The Nature of the Potential

Transcription

1 Lawrence May 2017 The Nature of the Potential Bita Moghaddam Professor and Chair Department of Behavioral Neuroscience Oregon Health and Science University Research Support: NIH/NIMH Andrew Mellon Foundation Pittsburgh Life Sciences Greenhouse

2 University of Pittsburgh OHSU

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5 Dopamine has been implicated in nearly all aspects of higher brain function Attention Goal-directed movement Motivation and affective processing Multiple forms of learning and memory Executive functions such as working memory and decision making These are slow processes involving multiple regions

6 How do dopamine neurons do all this? Dopamine neurons have a relatively discrete pattern of projections Dopamine neurons respond phasically and FAST (ms) to sensory stimuli or learned responses to reward-related cues

7 Dopamine neurons respond phasically and FAST (ms) to sensory stimuli or learned responses to reward-related cues Example Record from ventral tegmental area (VTA) during task performance Cue -> outcome sig08b Frequency (imp/sec) Firing rate (Hz) Kim et al 2010; 2012

8 Stimulate dopamine cells using patterns of activation that resemble the phasic bursting activity of dopamine neurons during cognitive/reward-guided behavioral tasks 1. Measure dopamine release in terminals 2. Measure postsynaptic response in dopamine-innerved areas 3. Measure global/fmri activity

9 How does dopamine neuron burst activity modulate brain wide activity? Opto-fMRI combines optogenetics and fmri

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11 The most prominent effect of VTA dopamine neuron burst stimulation is in the dorsal striatum CBV=Cerebral blood volume BOLD= Blood Oxygen Level Dependent

12 Statistical t-value maps overlaid on structural images show increased BOLD and CBVw activity Group activation maps

13 Ipsilateral ROI analysis

14 Why does burst activity of VTA dopamine neurons produce robust fmri activation in the dorsal striatum? unlikely a direct dopamine-mediated effect fmri activations are primarily attributed to changes in glutamate release We propose that the dorsal striatal activation is mediated, at least in part, by network-level interactions involving longrange basal ganglia-thalamic-cortical loops that may terminate in the striatum via convergent glutamate projections Several potential networks that may be involved

15 VTA DA Ventral Striatum GABA Thalamus (direct or indirect via pallidum) Glu Glu PFC (OFC ACC) Glu Dorsal striatum divergence of signal from the VS to thalamic and cortical areas -> convergence (and amplification of signal) in the DS Consistent with this scheme, we observed significant fmri responses to VTA dopamine stimulation in the thalamus, pallidum, and cortical areas such as the OFC.

16 Summary Opto-fMRI data establishes causation between VTA dopamine neuron burst activity and fmri responses in limbic and non-limbic basal ganglia regions Phasic activation of VTA dopamine neurons has a profound global impact and activates non-limbic regions that are not directly innervated by these neurons These findings further demonstrate the existence of a functional VTA -> basal ganglia connection

17 Acknowledgements Acknowledgments Current or recent lab Members: Lézio Bueno Corina Bondi Alberto Del Arco Gonzalez Yun-Bok Kim Timothy Gregory Swyeta Lohani Adria Martig Marguerite Matthews Eric Miller Junchol Park Nick Simon Karen Smithmeyer David Sturman Nelson Totah Jodi Tuck Meredyth Wegener Jesse Wood Research Support: NIH/NIMH Andrew Mellon Foundation Pittsburgh Life Sciences Greenhouse Collaborators: Susan Amara (NIMH) Seong-Gi Kim (Sungkyunkwan Univ) Alexander John Poplawsky (Pitt) Rob Kass (CMU) Susan Sesack (Pitt) Linda Rinaman (Pitt) Raj Narendaren (Pitt)

18 THANK YOU