Scaling API-first – The story of a global engineering organization
Therapeutic Potential of Designer Receptors, Gary Aston-Jones, PhD
1. Different types of neurons are interdigitated in the same brain areas: How selectively stimulate/inhibit? Guan et al, Intl J Obesity, 2002.
2. Gene transfer in brain in vivo viral vectors Davidson & Breakefield, Nat. Rev. Neurosci. 2003.
3. Cell-type-specific gene transfer & modulation of neuronal activity Calloway, E., Trends Neurosci. 2005. Allostatin (AL) = invertebrate peptide/receptor system
4. Evolving the lock to fit the key: Designer receptors exclusively activated by designer drugs (DREADDS) Conklin, B., PNAS (2007) Armbruster et al., PNAS (2007) directed evolution: muscarinic ACh receptor -> DREADD CNO=clozapine n-oxide Muscarinic Ach receptor DEADD
5. Courtesy of Bryan Roth, U North Carolina Specific neuronal inhibition with hM4D DREADD
6.
7. Photosensitive ion channels for control of neuronal activity Zhang et al., Nature Rev. Neurosci. (2007) Channelrhodopsin Halorhodopsin excitation inhibition
8. Photostimulation yields more specific effects than electrical stimulation Alternative to Deep Brain Stimulation Zhang et al., Nature Rev. Neurosci. (2007)
9. Cell-type specific expression of channelrhodopsin in brain norepinephrine neurons in vivo PRSx8 promoter; mCherry tag Microinjection in vivo in locus coeruleus TH (NE neurons) mCherry (ChR2 neurons) Merge David Moorman Elena Vazey
11. Photostimulation of neuronal activity in vivo Locus coeruleus neuronal recordings in anesthetized rat David Moorman Elena Vazey
12.
13. Acknowledgements Rachel Smith David Moorman Angie Cason Pouya Tashili-Fahadan Kimberlei Richardson Steve Mahler Lana Zhang Greg Sartor Elena Vazey Mike Smith Becky Fallon Glenda Harris (U Penn) Matt Wimmer (U Penn) MUSC Neuroscience of Addiction Research Center National Institute on Drug Abuse Lilly Pharmaceuticals
