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Contextual and spatial systems facilitate changes in emotional memory regulation brought on by traumatic stress. Cholinergic basal forebrain (chBF) neurons provide input to contextual/spatial systems and although chBF neurons are important for emotional memory, it is unknown how they contribute to the traumatic stress effects on emotional memory. Clusters of chBF neurons that project to the prefrontal cortex (PFC) modulate fear conditioned suppression and passive avoidance, while clusters of chBF neurons that project to the hippocampus (Hipp) and PFC (i.e. cholinergic medial septum and diagonal bands of Broca (chMS/DBB neurons) are critical for fear extinction. Interestingly, neither Hipp nor PFC projecting chMS/DBB neurons are critical for fear extinction. The retrosplenial cortex (RSC) is a contextual/spatial memory system that receives input from chMS/DBB neurons, but whether this chMS/DBB-RSC circuit facilitates traumatic stress effects on emotional memory remain unexplored. Traumatic stress leads to neuroinflammation and the buildup of reactive oxygen species. These two molecular processes may converge to disrupt chBF circuits enhancing the impact of traumatic stress on emotional memory.

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Repeated intermittent exposure to psychostimulants, such as amphetamine, leads to a progressive enhancement of the drug's ability to increase both behavioral and brain neurochemical responses. The expression of these enhancements, known as sensitization, can be regulated by Pavlovian conditioned stimuli. Cues that are associated with drug experience can facilitate sensitization so that it only occurs in the presence of these stimuli (context-specific sensitization). In contrast, cues that are explicitly related to the absence of drugs (conditioned inhibitors) can prevent the expression of sensitization. We hypothesized that disrupting conditioned inhibition would enable amphetamine sensitization in new contexts. Using male Sprague Dawley rats and a two-context amphetamine conditioning procedure, we found that extinguishing amphetamine experience in one environment led to the loss of conditioned inhibition in a separate context. Thus, amphetamine-induced sensitized locomotion, as well as both enhanced dopamine and glutamate neurotransmission in the nucleus accumbens, were observed in a context where the drug was never experienced before. A similar loss of contextual control of sensitization was seen after using baclofen/muscimol microinjections to transiently inhibit the medial prefrontal cortex, basolateral amygdala, or ventral subiculum of the hippocampus. In other words, compared to control infusions, these intracranial injections of GABA-receptor agonists were able to block conditioned inhibitors from preventing the expression of sensitized locomotion. Together, these findings reveal the importance of conditioned inhibitors for regulating addiction-like behavior. The results suggest that dopaminergic and glutamatergic brain circuitry controls the context-specific expression of amphetamine sensitization.

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Available two-way active avoidance paradigms do not provide contextual testing, likely due to challenges in performing repetitive trials of context exposure. To incorporate contextual conditioning in the two-way shuttle box, we contextually modified one of the chambers of a standard two-chamber rat shuttle box with visual cues consisting of objects and black and white stripe patterns. During the 5 training days, electrical foot shocks were delivered every 10 s in the contextually modified chamber but were signaled by a tone in the plain chamber. Shuttling between chambers prevented an incoming foot shock (avoidance) or aborted an ongoing one (escape). During contextual retention testing, rats were allowed to freely roam in the box. During auditory retention testing, visual cues were removed, and tone-signaled shocks were delivered in both chambers. Avoidance gradually replaced escape or freezing behaviors reaching 80% on the last training day in both chambers. Rats spent twice more time in the plain chamber during contextual retention testing and had 90% avoidance rates during auditory retention testing. Our modified test successfully assesses both auditory and contextual two-way active avoidance. By efficiently expanding its array of outcomes, our novel test will complement standard two-way active avoidance in mechanistic studies and will improve its applications in translational research.

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The relevance of contextual factors in shaping neural mechanisms underlying visceral pain-related fear learning remains elusive. However, benign interoceptive sensations, which shape patients' clinical reality, may context-dependently become conditioned predictors of impending visceral pain. In a novel context-dependent interoceptive conditioning paradigm, we elucidated the putative role of the central fear network in the acquisition and extinction of pain-related fear induced by interoceptive cues and pain-predictive contexts. In this fMRI study involving rectal distensions as a clinically-relevant model of visceroception, N = 27 healthy men and women underwent differential conditioning. During acquisition training, visceral sensations of low intensity as conditioned stimuli (CS) predicted visceral pain as unconditioned stimulus (US) in one context (Con+), or safety from pain in another context (Con-). During extinction training, interoceptive CS remained unpaired in both contexts, which were operationalized as images of different rooms presented in the MRI scanner. Successful contextual conditioning was supported by increased negative valence of Con+ compared to Con- after acquisition training, which resolved after extinction training. Although interoceptive CS were perceived as comparatively pleasant, they induced significantly greater neural activation of the amygdala, ventromedial PFC, and hippocampus when presented in Con+, while contexts alone did not elicit differential responses. During extinction training, a shift from CS to context differentiation was observed, with enhanced responses in the amygdala, ventromedial, and ventrolateral PFC to Con+ relative to Con-, whereas no CS-induced differential activation emerged. Context-dependent interoceptive conditioning can turn benign interoceptive cues into predictors of visceral pain that recruit key regions of the fear network. This first evidence expands knowledge about learning and memory mechanisms underlying interoceptive hypervigilance and maladaptive avoidance behavior, with implications for disorders of the gut-brain axis.

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Previous studies suggest that trace conditioning depends on the anterior cingulate cortex (ACC). To examine the role of ACC in trace fear conditioning further, 48 rats were surgically prepared for infusion with saline or 62.5 or 125 µg/side muscimol to inactivate ACC reversibly prior to conditioning. A noise stimulus was followed by a 1 mA footshock, with or without a 10-second trace interval between these events in a conditioned suppression procedure. The trace-conditioned groups (10 seconds) showed less test suppression than the control-conditioned groups (0 seconds). Counter to prediction, there was no effect of muscimol infusion on suppression to the noise stimulus in the 10-second trace groups.

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Permanently stored memories become labile through a process called reactivation. Once reactivated, these memories need reconsolidation to become permanent. Sleep is critical for memory consolidation. Is sleep necessary for memory reconsolidation? We hypothesized that sleep loss immediately after fear reactivation (FR) will prevent memory reconsolidation. To test our hypothesis, two experiments were performed in adult male C57BL/6J mice exposed to contextual fear conditioning paradigm with inescapable foot shock as unconditional stimulus (US) and contextual cage as conditional stimulus (CS). Sleep loss was achieved either by 5 h of sleep deprivation (SD; Experiment 1) or by systemic infusion of modafinil (200 mg/Kg, ip), an FDA approved wake-promoting agent (Experiment 2). One hour after light-onset, fear memory acquisition (FMA) was performed on Day 1. Mice were allowed to explore CS for 5 min followed by presentation of US (7 foot-shocks; 0.5 mA, 2.0 s duration) at pseudorandom intervals. Controls were exposed to similar CS but no shocks were delivered. On Day 2, mice were exposed to CS for 2 min (without US; for FR) followed by either sleep loss or no sleep loss. On Day 3, fear memory recall (FMR) was performed by exposing mice to CS (without US) for 12 min. Percent time spent in freezing was monitored during FC, FR and FMR. Our results suggested that as compared to sleeping controls, mice with sleep loss immediately after FR displayed a significant reduction in percent time freezing during FMR. These results suggest that sleep loss may prevent memory reconsolidation.

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Using contextual information to predict aversive events is a critical ability that protects from generalizing fear responses to safe contexts. Animal models have demonstrated the importance of spatial context representations within the hippocampal formation in contextualization of fear learning. The ventromedial prefrontal cortex (vmPFC) is known to play an important role in safety learning, possibly also through the incorporation of context information. However, if contextual representations are related to context-dependent expression of fear memory in humans remains unclear. Twenty-one healthy participants underwent functional MRI combined with a cue-context conditioning paradigm within a self-navigated virtual reality environment. The environment included two buildings (Threat and Safe context), which had distinct features outside but were identical inside. Within each context, participants saw two cues (CS+, CS-). The CS+ was consistently (100% reinforcement rate) paired with an electric shock in the Threat context, but never in the Safe context. The CS- was never paired with a shock. We found robust differential skin conductance responses (SCRs; CS+ â€‹> â€‹CS-) in the Threat context, but also within the Safe context, indicating fear generalization. Within the Safe context, vmPFC responses to the CS+ were larger than those in the Threat context. We furthermore found environment-specific representations for the two contexts in the training paradigm (i.e., before conditioning took place) in the hippocampus to be related to fear expression and generalization. Namely, participants with a weak context representation (z-score < 1.65) showed stronger fear generalization compared to participants with a strong context representation (z-score > 1.65). Thus, a weak neural representation strength of spatial context may explain overgeneralization of memory to safe contexts. In addition, our findings demonstrate that context-dependent regulation of fear expression engages ventromedial prefrontal pathways suggesting this involves a similar mechanism that is known to be involved in retrieval of extinction memory.

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The effects of the serotonergic (5-hydroxytryptamine, 5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.2 and 0.4 mg/kg i.p.) were examined in trace conditioning (Experiment 1) and overshadowing (Experiment 2) procedures. Both experiments used a fear conditioning procedure conducted off-the-baseline in water deprived male Wistar rats. 8-OH-DPAT was administered during conditioning and its effects were examined drug free as the suppression of an established licking response, both upon re-exposure to the cues provided by the conditioning chambers and upon presentation of experimental stimuli. There were no statistically significant effects of 8-OH-DPAT on conditioning to the discrete cue provided by a 5 s conditioned stimulus (CS), irrespective of the length of the trace interval used in Experiment 1, and irrespective of whether the CS took the form of a light alone, or a noise plus light compound in the Experiment 2 overshadowing procedure. The successful demonstration of overshadowing required the use of a second conditioning session which allowed further evaluation of the effects of 8-OH-DPAT in that neither a weak nor a strong overshadowing effect was modulated by either drug dose. Nonetheless conditioning to contextual cues was attenuated by treatment with 8-OH-DPAT at the 30 s trace interval. We therefore conclude that 8-OH-DPAT reduces competition from contextual but not discrete conditioning cues. This pattern of results lends further support to the view that contextual cue conditioning and discrete cue conditioning are modulated by different neuropharmacological mechanisms.

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Background and aims Pain is not a linear result of nociception, but is dependent on multisensory inputs, psychological factors, and prior experience. Since nociceptive models appear insufficient to explain chronic pain, understanding non-nociceptive contributors is imperative. Several recent models propose that cues associatively linked to painful events might acquire the capacity to augment, or even cause, pain. This experiment aimed to determine whether contexts associated with pain, could modulate mechanical pain thresholds and pain intensity. Methods Forty-eight healthy participants underwent a contextual conditioning procedure, where three neutral virtual reality contexts were paired with either unpredictable noxious stimulation, unpredictable vibrotactile stimulation, or no stimulation. Following the conditioning procedure, mechanical pain thresholds and pain evoked by a test stimulus were examined in each context. In the test phase, the effect of expectancy was equalised across conditions by informing participants when thresholds and painful stimuli would be presented. Results Contrary to our hypothesis, scenes that were associated with noxious stimulation did not increase mechanical sensitivity (p=0.08), or increase pain intensity (p=0.46). However, an interaction with sex highlighted the possibility that pain-associated contexts may alter pain sensitivity in females but not males (p=0.03). Conclusions Overall, our data does not support the idea that pain-associated contexts can alter pain sensitivity in healthy asymptomatic individuals. That an effect was shown in females highlights the possibility that some subgroups may be susceptible to such an effect, although the magnitude of the effect may lack real-world significance. If pain-associated cues prove to have a relevant pain augmenting effect, in some subgroups, procedures aimed at extinguishing pain-related associations may have therapeutic potential.

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Aggressive interactions between conspecific animals have been used as a social stressor with ethological characteristics to study how social interactions can modulate animal's behavior. Here, a new protocol based on aggressive and non-aggressive interactions was developed to study how different social interactions can alter the behavioral profile of animals re-exposed to the context in which the interaction occurred. We used factor analysis to trace the behavioral profile of socially defeated and non-defeated mice when they were re-exposed to the apparatus [three interconnected chambers: home chamber, tunnel and surface area]; we also compared the behavior presented before (habituation) and 24 h after (re-exposure) the non-aggressive or aggressive interactions. A final factor analysis from defeated animals yielded 4 factors that represented 72.09% of total variance; whereas non-defeated animal's analysis was loaded with 5 factors that represented 85.46% of total variance. A 5-min non-aggressive interaction reduced the frequency of stretched attend behavior in the tunnel, whereas a single social defeat reduced time in the tunnel and increased time spent performing self-grooming in the home chamber without conditioning any other spatio-temporal and complementary measures. Together, these results suggest that different social interactions may modulate distinct behavioral profiles in animals when re-exposed to the context.

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The median raphe nucleus (MRN) is related to stress resistance and defensive responses, a crucial source of serotonergic neurons that project to prosencephalic structures related to stress and anxiety. Estrogen receptors were identified in this mesencephalic structure. It is possible that the estrogen action is related to serotonin effect on somatodendritic 5-HT1A receptors, inhibiting the function of serotonergic neurons and thus preventing of the stress effect and inducing anxiolysis. So, in order to evaluate these aspects, female Wistar rats were ovariectomized and 21 days later were given a direct microinjection of estradiol benzoate (EB) (1200 ng) into the MRN, preceded by microinjections of saline or WAY100.635 (100 ng), a 5-HT1A receptor antagonist. Immediately after the two microinjections, the ovariectomized rats were conditioned with an aversive event (foot shock) session in a Skinner box. Twenty-four hours later, they were exposed to the same context in a test session for 5 min for behavioral assessment: freezing, rearing, locomotion, grooming, and autonomic responses (fecal boluses and micturition). EB microinjection in the MRN prior to the exposure of animals to the foot shocks in the conditioning session did not alter their behavior in this session, but neutralized the association of the aversive experience to the context: there was a decrease in the expression of freezing and an increased rearing activity in the test session. This effect was reversed by prior microinjection of WAY100.635. In conclusion, EB acted on serotonergic neurons in the MRN of the ovariectomized rats, impairing the association of the aversive experience to the context, by co-modulating the functionality of somatodendritic 5-HT1A.

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Post-traumatic stress disorder (PTSD) is characterized by memory disturbances following trauma. Acute predator threat has emerged as an ethological model of PTSD, yet the effects of predator odor on signaling cascades associated with long-term memory remain poorly understood. In this study, we exposed male and female Wistar rats to the synthetic predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to assess behavioral and physiological responses as well as rapid modulation of signal transduction cascades associated with learning and memory in the male and female hippocampus. During exposure to TMT in the homecage, both male and female animals displayed robust immobility, avoidance, and altered activity as a function of time. Physiologically, TMT exposure increased circulating corticosterone and blood glucose in both male and female rodents, suggesting that TMT evokes sex-independent behavioral and physiological responses. With respect to signal transduction, TMT exposure rapidly reduced phosphorylation of cyclic-adenosine monophosphate response element binding protein (CREB) in the male, but not the female hippocampus. Furthermore, TMT exposure reduced phosphorylation of extracellular signal-regulated kinase 1/2 and increased nuclear expression of the synapto-nuclear messenger protein Jacob in the male hippocampus, consistent with activation of the CREB shut-off pathway. In a follow-up behavioral experiment, post-training exposure to TMT did not affect spatial water maze performance of male rats. However, male rats re-introduced to the context in which TMT had previously been presented displayed avoidance and hyperactivity, but not freezing behavior or elevated corticosterone responses, suggesting that TMT exposure supports a form of contextual conditioning which is not characterized by immobility. Taken together, our findings suggest that TMT evokes similar behavioral and physiological responses in male and female Wistar rats, but affects distinct signaling cascades in the male and female hippocampus which may contribute to behavioral disruptions associated with predator exposure.

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We have used mutant mice to probe the roles of the endogenous co-agonists of the NMDA receptor (NMDAR), D-serine and glycine, in fear learning and memory. Serine racemase knockout (SR-/-) mice have less than 15% of wild type forebrain levels of D-serine, whereas glycine transporter 1 heterozygous knockout (GlyT1+/-) mice have elevated synaptic glycine. While cued fear was normal in both delay and trace conditioned mice of both mutant genotypes, contextual fear was affected in trace conditioned subjects: SR-/- mice showed decreased contextual freezing, whereas GlyT1+/- mice showed elevated contextual freezing. These results indicate that endogenous co-agonists of the NMDAR modulate the conditioning of contextual fear responses, particularly in trace conditioning. They further suggest that endogenous glycine can compensate for the D-serine deficiency in cued and contextual fear following delay conditioning.

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In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

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Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed.

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The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05µg/side) or D1 antagonist SCH23390 (0.5µg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning.

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Treatment with selective serotonin reuptake inhibitors (SSRIs) can reduce contextual conditioning. Since contexts comprise a variety of potentially competing cues, impaired overshadowing may provide an account of such effects. The present study therefore compared the effects of two SSRIs on overshadowing and contextual conditioning, testing suppression of an ongoing behavioral response (licking) by cues previously paired with foot shock. Conditioning to a 5 s light stimulus was reduced when it was presented in compound with a 5 s noise, thus overshadowing was demonstrated. In two experiments, this overshadowing was unaffected by treatment with either sertraline or fluvoxamine. However, unconditioned suppression to the noise (tested in a control group previously conditioned to the light alone) was reduced after sertraline (10 mg/kg, i.p.). The successful demonstration of overshadowing required the use of a second conditioning session or an additional conditioning trial within the same conditioning session. Neither weak nor strong overshadowing (of the light by the tone) was affected by any drug treatment. Moreover, counter to prediction, conditioning to contextual cues was increased rather than impaired by treatment with sertraline (10 mg/kg, i.p.) and fluvoxamine (30 mg/kg, i.p.).

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Learned associations between drugs and the places they are used are critical to the development of drug addiction. Contextual conditioning has long been studied in animals as an indirect measure of drug reward, but little is known about the process in humans. Here, we investigated de novo contextual conditioning with d-amphetamine in healthy humans (n = 34). Volunteers underwent four conditioning sessions conducted in two testing rooms with double-blind, alternating d-amphetamine (20 mg) and placebo administration. Before conditioning procedures began, they rated the two rooms to examine pre-existing preferences. One group (Paired, n = 19) always received d-amphetamine in their least preferred room and placebo in the other during conditioning sessions. Another group (Unpaired, n = 15) received d-amphetamine and placebo in both rooms. Subjective drug effects were monitored at repeated times. At a separate re-exposure test, preference ratings for the drug-associated room were increased among the Paired group only, and more subjects in the Paired than the Unpaired group switched their preference to their initially least preferred room. Also, ratings of d-amphetamine drug liking independently predicted room liking at test among the Paired group only. Further, Paired group subjects reported greater stimulation and drug craving after d-amphetamine on the second administration, relative to the first. This study supports preliminary findings that humans, like animals, develop a preference for a place associated with d-amphetamine that is related to its subjective effects. These findings also suggest that experiencing d-amphetamine in a consistent environment produces context-dependent changes in its subjective effects, including an enhanced rewarding efficacy and abuse potential.

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