Browsing by Subject "Dopamine"
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Item Behavioral, Neurochemical, and Histological Characterization of Mice Deficient for Parkin, DJ-1, and Antioxidant Proteins(2011-08-10) Seamans, Katherine Webster; Goldberg, Matthew S.Parkinson’s disease is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. The cause of Parkinson’s disease remains uncertain, however, evidence implicates mitochondrial dysfunction and oxidative stress with selective vulnerability of dopaminergic neurons. Although most cases of Parkinson’s disease are sporadic, 5-10% of cases are caused by mutations in a single gene. Loss-of-function mutations in parkin and DJ-1 were the first to be linked to recessively inherited parkinsonism. Surprisingly, mice bearing similar loss-of-function mutations in parkin and DJ-1 do not show age-dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum. Although the normal cellular functions of Parkin and DJ-1 remain unclear, we hypothesized that Parkin and DJ-1 protect cells from oxidative stress and that loss-of-function mutations in these genes cause neurodegeneration in Parkinson’s disease by rendering cells more sensitive to mitochondrial dysfunction and oxidative stress. We crossed mice deficient for Parkin and DJ-1 with mice deficient for the major mitochondrial antioxidant protein Mn-superoxide dismutase or Cu/Zn-superoxide dismutase. Previous studies have shown that mice with reduced levels of Cu/Zn-superoxide dismutase or Mn-superoxide dismutase are more sensitive to dopaminergic neurotoxins whereas mice with increased levels of superoxide dismutase are more resistant to dopaminergic neurotoxins. We predicted that reducing levels of antioxidant proteins in parkin-/-DJ-1-/- mice would result in age-dependent nigral cell loss, striatal dopamine depletion or behavioral abnormalities. Characterization of these mice for behavioral abnormalities, neurotransmitter defects and neuropathology, revealed significant behavioral abnormalities in the mutant mice even in the absence of significant changes to dopamine levels in the striatum, dopamine receptor density, or dopaminergic neuron numbers. Aged parkin-/-DJ-1-/- and Mn-superoxide dismutase triple deficient mice have a surprising enhanced rotorod performance without the presence of an anxiety phenotype or hyperactivity. Cu/Zn-superoxide dismutase and Mn-superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum, however none of the mice present with nigral cell loss. Levels of D1-like and D2-like dopamine receptors in the striatum were unchanged. It is evident from our studies that on a parkin/DJ-1 null background, additional loss of major antioxidant proteins does not lead to a progressive loss of dopaminergic neurons in mice.Item COMT Genotype, Schizophrenia, and Dopamine Transmission(2011-02-01) Birchfield, Thomas Richard; Ghose, SubrotoCatechol-o-methyltransferase (COMT) catabolism is the primary mechanism for dopamine signal deactivation in the dorsolateral prefrontal cortex, an area of the brain associated with working memory. Working memory deficits are found in persons with schizophrenia and their unaffected siblings. A single nucleotide polymorphism of the COMT gene results in a MET-->VAL shift at codon 158, increased enzyme thermostability, and increased enzymatic activity. The hypothesized result of this shift is decreased dopamine transmission in the brain area associated with working memory due to increased dopamine catabolism. The current study analyzed the effect of COMT genotype and schizophrenia on the mRNA expression of genes known to be influenced by dopamine signal transmission with qPCR of RNA extracted from high-quality, fresh-frozen postmortem dorsolateral prefrontal cortex tissue. While no significant difference was observed between genotypes, a significant effect of diagnosis was found for the D1 dopamine receptor, COMT, and tyrosine hydroxylase, the rate-limiting step of dopamine synthesis. The current findings support a model decreased dopamine synthesis and increased catabolism leading to deficient dopamine signal transmission in persons with schizophrenia.Item Locus Coeruleus-Dependent Dopamine Release in the Dorsal Hippocampus: Mechanisms and Modulation of Synaptic Plasticity(2019-12-02) Sonneborn, Alex Jay; Meeks, Julian P.; Huber, Kimberly M.; Kourrich, Said; Roberts, Todd; Greene, Robert W.Locus coeruleus (LC) neurons coordinate the overwhelming majority of norepinephrine (NE) signaling throughout the mammalian neocortex and hippocampus. Recent discoveries indicate that dopamine (DA), the biosynthetic precursor of NE, is also released from LC axons. These axons innervate most brain regions, and are especially prevalent in the rodent dorsal hippocampus, including area CA1. It was previously thought that the only supply of CA1 dopamine was the ventral tegmental area, but several recent studies have identified LC fibers as the main source of DA in this region. However, both the mechanism by which LC-DA is released, and whether or not it is released in sufficient quantities to influence DA-dependent processes in the hippocampus, remain unclear. These questions have major implications for theories concerning the molecular basis of learning, since the consolidation of episodic memories in CA1 requires activation of dopamine D1-like receptors. Therefore, the focus of this dissertation is to determine if LC-originating DA can modulate synaptic plasticity, and therefore learning and memory, in CA1 of the mouse hippocampus. We also sought to uncover the molecular mechanism of this LC-DA release. The following experiments study the effects of LC-dopamine on CA1 function using optogenetic, electrophysiological, pharmacological, and behavioral approaches. We show that optogenetically evoked LC-DA release is sufficient to activate D1/D5 receptors (D1/5R) on CA1 pyramidal neurons and modulate synaptic potentiation at Schaffer collateral synapses, a necessary step for the consolidation of learning. In accordance with this, we find that LC-specific knockdown of DA synthesis can block learning at the behavioral level (Chapter 2). We also demonstrate that one possible LC-DA release mechanism is reverse transport through the norepinephrine transporter (NET), and advance the idea that presynaptic NMDA receptors on LC terminals may play a role in this release. Furthermore, as DA and NE should be co-released in dorsal CA1, we show that they act together to enhance synaptic strength (Chapter 3). Since LC activity is known to be involved in attention and memory, our results contribute new insight into how the LC can link attentional processes to memory formation at the molecular, circuit, and behavioral levels (Chapter 4).Item [News](1983-01-12) Williams, AnnItem The Role of CLOCK in Regulation of Dopamine Neurotransmission in the CLOCKdelta19 Mutant Mouse Model(2012-07-17) Spencer, Sade Monique; McClung, Colleen A.Mice with a mutation in the circadian gene Clock (Clockdelta19) display a behavioral profile which parallels a euphoric manic-like state including hyperactivity, disrupted activity rhythms, increased substance abuse vulnerability, and decreases in anxiety and depression-related behavior. The molecular clock has significant cross-talk with many of the brain’s neurotransmitter systems. The purpose of this dissertation is to characterize the role of CLOCK in regulating dopamine transmission in mood and reward-related circuits. We present a mechanism by which CLOCK regulates dopaminergic activity in the mesoaccumbens circuit and contributes to anxiety-related behavior. In vivo recording of ventral tegmental area (VTA) dopamine cells throughout the 24 hour cycle revealed that firing and bursting was elevated in Clockdelta19 mutants with the most significant deviations early in the light cycle. Mimicking this increase in dopaminergic activity using optogenetic targeting resulted in decreased anxiety-related behavior similar to the Clockdelta19 phenotype. Consistent with the electrophysiological findings, tyrosine hydroxylase (TH) mRNA and protein was elevated in the VTA in a daytime-specific manner leading to increased dopamine synthesis in the nucleus accumbens. CLOCK binding was detected at E-box elements within the TH promoter with greater enrichment observed during the light phase when TH expression is low. These results suggest a negative regulation of TH by CLOCK. To examine alterations in the nigrostriatal dopamine circuit, HPLC measurements of dopamine and metabolites were performed in the dorsal striatum revealing significant increases in DOPAC and HVA. Dopamine receptor agonists and antagonists were used to pharmacologically probe dopamine receptor function. An enhancement of the locomotor suppressing response to dopamine antagonists in Clockdelta19 mice suggested increased dopaminergic tone. Clockdelta19 mice were insensitive to the locomotor stimulating effects of a D1 agonist, but displayed increased levels of D1DR protein. Conversely, the Clockdelta19 mutants displayed enhanced locomotor suppression to a D2 agonist and a coincident increase in D2DR protein. Forskolin stimulation of cAMP resulted in blunted molecular responses in the Clockdelta19 mutants consistent with impairments in D1 signaling and/or enhancements in D2 signaling. In summary, normal CLOCK function appears to be involved in the regulation of dopamine transmission in the striatum.Item [Southwestern News](2000-09-14) Baxter, MindyItem [UT News](1986-08-22) Rutherford, SusanItem [UT Southwestern Medical Center News](2013-08-12) Rian, RussellItem [UT Southwestern Medical Center News](2009-04-02) Ladson, LaKisha