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MCB141 Final Project

Pain Adaptation

Perry Choi

on 16 May 2013

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Transcript of MCB141 Final Project

MCB141 Research Proposal:
Reward Habituation & Pain Sensitization Perry Seo Choi Plasticity of sensory modality Functioning of sensory epithelium The Big 3 Sensory coding in the brain - How does the brain encode reward habituation?

- Ventral tegmental area (VTA), Nucleus accumbens (NAc), Amygdala (AMY), Prefrontal Cortex (PFC), Substantia Nigra (SNc), Hippocampal formation/subiculum (HIP/SUB) - Does this habituation coding differ for relief-of-pain reward paradigms? If so, how? If not, why?

- VTA? - Pain sensitization

- Can we induce sensitization of non-noxious pathways? http://www.projectknow.com/wp-content/uploads/effectsofdrugabuse.jpg Addiction http://www.drstubbeman.com/wp-content/uploads/2012/08/10CHRONICPAIN-image.jpeg Chronic Pain http://michaeldmann.net/pix_18/habituation.gif http://e-book.lib.sjtu.edu.cn/iupsys/Proc/mont2/images/icov2c11g006.jpg Reward habituation Motive 1 Motive 2 Motive 3 Background Information Motive 2 Motive 3 Cooper 2002 - PFC: working memory of reward quality (Miller & Cohen 2001)

- AMY: detecting novel stimuli associated w/ reward (Floresco et al. 2001)

- NAc: limbic-motor interface (Breiter & Rosen 1999)

- *VTA: Dopaminergic neurons for reward coding (Schultz 2000)

- SNc: Dopaminergic neurons for salient cues (Uchida 2012)

- HIP/SUB: context of reward receipt (Tabuchi et al. 2000) - DA neurons burst to novel, unexpected reward

- DA neurons do not burst
to expected reward

-*CS fires in expected condition = GABAergic interneurons (Cohen&Haesler 2012)

- DA neurons decrease below basal activity to unexpected absence of reward Schultz 2000 Brischoux et al. 2009 - VTA DA neurons also respond to noxious stimuli

- Possible mechanism for resistance to habituation? Sensitization - astroglial glutamate-glutamine shuttle is also involved (Chiang et al. 2007) - alpha-1-adrenoreceptors contribute to mustard oil induced central sensitizsation in the rat medullary dorsal horn (Chiang et al. 2013)

- two temporal phases: 1) phorsphorylation-dependent changes in Glu receptors, 2) transcription-dependent protein synthesis. (Woolf & Salter 2000)

- glutamate to AMPAR, NMDAR, mGluR (R1, 2, and 3), calcitonin gene-related peptide (CGRP) to CGRP1Rs, substance P to NK1Rs. , and brain-derived neurotrophic factor (BDNF) to TrkBRs. (Polgar et al. 2008; Latremoliere & Woolf 2009) Project 1: Methods Motive 2 Motive 3 Rabies Virus GABA-afferent staining Global sensitization control Look at inputs to VTA DA neurons Project 1 Project 2 - DAT-Cre
- Advantages:
- no damage to host cell
- infects only neurons
- spreads exclusively in retrograde direction
- moves across neurons only at synapses To look at neural activity of presynaptic inputs to VTA DA To differentiate excitatory and inhibitory inputs - GAD67/d-tomato transgene to label inhibitory neurons - help identify site of habituation/non-habituation To control for global sensitization of DA activity - food restriction (push toward 90% of body weight) is sufficient to raise basal impulse activity of DA neuron population under chloral hydrate anesthesia by 40% (Cooper 2002) Project 1: Experiments Reward Learning Paradigm - ~40 rats; box of 10 levers
- Learn to associate reward with pulling of correct lever
- Learning completion via DA neuron activity
- Train for 5 different, randomly chosen levers
- Measure learning curve across trials (i.e., how many pulls it takes for learning)
- Measure neural activity of DA neurons & presynaptic inputs Normal Reward (e.g., juice) Relief-of-Pain Reward http://media4.s-nbcnews.com/j/MSNBC/Components/Photo/_new/121004-science-rats-735p.grid-8x2.jpg - Reward is juice
- Expect habituation due to decreased perceptual significance of reward
- Control group has neutral tone associated with correct lever pull
- Compare neural activity across trials to look at processes involved in habituation - Reward is stopping of medium-strength electric shock from the floor
- Expect less habituation or non-habituation due to persistent perceptual significance of reward
- Control group is pain-insensitive rats
- Compare neural activity across trials against those from previous experiment to look for differences and structures involved in habituation processing Is habituation regulated via presynaptic inputs, DA neurons, or both? Major question answered: Project 2 Acknowledgments Thank you! Thank you! Thank you! Ryoma Hattori Dr. Catherine Dulac The Difference Non-noxious afferents glutamate to AMPAR, NMDAR, mGluR1, 2, and 3 Brain-derived neurotrophic factor (BDNF) to TrkBRs Sensitization induction calcitonin gene-related peptide (CGRP) to CGRP1Rs substance P to NK1Rs - appeasing, smooth touch afferents MRGPRB4+ CT fibers

- Other possibilities: sweet taste, odors, etc.

- Test receptive field and measure afferent activity after sequential stimulation
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