Transient strain differences in an operant delayed non-match to position task.

Working memory refers to the temporary retention of a small amount of information used in the execution of a cognitive task. Working memory impairments are one of the common hallmarks of many neuropsychiatric and neurological disorders including schizophrenia and Alzheimer's disease. Here, we investigated Fischer 344 and Long-Evans rats for strain and sex differences in working memory using the operant-based DNMTP task. Rats were required to press one of two levers presented during a sample phase and followed by a 2-32 second delay, the rats were then required to press the opposite, nonmatch, lever during the choice phase. We found a transient strain difference with Fischer 344 rats performing better than Long-Evans early in training. The Fischer 344 strain showed stable performance across sessions while the performance of Long-Evans increased in the later sessions. Since different background rat strains are used for transgenic rat models, it is critical to be able to compare the behavioral performance across different strains. These findings have implications in behavioral neuroscience research as understanding the typical behavioral endpoints in different background strains will aid our understanding of how different models affect behavioral performance.

Prelimbic cortex neural encoding dynamically tracks expected outcome value.

Animals must modify their behavior based on updated expected outcomes in a changing environment. Prelimbic cortex (PrL) neural encoding during learning predicts, and is necessary for, appropriately altering behavior based on a new expected outcome value following devaluation. We aimed to determine how PrL neural activity encodes reward predictive cues after the expected outcome value of those cues is decreased following conditioned taste aversion. In one post-devaluation session, rats were tested under extinction to determine their ability to alter their behavior to the expected outcome values (i.e., extinction test). In a second post-devaluation session, rats were tested with the newly devalued outcome delivered so that the rats experienced the updated outcome value within the session (i.e., re-exposure test). We found that PrL neural encoding of the cue associated with the devalued reward predicted the ability of rats to suppress behavior in the extinction test session, but not in the re-exposure test session. While all rats were able to successfully devalue the outcome during conditioned taste aversion, a subset of rats continued to consume the devalued outcome in the re-exposure test session. We found differential patterns of PrL neural encoding in the population of rats that did not avoid the devalued outcome during the re-exposure test compared to the rats that successfully avoided the devalued outcome. Our findings suggest that PrL neural encoding dynamically tracks expected outcome values, and differential neural encoding in the PrL to reward predictive cues following expected outcome value changes may contribute to distinct behavioral phenotypes.

Noninvasive Brain Stimulation Rescues Cocaine-Induced Prefrontal Hypoactivity and Restores Flexible Behavior.

BACKGROUND: To obtain desirable goals, individuals must predict the outcome of specific choices, use that information to direct appropriate actions, and adjust behavior accordingly in changing environments (behavioral flexibility). Substance use disorders are marked by impairments in behavioral flexibility along with decreased prefrontal cortical function that limits the efficacy of treatment strategies. Restoring prefrontal hypoactivity, ideally in a noninvasive manner, is an intriguing target for improving flexible behavior and treatment outcomes. METHODS: A behavioral flexibility task was used in Long-Evans male rats (n = 97) in conjunction with electrophysiology, optogenetics, and a novel rat model of transcranial alternating current stimulation (tACS) to examine the prelimbic cortex (PrL) to nucleus accumbens (NAc) core circuit in behavioral flexibility and determine whether tACS can restore cocaine-induced neural and cognitive dysfunction. RESULTS: Optogenetic inactivation revealed that the PrL-NAc core circuit is necessary for the ability to learn strategies to flexibly shift behavior. Cocaine self-administration history caused aberrant PrL-NAc core neural encoding and deficits in flexibility. Optogenetics that selectively activated the PrL-NAc core pathway prior to learning rescued cocaine-induced cognitive flexibility deficits. Remarkably, tACS prior to learning the task reestablished adaptive signaling in the PrL-NAc circuit and restored flexible behavior in a relatively noninvasive and frequency-specific manner. CONCLUSIONS: We establish a role of NAc core-projecting PrL neurons in behavioral flexibility and provide a novel noninvasive brain stimulation method in rats to rescue cocaine-induced frontal hypofunction and restore flexible behavior, supporting a role of tACS as a therapeutic to treat cognitive deficits in substance use disorders.

Drug-induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons.

Negative reinforcement models postulate that addicts use drugs to alleviate negative affective states (e.g. dysphoria) associated with withdrawal. In a pre-clinical model, rats exhibit negative affect to a normally rewarding tastant when it predicts impending, but delayed cocaine, and nucleus accumbens (NAc) neurons dynamically track this state. Here, we examined the effects of short versus prolonged experimenter-imposed cocaine abstinence on negative affect, cocaine seeking and self-administration. Rats were given 14 saccharin-cocaine sessions; NAc activity and affective responses to the taste (i.e. taste reactivity) were measured during sessions 1 and 14. Next, following 1 or 30 days of abstinence, taste reactivity and cell firing were recorded in a three-phase test session: (1) intraoral saccharin infusions, (2) extinction and (3) cocaine self-administration. Results showed that 30 days of abstinence led to a significant enhancement of aversive responses to the cocaine-paired tastant, accompanied by a dramatic decline in NAc phasic activity during tastant infusion. While extinction behavior did not differ across groups, NAc phasic firing reemerged during drug seeking. Further, when drug was again readily available, greater aversion to the drug-paired tastant before and after abstinence was associated with increased self-administration following prolonged (30-day) abstinence in rats classified as high (not low) aversive. Collectively, these findings show that drug-induced dysphoria is enhanced following prolonged cocaine abstinence and that NAc neural signaling is dynamic, dampening when negative affect is at its highest (phase 1), but transitioning back 'online' during subsequent drug seeking and taking (phases 2 and 3).

Engineering a Native Inducible Expression System in Shewanella oneidensis to Control Extracellular Electron Transfer.

Shewanella oneidensis MR-1 is a model organism for understanding extracellular electron transport, in which cells transfer intracellular electrons to an extracellular terminal electron acceptor such as insoluble minerals or poised electrodes. Biotechnological applications exploiting the respiratory capabilities of Shewanella species have led to their proposed use in wastewater treatment, bioremediation, and remote sensors. Transcriptional regulation tools can be used to rationally engineer S. oneidensis, optimizing performance in biotechnological applications, introducing new capabilities, or investigating physiology. Engineered gene expression in S. oneidensis has primarily involved the use of foreign regulatory systems from Escherichia coli. Here we characterize a native S. oneidensis pathway that can be used to induce gene expression with trimethylamine N-oxide, then engineer strains in which extracellular electron transfer is controlled by this compound. The ability to induce this pathway was assessed by measuring iron reduction over time and by analyzing anodic current produced by cells grown in bioreactors.

Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect.

BACKGROUND: Negative reinforcement theories of drug addiction posit that addicts use drugs to alleviate negative mood states. In a preclinical model developed in our laboratory, rats exhibit negative affect to a normally rewarding taste cue when it predicts impending but delayed cocaine. The emergence of this state is accompanied by a reduction in dopamine concentration in the rostral nucleus accumbens shell. However, the rostral and caudal regions of the shell have been implicated in promoting opposing appetitive and aversive states, respectively. Here, we tested whether dopamine transmission along the rostral-caudal axis of the shell plays differential roles in the emergence of drug-induced negative affect. METHODS: In TH::Cre rats, the dopaminergic pathways from the ventral tegmental area to the rostral and caudal regions of the shell were optogenetically stimulated during intraoral delivery of a taste cue signaling delayed cocaine. Affective responses to the taste cue were measured using taste reactivity, and optical self-stimulation of the rostral and caudal shells was also examined. RESULTS: Optical stimulation of the rostral shell during tastant infusion prevented the emergence of negative affect, but activation of the caudal shell exacerbated aversive responses. These effects endured in the absence of optical stimulation, and the degree of negative affect in our model predicted self-stimulation responding. CONCLUSIONS: These findings reveal unprecedented, pronounced, and opposing roles of rapid dopamine signaling across the rostral-caudal axis of the nucleus accumbens in the control of drug-induced negative affect, a hallmark of continued drug seeking and use in human addicts.

Amygdala selectively modulates defensive responses evoked from the superior colliculus in non-human primates.

Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g. the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models, little is known about this system in the primate brain. Employing focal pharmacological manipulations, we have previously shown that activation of the DLSC triggers reflexive defensive responses, including cowering, escape behaviors and defensive vocalizations. Here, we show that activation of the DLSC also disrupts normal dyadic social interactions between familiar pairs of monkeys. When the basolateral complex of the amygdala (BLA) was inhibited concurrent with DLSC activation, cowering behavior was attenuated, whereas escape behaviors and defensive vocalizations were not. Moreover, inhibition of the BLA, previously shown to produce a profound increase in dyadic social interactions, was unable to normalize the decrease in social behavior resulting from DLSC activation. Together these data provide an understanding of forebrain-midbrain interactions in a species and circuit with translational relevance for the psychiatry of anxiety and post-traumatic stress disorders.

Nucleus Accumbens Core and Shell Differentially Encode Reward-Associated Cues after Reinforcer Devaluation.

Nucleus accumbens (NAc) neurons encode features of stimulus learning and action selection associated with rewards. The NAc is necessary for using information about expected outcome values to guide behavior after reinforcer devaluation. Evidence suggests that core and shell subregions may play dissociable roles in guiding motivated behavior. Here, we recorded neural activity in the NAc core and shell during training and performance of a reinforcer devaluation task. Long-Evans male rats were trained that presses on a lever under an illuminated cue light delivered a flavored sucrose reward. On subsequent test days, each rat was given free access to one of two distinctly flavored foods to consume to satiation and were then immediately tested on the lever pressing task under extinction conditions. Rats decreased pressing on the test day when the reinforcer earned during training was the sated flavor (devalued) compared with the test day when the reinforcer was not the sated flavor (nondevalued), demonstrating evidence of outcome-selective devaluation. Cue-selective encoding during training by NAc core (but not shell) neurons reliably predicted subsequent behavioral performance; that is, the greater the percentage of neurons that responded to the cue, the better the rats suppressed responding after devaluation. In contrast, NAc shell (but not core) neurons significantly decreased cue-selective encoding in the devalued condition compared with the nondevalued condition. These data reveal that NAc core and shell neurons encode information differentially about outcome-specific cues after reinforcer devaluation that are related to behavioral performance and outcome value, respectively. SIGNIFICANCE STATEMENT: Many neuropsychiatric disorders are marked by impairments in behavioral flexibility. Although the nucleus accumbens (NAc) is required for behavioral flexibility, it is not known how NAc neurons encode this information. Here, we recorded NAc neurons during a training session in which rats learned that a cue predicted a specific reward and during a test session when that reward value was changed. Although encoding in the core during training predicted the ability of rats to change behavior after the reward value was altered, the NAc shell encoded information about the change in reward value during the test session. These findings suggest differential roles of the core and shell in behavioral flexibility.

Prelimbic and infralimbic cortical regions differentially encode cocaine-associated stimuli and cocaine-seeking before and following abstinence.

Cocaine stimuli often trigger relapse of drug-taking, even following periods of prolonged abstinence. Here, electrophysiological recordings were made in rats (n = 29) to determine how neurons in the prelimbic (PrL) or infralimbic (IL) regions of the medial prefrontal cortex (mPFC) encode cocaine-associated stimuli and cocaine-seeking, and whether this processing is differentially altered after 1 month of cocaine abstinence. After self-administration training, neurons (n = 308) in the mPFC were recorded during a single test session conducted either the next day or 1 month later. Test sessions consisted of three phases during which (i) the tone-houselight stimulus previously paired with cocaine infusion during self-administration was randomly presented by the experimenter, (ii) rats responded on the lever previously associated with cocaine during extinction and (iii) the tone-houselight was presented randomly between cocaine-reinforced responding during resumption of cocaine self-administration. PrL neurons showed enhanced encoding of the cocaine stimulus and drug-seeking behavior (under extinction and self-administration) following 30 days of abstinence. In contrast, although IL neurons encoded cocaine cues and cocaine-seeking, there were no pronounced changes in IL responsiveness following 30 days of abstinence. Importantly, cue-related changes do not represent a generalised stimulus-evoked discharge as PrL and IL neurons in control animals (n = 4) exhibited negligible recruitment by the tone-houselight stimulus. The results support the view that, following abstinence, neural encoding in the PrL but not IL may play a key role in enhanced cocaine-seeking, particularly following re-exposure to cocaine-associated cues.

When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine.

An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use where previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite serious negative consequences. Here, research in the Carelli laboratory is reviewed that examined neurobiological mechanisms that may underlie these processes using a novel animal model. Oromotor responses (taste reactivity) were examined as rats learned that intraoral infusion of a sweet (e.g., saccharin) predicts impending but delayed access to cocaine self-administration. We showed that rats exhibit aversive taste reactivity (i.e., gapes/rejection responses) during infusion of the sweet paired with impending cocaine, similar to aversive responses observed during infusion of quinine, a bitter tastant. Critically, the expression of this pronounced aversion to the sweet predicted the subsequent motivation to self-administer cocaine. Electrophysiology studies show that this shift in palatability corresponds to an alteration in nucleus accumbens (NAc) cell firing; neurons that previously responded with inhibition during infusion of the palatable sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during infusion of quinine, indicating that the once palatable sweet becomes aversive following its association with impending but delayed cocaine, and NAc neurons encode this aversive state. We also review electrochemical studies showing a shift (from increase to decrease) in rapid NAc dopamine release during infusion of the cocaine-paired tastant as the aversive state developed, again, resulting in responses similar to quinine infusion. Collectively, our findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc neurons and rapid dopamine signaling, and promotes cocaine-seeking behavior. Finally, we present data showing that experimentally induced abstinence (30 days) exacerbates this natural reward devaluation by cocaine, and this effect is correlated with a greater motivation to lever press during extinction. Dissecting the neural mechanisms underlying these detrimental consequences of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive (craving) for the drug. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Differential effects of serotonin-specific and excitotoxic lesions of OFC on conditioned reinforcer devaluation and extinction in rats.

The orbitofrontal cortex (OFC) is critical for behavioral adaptation in response to changes in reward value. Here we investigated, in rats, the role of OFC and, specifically, serotonergic neurotransmission within OFC in a reinforcer devaluation task (which measures behavioral flexibility). This task used two visual cues, each predicting one of two foods, with the spatial position (left-right) of the cues above two levers pseudorandomized across trials. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received either excitotoxic OFC lesions made by NMDA (N-methyl-d-aspartic acid), serotonin-specific OFC lesions made by 5,7-DHT (5,7-dihydroxytryptamine), or sham lesions. In sham-lesioned rats, devaluation of one food (by feeding to satiety) significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. Both types of OFC lesions disrupted the devaluation effect. In contrast, extinction learning was not affected by serotonin-specific lesions and was only mildly retarded in rats with excitotoxic lesions. Thus, serotonin within OFC is necessary for appropriately adjusting behavior toward cues that predict reward but not for reducing responses in the absence of reward. Our results are the first to demonstrate that serotonin in OFC is necessary for reinforcer devaluation, but not extinction.

Superior colliculus mediates cervical dystonia evoked by inhibition of the substantia nigra pars reticulata.

Cervical dystonia (CD; spasmodic torticollis) can be evoked by inhibition of substantia nigra pars reticulata (SNpr) in the nonhuman primate (Burbaud et al., 1998; Dybdal et al., 2012). Suppression of GABAergic neurons that project from SNpr results in the disinhibition of the targets to which these neurons project. It therefore should be possible to prevent CD by inhibition of the appropriate nigral target region(s). Here we tested the hypothesis that the deep and intermediate layers of the superior colliculus (DLSC), a key target of nigral projections, are required for the emergence of CD. To test this hypothesis, we pretreated the DLSC of four macaques with the GABA(A) agonist muscimol to determine whether this treatment would prevent CD evoked by muscimol infusions in SNpr. Our data supported this hypothesis: inhibition of DLSC attenuated CD evoked by muscimol in SNpr in all four animals. In two of the four subjects, quadrupedal rotations were evoked by muscimol application into SNpr sites that were distinct from those that induced dystonia. We found that inhibition of DLSC did not significantly alter quadrupedal rotations, suggesting that this response is dissociable from the SNpr-evoked CD. Our results are the first to demonstrate a role of DLSC in mediating the expression of CD. Furthermore, these data reveal a functional relationship between SNpr and DLSC in regulating posture and movement in the nonhuman primate, raising the possibility that the nigrotectal pathway has potential as a target for therapeutic interventions for CD.

Transient inactivation of basolateral amygdala during selective satiation disrupts reinforcer devaluation in rats.

Basolateral amygdala (BLA) function is critical for flexible, goal-directed behavior, including performance on reinforcer devaluation tasks. Here we tested, in rats, the hypothesis that BLA is critical for conditioned reinforcer devaluation during the period when the primary reinforcer (food) is being devalued (by feeding it to satiety), but not thereafter for guiding behavioral choices. We used a spatially independent task that used two visual cues, each predicting one of two foods. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received BLA or sham lesions, or cannulae implanted in BLA. Under control conditions (sham lesions, saline infusions), devaluation of one food significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. BLA lesions impaired this devaluation effect. Transient inactivation of BLA by microinfusion of the γ-aminobutyric acid receptor type A agonist muscimol resulted in an impairment only when BLA was inactivated during satiation. When muscimol was infused after satiation and therefore, BLA was inactivated only during the choice test, rats showed no impairment. Thus, BLA is necessary for registering or updating cues to reflect updated reinforcer values, but not for guiding choices once the value has been updated. Our results are the first to describe the contribution of rat BLA to specific components of reinforcer devaluation and are the first to show impairment in reinforcer devaluation following transient inactivation in the rat.

Ventral pallidum mediates amygdala-evoked deficits in prepulse inhibition.

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. It is defined as a reduction in magnitude of a startle response when a startling stimulus is preceded by a weaker "prepulse." PPI has been found to be altered in patients with schizophrenia, autism spectrum disorders, and other neuropsychiatric illnesses. As such, the neural substrates regulating PPI are of particular interest. Previous studies using lesions, selective blockade of N-methyl-d-aspartate (NMDA) receptors, and pharmacological disinhibition have demonstrated that impairment of the function of the basolateral and lateral nuclei of the amygdala (BLA) disrupts PPI. However, transient gamma aminobutyric acid-mediated (GABA-mediated) inactivation of BLA has not been evaluated for effects on PPI. Furthermore, the downstream projection targets that mediate BLA-evoked disruptions of PPI have not been elucidated. Thus, in the present study, we evaluated the effect on PPI of bilateral and unilateral inactivation of BLA, by microinfusion of the GABA-A receptor agonist, muscimol. We found that either bilateral or unilateral inactivation impaired PPI. Because unilateral inactivation was sufficient to impair PPI, we hypothesized that this was due to an indirect activation of a downstream target of BLA, the ventral pallidum (VP). Because VP inhibition normalizes PPI deficits evoked from nucleus accumbens (Kodsi & Swerdlow, 1994), we next tested the degree to which VP inhibition would normalize PPI deficits evoked from BLA. We unilaterally inactivated BLA with concurrent inactivation of VP and found that VP inactivation blocked BLA-evoked deficits in PPI. We suggest that BLA inactivation disrupts PPI through disinhibition of VP.

Transient inactivation of orbitofrontal cortex blocks reinforcer devaluation in macaques.

The orbitofrontal cortex (OFC) and its interactions with the basolateral amygdala (BLA) are critical for goal-directed behavior, especially for adapting to changes in reward value. Here we used a reinforcer devaluation paradigm to investigate the contribution of OFC to this behavior in four macaques. Subjects that had formed associations between objects and two different primary reinforcers (foods) were presented with choices of objects overlying the two different foods. When one of the two foods was devalued by selective satiation, the subjects shifted their choices toward the objects that represented the nonsated food reward (devaluation effect). Transient inactivation of OFC by infusions of the GABA(A) receptor agonist muscimol into area 13 blocked the devaluation effect: the monkeys did not reduce their selection of objects associated with the devalued food. This effect was observed when OFC was inactivated during both satiation and the choice test, and during the choice test only. This supports our hypothesis that OFC activity is required during the postsatiety object choice period to guide the selection of objects. This finding sharply contrasts with the role of BLA in the same devaluation process (Wellman et al., 2005). Whereas activity in BLA was required during the selective satiation procedure, it was not necessary for guiding the subsequent object choice. Our results are the first to demonstrate that transient inactivation of OFC is sufficient to disrupt the devaluation effect, and to document a role for OFC distinct from that of BLA for the conditioned reinforcer devaluation process in monkeys.

A visual, position-independent instrumental reinforcer devaluation task for rats.

Flexible goal-directed behavior has been studied across species using reinforcer devaluation tasks, in which subjects form associations between specific stimuli (cues) and specific reinforcer(s). The reinforcer is subsequently devalued by selective satiation or taste aversion. Following devaluation, subjects adjust their responding to the cues reflecting the new value of the reinforcer. Tasks currently used in rats differ in several ways from tasks used in monkeys and this may explain contrasting results between the two species. To address one of the differences, we developed a rat task independent of spatial cues. It employs two visual cues presented simultaneously, changing left and right positions pseudorandomly. Each cue predicts one of two food reinforcers. Rats were trained to lever press in response to the two visual cues. Subsequently, they were satiated on one of the foods followed by an extinction test where in each trial they could choose to respond to one of the two cues, one predicting the devalued reinforcer and the other the non-devalued. This procedure was repeated later with the alternative food devalued. The rats adjusted their responding by choosing the cue predicting the devalued food significantly less (p<0.05) than the alternative cue. These results show that rats can discriminate two visual stimuli presented simultaneously, devalue two different foods by selective satiation, and transfer the new value to the visual cues. Discrimination of the visual cues is not aided by spatial cues, thereby eliminating a major difference between the instrumental tasks used in rats and the task used in monkeys.

Positive behaviour support and supported employment for adults with severe disability.

BACKGROUND: Functional assessments and supported employment procedures have the potential to enhance quality of life factors for adults who have historically been isolated. METHOD: Functional assessments and supported employment procedures were used to assist four adults with severe disability who exhibited challenging behaviour, to achieve community access and employment. Hypothesis-driven interventions were used to decrease problem behaviours and increase access to job-related activities in the community. RESULTS: All participants met criterion on task analysed job performance. When participants were involved in community settings and job training, an immediate and complete absence of problem behaviour occurred within those settings. CONCLUSIONS: Findings emphasise the importance of positive behavioural supports and community access in the lives of adults who have historically been isolated.

Chronic corticosterone administration does not potentiate unconditioned freezing to the predator odor, trimethylthiazoline.

Chronic high levels of corticosterone (CORT) are known to facilitate learning and memory of aversive events. Whether this effect of chronic CORT also generalizes to unconditioned or unlearned fear behavior is not known. The present study investigated whether high levels of chronic CORT enhance unconditioned fear to a predator odor, trimethylthiazoline (TMT), an innate fear stimulus to rodents. TMT induces a dose-related freezing response, a prototypical behavior to fearful stimuli, in rats. The first experiment demonstrated that dose-related freezing to repeated exposures of TMT does not habituate, sensitize or produce contextually conditioned fear, and therefore can be used to measure the effects of chronic CORT on unconditioned fear to repeated exposures of TMT. In Experiment 2, 21-day release corticosterone pellets (200mg) were implanted subcutaneously in male, Sprague-Dawley rats. Control rats received sham implantation. On days when TMT was not present, chronic CORT rats froze significantly more than sham rats. However, while TMT-induced freezing in both chronic CORT and sham rats, freezing during exposure to TMT was not further enhanced in chronic CORT rats. Thus, chronic CORT appears to increase fear as measured by freezing, possibly by enhancing vigilance, but does not facilitate fear behavior induced by the innate fear stimulus, TMT.

Not all rat strains are equal: differential unconditioned fear responses to the synthetic fox odor 2,4,5-trimethylthiazoline in three outbred rat strains.

Predator odors induce unconditioned fear in rats; however, the synthetic predator odor 2,4,5-trimethylthiazoline (TMT) either elicits robust fear behavior (e.g., freezing) or no fear responses at all. The authors investigated whether this is due to the use of different outbred rat strains. TMT induced robust freezing in Sprague-Dawley and Long-Evans rats but not in Wistar rats. All 3 strains avoided TMT, but Wistar rats were less sensitive to TMT. Wistar rats are capable of freezing; all 3 strains displayed the same amount of odor-cue conditioned freezing. Thus, TMT is a robust unconditioned fear stimulus in rats, and prior negative results from other laboratories were due to the choice of a rat strain (Wistar) that is less responsive to TMT.