פרויקט זה נתמך על ידי NIH מענקים DA19112 (DGW) ו DA026994 (CMO). איור סופק על ידי קתרין Louderback. ניסויים שבוצעו במעבדה ונדרבילט Murine neurobehavioral.

1. כתוב תוכנית לרוץ הפעלות מבחן אופרנטית באמצעות גירויים חזותיים וקוליים מגוונים כמו חיזוק <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> עבור (FR) מפגשים קבועים יחס: להפוך את המפגשים שעה אחת באורך באור הבית מאוורר מופעל במהלך הפגישה. הפעלות יחס פרוגרסיבי, לעשות מפגשים שעתיים אורך. האם מנופים הן הוארך משך הפגישה ואת לאזן אשר מנוף המיועד &quot;פעיל&quot; לעומת &quot;פעילות&quot; על פני בעלי חיים (משימה מנוף עבור כל חיה לא משנה). </li><li style=";text-align:right;direction:rtl"> קוד התוכנית באופן כזה שכל חיזוק מגוונת על פי הפרמטרים הבאים: <ul style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> חיזוק לכל אחד המשכים הבאים שנבחרו באקראי: 2, 4, 6 או 8 שניות. </li><li style=";text-align:right;direction:rtl"> חיזוק לכל אחד המנורה הבאה גירוי שיעורי פלאש שנבחרו באקראי: 0.625, 1.25, 2.5, 5 או הרץ, כל אחד עם מחזור עבודה של 50%. </li><li style=";text-align:right;direction:rtl"> כל מנורה גירוי הפלאש אקראי בצד שמאל או בצד ימין של החדר. </li><li style=";text-align:right;direction:rtl"> לספק גירוי שמיעתי למשך חיזוק; במעבדה שלנו, אנו לעורר משאבת עירוי אשר מספק כ -3 dB קול מעל רעש הרקע בחדר. </li></ul></li><li style=";text-align:right;direction:rtl"> קוד התוכנית כדי להציג את הערכים הבאים בזמן אמת: 1. מספר בתי מנוף פעילים, 2. מספר בתי מנוף פעיל, 3. מספר החיזוקים, 4. זמן (ב 0.1 במרווחים שנייה). </li></ol> 2. טיפול בבעלי חיים (3 נוהל יום) <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> לאחר הסתגלות למתקן בעלי חיים, להתחיל בטיפול בבעלי חיים. זה יהיה להרגיל את בעלי החיים כדי להיות הרים והעבירו. </li><li style=";text-align:right;direction:rtl"> התחל על ידי הנחת הידיים בכפפות לכלוב ולתת להם לשבת במשך 90 שניות. אם העכבר כל לא חקרה את הידיים בזמן הזה, בעדינות להזיז את הידיים כלפי עכברים לחכות לכל אחד לרחרח ו / או מגע הידיים שלך לפני שתמשיך. </li><li style=";text-align:right;direction:rtl"> בזהירות להרים כל עכבר אחד אחד על ידי בבסיס הזנב ולמקם אותו על היד שלך, במהירות מרימה אותו ולהביא אותו בחזרה למטה, כדי לאפשר את העכבר ללכת את היד לתוך הכלוב. </li><li style=";text-align:right;direction:rtl"> חזור עבור כל הזמנים עכבר 5-10, תלוי בהתנהגות של העכבר. בפעם האחרונה שזה נעשה, להחזיק את העכבר גבוהה (עם אותו עומד על היד שלך) לתקופה של זמן, תלוי ביום. יום 1: 5 שניות, יום 2: 10 שניות, יום 3: 15 שניות. ודא כי כל עכבר פוגש את הקריטריון הזה היום. ביום 1, לשנות כפפות בין הכלובים. </li><li style=";text-align:right;direction:rtl"> החל מתאריך 2 הימים חזרה שבץ של החיה בעוד סמן העכבר נמצא על ידך. כמו כן, ביום 2, שוקל את החיות יומי. מרק זנב של כל חיה עם לנוכל לציון מספר הנושא. </li><li style=";text-align:right;direction:rtl"> אם זריקות תינתן במהלך הניסוי, להתחיל הרגלה עכברים זריקות ביום 2. זה צריך להיעשות אחרי כל העכברים בכלוב טופלו ונפגש הקריטריון היום. </li></ol> 3. נקו ציוד בדיקה <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> לשטוף מחבת התחתונה עם מים חמים. </li><li style=";text-align:right;direction:rtl"> נקה קירות החדר אופרנטית ורצפות עם אתנול 30%. </li><li style=";text-align:right;direction:rtl"> הפעלת תוכנית מבחן שמדליק את האור בבית, מאוורר, ואורות גירוי, מרחיבה מנופים, רשומות בתי מנוף. </li><li style=";text-align:right;direction:rtl"> ודא שכל האורות ואת האוהדים פועלים כראוי ולבדוק את התוכנית כדי להבטיח שכל בתי מנוף נרשמות. </li><li style=";text-align:right;direction:rtl"> מנופים נקי עם אתנול 30%. </li></ol> 4. בצע הפעלה אופרנטית (מפגשים צריך להיות 5-6 ימים / שבוע באותו זמן של יום) <ol style=";text-align:right;direction:rtl"><li style=";text-align:right;direction:rtl"> לשקול את כל העכבר. </li><li style=";text-align:right;direction:rtl"> טען את התוכנית לתוך תא כל ויסמנו את הניסוי בהתאם. מנוף פעיל צריך להתקזז בין חיות (כלומר, את הידית פעיל מוקצה המנוף השמאלי למחצית העכברים; את הידית ימינה הוא פעיל החצי השני), אלא את הצד הפעיל מנוף פעם לא משתנה עכבר עכבר כבר מוקצה. </li><li style=";text-align:right;direction:rtl"> התחבורה כל עכבר לתא המיועד שלה, לסגור את החדר, ולהתחיל את הפגישה. </li><li style=";text-align:right;direction:rtl"> לאחר הפגישה מסתיימת, מיד להסיר את העכבר מחדש לסמן את הזנב. </li><li style=";text-align:right;direction:rtl"> החדרים נקיים כמתואר בסעיף 3. </li><li style=";text-align:right;direction:rtl"> ניתוח נתונים עבור מספר בתי מנוף פעיל פעיל. מספר חיזוקים ו / או דיוק מנוף (פעיל% לוחץ מנוף) יכול להיות גם דיווח. אם העכברים הולכים להיבדק על ההשפעה של טיפול ב-OSS, להבטיח כי כל העכברים להיבדק פגשתי קריטריונים הרכישה (לדוגמה,&gt; 20 מנוף בתי פעיל&gt; 65% לוחץ מנוף פעיל הסופי three FR-1 הפעלות ) לפני תחילת הטיפול. </li><li style=";text-align:right;direction:rtl"> לאחר הרכישה של FR-1 להגיב, את לוח הזמנים של החיזוק ניתן לשנות (למשל, יחס קבוע גבוה יותר, יחס פרוגרסיבי, יחס אקראי וכו &#39;). </li></ol> 5. נציג תוצאות דוגמה רכישת ה-OSS של עכברים זכרים C57Bl/6J מוצג באיור 1 (לשכפל מ 23). העכברים עברו בקרה תנאים זהים, למעט העובדה לוחץ על מנוף הידית או לא והתוצאותquence. קבוצה נוספת של עכברים מוצג באיור 2. בניסוי זה, קבוצה אחת של עכברים קיבלו חיזוק OSS, ואילו קבוצה אחרת קיבלה חיזוק מזון. מצאנו כי בתנאים של גישה כרצונך למזון, גם יחס קבוע ומתקדמת להגיב דומים בין OSS ותגובה 10% ודאו (איור 2, A ו-B). זה מאפשר השוואה אפקטיבית של מניפולציה על שני סוגי חיזוקים שונים (חושי מזון) כי ימנע מקעקעת את הפוטנציאל הנובע המדינה רעב או הבדלים שיעור התגובה. <img src="/files/ftp_upload/2292/2292fig1.jpg" alt="איור 1" /> איור 1:. ולוחץ על ידי מנוף עכברים OSS בקרות OSS עכברים שקיבלו גירויים חזותיים וקוליים מגוונים הבאים פעיל כל מנוף לחץ (FR-1 לוח זמנים של חיזוקים), בעוד בתי מנוף פעיל לא היה תוצאה. העכברים עברו בקרה באותם תנאים אך לא היה תוצאה של לחיצה או מנוף (מנופים מסומנים 1 ו 2 ו מאוזנים על פני בעלי החיים באותו אופן כי מנופים פעיל פעיל מאוזנים עבור עכברים OSS). מנוף פעילים על ידי לחיצה על עכברים OSS הוגדל ביחס מנוף פעיל הקשת (* p &lt;0.05 ** p &lt;0.01) ואת הידית הלא מחוזקים על ידי לחיצה על שולטת (n = 7 8, $ p &lt;0.05, p $ $ &lt;0.01 ). איור לשכפל מתוך 23. <img src="/files/ftp_upload/2292/2292fig2.jpg" alt="איור 2" /> איור 2:. ולוחץ על ידי מנוף עכברים OSS ועכברים מגיבים למזון א) עכברים הגיב על לוח הזמנים FR-1 של חיזוק עבור גירויים OSS או חיזוק מזון (10% ודאו). כל העכברים היו libidum מודעה גישה למזון למשך הניסויים. ב) לאחר FR-1 הפעלות, העכברים היו מתקדמים יחס לוח זמנים פרוגרסיבי (PR) של חיזוק במשך חמישה ימים. הנתונים מייצגים את אמצעי ערכים ימים ארבע וחמש עבור כל חיה. היחס הסופי הושלמה הוא דיווח על הזכות ציר Y ו מתייחס למספר התגובות הנדרש כדי להשיג את חיזוק המתאים (כלומר 30 תגובות נדרשים להשיג את חיזוק ה 10 לאחר השתכרות בעבר nine החיזוקים).

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C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multivariate+analyses+reveal+common+and+drug-specific+genetic+influences+on+responses+to+four+drugs+of+abuse.">Multivariate analyses reveal common and drug-specific genetic influences on responses to four drugs of abuse.</a> Trends Pharmacol Sci. 29, 537-543 (2008).</li><li>Mozhui, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Strain+differences+in+stress+responsivity+are+associated+with+divergent+amygdala+gene+expression+and+glutamate-mediated+neuronal+excitability.">Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.</a> J Neurosci. 30, 5357-5367 (2010).</li><li>Hefner, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Impaired+fear+extinction+learning+and+cortico-amygdala+circuit+abnormalities+in+a+common+genetic+mouse+strain.">Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain.</a> J Neurosci. 28, 8074-8085 (2008).</li><li>Elmer, G. I., Pieper, J. O., Hamilton, L. R., Wise, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Qualitative+differences+between+C57BL/6J+and+DBA/2J+mice+in+morphine+potentiation+of+brain+stimulation+reward+and+intravenous+self-administration.">Qualitative differences between C57BL/6J and DBA/2J mice in morphine potentiation of brain stimulation reward and intravenous self-administration.</a> Psychopharmacology (Berl). 208, 309-321 (2010).</li></ol>

אין ניגודי אינטרסים הכריז.

תחושה אופרנטית המבקשים היא אלטרנטיבה יעילה סמים תוך ורידית מינהל עצמי כאשר העכבר הוא בעל החיים של בחירה. העובדה כי לא ניתוח ולא תחזוקה קטטר שנדרש הוא יתרון, שכן הם מהווים מכשולים טכניים משמעותיים העכבר. OSS הוא גם מושך כי הוא עשוי להיות מדידת ההיבטים של חיזוק נבדל החיזוקים טבעיים אחרים כגון מזון. כדאי לציין כי אמצעים התנהגותיים העכבר יכול להיות משתנה מאוד על פני תנאים סביבתיים שונים 24. הנושא עלה במעבדה שלנו עם ה-OSS. כאשר הליך התאפיינה הראשון, בעלי חיים שוכנו במתקן אשר תעבורה גבוהה ומספר גדול של אנשים שעובדים בו במשך היום. במהלך תקופה זו, עכברים שוכנו על מחזור &quot;נורמלי&quot; אור (אורות: 0600-1800 שעות; ניסויים לרוץ ~ 0800-1400). לאחר המעבר למתקן דיור ייעודי בתוך המעבדה ונדרבילט neurobehavioral, מצאנו כי יחס ביצועים מתקדמים של OSS היה נמוך בהרבה ממה שהיה לנו שנצפה קודם לכן, סירב להגיב על פני חמישה ימים במקום יציבות. מתקן זה יש הרבה פחות תנועה ואנשי מאומנים לעבוד בשקט להיות מודעים לאופי הרגיש של ניסויים שבוצעה במתקן. יש לנו מותאם מאז עכברים מחזור אור שמקדם ערות בתקופת התנסות (אורות: 1500-0300 שעות; ניסויים לרוץ ~ 0800-1400 ח) וביצועים OSS חזר מה שציינו קודם לכן. להלן תיאור של תנאים סטנדרטיים שלנו עבור ניסויים OSS. זכר עכברים C57Bl/6J מסודרות ב 3 שבועות מגיל ג&#39;קסון מעבדות (בר הרבור, ME) ו שוכנו מחזור אור שונה במשך שבוע אחד לפחות לפני ניסויים. בעלי חיים הם שוכנו בקבוצות של 2-5 על מצעי קוב תירס בתוספת כמות קטנה של תאית (טיפול טריים). הניסויים מבוצעים 5-6 ימים בשבוע ושינויים בכלוב מבוצעות רק לפני יום בלי ניסויים. בעוד אלה הם תנאים סטנדרטיים שלנו, מצאנו כי נקבות העכברים ומעלה (עד 20 שבועות) הם גם מסוגלים לרכוש OSS. אנו בוחנים בימים אלו משתנים אחרים שעלולים להשפיע על ביצועי ה-OSS. אמנם ידוע כי גירויים חזותיים סטטיים מסוגלים לשמש החיזוקים בעכברים 17, לא ידוע אם הגישה של שיפור הדינמיקה של גירויים שאנו ואחרים מועסקים 20,22,23 להוביל חיזוק גדל בתנאים הנוכחיים . משתנה נוסף שעשוי להשפיע על OSS היא זן העכבר. ההבדלים מסננים תוארו בעכברים עבור מגוון רחב של אמצעים התנהגותיים נוירולוגיות 25-29, וביצועים ההפרש על OSS ו אופרנטית להגיב למזון עשויה לספק תובנות לגבי הבסיס הגנטי של התנהגות זו.

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<td>Drug self-administration test package for mouse: extra-wide chamber and retractable levers</td>
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<td><a href="http://www.med-associates.com/">Med Associates, Inc</a></td>
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<td><a href="http://www.med-associates.com/">Med Associates, Inc</a></td>
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operant sensation seeking in the mouse

Operant methods are powerful behavioral tools for the study of motivated behavior. These 'self-administration' methods have been used extensively in drug addiction research due to their high construct validity. Operant studies provide researchers a tool for preclinical investigation of several aspects of the addiction process. For example, mechanisms of acute reinforcement (both drug and non-drug) can be tested using pharmacological or genetic tools to determine the ability of a molecular target to influence self-administration behavior1-6. Additionally, drug or food seeking behaviors can be studied in the absence of the primary reinforcer, and the ability of pharmacological compounds to disrupt this process is a preclinical model for discovery of molecular targets and compounds that may be useful for the treatment of addiction3,7-9. One problem with performing intravenous drug self-administration studies in the mouse is the technical difficulty of maintaining catheter patency. Attrition rates in these experiments are high and can reach 40% or higher10-15. Another general problem with drug self-administration is discerning which pharmacologically-induced effects of the reinforcer produce specific behaviors. For example, measurement of the reinforcing and neurological effects of psychostimulants can be confounded by their psychomotor effects. Operant methods using food reinforcement can avoid these pitfalls, although their utility in studying drug addiction is limited by the fact that some manipulations that alter drug self-administration have a minimal impact on food self-administration. For example, mesolimbic dopamine lesion or knockout of the D1 dopamine receptor reduce cocaine self-administration without having a significant impact on food self-administration 12,16. 
Sensory stimuli have been described for their ability to support operant responding as primary reinforcers (i.e. not conditioned reinforcers)17-22. Auditory and visual stimuli are self-administered by several species18,21,23, although surprisingly little is known about the neural mechanisms underlying this reinforcement. The operant sensation seeking (OSS) model is a robust model for obtaining sensory self-administration in the mouse, allowing the study of neural mechanisms important in sensory reinforcement24. An additional advantage of OSS is the ability to screen mutant mice for differences in operant behavior that may be relevant to addiction. We have reported that dopamine D1 receptor knockout mice, previously shown to be deficient in psychostimulant self-administration, also fail to acquire OSS24. This is a unique finding in that these mice are capable of learning an operant task when food is used as a reinforcer. While operant studies using food reinforcement can be useful in the study of general motivated behavior and the mechanisms underlying food reinforcement, as mentioned above, these studies are limited in their application to studying molecular mechanisms of drug addiction. Thus, there may be similar neural substrates mediating sensory and psychostimulant reinforcement that are distinct from food reinforcement, which would make OSS a particularly attractive model for the study of drug addiction processes. The degree of overlap between other molecular targets of OSS and drug reinforcers is unclear, but is a topic that we are currently pursuing. While some aspects of addiction such as resistance to extinction may be observed with OSS, we have found that escalation 25 is not observed in this model24. Interestingly, escalation of intake and some other aspects of addiction are observed with self-administration of sucrose26. Thus, when non-drug operant procedures are desired to study addiction-related processes, food or sensory reinforcers can be chosen to best fit the particular question being asked. 
In conclusion, both food self-administration and OSS in the mouse have the advantage of not requiring an intravenous catheter, which allows a higher throughput means to study the effects of pharmacological or genetic manipulation of neural targets involved in motivation. While operant testing using food as a reinforcer is particularly useful in the study of the regulation of food intake, OSS is particularly apt for studying reinforcement mechanisms of sensory stimuli and may have broad applicability to novelty seeking and addiction.

Watch this Scientific Journal Video about Operant Sensation Seeking in the Mouse at JoVE.com

Operant Sensation Seeking in the Mouse

בפרוטוקול זה אנו מתארים שיטה של ​​למידה אופרנטית באמצעות גירויים חושיים כמו חיזוק בתוך העכבר. זה לא דורש הכשרה מוקדמת או הגבלת מזון, והיא מאפשרת לימוד של התנהגות מוטיבציה ללא שימוש חיזוק תרופתי או טבעי כמו מזון.

Sensation Seeking אופרנטית ב העכבר

Operant methods are powerful behavioral tools for the study of motivated behavior.  These 'self-administration' methods have been used extensively in drug ...

Nanyang Technological University

Research

JoVE Journal

Neuroscience

12.9K Views.  Vanderbilt University Medical Center. בפרוטוקול זה אנו מתארים שיטה של ​​למידה אופרנטית באמצעות גירויים חושיים כמו חיזוק בתוך העכבר. זה לא דורש הכשרה מוקדמת או הגבלת מזון, והיא מאפשרת לימוד של התנהגות מוטיבציה ללא שימוש חיזוק תרופתי או טבעי כמו מזון.

Video: Operant Sensation Seeking in the Mouse

A Procedure for Studying the Footshock-Induced Reinstatement of Cocaine Seeking in Laboratory Rats

The most insidious aspect of drug addiction is the high propensity for relapse. Animal models of relapse, known as reinstatement procedures, have been used extensively to study the neurobiology and phenomenology of relapse to drug use. Although procedural variations have emerged over the past several decades, the most conventional reinstatement procedures are based on the drug self-administration (SA) model. In this model, an animal is trained to perform an operant response to obtain drug. Subsequently, the behavior is extinguished by withholding response-contingent reinforcement. Reinstatement of drug seeking is then triggered by a discrete event, such as an injection of the training drug, re-exposure to drug-associated cues, or exposure to a stressor 1.
Reinstatement procedures were originally developed to study the ability of acute non-contingent exposure to the training drug to reinstate drug seeking in rats and monkeys 1, 2. Reinstatement procedures have since been modified to study the role of environmental stimuli, including drug-associated cues and exposure to various forms of stress, in relapse to drug seeking 1, 3, 4.
Over the past 15 years, a major focus of the reinstatement literature has been on the role of stress in drug relapse. One of the most commonly used forms of stress for studying this relationship is acute exposures to mild, intermittent, electric footshocks. The ability of footshock stress to induce reinstatement of drug seeking was originally demonstrated by Shaham and colleagues (1995) in rats with a history of intravenous heroin SA5. Subsequently, the effect was generalized to rats with histories of intravenous cocaine, methamphetamine, and nicotine SA, as well as oral ethanol SA 3, 6.
Although footshock-induced reinstatement of drug seeking can be achieved reliably and robustly, it is an effect that tends to be sensitive to certain parametrical variables. These include the arrangement of extinction and reinstatement test sessions, the intensity and duration of footshock stress, and the presence of drug-associated cues during extinction and testing for reinstatement. Here we present a protocol for footshock-induced reinstatement of cocaine seeking that we have used with consistent success to study the relationship between stress and cocaine seeking.

Animal models of relapse, known as reinstatement procedures, have been used extensively to study the role of stress in relapse to drug seeking. Here, we report on a method for inducing the reinstatement of cocaine seeking in laboratory rats via acute exposures to mild, intermittent electric footshock.

נוהל לימוד החזרה Footshock-induced של קוקאין מחפשים אצל חולדות מעבדה

The most insidious aspect of drug addiction is the high propensity for relapse.  Animal models of relapse, known as reinstatement procedures, have been ...

Multiple-mouse Neuroanatomical Magnetic Resonance Imaging

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. MRI is an excellent modality for investigating genetically altered animals. It is capable of whole brain coverage, can be used in vivo, and provides multiple contrast mechanisms for investigating different aspects of neuranatomy and physiology. The advent of high-field scanners along with the ability to scan multiple mice simultaneously allows for rapid phenotyping of novel mutations.
Effective mouse MRI studies require attention to many aspects of experiment design. In this article, we will describe general methods to acquire quality images for mouse phenotyping using a system that images mice concurrently in shielded transmit/receive radio frequency (RF) coils in a common magnet (Bock et al., 2003). We focus particularly on anatomical phenotyping, an important and accessible application that has shown a high potential for impact in many mouse models at our imaging centre. Before we can provide the detailed steps to acquire such images, there are important practical considerations for both in vivo brain imaging (Dazai et al., 2004) and ex vivo brain imaging (Spring et al., 2007) that should be noted. These are discussed below.

Magnetic resonance imaging (MRI) has become an increasingly popular tool for examining the phenotype of genetically altered mice. This article illustrates the methods necessary to achieve high-throughput phenotyping of genetically altered mice using multiple-mouse MRI.

מרובה עכבר Neuroanatomical תהודה מגנטית

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and ...

Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks of Alzheimer's disease. The central component of neuritic plaques is a small filamentous protein called amyloid &beta; protein (A&beta;)1, which is derived from sequential proteolytic cleavage of the beta-amyloid precursor protein (APP) by &beta;-secretase and &gamma;-secretase. The amyloid hypothesis entails that A&gamma;-containing plaques as the underlying toxic mechanism in AD pathology2. The postmortem analysis of the presence of neuritic plaque confirms the diagnosis of AD. To further our understanding of A&gamma; neurobiology in AD pathogenesis, various mouse strains expressing AD-related mutations in the human APP genes were generated. Depending on the severity of the disease, these mice will develop neuritic plaques at different ages. These mice serve as invaluable tools for studying the pathogenesis and drug development that could affect the APP processing pathway and neuritic plaque formation. In this protocol, we employ an immunohistochemical method for specific detection of neuritic plaques in AD model mice. We will specifically discuss the preparation from extracting the half brain, paraformaldehyde fixation, cryosectioning, and two methods to detect neurotic plaques in AD transgenic mice: immunohistochemical detection using the ABC and DAB method and fluorescent detection using thiofalvin S staining method.

One of the pathological characteristics of AD is the formation of Amyloid &#x03B2; protein positive neuritic plaques. In this protocol we describe two methods to detect neuritic plaques in transgenic AD model mice: immunohistochemical detection using the ABC and DAB method and fluorescent detection using thioflavin S staining method.

איתור של הפלאק מדלקת עצבים במודל מחלת אלצהיימר עכבר

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks ...

The Mouse Forced Swim Test

The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental manipulations that are aimed at rendering or preventing depressive-like states. Mice are placed in an inescapable transparent tank that is filled with water and their escape related mobility behavior is measured. The forced swim test is straightforward to conduct reliably and it requires minimal specialized equipment. Successful implementation of the forced swim test requires adherence to certain procedural details and minimization of unwarranted stress to the mice. In the protocol description and the accompanying video, we explain how to conduct the mouse version of this test with emphasis on potential pitfalls that may be detrimental to interpretation of results and how to avoid them. Additionally, we explain how the behaviors manifested in the test are assessed.

The forced swim test is validated as an experimental approach to assess potential antidepressant efficacy in rodents. Experimental animals are placed in a tank of water and escape-related mobility behavior is quantified. The common procedures for the mouse version of this test are described.

עכבר בכפייה לשחות מבחן

The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental ...

Microdialysis of Ethanol During Operant Ethanol Self-administration and Ethanol Determination by Gas Chromatography

Operant self-administration methods are commonly used to study the behavioral and pharmacological effects of many drugs of abuse, including ethanol. However, ethanol is typically self-administered orally, rather than intravenously like many other drugs of abuse. The pharmacokinetics of orally administered drugs are more complex than intravenously administered drugs. Because understanding the relationship between the pharmacological and behavioral effects of ethanol requires knowledge of the time course of ethanol reaching the brain during and after drinking, we use in vivo microdialysis and gas chromatography with flame ionization detection to monitor brain dialysate ethanol concentrations over time. 
Combined microdialysis-behavioral experiments involve the use of several techniques. In this article, stereotaxic surgery, behavioral training and microdialysis, which can be adapted to test a multitude of self-administration and neurochemical centered hypotheses, are included only to illustrate how they relate to the subsequent phases of sample collection and dialysate ethanol analysis. Dialysate ethanol concentration analysis via gas chromatography with flame-ionization detection, which is specific to ethanol studies, is described in detail. Data produced by these methods reveal the pattern of ethanol reaching the brain during the self-administration procedure, and when paired with neurochemical analysis of the same dialysate samples, allows conclusions to be made regarding the pharmacological and behavioral effects of ethanol.

A method to determine the time course of ethanol concentration in the brains of rats during operant ethanol self-administration is described. Gas chromatography with flame ionization detection is used to quantify ethanol in the dialysate samples, because it has the sensitivity required for the small volumes that are generated.

Microdialysis של אתנול במהלך אתנול נחישות ממשל עצמי ואתנול אופרנטית על ידי גז כרומטוגרפיה

Operant self-administration methods are commonly used to study the behavioral and pharmacological effects of many drugs of abuse, including ethanol.  ...

A Simple Way to Measure Alterations in Reward-seeking Behavior Using Drosophila melanogaster

We describe a protocol for measuring ethanol self-administration in fruit flies (Drosophila melanogaster) as a proxy for changes in reward states. We demonstrate a simple way to tap into the fly reward system, modify experiences related to natural reward, and use voluntary ethanol consumption as a measure for changes in reward states. The approach serves as a relevant tool to study the neurons and genes that play a role in experience-mediated changes of internal state. The protocol is composed of two discrete parts: exposing the flies to rewarding and nonrewarding experiences, and assaying voluntary ethanol consumption as a measure of the motivation to obtain a drug reward. The two parts can be used independently to induce the modulation of experience as an initial step for further downstream assays or as an independent two-choice feeding assay, respectively. The protocol does not require a complicated setup and can therefore be applied in any laboratory with basic fly culture tools.

A Simple Way to Measure Alterations in Reward-seeking Behavior Using Drosophila melanogaster

We describe a protocol for inducing rewarding and nonrewarding experiences in fruit flies (Drosophila melanogaster) using voluntary ethanol consumption as a measure for changes in reward states.

דרך פשוטה למדוד שינויים בהתנהגות שוחרת זכה שימוש<em&gt; תסיסנית</em

We describe a protocol for measuring ethanol self-administration in fruit flies (Drosophila melanogaster) as a proxy for changes in reward states. We ...

Operant Protocols for Assessing the Cost-benefit Analysis During Reinforced Decision Making by Rodents

Reinforcement-guided decision making is the ability to choose between competing courses of action based on the relative value of the benefits and their consequences. This process is integral to the normal human behavior and has been shown to be disrupted by neurological and psychiatric disorders such as addiction, schizophrenia, and depression. Rodents have long been used to uncover the neurobiology of human cognition. To this end, several behavioral tasks have been developed; however, most are non-automated and are labor-intensive. The recent development of the open-source microcontroller has enabled researchers to automate operant-based tasks for assessing a variety of cognitive tasks, standardizing the stimulus presentation, improving the data recording and consequently, improving the research output. Here, we describe an automated delay-based reinforcement-guided decision-making task, using an operant T-maze controlled by custom-written software programs. Using these decision-making tasks, we show the changes in the local field potential activities in the anterior cingulate cortex of a rat whilst it performs a delay-based cost-and-benefit decision-making task.

A cost-benefit analysis is a weighing-scale approach that the brain performs during the course of decision making. Here, we propose a protocol to train rats on an operant-based decision-making paradigm where rats choose higher rewards at the expense of waiting for 15 s to receive them.

פרוטוקולים operant להערכת ניתוח עלות-תועלת במהלך קבלת החלטות מחוזק על ידי מכרסמים

Reinforcement-guided decision making is the ability to choose between competing courses of action based on the relative value of the benefits and their ...

Localization of the Locus Coeruleus in the Mouse Brain

The locus coeruleus (LC) is a major hub of norepinephrine producing neurons that modulate a number of physiological functions. Structural or functional abnormalities of LC impact several brain regions including cortex, hippocampus, and cerebellum and may contribute to depression, bipolar disorder, anxiety, as well as Parkinson disease and Alzheimer disease. These disorders are often associated with metal misbalance, but the role of metals in LC is only partially understood. Morphologic and functional studies of LC are needed to better understand the human pathologies and contribution of metals. Mice are a widely used experimental model, but the mouse LC is small (~0.3 mm diameter) and hard to identify for a non-expert. Here, we describe a step-by-step immunohistochemistry-based protocol to localize the LC in the mouse brain. Dopamine-&#946;-hydroxylase (DBH), and alternatively, tyrosine hydroxylase (TH), both enzymes highly expressed in the LC, are used as immunohistochemical markers in brain slices. Sections adjacent to LC-containing sections can be used for further analysis, including histology for morphological studies, metabolic testing, as well as metal imaging by X-ray fluorescence microscopy (XFM).

The locus coeruleus is a small cluster of neurons involved in a variety of physiological processes. Here, we describe a protocol to prepare mouse brain sections for studies of proteins and metals in this nucleus.

לוקליזציה של Coeruleus לוקוס במוח העכבר

The locus coeruleus (LC) is a major hub of norepinephrine producing neurons that modulate a number of physiological functions. Structural or functional ...

Cochlear Surface Preparation in the Adult Mouse

Auditory processing in the cochlea depends on the integrity of the mechanosensory hair cells. Over a lifetime, hearing loss can be acquired from numerous etiologies such as exposure to excessive noise, the use of ototoxic medications, bacterial or viral ear infections, head injuries, and the aging process. Loss of sensory hair cells is a common pathological feature of the varieties of acquired hearing loss. Additionally, the inner hair cell synapse can be damaged by mild insults. Therefore, surface preparations of cochlear epithelia, in combination with immunolabeling techniques and confocal imagery, are a very useful tool for the investigation of cochlear pathologies, including losses of ribbon synapses and sensory hair cells, changes in protein levels in hair cells and supporting cells, hair cell regeneration, and determination of report gene expression (i.e., GFP) for verification of successful transduction and identification of transduced cell types. The cochlea, a bony spiral-shaped structure in the inner ear, holds the auditory sensory end organ, the organ of Corti (OC). Sensory hair cells and surrounding supporting cells in the OC are contained in the cochlear duct and rest on the basilar membrane, organized in a tonotopic fashion with high-frequency detection occurring in the base and low-frequency in the apex. With the availability of molecular and genetic information and the ability to manipulate genes by knockout and knock-in techniques, mice have been widely used in biological research, including in hearing science. However, the adult mouse cochlea is miniscule, and the cochlear epithelium is encapsulated in a bony labyrinth, making microdissection difficult. Although dissection techniques have been developed and used in many laboratories, this modified microdissection method using cell and tissue adhesive is easier and more convenient. It can be used in all types of adult mouse cochleae following decalcification.

This article presents a modified cochlear surface preparation method that requires decalcification and use of a cell and tissue adhesive to adhere the pieces of cochlear epithelia to 10 mm round cover slips for immunohistochemistry in adult mouse cochleae.

הכנה לפני שבלול בעכבר למבוגרים

Auditory processing in the cochlea depends on the integrity of the mechanosensory hair cells. Over a lifetime, hearing loss can be acquired from numerous ...

Transpupillary Two-Photon In Vivo Imaging of the Mouse Retina

The retina transforms light signals from the environment into electrical signals that are propagated to the brain. Diseases of the retina are prevalent and cause visual impairment and blindness. Understanding how such diseases progress is critical to formulating new treatments. In vivo&#160;microscopy in animal models of disease is a powerful tool for understanding neurodegeneration and has led to important progress towards treatments of conditions ranging from Alzheimer&#39;s disease to stroke. Given that the retina is the only central nervous system structure inherently accessible by optical approaches, it naturally lends itself towards in vivo imaging. However, the native optics of the lens and cornea present some challenges for effective imaging access.
This protocol outlines methods for in vivo two-photon imaging of cellular cohorts and structures in the mouse retina at cellular resolution, applicable for both acute- and chronic-duration imaging experiments. It presents examples of retinal ganglion cell (RGC), amacrine cell, microglial, and vascular imaging using a suite of labeling techniques including adeno-associated virus (AAV) vectors, transgenic mice, and inorganic dyes. Importantly, these techniques extend to all cell types of the retina, and suggested methods for accessing other cellular populations of interest are described. Also detailed are example strategies for manual image postprocessing for display and quantification. These techniques are directly applicable to studies of retinal function in health and disease.

In vivo imaging is a powerful tool for the study of biology in health and disease. This protocol describes transpupillary imaging of the mouse retina with a standard two-photon microscope. It also demonstrates different in vivoimaging methods to fluorescently label multiple cellular cohorts of the retina.

הדמיה טרנס-אימונית של שני פוטונים In vivo של רשתית העכבר

The retina transforms light signals from the environment into electrical signals that are propagated to the brain. Diseases of the retina are prevalent ...