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Antonello Bonci, MD NIDA/NIH Antonello.Bonci@Nih.Gov from Single Synapses to Clinical Studies: Therapeutic Developments From From Single Synapses to Clinical Studies: Therapeutic Developments from Optogenetics Antonello Bonci, MD NIDA/NIH [email protected] Dopamine Addiction Apathy motivation Aggressive behaviors Sexual behaviors Appetitive behaviors Reward Deficiency Syndrome Parkinson’s disease ADHD Schizophrenia Sensory neglect Learning and memory LTP and dopamine neurons AMPAR dopamine neuron CaMKII glutamate Ca++ NMDAR Bonci and Malenka, 1999; Overton and Clark, 1999 The time course of VTA cocaine‐dependent synaptic plasticity Ungless et al., Nature (2001) LTP 3 hours 1 day 3 days 5 days 1 week 3 weeks 3 months time The time course of VTA cocaine‐dependent synaptic plasticity Ungless et al., Nature (2001) Chen et al., Neuron (2008) LTP Cocaine self‐administration Single cocaine 3 hours 1 day 3 days 5 days 1 week 3 weeks 3 months time The time course of VTA cocaine‐dependent synaptic plasticity Chen et al., Neuron (2008) LTP Cocaine self‐administration Stuber et al., Science (2010) How Reward related learning 3 hours 1 day 3 days 5 days 1 week 3 weeks 3 months time The other players Alterations in microglia have been described in a variety of psychiatric diseases From Aguzzi, Barres and Bennet, Science (2013) Basic properties of microglial cells in the midbrain and accumbens Lindsay de Biase Mirror project: Wendy Xin (astrocytes) TH Iba1 = Microglia NG2 = Oligodendrocyte Precursors Not shown – Oligodendrocytes, Astrocytes deBiase et al., under submission Regions of interest for study of basal ganglia (BG) microglia (knock‐in) • P58‐62 CX3CR1 EGFP • ♂ and ♀ Jackson Labs • perfusion‐fixed TH SNc NAc SNr VTA m Medial Lateral deBiase et al., under submission Density of microglia varies dramatically across BG nuclei NAc VTA SNc SNr TH * P < 0.02, all comparisons; (sequential Bonferroni correction) * m * EGFP * * m deBiase et al., under submission Morphology of microglia varies dramatically across BG nuclei * P < 0.006 all comparisons ex. NAc vs. SNr and VTA vs. SNc deBiase et al., under submission Quantitative analysis of microglial cell morphology Electrophysiology to probe microglial membrane properties in acute brain slices (knock‐in) CX3CR1 EGFP Jackson Labs • P35‐42 • ♂ and ♀ • Horizontal midbrain section MT Anterior Medial deBiase et al., under submission SNr microglia express more voltage-activated conductances 10% 0% 60% (2/21 cells) (0/7 cells) (12/20 cells) deBiase et al., under submission Analysis of gene expression in microglia FACS isolation of microglia from specific basal ganglia nuclei NAc VTA SN Ctx Ion Torrent RNA sequencing Whole Transcriptome Analysis (collaboration with NIAAA) Relative regional differences in microglial cell density are established early in development and persist throughout life P12P58‐62 18 mo deBiase et al., under submission Microglial responses to aging are not uniform across the BG 57% 18 mo P58‐62 77% 100% 78% Clustering Abnormal morphology (prevalent in midbrain) Under analysis A biomarker for aging? Microglial cell density is not correlated with neuronal density NAc VTA SNc SNr EGFP 100m NeuN deBiase et al., under submission SUMMARY: Distinct microglial phenotypes across the basal ganglia DENSITY EGFP m SUMMARY: Distinct microglial phenotypes across the basal ganglia MORPHOLOGY SUMMARY: Distinct microglial phenotypes across the basal ganglia MEMBRANE PROPERTIES Summary • Microglia within the BG exhibit regionally specific phenotypes and may possess differential capacity to respond to CNS insults • Foundation for defining how microglia impact synaptic transmission and synaptic plasticity within the BG / reward circuitry in both physiological and pathological contexts (substance abuse, stress-dependent behaviors, psychiatric diseases, neurodegeneration) Part III: from optogenetic studies to a treatment against cocaine craving Courtesy of Ed Boyden, MIT Optogenetics can be also used to silence neurons Courtesy of Ed Boyden, MIT Part II: from optogenetic studies to a treatment against cocaine craving Kusumoto et al., PNAS (2015) Seif et al., Nature N. (2013) Chen et al., Nature (2013) Insula PFC Stuber et al., Nature (2011) BLA Accumbens McDevitt et al., Cell R. (2014) V. Subiculum Hipp Dorsal Britt et al., Neuron (2012) Raphe VTA Stuber et al., J Neurosci (2010) LH Kempadoo et al, J Neurosci (2013) An optogenetic study inspired by human studies based on the broad concept of “hypofrontality” on cocaine abusers PFC Billy T. Chen Decision making processes Evaluation of expected outcome Inhibitory control Self-administration paradigm 1. Rats are trained to self-administer cocaine on a seek-take chain schedule (about 2 months) with progressively longer Random Intervals. 2. At the very end of training, rats receive 4 sessions of non-contingent foot shock in 30% of trials Take Seek RI 5 Cocaine RI 30 (30 inf. or 6hrs) RI 60 1. Rats are divided into non-compulsive and compulsive groups shock sensitive Shock‐resistant Chen et al., Nature (2013) The prelimbic cortex is involved in many physiological functions, including decision making processes Adapted from Vertes, Neuroscience 2006; 142 1‐20) In vivo Patch‐Clamp recordings in the prelimbic cortex CourtesyCourtesy ofof EdEd Boyden,Boyden, MITMIT Hypoactivity in prelimbic PFC neurons after long-access cocaine self-administration Naive 5,0 Naive 4,0 Cocaine Cocaine 3,0 2,0 1,0 Baseline firing freq. (Hz) 0,0 Thanks to Rob Froemke, NYU Long‐access to cocaine decreases excitability of deep‐layer prelimbic neurons 16 Naive Naive 12 Sensitive Resistant 8 Sensitive 4 Number of APs Number of Resistant 0 0 200 400 input (pA) Chen et al., Nature (2013) Hypothesis: If hypoactivity of the prelimbic cortex is causally linked with cocaine seeking, then Optogenetic activation of the prelimbic area should reduce cocaine seeking Laser stimulation procedure ‐ 4 days of “shock” training ‐ On day 5, ChR stimulationin the PLCx (@1 Hz) throughout the seek period Seek Take 30% Cocaine Chen et al., Nature (2013) Prelimbic photostimulation decreases compulsive cocaine seeking only after Shock sessions Chen et al., Nature (2013) Summary • ~30% of rats will self-administer cocaine despite negative consequences (SR rats). • Neurons in the prelimbic region of the PFC are significantly hypoactive active after prolonged cocaine self-administration, with shock resistant rats being the least active. • Activation of prelimbic neurons via optogenetic decreases cocaine seeking and taking behavior in shock resistant rats • Inhibition of prelimbic neurons via optogenetics in shock sensitve rats triggers cocaine seeking during shock sessions • Therapeutic applications testable, immediately .
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