What is Learned Determines How Pavlovian Conditioned Fear is Consolidated in the Brain.

Activity in the basolateral amygdala complex (BLA) is needed to encode fears acquired through contact with both innate sources of danger (i.e., things that are painful) and learned sources of danger (e.g., being threatened with a gun). However, within the BLA, the molecular processes required to consolidate the two types of fear are not the same: protein synthesis is needed to consolidate the first type of fear (so-called first-order fear) but not the latter (so-called second-order fear). The present study examined why first- and second-order fears differ in this respect. Specifically, it used a range of conditioning protocols in male and female rats, and assessed the effects of a BLA infusion of the protein synthesis inhibitor, cycloheximide, on first- and second-order conditioned fear. The results revealed that the differential protein synthesis requirements for consolidation of first- and second-order fears reflect differences in what is learned in each case. Protein synthesis in the BLA is needed to consolidate fears that result from encoding of relations between stimuli in the environment (stimulus-stimulus associations, typical for first-order fear) but is not needed to consolidate fears that form when environmental stimuli associate directly with fear responses emitted by the animal (stimulus-response associations, typical for second-order fear). Thus, the substrates of Pavlovian fear conditioning in the BLA depend on the way that the environment impinges upon the animal. This is discussed with respect to theories of amygdala function in Pavlovian fear conditioning, and ways in which stimulus-response associations might be consolidated in the brain.

Second-order fear conditioning involves formation of competing stimulus-danger and stimulus-safety associations.

How do animals process experiences that provide contradictory information? The present study addressed this question using second-order fear conditioning in rats. In second-order conditioning, rats are conditioned to fear a stimulus, S1, through its pairings with foot-shock (stage 1); and some days later, a second stimulus, S2, through its pairings with the already-conditioned S1 (stage 2). However, as foot-shock is never presented during conditioning to S2, we hypothesized that S2 simultaneously encodes 2 contradictory associations: one that drives fear to S2 (S2-danger) and another that reflects the absence of the expected unconditioned stimulus and partially masks that fear (e.g. S2-safety). We tested this hypothesis by manipulating the substrates of danger and safety learning in the brain (using a chemogenetic approach) and assessing the consequences for second-order fear to S2. Critically, silencing activity in the basolateral amygdala (important for danger learning) reduced fear to S2, whereas silencing activity in the infralimbic cortex (important for safety learning) enhanced fear to S2. These bidirectional changes are consistent with our hypothesis that second-order fear conditioning involves the formation of competing S2-danger and S2-safety associations. More generally, they show that a single set of experiences can produce contradictory associations and that the brain resolves the contradiction by encoding these associations in distinct brain regions.

Chronic exposure to cafeteria-style diet in rats alters sweet taste preference and reduces motivation for, but not 'liking' of sucrose.

Obesity is associated with changes to taste perception and brain reward circuitry. It is important to understand how these effects alter the preference for palatable foods and drinks, given that these are widely consumed, and leading risk factors for obesity. This study examined the effects of diet-induced obesity on sweet taste preference by analysing the microstructure of licking for sugar solutions and assessing pERK expression in the nucleus accumbens shell and insula. Adult male Sprague-Dawley rats were fed standard chow (Control; n = 16) or a varied, palatable cafeteria diet (Caf; n = 16) for 12 weeks. Two-choice preference tests between 2%, 8% and 32% sucrose solutions were conducted at baseline and in weeks 11-12 of the diet. Rats in the Caf group trebled energy intake and doubled weight gain relative to controls. In tests held under water restriction after 11 weeks of diet, the Control group reliably preferred higher sucrose concentrations (i.e., 32% > 8% > 2%). Relative to controls, the Caf group showed a stronger preference for 32% vs. 2% sucrose, lower preference for 32% vs. 8% sucrose, and were indifferent to 8% vs. 2% sucrose. Testing without water restriction increased preference for higher sucrose concentrations in both groups. Chronic Caf diet increased the latency to lick, decreased total licks and reduced alternations between spouts, but did not alter lick cluster size, a measure of hedonic appraisal, on any test. Following a final exposure to a novel sucrose concentration, neuronal activity (pERK) in the insula and nucleus accumbens shell was significantly reduced in the Caf group. Results indicate that differences in 'liking' do not underlie obesity-induced changes to sweet taste preference.

Rats quit nicotine for a sweet reward following an extensive history of nicotine use.

Drug use may be exacerbated in environments which lack alternative means of engaging in rewarding behaviour. When alternative rewards are available, drug use may decrease-an effect that can be harnessed for therapeutic benefit. This idea is particularly well-supported by recent preclinical evidence demonstrating that a majority of rats will readily choose a potent non-drug reward over cocaine or heroin. Here we examine whether the same holds true for nicotine, a drug considered to have one of the highest addiction liabilities amongst drugs of abuse. Rats were trained to nose-poke separately for saccharin or nicotine on alternate days. Using a discrete-trial, forced-choice procedure, rats were then allowed to choose between nicotine and saccharin. This was followed by choice testing after a decrease in saccharin concentration (0.2-0%), omission of the fluid reward, an increase in nicotine concentration and following an extended nicotine self-administration history. All rats demonstrated a clear and immediate preference for saccharin at all times. This was despite variations in reward concentrations, or after an extensive nicotine history. Notably, rats preferred to nose-poke for water over nicotine and would omit responses when no fluid was delivered, rather than resume responding for nicotine. Overall, this study confirms and extends to nicotine previous research on other drugs of abuse, including cocaine and heroin. The ease with which rats quit nicotine in the present study contrasts with the well-known difficulty of humans to quit tobacco smoking. Possible factors that could explain this apparent discrepancy are discussed.

Dynamics of pre- and post-choice behaviour: rats approximate optimal strategy in a discrete-trial decision task.

We simulate two types of environments to investigate how closely rats approximate optimal foraging. Rats initiated a trial where they chose between two spouts for sucrose, which was delivered at distinct probabilities. The discrete trial procedure used allowed us to observe the relationship between choice proportions, response latencies and obtained rewards. Our results show that rats approximate the optimal strategy across a range of environments that differ in the average probability of reward as well as the dynamics of the depletion-renewal cycle. We found that the constituent components of a single choice differentially reflect environmental contingencies. Post-choice behaviour, measured as the duration of time rats spent licking at the spouts on unrewarded trials, was the most sensitive index of environmental variables, adjusting most rapidly to changes in the environment. These findings have implications for the role of confidence in choice outcomes for guiding future choices.

Stimulating oxytocin receptors in the basolateral amygdala enhances stimulus processing: Differential and consistent effects for stimuli paired with fear versus sucrose in extinction and reversal learning.

Oxytocin (OT) influences a range of social behaviors by enhancing the salience of social cues and regulating the expression of specific social behaviors (e.g., maternal care versus defensive aggression). We previously showed that stimulating OT receptors in the basolateral amygdala of rats also enhanced the salience of fear conditioned stimuli: relative to rats given vehicle infusions, rats infused with [Thr4,Gly7]-oxytocin (TGOT), a selective OT receptor agonist, showed greater discrimination between a cue predictive of danger, and one that signaled safety. In the present series of experiments using male rats, the effects of OT receptor activation in the basolateral amygdala on stimulus processing were examined further using conditioning protocols that consist of changes in stimulus-outcome contingencies (i.e., extinction and reversal), and with stimuli paired with aversive (i.e., foot shock) and appetitive (i.e., sucrose) outcomes. It was revealed that the effects of OTR stimulation diverge for aversive and appetitive learning - enhancing the former but not the latter. However, across both types of learning, OTR stimulation enhanced the detection of conditioned stimuli. Overall, these results are consistent with an emerging view of OT's effects on stimulus salience; facilitating the detection of meaningful stimuli while reducing responding to those that are irrelevant.

The role of uncertainty in regulating associative change.

Rescorla (2000, 2001) interpreted his compound test results to show that both common and individual error terms regulate associative change such that the element of a conditioned compound with the greater prediction error undergoes greater associative change than the one with the smaller prediction error. However, it has recently been suggested that uncertainty, not prediction error, is the primary determinant of associative change in people (Spicer et al., 2020, 2022). The current experiments use the compound test in a continuous outcome allergist task to assess the role of uncertainty in associative change, using two different manipulations of uncertainty: outcome uncertainty (where participants are uncertain of the level of the outcome on a particular trial) and causal uncertainty (where participants are uncertain of the contribution of the cue to the level of the outcome). We replicate Rescorla's compound test results in the case of both associative gains (Experiment 1) and associative losses (Experiment 3) and then provide evidence for greater change to more uncertain cues in the case of associative gains (Experiments 2 and 4), but not associative losses (Experiments 3 and 5). We discuss the findings in terms of the notion of theory protection advanced by Spicer et al., and other ways of thinking about the compound test procedure, such as that proposed by Holmes et al. (2019). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The neural substrates of higher-order conditioning: A review.

Sensory preconditioned and second-order conditioned responding are each well-documented. The former occurs in subjects (typically rats) exposed to pairings of two relatively neutral stimuli, S2 and S1, and then to pairings of S1 and a motivationally significant event [an unconditioned stimulus (US)]; the latter occurs when the order of these experiences is reversed with rats being exposed to S1-US pairings and then to S2-S1 pairings. In both cases, rats respond when tested with S2 in a manner appropriate to the affective nature of the US, e.g., approach when the US is appetitive and withdrawal when it is aversive. This paper reviews the neural substrates of sensory preconditioning and second-order conditioning. It identifies commonalities and differences in the substrates of these so-called higher-order conditioning protocols and discusses these commonalities/differences in relation to what is learned. In so doing, the review highlights ways in which these types of conditioning enhance our understanding of how the brain encodes and retrieves different types of information to generate appropriate behavior.

The effect of early list manipulations on the DRM illusion.

The Deese-Roediger-McDermott (DRM) paradigm is widely used to study false memory in the laboratory. It tests memory for lists of semantically related words (correct list item memories) and their non-presented associates (false lure memories). Evidence suggests that early items in DRM lists could make an especially significant contribution to false memories of lures, as they may critically influence the underlying associative activation and/or gist extraction processes. The present study tested this suggestion by using two manipulations that were intended to affect processing of early DRM list items. The first was interpolation of a semantically unrelated distractor item among the list items (Experiments 1 and 2). The second was arranging for these items to be either the strongest or weakest associates of the lure (Experiment 2). In Experiment 1, a distractor item reduced both list item and lure recall when presented early in a DRM list, but selectively disrupted list item recall when presented late in the list. In Experiment 2, arranging for the early list items to be the weakest associates of the lure reduced false recall of the lure but had no effect on list item recall. The findings are discussed with respect to theories that explain false memory in the DRM protocol, including fuzzy trace theory (FTT) and activation-monitoring theory (AMT). They are also discussed with respect to general theories of memory and the potential role of category/context information in generating false memories.

Oxytocin receptor activation in the basolateral complex of the amygdala enhances discrimination between discrete cues and promotes configural processing of cues.

Oxytocin (OT) is a neuropeptide which influences the expression of social behavior and regulates its distribution according to the social context - OT is associated with increased pro-social effects in the absence of social threat and defensive aggression when threats are present. The present experiments investigated the effects of OT beyond that of social behavior by using a discriminative Pavlovian fear conditioning protocol with rats. In Experiment 1, an OT receptor agonist (TGOT) microinjected into the basolateral amygdala facilitated the discrimination between an auditory cue that signaled shock and another auditory cue that signaled the absence of shock. This TGOT-facilitated discrimination was replicated in a second experiment where the shocked and non-shocked auditory cues were accompanied by a common visual cue. Conditioned responding on probe trials of the auditory and visual elements indicated that TGOT administration produced a qualitative shift in the learning mechanisms underlying the discrimination between the two compounds. This was confirmed by comparisons between the present results and simulated predictions of elemental and configural associative learning models. Overall, the present findings demonstrate that the neuromodulatory effects of OT influence behavior outside of the social domain.

An examination of changes in behavioral control when stimuli with different associative histories are conditioned in compound.

This series of experiments used rats to examine changes in behavioral control when stimuli with different associative histories are conditioned in compound. The initial experiments used blocking designs. Experiment 1 provided a within-subject demonstration of blocking, and Experiment 2 used the compound test procedure to show that, when a novel stimulus, X, is conditioned in compound with an already conditioned stimulus (CS), A, these audiovisual compound stimulus (AX)+ conditioning trials produce a greater increase in behavioral control for X than A. Experiment 3 showed that, when the blocked X is subject to further conditioning in compound with the blocking A (achieved by increasing the shock intensity on AX-shock trials), the compound trials again produce a greater increase in behavioral control for X than A. Finally, Experiment 4 showed that the unequal change in behavioral control for X and A was because of the difference in their training histories and not the test procedure. The overall pattern of results is consistent with the proposal (Rescorla, 2001) that associative change is regulated by the product of common and individual error terms rather than by common (Pearce & Hall, 1980; Rescorla & Wagner, 1972) or individual (Mackintosh, 1975) error terms. The pattern is also consistent with comparator theory (e.g., Miller & Matzel, 1988), which holds that the level of responding to a target is regulated by the strength of its comparator stimuli established in training. (PsycINFO Database Record

Temporal dynamics of choice behavior in rats and humans: an examination of pre- and post-choice latencies.

Identifying similarities and differences in choice behavior across species is informative about how basic mechanisms give rise to more complex processes. In the present study, we compared pre- and post-choice latencies between rats and humans under two paradigms. In Experiment 1, we used a cued choice paradigm where subjects were presented with a cue that directed them as to which of two options to respond for rewards. In Experiment 2, subjects were free to choose between two options in order to procure rewards. In both Experiments rewards were delivered with distinct probabilities. The trial structure used in these experiments allowed the choice process to be decomposed into pre- and post-choice processes. Overall, post-choice latencies reflected the difference in reward probability between the two options, where latencies for the option with higher probability of reward were longer than those for the option with lower probability of reward. An interesting difference between rats and humans was observed: the choice behavior for humans, but not rats, was sensitive to the free-choice aspect of the tasks, such that in free-choice trials post-choice latencies no longer reflected the difference in reward probabilities between the two options.

Incentive contrast effects regulate responding to a flavor presented in compound with a saccharin unconditioned stimulus in rats.

A flavor conditioned stimulus (conditional stimulus; CS) presented in simultaneous compound with a sweet-tasting unconditioned stimulus (US) acquires a certain sweetness and/or hedonic value. The present study examined whether responding to the flavor CS is influenced by postconditioning changes in the strength of the sweet US representation. In each experiment, rats were exposed to presentations of each of 2 flavors, A and B, in simultaneous compound with a 0.4% saccharin solution, and then tested with presentations of CS A in water. Experiments 1 and 2 showed that responding to CS A depended on its pairing with saccharin and increased with the training-to-test interval. Experiment 3 showed that a progressive reduction in the saccharin concentration of the trained compounds led to an increase in responding to CS A when tested in the absence of saccharin. Experiments 4 and 5 showed that, after a 7-day training-to-test delay, responding to CS A decreased following pretest exposure to a strong saccharin solution, and increased following pretest exposure to a very weak saccharin solution. These findings are taken to imply that incentive contrast effects regulate responding to a flavor CS. Hence, responding to the flavor CS increases with the training-to-test interval as the representation of the sweet US decays; decreases following pretest exposure to very sweet solutions as these reinstate the decayed sweet US representation (negative contrast); and increases following pretest exposure to weakly sweet solutions as these are perceived as less attractive than the CS itself (positive contrast). (PsycINFO Database Record

Behavioral correlates of the decision process in a dynamic environment: post-choice latencies reflect relative value and choice evaluation.

One characteristic of natural environments is that outcomes vary across time. Animals need to adapt to these environmental changes and adjust their choices accordingly. In this experiment, we investigated the sensitivity with which rats could detect, and adapt to, multiple changes in the environment. Rats chose between two spouts which delivered 5% sucrose rewards with distinct probabilities. Across three phases, reward probabilities changed in size (large or small) and direction (increase or decrease). A discrete trial-structure was used, which allowed the choice process to be decomposed into three distinct response latency measures (choice execution latency, spout sampling duration, and trial-initiation latency). We found that a large decrease in reward probabilities rapidly produced the greatest change in choice proportions. The time taken to execute a choice reflected the differences in reward probabilities across the two spouts in some cases, but also reflected training history. By contrast, the amount of time rats spent responding at reward spouts in anticipation of reward consistently reflected the relative likelihood of reward across the two spouts and not the absolute probability of reward. The latency to initiate the subsequent trial reflected choice evaluation. These three response latencies thus indexed key behavioral correlates of the choice process as it unfolds in time. We discuss how this paradigm can be used to assess the corresponding neural correlates of decision-making.