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![Page 1: Chronic Intermittent Cold Stress and Serotonin Depletion Induce Deficits of Reversal Learning in an Attentional Set-shifting Task in Rats M. Danet S. Lapiz-Bluhm,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649cdc5503460f949a689d/html5/thumbnails/1.jpg)
Chronic Intermittent Cold Stressand Serotonin Depletion Induce
Deficits of Reversal Learning in an Attentional Set-shifting Task in Rats
M. Danet S. Lapiz-Bluhm, Alexandra E. Soto-Piña,
Julie G. Hensler,David A. Morilak
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Brain Jargon• Primarily concerned with
the Prefrontal Cortex (PFC)in the main paper, specifically the Orbitofrontal Cortex (OFC).
• PFC – implicated in cognitive flexibility, ability to attend tochanges in the environment, and adapt behavioral response strategies accordingly– mPFC involved in shifting
attention b/n perceptual features of complex stimuli.
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Brain Jargon (cont.)
• Output of decision making processes influenced/determined by interaction b/n two forebrain loops.– Limbic (affective/motivational)
loop• OFC, amygdala, and ventral
striatum– Cognitive (executive/motor)
loop• Dorso-lateral prefrontal cortex
and dorsal striatus
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Cold Stress
• CIC leads to an increase in Hypothalamic-Pituitary-Adrenal response.– Hypersensitizes the individual to respond to acute
stress, specifically increases noradrenergic receptor activity.
• Dysregulation of both the HPA axis and noradrenergic system leads to anxiety like behaviors
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Cold Stress
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Serotonin Depletion
• Tryptophan -> 5-HT– Depleted through pharmacological (main paper)
or dietary means (background paper)
• Low 5-HT levels linked to poor decision making and gambling proneness– Assesed through the rIGT and rodent Probabilistic
Delivery Test (rPDT)
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Serotonin Depletion
• rIGT– Istead of four
choices, onlytwo this time• Advantageous• Disadvantageous
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Serotonin Depletion
• rPDT– 10 days – 2 choices• Large Luck Linked• Small Sure
– 6 vs. 2 pellets
– Indifferent point• LLL and SS choice
equally wise.
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Serotonin Depletion
• The authors believe that– 5-HT depletion leads to a lower sensitivity to
punishment– 5-HT depleted rats (T-) show only slight reduction
in LLL preference. Indicative of a tolerance of reward uncertainty
– (T-) rats also exhibit motor impulsivity. Not hitting the button long enough
– (T-) rats stuck on short term focus
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The Paper Proper
• Objectives– To assess the effects of chronic intermittent cold
(CIC) stress on performance of rats in an attentional set-shifting task (AST)
– Assess a possible role for serotonin in CIC-induced deficits and test the effects of acute serotonin reuptake blockade
• Model organism– Sprague-Dawley rats
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Attentional Set-shifting Task (AST)• …subjects must learn a series of reward contingencies,
using cues that vary along multiple stimulus dimensions (e.g., odor and texture, shape and color, etc). Extra Dimensional set shifting involves the acquisition of a new contingency requiring a shift in attention (and responding) away from the stimulus dimension that had been established previously as the relevant or informative dimension (i.e., formation of a cognitive set) to a previously irrelevant stimulus dimension…
• …reversal learning, another form of cognitive flexibility in which a previously positive cue becomes negative and a previously negative cue becomes positive, but within the same stimulus dimension.
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AST
Rem
ovab
le D
ivid
er
Terracota pots
Divider
Hypothetical “no-mans land”
Rat
-Various digging media-Various scents-¼ cheerio as reward
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Procedure
• Immediately following 14 day CIC treatment (or control housing)
• Day 15 – Habituation. Train rat to dig for food.• Day 16 – Training. Train to a series of SD. First
odor, then medium• Day 17 – Testing. Increasingly difficult
discriminations.– Trials to criterion• 6 correct choices in a row.
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Testing
• 1st stage – Simple Discrimination (SD)– Discriminate b/n two odors or two types of
medium.
• 2nd stage – Compound Discrimination (CD)– Same as above but also included a second
irrelevant stimulus (medium or odor)
• 3rd stage – Reversal 1 (R1)– Same as above, but the (-) stimulus is now (+)
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Testing (cont.)
• 4th stage – Intradimensional shift (ID)– Same setup as CD except all new odor and
medium. Relevant stimulus still the same as 2nd stage.
• 5th stage – Reversal (R2)– Same setup as above except (-) stimulus now (+)
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Testing (cont.)
• 6th stage – Extradimensional shift (ED)– All new mediums and odor introduced, relevent
stimulus now switched. If odor was relevant cue originally, now medium is the relevant cue.
• 7th stage – Reversal 3 (R3)– Same as above but (-) stimulus now (+)
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Protocol
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Experiments
• Experiment 1– Effect of CIC stress on rAST• 24 rats. 12 control - 12 CIC
– Note – CIC protocol was 14 days not 7 as in previous papers– 7 days prior to testing food was restricted to 14g/day
(promote reward seeking)
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Results – Exp. 1
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Experiment 2
• Effect of 5-HT depletion on rAST performance– 20 rats randomly assigned to two groups, vehicle
(control) or PCPA (4-chloro-DL-phenylalanine methyl ester hydrochloride) delivered intraperitonealy.
– PCPA – tryptophan hydroxylase inhibitor. Depletes serotonin levels (96.6%)• Note: 5-HT depletion isn’t localized, whole body.
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Results – Exp. 2
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Experiment 3
• Effects of acute citalopram administration on CIC rats in the rAST– Citalopram – SSRI, not sure of exact mechanism– 43 rats randomly assigned to two groups. • Control
– Citalopram– Vehicle Control
• CIC– Citalopram – Vehicle Control
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Results – Exp. 3
Citalopram = 5-HT reuptake inhibitor.
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Experiment 4
• Effects of CIC on 5-HT release in Orbitofrontal cortex– 24 rats randomly assigned to two groups• CIC • Control
– All had microdialysis probes implanted into the Orbitofrontal Cortex to monitor 5-T release.
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Results – Exp 4
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Reversal Learning
Effective reversal learning involves a number of specific and distinct operations, including:
1.Detection of the shift in contingency (i.e. “error detection”)
2.Inhibition of the prepotent, previously learned positive response
3.Overcoming learned avoidance of the previously negative stimulus
4.Acquisition of the new association.
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Conclusions
• Apparent dysregulation of serotonergic function in the OFC of rats exposed to CIC stress.
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