Browsing by Subject "Dopaminergic neurons"
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Item Behavioral alterations in models of Parkinson's disease(2002) Tillerson, Jennifer Layne; Miller, Gary W.This work characterizes the behavioral effects of altered dopamine transmission and tests the hypothesis that manipulating behavior impacts recovery following injury in models of Parkinson’s disease (PD). The MPTP mouse model of PD has been limited by the lack of measurable and persistent motor deficits. We developed several sensitive measures of motor impairment in MPTP mice. These tests could detect motor deficits that were persistent over time, reversed through L-DOPA treatment, and highly correlated to striatal dopamine and dopaminergic terminal markers. We also identified a specific olfactory deficit in mice with altered dopamine neurotransmission (dopamine transporter or D2 receptor knockout mice) implicating the D2 receptor in the olfactory dysfunction seen in patients with disorders involving dopamine systems. Understanding of these early behavioral and sensory symptoms of altered dopamine transmission will allow for earlier detection of the disorder and improved prognosis for PD patients. Significant declines in physical activity begin years before the diagnosis of PD. We believe that this striking inactivity is not only a symptom of the dopamine neuron degeneration, but could also be contributing to the progression of the disease. Therefore, we manipulated the level of activity following nigrostriatal injury in both 6-hydroxydopamine (6-OHDA) and MPTP retirebreeder mouse models of PD. In both models, moderate running following injury resulted in long-term behavioral improvements and increased striatal dopamine system integrity. In addition, we tested the hypothesis that decreased physical activity during nigrostriatal degeneration could augment dopamine cell loss. Rats given doses of 6-OHDA that would normally result in only mild loss of DA and no measurable behavioral deficit were forced to disuse the lesioned motor system. In these animals, the neurochemical and behavioral deficit was similar to that of a severe lesion. MPTP mice with lateralized use of the forelimbs (one forelimb casted to prevent movement) showed sustained asymmetry of behavior and striatal dopaminergic markers. These studies support the role of physical therapy in the treatment of PD, and strongly suggest that decreased activity is not only a symptom of dopamine loss, but plays an active role in the progressive degeneration in PD.Item Differential regulation of Ca²⁺ signals in dopamine neurons : a potential mechanism for neuroadaptive changes underlying drug addiction(2007-05) Cui, Guohong, 1974-; Morikawa, HitoshiA key adaptive change in the brain reward circuitry during the development of drug addiction is augmented dopamine (DA) release in response to addictive drugs. Potentiated glutamatergic synaptic transmission onto midbrain DA neurons has been suggested to be one of the cellular mechanisms mediating this change. Intracellular Ca2+ ([Ca2+ ]i) rise associated with postsynaptic bursts of action potentials (APs) and metabotropic glutamate receptor (mGluR) activation has been implicated in the induction of long-term potentiation (LTP) and long-term depression (LTD), respectively, of glutamate transmission in DA neurons. In this dissertation, we found a unique mechanism that differentially regulates these two opposing Ca2+ signals. We performed patch-clamp recordings from DA neurons in acutely cut brain slices, and showed that tonic activation of metabotropic neurotransmitter receptors (such as mGluRs, α1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by weak, sustained (~1 sec) synaptic stimulation or bath application of selective agonists, augmented AP-induced Ca2+ transients while inhibiting Ca2+ signals elicited by strong, transient activation of mGluRs. This differential regulation is mediated by increased intracellular inositol 1,4,5-triphosphate (IP3) levels, since it was blocked by IP3 receptor antagonist heparin and reproduced by photolytic application of IP3. We further showed that AP-induced Ca2+ transients were regulated by the firing context of dopamine neurons. Evoking APs repetitively at low frequency (2 Hz) mimicking the basal firing of DA neurons caused inactivation of IP3 receptors and inhibited AP-induced Ca2+ transients. IP3 facilitation of single AP-induced Ca2+ signals was completely abolished during the AP train, while facilitation of Ca2+ signals triggered by bursts of APs (5 spikes at 20 Hz) was attenuated by less than half, indicating that increased IP3 level selectively amplifies Ca2+ signals associated with bursts but not single APs in a tonicly firing neuron. Finally, we obtained evidence suggesting that psychostimulant amphetamine may augment burst-induced Ca2+ signals via both depression of basal firing and production of IP3. We propose that the differential Ca2+ regulation mechanisms described in this dissertation may induce a shift in the balance of plasticity toward burst-dependent LTP in DA neurons and may contribute to the development of drug addiction.Item Differential regulation of Ca²⁺ signals in dopamine neurons: a potential mechanism for neuroadaptive changes underlying drug addiction(2007) Cui, Guohong; Morikawa, HitoshiA key adaptive change in the brain reward circuitry during the development of drug addiction is augmented dopamine (DA) release in response to addictive drugs. Potentiated glutamatergic synaptic transmission onto midbrain DA neurons has been suggested to be one of the cellular mechanisms mediating this change. Intracellular Ca2+ ([Ca2+ ]i) rise associated with postsynaptic bursts of action potentials (APs) and metabotropic glutamate receptor (mGluR) activation has been implicated in the induction of long-term potentiation (LTP) and long-term depression (LTD), respectively, of glutamate transmission in DA neurons. In this dissertation, we found a unique mechanism that differentially regulates these two opposing Ca2+ signals. We performed patch-clamp recordings from DA neurons in acutely cut brain slices, and showed that tonic activation of metabotropic neurotransmitter receptors (such as mGluRs, α1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by weak, sustained (~1 sec) synaptic stimulation or bath application of selective agonists, augmented AP-induced Ca2+ transients while inhibiting Ca2+ signals elicited by strong, transient activation of mGluRs. This differential regulation is mediated by increased intracellular inositol 1,4,5-triphosphate (IP3) levels, since it was blocked by IP3 receptor antagonist heparin and reproduced by photolytic application of IP3. We further showed that AP-induced Ca2+ transients were regulated by the firing context of dopamine neurons. Evoking APs repetitively at low frequency (2 Hz) mimicking the basal firing of DA neurons caused inactivation of IP3 receptors and inhibited AP-induced Ca2+ transients. IP3 facilitation of single AP-induced Ca2+ signals was completely abolished during the AP train, while facilitation of Ca2+ signals triggered by bursts of APs (5 spikes at 20 Hz) was attenuated by less than half, indicating that increased IP3 level selectively amplifies Ca2+ signals associated with bursts but not single APs in a tonicly firing neuron. Finally, we obtained evidence suggesting that psychostimulant amphetamine may augment burst-induced Ca2+ signals via both depression of basal firing and production of IP3. We propose that the differential Ca2+ regulation mechanisms described in this dissertation may induce a shift in the balance of plasticity toward burst-dependent LTP in DA neurons and may contribute to the development of drug addiction.