A5002405804- Neurotransmitter Receptor Influence on Behavior
- Receptor Mechanisms and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Neuroscience and Neuropharmacology Research
- RNA modifications and cancer
- Neurological disorders and treatments
- Neuroendocrine regulation and behavior
- Cancer-related gene regulation
- Nuclear Receptors and Signaling
- Nicotinic Acetylcholine Receptors Study
- Mitochondrial Function and Pathology
- Amino Acid Enzymes and Metabolism
- Neural dynamics and brain function
- Metabolism and Genetic Disorders
- Autism Spectrum Disorder Research
- RNA Research and Splicing
- Hypothalamic control of reproductive hormones
- Physiological and biochemical adaptations
- Mast cells and histamine
- Autophagy in Disease and Therapy
- Neurobiology and Insect Physiology Research
- Neuroscience and Neural Engineering
- Regulation of Appetite and Obesity
- Olfactory and Sensory Function Studies
- Genetics, Aging, and Longevity in Model Organisms
University of Chicago
2014-2024
Shandong University of Technology
2024
Joint Center for Structural Genomics
2021
Research Center for Eco-Environmental Sciences
2018
Chinese Academy of Sciences
2018
University of Chinese Academy of Sciences
2018
Institute of Neurobiology
2009-2016
University of California, San Diego
2009
VA San Diego Healthcare System
2009
Committee on Climate Change
2009
Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration Parkinson's disease (PD), but how these pathways are linked human neurons remains unclear. Here we studied derived from patients with idiopathic familial PD. We identified a time-dependent pathological cascade beginning mitochondrial oxidant stress leading to oxidized dopamine accumulation ultimately resulting reduced glucocerebrosidase enzymatic activity, dysfunction, α-synuclein...
What is the role of dopamine in natural rewards? A genetic mutant approach was taken to examine consequences elevated synaptic on (1) spontaneous food and water intake, (2) incentive motivation learning obtain a palatable sweet reward runway task, (3) affective "liking" reactions elicited by taste sucrose. transporter (DAT) knockdown mutation that preserves only 10% normal DAT, therefore causes mice have 70% levels dopamine, used identify effects intake reward. We found hyperdopaminergic DAT...
Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression the dopamine transporter (DAT) 10% wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry vivo microdialysis revealed that released was cleared at a slow rate knockdown mice, which resulted higher extracellular concentration. Unlike DAT...
Mutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations these genes lead the same state, functional relationships between them how their respective disease-associated cause PD largely unknown. Here, we show that Parkin, PINK1, formed a complex (termed PPD complex) promote ubiquitination degradation Parkin substrates, including itself Synphilin-1 neuroblastoma...
Mitochondrial dysfunction has been reported in both familial and sporadic Parkinson's disease (PD). However, effective therapy targeting this pathway is currently inadequate. Recent studies suggest that manipulating the processes of mitochondrial fission fusion considerable potential for treating human diseases. To determine therapeutic impact these pathways on PD, we used two complementary mouse models impairments as seen PD. We show here blocking neuroprotective PTEN-induced putative...
Abstract Background Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction nigrostriatal dopamine systems. In super-stereotypy, patients become trapped overly rigid action, language, or thought. Some instinctive animals, such as the syntactic grooming chain pattern rodents, have sufficiently complex stereotyped serial structure detect potential production...
Mutations in the DJ-1 gene were recently identified an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions oxidative stress, protein folding, degradation pathways. However, animal models are needed to determine whether how loss function leads We generated null mice with a mutation that resembles large deletion reported patients. Our behavioral analyses indicated deficiency led...
The role of dopamine as a vulnerability factor and toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed toxicity partly responsible for “DOPA-sparing” clinical practice that avoids using l -3,4-dihydroxyphenylalanine ( -DOPA), precursor, early PD. There lack studies on animal models directly isolate one determining causing neurodegeneration. To address this, we have generated novel transgenic mouse model which striatal neurons are engineered to take up...
Dopamine neurons are thought to convey a fast, incentive salience signal, faster than can be mediated by dopamine. A resolution of this paradox may that midbrain dopamine exert fast excitatory actions. Using transgenic mice with fluorescent neurons, in which the axonal projections visible, we made horizontal brain slices encompassing mesoaccumbens projection. Focal extracellular stimulation ventral tegmental area evoked release and early monosynaptic late polysynaptic responses postsynaptic...
It is generally assumed that the coupling of dopamine D1 receptors to adenylyl cyclase mediated by stimulatory GTP-binding protein G(s). However, striatum contains little G(s)alpha subunit, whereas it expresses high levels G(olf)alpha, a close relative also expressed in olfactory receptor neurons. We used G(olf)alpha knockout mice examine functional receptors. found these showed no hyperlocomotor response either agonist SKF-81297 or psychostimulant cocaine. Moreover, did not display...
Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived factor (GDNF) and brain-derived (BDNF) may determine whether the resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for treatment Parkinson disease (PD), a common neurodegenerative disorder characterized loss midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions rescues DA PD animal models. The physiological roles signaling adult system are unknown....
In order to determine the distribution and function of 5-HT5A serotonin receptor subtype, we generated knockout mice lacking gene. Comparative autoradiography studies brains wild-type (wt) (5A-KO) revealed existence binding sites with high affinity for [125I]LSD that correspond receptors are concentrated in olfactory bulb, neocortex, medial habenula. When exposed novel environments, 5A-KO displayed increased exploratory activity but no change anxiety-related behaviors. addition, stimulatory...
<h3>Context</h3> Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, which raises the question of whether they same disorder on different ends a continuum. The lack distinct endophenotypes bipolar has complicated development animal models that specific to these disorders. Exploration is fundamental survival dysregulated in 2 Although exploratory behavior rodents been widely studied, surprisingly little work examined this critical function...
The impact of dopamine on adaptive behavior in a naturalistic environment is largely unexamined. Experimental work suggests that phasic central to reinforcement learning whereas tonic may modulate performance without altering per se; however, this idea has not been developed formally or integrated with computational models function. We quantitatively evaluate the role these functions by studying hyperdopaminergic DAT knockdown mice an instrumental task semi-naturalistic homecage environment....
In vitro evidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson's disease (PD). Using a tissue-specific gene amplification strategy, we generated transgenic mouse line with human α-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice showed profound early-onset abnormalities, characterized marker-positive cytoplasmic inclusions containing mainly mitochondrial remnants, which preceded degeneration DA...
Accumulating evidence indicates integration of dopamine function with metabolic signals, highlighting a potential role for in energy balance, frequently construed as modulating reward response to homeostatic state. Though its precise remains controversial, the perspective has dominated investigation motivational disorders, including obesity. In hypothesis outlined here, we suggest instead that primary behavior is modulate activity adapt behavioral expenditure prevailing environmental...