2007 — 2020 |
Paladini, Carlos Antonio |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cellular Mechanisms of Dopamine Neuron Bursting @ University of Texas San Antonio
[unreadable] DESCRIPTION (provided by applicant): The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, encode perhaps one of the most important signals for reinforcement learning in the brain - reward prediction error. This signal is encoded by the firing pattern of dopamine neurons, which controls the release of dopamine at target regions. Specifically, transient, impulse- dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Just as critical, pauses in dopamine cell activity have opposite psychological meaning for reward information coding and are thought to signal the absence of an expected reward. It is likely the essential nature of this signal that connects disruptions of DA function to many of the symptoms of a wide range of psychiatric diseases, and in the extreme case of the degeneration of these cells, to Parkinson's disease, including many of its cognitive aspects. Identification of the input pathways responsible for bursts and pauses is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive, and the cellular mechanism underlying burst and pause production in dopamine neurons has not been fully characterized. This is largely due to the difficulty in accurately duplicating bursts and pauses under controlled experimental conditions such as those attainable during in vitro experiments. Recently, we have determined a simple procedure to induce bursts and pauses in vitro that resemble those observed in vivo in every detail. This technical breakthrough allows for direct tests of the predictions of a mathematical model and a detailed cellular mechanism of bursting can be obtained. Computer simulations suggest NMDA receptors uniquely act to amplify the influence that the intrinsic frequencies of calcium- dependent oscillations within the dendrites have on the slower oscillations within the soma to initiate burst production. We have also recently shown that pauses in DA neurons may be generated by a mechanism completely different from that responsible for bursts. The specific aims in this proposal are designed to investigate the dopamine neuron pause and bursting mechanism and determine the effects of GABAergic receptors and of two phosphoinositide (Pl)- coupled receptors: the metabotropic glutamate receptor (mGluR) and the a-adrenoceptor. All these receptors can have differential effects on DA neuron firing pattern depending on the timing and duration of receptor activation. The experiments in this proposal implement both electrophysiological and confocal imaging techniques, along with computational modeling, to determine the cellular mechanisms of the reward prediction error. [unreadable] [unreadable] [unreadable]
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0.958 |
2008 — 2012 |
Paladini, Carlos Antonio |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Control of Dopamine Neuron Firing by Phosphoinosotide-Coupled Receptors @ University of Texas San Antonio
3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; Adrenergic Receptor; Adrenoceptors; Affect; Agonist; Animals; Attention; Bathing; Baths; Bed Nucleus of Stria Terminalis; Behavior; Behavioral; Brain; Cell Nucleus; Cells; Chromosome Pairing; Cognitive; Common Rat Strains; Complex; Condition; DA Neuron; Disease; Disorder; Disruption; Dopamine; Dopamine Agonists; Dopamine Receptor Agonists; Dopamine neuron; Dopaminergic Agonists; Drug Iontophoresis; Drugs; Dysfunction; Ekbom Syndrome; Electric Stimulation; Electrical Stimulation; Encephalon; Encephalons; Fire - disasters; Fires; Food; Functional disorder; G Protein-Complex Receptor; G-Protein-Coupled Receptors; Gelineau Syndrome; Gilles de la Tourette syndrome; Gilles de la Tourette's Disease; Glutamates; Goals; Guinon's disease; Hydroxytyramine; Idiopathic Parkinson Disease; In Vitro; Individual; Inositide Phospholipids; Inositol Phosphoglycerides; Inositol Phospholipids; Iontophoresis; L-Glutamate; Learning; Learning Disorders; Lewy Body Parkinson Disease; Maintenance; Maintenances; Mammals, Rats; Measures; Mediating; Medical; Medication; Memory; Mesencephalon; Metabotropic Glutamate Receptors; Mid-brain; Midbrain; Midbrain structure; Msec; Muscarinic Acetylcholine Receptor; Narcolepsy; Narcoleptic Syndrome; Nervous; Nervous System Diseases; Nervous System, Brain; Neurologic Disorders; Neurological Disorders; Nocturnal Myoclonus Syndrome; Nucleus; Nucleus tegmentalis pedunculopontinus; Numbers; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's disease; Parkinsons disease; Paroxysmal Sleep; Pathology; Patients; Pattern; Pedunculopontine Tegmental Nucleus; Periodic Limb Movement Disorder; Periodic Movements of the Limbs in Sleep Syndrome; Pharmaceutic Preparations; Pharmaceutical Preparations; Phosphatidyl Inositol; Phosphatidylinositols; Phosphoinositides; Physiology; Physiopathology; Prefrontal Cortex; Primary Parkinsonism; Process; Protocol; Protocols documentation; Psychological reinforcement; PtdIns; Range; Rat; Rate; Rattus; Receptor Activation; Receptor Protein; Receptors, Epinephrine; Receptors, Metabotropic Glutamate; Receptors, Muscarinic; Reinforcement; Reinforcement (Psychology); Restless Legs; Restless Legs Syndrome; Rewards; Series; Sleep Disorder, Periodic Movements; Sleep Myoclonus Syndrome; Sleep-Related Periodic Leg Movements, Excessive; Slice; Stria Terminalis Nucleus; Structure of terminal stria nuclei of preoptic region; Symptoms; Synapses; Synapsis; Synapsis, Chromosomal; Synaptic; Thinking; Thinking, function; Tic Disorder, Combined Vocal and Multiple Motor; Time; Tourette Syndrome; Tourette's; Tourette's Disease; Tourette's Disorder; Tourette's Syndrome; Ventral Tegmental Area; adenoreceptor; base; design; designing; disease/disorder; dopaminergic neuron; drug/agent; experiment; experimental research; experimental study; extracellular; in vivo; iontophoresis therapy; maladie des tics; millisecond; nervous system disorder; neural; neural circuit; neural circuitry; neurological disease; pathophysiology; preference; psychostimulant; receptor; receptor coupling; relating to nervous system; research study; response; theories; tic de Guinon; ventral tegmentum
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0.958 |
2011 — 2015 |
Paladini, Carlos Antonio |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Synaptic Origin of Reward Prediction Error Signal in Dopaminergic Neurons @ University of Texas San Antonio
DESCRIPTION (provided by applicant): The dopaminergic neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, encode perhaps one of the most important signals for reinforcement learning in the brain: reward prediction error. This signal is encoded by the firing pattern of dopaminergic neurons, which controls the release of dopamine at target regions. Specifically, transient, impulse-dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Just as critical, pauses in dopaminergic cell activity have opposite psychological meaning for reward information coding and are thought to signal the absence of an expected reward. It is likely the essential nature of this signal that connects disruptions of dopamine function to many of the symptoms of a wide range of psychiatric diseases, drug addiction, and in the extreme case of the degeneration of these cells, to Parkinson's Disease, including many of its cognitive aspects. Identification of the input pathways responsible for bursts and pauses is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. This is largely due to the difficulty in accurately duplicating bursts and pauses under controlled experimental conditions such as those attainable during in vitro experiments. A second difficulty has been the inability to selectively activate identified afferents to dopaminergic neurons during controlled in vitro experiments. The specific aims in this proposal are designed to investigate the synaptic mechanisms by which specific identified afferents induce bursts and pauses, and how psychostimulants alter the input from those same afferents. This will identify the circuit basis and synaptic origin of the reward prediction error signal, and provide a mechanistic understanding of how drugs of abuse alter the reward prediction error signal. To achieve this, we will use recordings in conductance-clamp, where specific conductances can be imposed in a defined manner directly on dopaminergic neurons, along with selective in vitro stimulation of specific afferents following prior viral infection in vivo with channelrhodopsin (ChR2). The ChR2 strategy provides a clear advantage over simultaneous activation of all afferents by electrical stimulation since it will selectively identify the afferents responsible for bursts and pauses, in addition to those afferents with affected synaptic input after in vivo cocaine exposure.
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0.958 |
2015 — 2019 |
Paladini, Carlos Antonio Weinshenker, David [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Cocaine Hypersensitivity Following Chronic Dbh Inhibition
DESCRIPTION (provided by applicant): Norepinephrine (NE) provides excitatory drive onto midbrain dopamine (DA) neurons and modulates responses to dopaminergic drugs, including psychostimulants. Chronic loss of noradrenergic tone impairs DA neuron firing and DA release, leading to compensatory alterations in postsynaptic DA receptor signaling and a paradoxical hypersensitivity to dopaminergic drugs. The goal of this proposal is to identify the molecular and cellular mechanisms underlying the behavioral hypersensitivity to cocaine following chronic inhibition of the NE biosynthetic enzyme, dopamine ?ydroxylase (DBH). Based on our preliminary data, we propose that a chronic loss of NE produces a decrease in ?rrestin2 (?r2) in the nucleus accumbens (NAc), which promotes a reversal in the valence of D2 responses from inhibitory to excitatory, potentially via a G?to-G?switch in D2 receptor coupling. In Aim 1, we will determine the consequences of increasing or reducing the amount of ?r2 selectively in D1 or D2 NAc neurons on behavioral responses to D2 agonist and cocaine. We will also test whether decreasing NAc neuron excitability normalizes cocaine responses following chronic DBH inhibition. In Aim 2, we will use slice electrophysiology to determine whether decreasing ?r2 specifically in D1 or D2 NAc neurons is necessary and sufficient to trigger the switch from D2-mediated inhibition to excitation and further investigate alterations in D2 G protein coupling. In Aim 3, we will assess the effects of chronic DBH inhibition and reduction of ?r2 on the aversive properties of cocaine using the runway model of cocaine self-administration in rats. Completion of these Specific Aims will contribute to our understanding of noradrenergic modulation of mesolimbic DA transmission, the plasticity of DA receptor signaling pathways, and NE-DA interactions underlying aversive responses to drugs of abuse.
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0.923 |
2017 — 2018 |
Paladini, Carlos Antonio |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
In Vivo Whole-Cell Recordings of Dopamine Neurons in Awake Behaving Mice @ University of Texas San Antonio
Activity patterns in the brain establish the manner in which sensory information is perceived and salience is assigned. Disruptions of these patterns are likely a major cause of mental illness. The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, locat- ed within the ventral mesencephalon, encode perhaps one of the most important signals for re- inforcement learning in the brain: reward prediction error. This signal is encoded by the firing pattern of dopamine neurons, which controls the release of dopamine at target regions. Specifi- cally, transient, impulse-dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Just as critical, pauses in dopamine cell activity have opposite psychological meaning for reward information coding and are thought to signal the ab- sence of an expected reward. In vitro studies have determined that ion channels drive the firing patterns of dopamine neurons. Also, the multitude of physiological consequences of their open- ing and closing makes ion channels and their associated receptors highly compelling as impor- tant therapeutic targets for treating many of the symptoms of mental illnesses. However, de- spite their importance virtually nothing is known of the impact of specific ion channels on dopamine firing pattern during behavior. Identification of the ion channels responsible for bursts and pauses is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. This is largely due to the difficulty in obtaining intracellular whole- cell recordings of dopamine neurons in awake, behaving animals. A method to routinely obtain in vivo whole-cell recordings from identified dopamine neurons in mice has been developed in our lab. For this R21 ?Exploratory/Developmental Research Grant Award? to ?support devel- opment of novel techniques? further success in obtaining whole-cell recordings in awake behav- ing mice will be developed to determine the underlying conductances that drive dopamine neu- rons to burst and pause during reward-related behavior.
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0.958 |
2017 |
Paladini, Carlos Antonio Weinshenker, David [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Cocaine Hypersensitivity Following Chronic Dbh Inhibition 5r01da038453-02 Diversity Supplement
DESCRIPTION (provided by applicant): Norepinephrine (NE) provides excitatory drive onto midbrain dopamine (DA) neurons and modulates responses to dopaminergic drugs, including psychostimulants. Chronic loss of noradrenergic tone impairs DA neuron firing and DA release, leading to compensatory alterations in postsynaptic DA receptor signaling and a paradoxical hypersensitivity to dopaminergic drugs. The goal of this proposal is to identify the molecular and cellular mechanisms underlying the behavioral hypersensitivity to cocaine following chronic inhibition of the NE biosynthetic enzyme, dopamine ?ydroxylase (DBH). Based on our preliminary data, we propose that a chronic loss of NE produces a decrease in ?rrestin2 (?r2) in the nucleus accumbens (NAc), which promotes a reversal in the valence of D2 responses from inhibitory to excitatory, potentially via a G?to-G?switch in D2 receptor coupling. In Aim 1, we will determine the consequences of increasing or reducing the amount of ?r2 selectively in D1 or D2 NAc neurons on behavioral responses to D2 agonist and cocaine. We will also test whether decreasing NAc neuron excitability normalizes cocaine responses following chronic DBH inhibition. In Aim 2, we will use slice electrophysiology to determine whether decreasing ?r2 specifically in D1 or D2 NAc neurons is necessary and sufficient to trigger the switch from D2-mediated inhibition to excitation and further investigate alterations in D2 G protein coupling. In Aim 3, we will assess the effects of chronic DBH inhibition and reduction of ?r2 on the aversive properties of cocaine using the runway model of cocaine self-administration in rats. Completion of these Specific Aims will contribute to our understanding of noradrenergic modulation of mesolimbic DA transmission, the plasticity of DA receptor signaling pathways, and NE-DA interactions underlying aversive responses to drugs of abuse.
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0.923 |
2020 |
Paladini, Carlos Antonio Wadiche, Jacques [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cocaine Modulation of Synapses Onto Dopamine Neurons @ University of Alabama At Birmingham
Abstract Identification of the mechanism(s) responsible for drug reinforcement is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, are a central locus for drug reinforcement. Even a single exposure to cocaine is sufficient to alter synaptic transmission to dopamine neurons, with attention focused on postsynaptic mechanisms of plasticity mediated by AMPA receptors (AMPARs). Most AMPARs are impermeable to Ca2+ (CI-AMPAR) whereas receptors that lack the GluR2 subunit are permeable to Ca2+ (CP-AMPAR). A biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from the more common CI-AMPARs . It is commonly accepted that cocaine exposure alters rectification of AMPAR synaptic currents on dopamine neurons without affecting measures of release probability, pointing to postsynaptic mechanisms of synaptic plasticity. However, our new data challenges the assumptions that rectification is sufficient to infer AMPAR subunit composition and that release probability is sufficient to assess presynaptic efficacy. Rather, our data shows that changes in the readily-releasable pool of vesicles can robustly alter presynaptic efficacy without a change in the release probability and that presynaptic mechanisms can affect rectification properties of AMPAR synaptic currents. Based on our data, we hypothesize that presynaptic mechanisms contribute to synaptic changes in dopamine neurons following cocaine exposure. We will first test AMPAR properties in dopamine neurons from naïve and cocaine-treated mice under conditions that isolate postsynaptic mechanisms. We will then follow up to test whether presynaptic changes contribute to synaptic plasticity induced by cocaine exposure. Presynaptic efficacy and AMPAR subunit composition have important functional consequences ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating Ca2+ influx that can trigger plasticity or pathology like addiction. Successful completion of the proposed studies has potential to reveal novel mechanisms underlying synaptic plasticity at synapses onto dopamine neurons following exposure to drugs of abuse.
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0.902 |