Vagus nerve stimulering som et verktøy for å indusere plastisitet i Pathways Relevante for Extinction Learning
Summary
Vagus nerve stimulering (VNS) har dukket opp som et verktøy for å indusere målrettet synaptisk plastisitet i forhjernen å endre en rekke atferd. Denne protokollen beskriver hvordan å implementere VNS å lette konsolidering av utryddelse frykt minne.
Abstract
Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been maintaining the behavior. There is close correspondence between fear and human anxiety, and therefore studies of extinction learning might provide insight into the biological nature of anxiety-related disorders such as post-traumatic stress disorder, and they might help to develop strategies to treat them. Preclinical research aims to aid extinction learning and to induce targeted plasticity in extinction circuits to consolidate the newly formed memory. Vagus nerve stimulation (VNS) is a powerful approach that provides tight temporal and circuit-specific release of neurotransmitters, resulting in modulation of neuronal networks engaged in an ongoing task. VNS enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here, we provide a detailed protocol for the preparation of custom-made parts and the surgical procedures required for VNS in rats. Using this protocol we show how VNS can facilitate the extinction of conditioned fear responses in an auditory fear conditioning task. In addition, we provide evidence that VNS modulates synaptic plasticity in the pathway between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA), which is involved in the expression and modulation of extinction memory.
Introduction
Klassiske frykt kondisjone gir en mye brukt dyremodell for å studere biologiske basis av angstlidelser. Under frykt conditioning, er en motvilje stimulus (det ubetingede stimulus, USA, for eksempel, en fotsjokk) presentert i forbindelse med en nøytral stimulus, for eksempel en tone og / eller en kontekst (den betingede stimulus, CS). Under frykt condition, er assosiasjoner mellom CS og USA dannet. Omsider presentasjonen av CS alene utløser en frykt respons (betinget reaksjon, CR). I utryddelse frykt, er CS presentert flere ganger i fravær av USA, forårsaker den CR til gradvis å avta 1. Dermed er utryddelse av betinget frykt en aktiv prosess hvor engstelig atferdsmessige reaksjoner til nøytrale stimuli blir svekket når de ikke lenger spå aversive utfall. Utryddelse av betingede responser krever konsolidering av nye minner som konkurrerer med lært foreninger. Et kjennetegn på angstlidelser er IMPAIRED utryddelse 2-4. Dermed utryddelse av betinget frykt i dyremodeller er et viktig paradigme både for hemmende læring og som en modell for atferdsterapi for menneskeangstlidelser 5,6.
Fordi det er nær sammenheng mellom frykt og menneskelig angst, er det tenkt at disse studiene kan gi innsikt i den biologiske natur angstrelaterte lidelser som posttraumatisk stresslidelse og vil bidra til å utvikle strategier for å behandle dem. Et viktig mål for preklinisk forskning er å hjelpe utryddelse læring og å indusere målrettet plastisitet i utryddelse kretser å konsolidere utryddelse læring. Vagus nerve stimulering (VNS) er en minimal invasiv neuroprosthetic tilnærming som kan brukes til å gi stramt tidsmessig og kretsspesifikke modulering av hjerneområder og synapser engasjert i en pågående oppgave. En rekke nyere studier fra Michael Kilgard gruppe ved The University of Texas at Dallas harvist at sammenkoblingen VNS med diskrete sensoriske eller motoriske stimuli (for eksempel en tone eller en spak pull) er svært effektiv i å fremme kortikale plastisitet å behandle tinnitus 7, eller å overvinne motoriske underskudd etter hjerneslag 8-10. I tillegg er ikke-betinget VNS som oppstår innen kort tid etter å ha lært vindu på samme måte fremmer kortikal plastisitet og forbedrer hukommelsen konsolidering i rotter og hos mennesker 11-13.
Tatt i betraktning den rolle nervus vagus i det parasympatiske vei, er det ikke overraskende at det kan delta i modulering av minnene og synaptisk plastisitet. Svært emosjonelle hendelser har en tendens til å produsere sterkere minner enn ikke-emosjonelle minner. Dette er sannsynligvis på grunn av påvirkning av stresshormoner på hukommelsen konsolidering. Etter trening administrasjon av stresshormonet adrenalin forbedrer hukommelsen konsolidering i menneskelige og ikke-menneskelige dyr, men adrenalinet ikke krysse blod-hjerne-barrieren 14, 15 </sup>. Derfor må stressindusert adrenalin utgivelsen påvirke hjernen indirekte å forbedre hukommelsen konsolidering. Sterke bevis tyder på at vagus nerve kan være bindeleddet mellom sirkulerende adrenalin og hjernen. Miyashita og Williams 16 opplevde at systemisk administrasjon av adrenalin økt vagal nerve avfyring, og økte nivåer av noradrenalin i amygdala 17. Systemisk administrasjon av adrenalin ikke forbedre hukommelsen konsolidering når β-adrenerge reseptorer blokkeres i amygdala 18 tyder på at vagus nerve spiller en rolle i veien som svinger emosjonelt opphissende opplevelser inn i langsiktige minner.
Således sammenkobling VNS med trening har potensial til å forbedre hjernen endringer som støtter hukommelse konsolidering og eksponering for klimaanlegg signaler i fravær av armering forbedrer konsolidering av utryddelse læring hos rotter 19,20. Her beskriver vi bruk av VNS enet verktøy for å fremme kortikal plastisitet og legge til rette for utryddelse av en betinget frykt respons.
Protocol
Representative Results
Discussion
Vi presenterer her en protokoll som brukes til å legge til rette for utryddelse av betinget frykt under en enkelt økt eksponering for betinget signaler 19 og å modulere plastisitet i veien mellom infralimbic cortex og basolaterale amygdala som kan megle utryddelse læring 20. Et viktig skritt for å lykkes med denne protokollen er riktig levering av VNS under utryddelse trening. Derfor må spesiell forsiktighet utvises for utførelse av mansjetten elektrodene og plassering av mansjetten rundt va…
Disclosures
The authors have nothing to disclose.
Acknowledgements
This research was supported by the National Institute of Mental Health MH 086960-01A1 (Christa K. McIntyre).
Materials
| Alcohol | |||
| Atropine | Fisher | A0132-5G | |
| Betadine | Henry Schein | 69066950 | |
| Hydrogen peroxide | CVS | 209478 | |
| Ketamine | Henry Schein | 1129300 | |
| Marcaine | Henry Schein | 6312615 | |
| Mineral Oil | CVS | 152355 | |
| Neosporin | CVS | 629451 | |
| Oxygen | Home Depot | 304179 | |
| Pennicillin | Fisher | PENNA-10MU | |
| Propane | Home Depot | 304182 | |
| Xylazine | Henry Schein | 4019308 | |
| Tools | |||
| Jewelery Torch | Smith Equipment | 23-1001D | |
| Sewing Needle | Walgreens | 441831 | |
| #5 Forceps (2) | Fine Science Tools | 11254-20 | |
| Soldering Iron | Home Depot | 203525863 | |
| AmScope SM-4TX-144A 3.5X-45X Circuit Board Boom Stereo Microscope + 144 LED | AmScope | SM-4TX-144A | |
| Helping Hands | A-M Systems | 726200 | |
| Scalpel Blade Holder | Fine Science Tools | 10003-12 | |
| Metal File | Home Depot | 6601 | |
| Ruler | Home Deopt | 202035324 | |
| Curved Hemostats | Fine Science Tools | 130009-12 | |
| Fine Scissors | Fine Science Tools | 14058-09 | |
| Spatula | Fine Science Tools | ||
| Small Screwdriver | Home Depot | 646507 | |
| Magnetic Fixator Retraction System | Fine Science Tools | 18200-04, 18200-01, 18200-05 | |
| Heating Pad | Walgreens | 30294 | |
| Clippers | Walgreens | 277966 | |
| Sharpie | Staples | 125328 | |
| Ring Forceps | Fine Science Tools | 11103-09 | |
| Custom Micropipette Glass Tools (J shape and Straight) – Borosilicate glass | Sutter Instrument | B150-110-10 | |
| Adson Forceps | Fine Science Tools | 11006-12 | |
| Cuffs | |||
| Tubing | Braintree Scientific Inc | MRE-065 | |
| Platinum Iridium Wire | Medwire | 10IR9/49T | |
| Gold Pins | Mill-Max | 1001-0-15-15-30-27-04-0 | |
| Suture Thread | Henry Schein | 100-5797 | |
| 22 G Needles | Fisher | 14-815-525 | |
| Paper Tape | Fisher | 03-411-602 | |
| Solder | Home Deopt | 327793 | |
| Flux | Home Deopt | 300142 | |
| Scalpel Blade, 10 or 15 | Stoelting | 52173-10 | |
| Silastic Laboratory Tubing .51 mm ID x .94 mm OD | Fisher | 508-002 | |
| Headcaps | |||
| Connector Pieces (male) | Omnetics Connector Corporation | A25001-004 | |
| Headcap pieces (female) | Omnetics Connector Corporation | A24001-004 | |
| Teets Dental Acrylic, Liquid and Powder | A-M Systems | 525000, 526000 | |
| 26 Gauge Solid Copper Wire | Staples | 1016882 | |
| Surgery | |||
| Bone Screws | Stoelting+CB33:C61 | 51457 | |
| Scalpel Blades, 10 or 15 | Stoelting | 52173-10 | |
| 1 ml syringes | Fisher | 14-826-261 | |
| 22 G Needles | Fisher | 14-815-525 | |
| 27 G Needles | Fisher | 14-826-48 | |
| 2" x 2" Gauze | Fisher | 22-362-178 | |
| Swabs | Fisher | 19-120-472 | |
| Puppy Pads | PetCo | 1310747 | |
| Kim Wipes | Fisher | 06-666-A | |
| Chamber and Behavioral Setting | |||
| Husky Metal Front Base Cabinet (30WX19DX34H) | Home Depot | 100607961 | |
| Quiet Barrier HD Soundproofing Material (Sheet) (PSA) | soundproofcow.com | 10203041 | |
| Convoluted Acoustic Foam Panel | soundproofcow.com | 10432400 | |
| Isolated Pulse Stimulator Model 2100 | A-M Systems | 720000 | |
| Digital Camera – Logitech Webcam C210 | Logitech | B003LVZO88 | |
| MatLab | Mathworks.com | ||
| Sinometer 10MHz Single Channel Oscilloscope | Sinometer | CQ5010C | |
| OxyLED T-01 DIY Stick-on Anywhere 4-LED Touch Tap Light | OXYLED | B00GD8OKY0 | |
| 5k ohm potentiomter | Alpha Electronics | B00CTWDHIO | |
| Extech 407730 40-to-130-Decibel Digital Sound Level Meter | Extech Instruments | B000EWY67W | |
| DSCK-C Dual Output, scrambled shocker | Kinder Scientific Co | ||
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