M. Danet S. Lapiz-Bluhm, Alexandra E. Soto-Piña, 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, Alexandra E. Soto-Piña, Julie G. Hensler, David A. Morilak

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 to changes in the environment, and adapt behavioral response strategies accordingly mPFC involved in shifting attention b/n perceptual features of complex stimuli.

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

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

Cold Stress

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)

Serotonin Depletion rIGT Istead of four choices, only two this time Advantageous Disadvantageous

Serotonin Depletion rPDT 10 days 2 choices Indifferent point Large Luck Linked Small Sure 6 vs. 2 pellets Indifferent point LLL and SS choice equally wise.

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

The Paper Proper Objectives Model organism 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

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.

AST Terracota pots Rat Various digging media Various scents ¼ cheerio as reward Divider Removable Divider Hypothetical “no-mans land”

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.

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 (+)

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 (+)

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 (+)

Protocol

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)

Results – Exp. 1

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.

Results – Exp. 2

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

Results – Exp. 3 Citalopram = 5-HT reuptake inhibitor.

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.

Results – Exp 4

Reversal Learning Effective reversal learning involves a number of specific and distinct operations, including: Detection of the shift in contingency (i.e. “error detection”) Inhibition of the prepotent, previously learned positive response Overcoming learned avoidance of the previously negative stimulus Acquisition of the new association.

Conclusions Apparent dysregulation of serotonergic function in the OFC of rats exposed to CIC stress.

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