Reference number : GC-2017-Q1-02984, amendment number : , agreement type : G, recipient legal name : Seamans, Jeremy (The University of British Columbia), recipient country : CA, recipient province : nan, recipient city : British Columbia|Colombie-Britannique, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : Dopamine (DA) is an important neuromodulator that affects behaviors involving the striatum and prefrontal cortex (PFC). The temporal dynamics of DA signaling strongly constrain proposed theories about DA function. In the PFC, DA release is slow and even a brief application of DA exerts sustained effects on the biophysical properties of PFC neurons recorded in vitro and in vivo that lasts minutes to hours. Based on the known characteristics of the PFC DA system, we proposed the &lsquo;dual-state theory&rsquo;, positing that the DA modulation of ionic currents in PFC neurons causes networks to switch into one of two distinct states or modes over prolonged periods. 
In contrast, another more prominent theory posits that DA encodes temporally precise &lsquo;Reward Prediction Errors&rsquo; (RPEs) that are proposed to underlie &lsquo;reinforcement&rsquo; learning. This theory is based on data showing that reward predictive cues or outcomes are associated with brief bursts of spikes in DA neurons (&lt;100ms) and transient DA elevations in the striatum. In 2007 we argued that the RPE-based reinforcement learning model is not feasible for the PFC because PFC DA release is far too slow and temporally imprecise and does not differentiate between unexpectedly &lsquo;good&rsquo; and &lsquo;bad&rsquo; outcomes. 
However, the tools necessary to accurately characterize transient DA signaling in PFC were not available at that time. New technologies have emerged within the last 5 years that can now address this issue. The present proposal will utilize these new technologies to investigate the effects of fast and slow DA signaling in the PFC. 
Specific Aims 
1. Aim 1 is to characterize the temporal dynamics of phasic DA release in the PFC. Changes in DA levels will be measured using fast-scan cyclic voltammetry and DA release will be precisely controlled using optogenetic technology. We will quantify the specific DA concentrations in PFC produced by different optical stimulation parameters. 
2. Aim 2 is to determine how optogenetic DA release characterized in Aim 1 affects the firing of PFC neurons in vivo and synaptic interactions between neurons in vitro. This will involve evoking optogenetic release of DA in PFC while simultaneously performing opto-tetrode recordings of multiple PFC neurons in behaving animals or patch-clamp recordings of synaptic currents in brain slices. 
The proposed experiments build on a history of studies where we have characterized the effects of exogenous DA on the biophysical properties of PFC neurons. We propose to incorporate powerful new technologies to evoke precisely timed release of DA from axons in PFC and determine its effects on PFC neurons and circuits. Understanding the temporal dynamics of DA release and its effects in the PFC could have significant impact on our understanding of the PFC and DA signaling throughout the brain., program purpose french : Dopamine (DA) is an important neuromodulator that affects behaviors involving the striatum and prefrontal cortex (PFC). The temporal dynamics of DA signaling strongly constrain proposed theories about DA function. In the PFC, DA release is slow and even a brief application of DA exerts sustained effects on the biophysical properties of PFC neurons recorded in vitro and in vivo that lasts minutes to hours. Based on the known characteristics of the PFC DA system, we proposed the &lsquo;dual-state theory&rsquo;, positing that the DA modulation of ionic currents in PFC neurons causes networks to switch into one of two distinct states or modes over prolonged periods. 
In contrast, another more prominent theory posits that DA encodes temporally precise &lsquo;Reward Prediction Errors&rsquo; (RPEs) that are proposed to underlie &lsquo;reinforcement&rsquo; learning. This theory is based on data showing that reward predictive cues or outcomes are associated with brief bursts of spikes in DA neurons (&lt;100ms) and transient DA elevations in the striatum. In 2007 we argued that the RPE-based reinforcement learning model is not feasible for the PFC because PFC DA release is far too slow and temporally imprecise and does not differentiate between unexpectedly &lsquo;good&rsquo; and &lsquo;bad&rsquo; outcomes. 
However, the tools necessary to accurately characterize transient DA signaling in PFC were not available at that time. New technologies have emerged within the last 5 years that can now address this issue. The present proposal will utilize these new technologies to investigate the effects of fast and slow DA signaling in the PFC. 
Specific Aims 
1. Aim 1 is to characterize the temporal dynamics of phasic DA release in the PFC. Changes in DA levels will be measured using fast-scan cyclic voltammetry and DA release will be precisely controlled using optogenetic technology. We will quantify the specific DA concentrations in PFC produced by different optical stimulation parameters. 
2. Aim 2 is to determine how optogenetic DA release characterized in Aim 1 affects the firing of PFC neurons in vivo and synaptic interactions between neurons in vitro. This will involve evoking optogenetic release of DA in PFC while simultaneously performing opto-tetrode recordings of multiple PFC neurons in behaving animals or patch-clamp recordings of synaptic currents in brain slices. 
The proposed experiments build on a history of studies where we have characterized the effects of exogenous DA on the biophysical properties of PFC neurons. We propose to incorporate powerful new technologies to evoke precisely timed release of DA from axons in PFC and determine its effects on PFC neurons and circuits. Understanding the temporal dynamics of DA release and its effects in the PFC could have significant impact on our understanding of the PFC and DA signaling throughout the brain., agreement title english : Tonic and phasic dopamine-mediated modulation of prefrontal cortex neurons, agreement title french : Tonic and phasic dopamine-mediated modulation of prefrontal cortex neurons, agreement number : RGPIN, agreement value : 160000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada