-5. Epub 2011 Nov 15.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitaetstrasse 1, 40225 Düsseldorf, Germany.

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.
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http://dx.doi.org/10.1016/j.brainresbull.2011.11.004DOI Listing
February 2012