Presentation Of Conditioned Stimulus Research Articles

Relapse after intermittent access to cocaine: Discriminative cues more effectively trigger drug seeking than do conditioned cues.

When people with drug addiction encounter cues associated with drug use, this can trigger cravings and relapse. These cues can include conditioned stimuli (CSs) signaling drug delivery and discriminative stimuli (DSs) signaling drug availability. Compared to CS effects, DS effects are less explored in preclinical studies on cue-induced relapse. We compared CS and DS effects on reward seeking following abstinence from intermittent-access cocaine (or sucrose) self-administration. During 15-20 intermittent-access sessions, rats self-administered i.v. cocaine or sucrose pellets paired with a light-tone CS. Cocaine/sucrose was available for 5-min (signalled by a light; DS+) and unavailable for 25min (signalled by different lighting conditions; DS-), and this cycled for 4h/session. Following abstinence, we measured cocaine/sucrose seeking under extinction triggered by CS and DS presentation, and instrumental responding reinforced by these cues. Across intermittent-access sessions, rats increased lever pressing for cocaine or sucrose during DS+ periods and decreased responding during DS- periods. On days 2 and 21 of abstinence, only presentation of the DS+ or DS+ and CS combined elicited increased cocaine/sucrose-seeking behaviour (i.e., increased active lever presses). Presenting the DS- alongside the DS+ suppressed the increased cocaine-seeking behaviour otherwise produced by the DS+ . Finally, on day 21 of abstinence, rats showed equivalent levels of lever pressing reinforced by the DS+ , CS and by the DS+ and CS combined, suggesting comparable conditioned reinforcing value. After intermittent self-administration, cocaine-associated DSs and CSs acquire similar conditioned reinforcing properties, but DSs more effectively trigger increases in drug seeking.

Spaced conditioned stimulus presentation facilitates the extinction of strong fear memory in mice

Inducing fear memory extinction by re-presenting a conditioned stimulus (CS) is the foundation of exposure therapy for post-traumatic stress disorder (PTSD). Investigating differences in the ability of different CS presentation patterns to induce extinction learning is crucial for improving this type of therapy. Using a trace fear conditioning paradigm in mice, we demonstrate that spaced presentation of the CS facilitated the extinction of a strong fear memory to a greater extent than continuous CS presentation. These results lay the groundwork for developing more effective exposure therapy techniques for PTSD.

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats.

Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.

Fear extinction is impaired in aged rats.

Normal aging is accompanied by broad loss of cognitive function in humans and rodents, including declines in cognitive flexibility. In extinction, a conditional stimulus (CS) that was previously paired with a footshock is presented alone. This procedure reliably reduces conditional freezing behavior in young adult rats. Here, we aimed to investigate how normal aging affects extinction learning. Using young (3months) and aged (20months) male and female Long Evans rats, we compared extinction (using 20 CS-alone presentations) to a no extinction control (equal exposure to the conditioning chamber without CS presentations) following delay fear conditioning. We found that young animals in the extinction group showed a decrease in freezing following extinction; aged animals did not. We next examined changes in neural activity using expression of the immediate early gene zif268. In young animals, extinction corresponded with decreased expression of zif268 in the basolateral amygdala and anterior retrosplenial cortex; this was not observed in aged animals. Further, aged animals showed increased zif268 expression in each region examined, suggesting that dysfunction in neural activity precedes cognitive deficits. These results demonstrate that aging impacts both extinction learning and neural activity.

ЗРИТЕЛЬНОЕ ВОСПРИЯТИЕ МЛАДШИХ ШКОЛЬНИКОВ ПРИ ВАРЬИРОВАНИИ ВРЕМЕНИ ПРЕДЪЯВЛЕНИЯ ИНФОРМАЦИИ

The paper presents the study of differential thresholds of visual perception of children 7-11 years old in conditions of limited presentation of stimulus. The method of constant stimuli is used. The findings suggest that the conditions of stimulus presentation, being a stress factor, have an impact on the accuracy of the assessment of visual perception of primary school children, expressed in the indicators of their difference thresholds and in the manifestation of the probability of answers “greater.” At the same time, boys and girls have different configurations of differences, which may correspond to different cognitive strategies for assessing stimuli.

Autonomic and facial electromyographic responses to watching eyes.

We measured participants' psychophysiological responses and gaze behavior while viewing a stimulus person's direct and averted gaze in three different conditions manipulating the participants' experience of being watched. The results showed that skin conductance responses and heart rate deceleration responses were greater to direct than averted gaze only in the condition in which the participants had the experience of being watched by the other individual. In contrast, gaze direction had no effects on these responses when the participants were manipulated to believe that the other individual could not watch them or when the stimulus person was presented in a pre-recorded video. Importantly, the eye tracking measures showed no differences in participants' looking behavior between these stimulus presentation conditions. The results of facial electromyography responses suggested that direct gaze elicited greater zygomatic and periocular responses than averted gaze did, independent of the presentation condition. It was concluded that the affective arousal and attention-orienting indexing autonomic responses to eye contact are driven by the experience of being watched. In contrast, the facial responses seem to reflect automatized affiliative responses which can be elicited even in conditions in which seeing another's direct gaze does not signal that the self is being watched.

Amplitude modulation pattern of rat distress vocalisations during fear conditioning

In humans, screams have strong amplitude modulations (AM) at 30 to 150 Hz. These AM correspond to the acoustic correlate of perceptual roughness. In bats, distress calls can carry AMs, which elicit heart rate increases in playback experiments. Whether amplitude modulation occurs in fearful vocalisations of other animal species beyond humans and bats remains unknown. Here we analysed the AM pattern of rats’ 22-kHz ultrasonic vocalisations emitted in a fear conditioning task. We found that the number of vocalisations decreases during the presentation of conditioned stimuli. We also observed that AMs do occur in rat 22-kHz vocalisations. AMs are stronger during the presentation of conditioned stimuli, and during escape behaviour compared to freezing. Our results suggest that the presence of AMs in vocalisations emitted could reflect the animal’s internal state of fear related to avoidance behaviour.

Effect of Different Eye Movement Training Methods on Postural Oscillations of Older Women

Background and Aims Postural control is one of the most important abilities to maintain body stability and upright posture in the elderly. This study aims to investigate the effect of different patterns of eye movement training on postural oscillations in older women. Methods This is a quasi-experimental study with a pretest-posttest design using a control group. Participants were 72 older women in Mashhad, Iran (Mean±SD age= 68.7±2.4 years, weight= 67.7±4.4 kg, height=163.1±3.2 cm) who were selected purposefully and randomly divided into four groups including three experimental groups (saccade, anti-saccadic, and pursuit training) and one control group. All groups were evaluated under four different conditions of visual stimulus presentation. The training groups performed the training for 4 weeks. A repeated measures analysis of variance was used to analyze the collected data. All analyses were carried out in SPSS software, version 25. Results The results of ANOVA showed that the main effect of time for postural oscillations in the anterior-posterior and mediolateral directions was significant with the effect sizes of 0.57 and 0.492, respectively (P<0.05). This indicates that, regardless of the effect of group, postural oscillations in the experimental groups showed a significant difference over time. The interaction effect of time and group at the anterior-posterior and mediolateral directions was significant with the effect sizes of 0.168 and 0.28, respectively (P=0.010), where there was a significant decrease in the postural oscillations over time in the groups. The saccade training group showed the greatest decrease in the number of postural oscillations at the anterior-posterior and mediolateral directions (P<0.05). Conclusion Eye movement training with different patterns in older adults can reduced postural oscillations in the mediolateral and anterior-posterior directions. Saccade training cause less postural oscillation than anti-saccade and pursuit training in both directions. It is recommended that these training methods be included in the training program of the elderly to reduce their postural oscillation.

Does CUD measure interhemispheric transfer time? The allocation of attention influences the Poffenberger effect

A simple reaction time (SRT) difference between responses to visual stimuli presented ipsilaterally and contralaterally to the responding hand, known as the Poffenberger effect or the crossed–uncrossed difference (CUD), has been commonly interpreted as a measure of interhemispheric transfer time (IHTT). However, the validity of this interpretation and the measure's reliability have been debated. The present study aimed at obtaining reliable evidence of the influence of spatial attention on the CUD, which would provide an argument against the classical interpretation of CUD. To meet the high statistical power requirements, over 100 thousand SRTs in total were collected from 12 participants. The task had three stimulus presentation conditions differing in the degree of stimulus location uncertainty: blocked (no uncertainty), randomized (full uncertainty), and mixed (25% uncertainty). The results showed robust effects of location uncertainty, proving spatial attention's contribution to the CUD. Further, we observed a strong visual-field asymmetry reflecting the right hemisphere specialization in target detection and spatial reorienting. Lastly, despite exceptional reliability of the component SRT measures, the CUD reliability was still too low to justify using this measure as an index of individual differences.

Optogenetic activation of basolateral amygdala-to-nucleus accumbens core neurons promotes Pavlovian approach responses but not instrumental pursuit of reward cues

Reward-associated conditioned stimuli (CSs) can acquire predictive value, evoking conditioned approach behaviours that prepare animals to engage with forthcoming rewards. Such CSs can also acquire conditioned reinforcing value, becoming attractive and pursued. Through their conditioned effects, CSs can promote adaptive (e.g., locating food) but also maladaptive behaviours (e.g., drug use). Basolateral amygdala neurons projecting to the nucleus accumbens core (BLA→NAc core neurons) mediate the response to appetitive CSs, but the extent to which this involves effects on the predictive and/or conditioned reinforcing properties of CSs is unclear. Thus, we examined the effects of optogenetic stimulation of BLA→NAc core neurons on i) CS-triggered approach to the site of reward delivery, a Pavlovian conditioned approach response and ii) the instrumental pursuit of a CS, a measure of conditioned reinforcement. Water-restricted, adult male rats learned that a light-tone compound cue (the CS) predicts water delivery into a receptacle. Pairing optogenetic stimulation of BLA→NAc core neurons with CS presentation potentiated CS-triggered water receptacle visits. This suggests that activity in BLA→NAc core neurons promotes Pavlovian goal-approach behaviour. Next, rats could lever press for CS presentations, without water delivery. Optogenetic stimulation of BLA→NAc core neurons either during instrumental test sessions or during prior CS-water conditioning did not influence lever responding for the CS. This suggests that activity in BLA→NAc core neurons does not influence the instrumental pursuit of a water-paired CS. We conclude that activation of BLA→NAc core neurons promotes cue-induced control over behaviour by increasing conditioned goal-approach responses, without affecting the operant pursuit of reward cues.

Acquisition and extinction across multiple virtual reality contexts

This experiment examined the effects on recovery following a human contingency learning task across multiple virtual contexts. Specifically, if recovery of excitatory responding can be attenuated by experimental extinction in a single context or across multiple contexts when acquisition was also conducted in a single context or across multiple contexts. Sixty-one participants received conditioned stimulus (CS) and unconditioned stimulus (US) pairings in one or three virtual contexts. Orthogonal to this, participants received experimental extinction (CS presentations alone) in one or three different virtual contexts. Participants were then tested in a novel virtual context and the differences in expectation levels of the US in the presence of the CS were compared. Participants that experienced acquisition in one context and extinction in multiple contexts showed lower expectation of the US relative to participants that experienced acquisition and extinction in one context. Participants that experienced acquisition across multiple contexts, however, had higher expectation of the US regardless of whether extinction was also conducted across multiple contexts. This study demonstrated that learning across multiple contexts can negatively impact subsequent extinction; it is the first to do so using interactive VR-generated contexts, and it is the first to demonstrate this effect in humans and only the second study to demonstrate this effect at all. These findings highlight the importance of learning history and the likelihood that first-learned associations acquired across multiple contexts may interfere with subsequent extinction treatment. Availability of data and materialsThe dataset generated during and/or analysed during the current study is available on the Open Science Framework at https://osf.io/64tzw/?view_only= 20aaa34f9fd44f108a8391ca426a7031.

Learning-related changes in cellular activity within mouse dentate gyrus during trace eyeblink conditioning.

Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity. To explore these changes further, we did in vivo single-neuron recording in conjunction with physiological determination of cell types to investigate the functional role of granule cells, mossy cells, and interneurons in dentate gyrus during learning. Tetrode recordings were performed in young-adult mice during training on trace eyeblink conditioning, a hippocampal-dependent temporal associative memory task. Conditioned mice were able to successfully learn the task, with male mice learning at a faster rate than female mice. In the conditioned group, granule cells tended to show an increase in firing rate during conditioned stimulus presentation while mossy cells showed a decrease in firing rate during the trace interval and the unconditioned stimulus. Interestingly, populations of interneurons demonstrated learning-related increases and decreases in activity that began at onset of the conditioned stimulus and persisted through the trace interval. The current study also found a significant increase in theta power during stimuli presentation in conditioned animals, and this change in theta decreased over time. Ultimately, these data suggest unique involvement of granule cells, mossy cells, and interneurons in dentate gyrus in the formation of a trace associative memory. This work expands our knowledge of dentate gyrus function, helping to discern how aging and disease might disrupt this process.

Conditioned stimulus effects on paired or alternative reinforcement depend on presentation duration: Implications for conceptualizations of craving.

Conditioned stimuli (CS) associated with alcohol ingestion are thought to play a role in relapse by producing a craving that in turn increases motivation to drink which increases ethanol-seeking and disrupts other ongoing behavior. Alternatively, such CS may provide information indicating a likely increase in the density of the paired unconditioned stimulus and simultaneously elicit behavior that may be incompatible with other ongoing behavior, i.e., approach toward the CS. To explore these possibilities, rats were trained to respond for ethanol or food in two different components of the same session after which a light above the ethanol-lever was lighted twice during each component and each light presentation was followed by ethanol delivery. The duration of this CS was 10 s initially and then increased to 30 s, then to 100 s, and finally returned to 30 s. The change in responding for ethanol or food was compared to a matched period immediately preceding CS presentation. The CS presentation increased responding to ethanol, and this effect increases with longer CS presentations. In contrast, the CS presentation decreased responding to food, and this effect decreases with longer CS presentations. These results appear to support the informational account of CS action rather than simply a change in the motivation to seek and consume ethanol. This suggests that craving as it is commonly understood likely represents multiple behavioral processes, not simply increased desire for alcohol and that reports of craving likely reflect labeling based upon past experiences rather than a cause of future drug-taking.

Does vendor breeding colony influence sign- and goal-tracking in Pavlovian conditioned approach? A preregistered empirical replication

Vendor differences are thought to affect Pavlovian conditioning in rats. After observing possible differences in sign-tracking and goal-tracking behaviour with rats from different breeding colonies, we performed an empirical replication of the effect. 40 male Long-Evans rats from Charles River colonies ‘K72’ and ‘R06’ received 11 Pavlovian conditioned approach training sessions (or “autoshaping”), with a lever as the conditioned stimulus (CS) and 10% sucrose as the unconditioned stimulus (US). Each 58-min session consisted of 12 CS-US trials. Paired rats (n = 15/colony) received the US following lever retraction. Unpaired control rats (n = 5/colony) received sucrose during the inter-trial interval. Next, we evaluated the conditioned reinforcing properties of the CS, by determining whether rats would learn to nose-poke into a new, active (vs. inactive) port to receive CS presentations alone (no sucrose). Preregistered confirmatory analyses showed that during autoshaping sessions, Paired rats made significantly more CS-triggered entries into the sucrose port (i.e., goal-tracking) and lever activations (sign-tracking) than Unpaired rats did, demonstrating acquisition of the CS-US association. Confirmatory analyses showed no effects of breeding colony on autoshaping. During conditioned reinforcement testing, analysis of data from Paired rats alone showed significantly more active vs. inactive nosepokes, suggesting that in these rats, the lever CS acquired incentive motivational properties. Analysing Paired rats alone also showed that K72 rats had higher Pavlovian Conditioned Approach scores than R06 rats did. Thus, breeding colony can affect outcome in Pavlovian conditioned approach studies, and animal breeding source should be considered as a covariate in such work.

Divergent encoding of active avoidance behavior in corticostriatal and corticolimbic projections

Active avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of dmPFC projections during active avoidance learning has never been recorded. Here we utilized fiber photometry to record from the dmPFC and its axonal projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in both male and female mice. We examined neural activity during conditioned stimulus (CS) presentations and during clinically relevant behaviors such as active avoidance or cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased and decreased patterns of activity during avoidance and cued freezing, respectively. Finally, dmPFC-DMS and dmPFC-BLA projections show divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA projection showing decreased activity during active avoidance. Our results demonstrate task-relevant encoding of active avoidance in projection-specific dmPFC subpopulations that play distinct but complementary roles in active avoidance learning.

FOCAL EPILEPSY AND EXECUTIVE DYSFUNCTION IN AUTISM SPECTRUM DISORDER (ASD)

Recent advances in neuroscience have allowed researchers to introduce functional neuromarkers of autism spectrum disorders (ASD) into clinical practice. Most promising are studies of brain work in milliseconds, such as quantitative EEGs, event-related potentials (ERPs), low resolution electromagnetic tomography(sLORETA), especially when it is possible to use Human Brain Index (HBI) methodology to compare test results obtained by a child with ASD with the normative database. The use of HBI methodology make possible to determine functional neuromarkers of ASD and comorbidities, such as epilepsy, impaired cognitive and emotional control or executive function (FF) disorders. Such procedure can contribute to more effective diagnosis, as well as provide personalized care for patients with ASD. In this case study we use the HBI methodology for more effective diagnosis of the child with ASD (level 2) with focal epilepsy and EF dysfunction in hope that we can provide more effective therapies which might improve her quality of life. We present the case of a 11-years-old girl with an initial diagnosis of ASD with focal epilepsy and EF dysfunction. The patient was sent to the Teaching-Reintegration Centre in Kraków with remarks that she simply could not function in everyday life. A neuropsychological examination using standardized batteries to assess the girl's cognitive, emotional and social functioning confirmed the presence of ASD (level 2), and co-occurring executive function disorders (EF). She was also analyzed from the clinical EEG perspective as well as from the QEEG/ERPs perspective and current coexistence of 3 Hz Spike-Wave Discharges on EEG and focal epilepsy was found. In the examination several episodes of 3 Hz paroxysms were found in the ventro-lateral prefrontal cortex (BA 11) in 40 min EEG recoding in Eyes open, Eyes closed as well as in task conditions. The patient’s ERPs showed that to the first stimulus (continue cue) temporal P2 wave with larger duration and longer latency was elicited in comparison to the average of the norm for her age from the Human Brain Index (HBI) normative database at Chur, Switzerland. The P30 cue was smaller in the patient than in the healthy controls from HBI and statistically significant deviations from the average were found. Also in response to NOGO stimulus no positive parietal-central P3 was observed, which appears in the ERPs of ealthy controls from HBI. The ERPs differences in the VCPT show statistically significant deviations in the patient’s brain function when compared to the ealthy controls from HBI. It should be stressed that the number of trials for the first stimulus presentation and NOGO condition were large enough for computing reliable ERPs, as it was indicated by Kropotov (2009; 2016). HBI methodology was helpful in finding functional neuromarkers of co-existence of 3 Hz Spike-Wave Discharges on EEG with focal epilepsy and EF disorder in girl with ASD (level 2). Therefore, it was possible to offer more effective rehabilitation of the disorders, which will contribute to the integration of the self system and better quality of her life.

The effect of noise on the amplitude and morphology of cortical auditory evoked potentials

ObjectiveTo analyze the effect of noise on electrophysiological measurements (P1-N1-P2 complex) of cortical auditory evoked potentials in normal hearing individuals of different ages. MethodsThe inclusion criteria for the study were young individuals, adults and elderly, aged 18–75 years, with auditory thresholds up to 25 dB. Participants were separated according to their age group: G1 (18–25 years old), G2 (31–59 years old) and G3 (60–75 years old). Cortical auditory evoked potentials were elicited with synthetic speech stimulus /da/ presented in two conditions: without masking and with masking (Delta-t 64 ms). The results were expressed and analyzed using statistical measures. ResultsHigh latencies and reduced amplitudes were observed in the Delta-t 64 ms condition, in all age groups. There were significant differences between the groups, both in P1 latencies for the two conditions and in N1 latencies in the Delta-t 64 ms condition. P1 latencies in the condition without masking were lower in G1 and P1 and N1 latencies in the Delta-t 64 ms condition were higher in G3. The described results show the influence of noise on cortical responses in all age groups, with G3 being the most affected by the masking presentation. ConclusionThe latency and amplitude measurements vary according to the stimulus presentation condition and age group. The forward masking phenomenon occurred with greater precision in G3. Level of evidence(2c).

Spontaneous recovery can be prevented in appetitive conditioning with rats

Two Pavlovian appetitive conditioning experiments with rats demonstrated that spontaneous recovery can be strongly reduced (prevented). The experiments also investigated potential common factors associated with that prevention of spontaneous recovery after extinction. After pairings of a conditioned stimulus (CS) with a food unconditioned stimulus (US), an extinction cue (EC) was presented during extinction and spontaneous recovery testing with the CS. Replicating Brooks and Bowker (2001), EC–US pairings in the CS extinction–test interval subsequently resulted in the EC strongly reducing (preventing) spontaneous recovery to the CS (Experiment 1). Experiment 1 also assessed an “erasure” hypothesis of how the EC may reduce spontaneous recovery. Experiment 2 assessed EC– or US–alone presentations, or unpairings of EC and US, in the CS extinction–test interval. Spontaneous recovery was also prevented when the EC was presented alone or unpaired with the US, but USs alone interfered with the EC’s spontaneous recovery–preventing effect. No evidence was found for the EC operating by erasure, conditioned inhibition, generalized extinction, or generalized extinction. Together the results suggest that after CS extinction additional EC presentations are sufficient to prevent spontaneous recovery.

Is a paired-stimuli configuration necessary to obtain typical evoked response differences in studies of psychosis? An MEG study.

Paired-stimuli (S1-S2) procedures have long been used to assess auditory processing in psychosis. Such studies have shown aberrant evoked responses (ERPs) following long (S1 response) and/or short (S2 response) inter-stimulus intervals. The historical tendency from paired stimuli outcomes in the schizophrenia (SZ) literature is for (i) response to the first stimulus (S1) to be smaller among SZ, and (ii) response to the second stimulus (S2) to be larger among SZ in relation to the size of their S1. An interpretation of these two findings is that SZ have poor auditory response suppression to redundant stimuli ("poor gating"). The present study sought to determine if the reported S1 and S2 effects in SZ (smaller S1 and larger S2 in relation to S1 magnitude) require the paired-stimuli presentation format. Participants (18 schizophrenia and 17 healthy persons) were administered the equivalent of S1 (after a 4.5-sec ISI - "long ISI") and S2 (after a 500-ms ISI - "short ISI") stimuli under four conditions (traditional paired long and short, randomly interleaved long and short, block of long, block of short). Neural activity differences were consistent between-groups independent of condition: (i) schizophrenia cases had greater activity in the pre-stimulus to very early post-stimulus period, (ii) healthy persons had greater M100 activity to long ISI stimuli, and (iii) healthy persons had greater activity after the M50/M100 evoked fields (recovery phase) following short ISI stimuli. Simple early auditory processing in psychosis may be largely independent of stimulus presentation condition, an outcome that may help re-frame future translational studies. Traditional paired-stimuli auditory neural response effects may not require the paired-stimuli format.

A Signaled Locomotor Avoidance Action Is Fully Represented in the Neural Activity of the Midbrain Tegmentum

Animals, including humans, readily learn to avoid harmful and threatening situations by moving in response to cues that predict the threat (e.g., fire alarm, traffic light). During a negatively reinforced sensory-guided locomotor action, known as signaled active avoidance, animals learn to avoid a harmful unconditioned stimulus (US) by moving away when signaled by a harmless conditioned stimulus (CS) that predicts the threat. CaMKII-expressing neurons in the pedunculopontine tegmentum area (PPT) of the midbrain locomotor region have been shown to play a critical role in the expression of this learned behavior, but the activity of these neurons during learned behavior is unknown. Using calcium imaging fiber photometry in freely behaving mice, we show that PPT neurons sharply activate during presentation of the auditory CS that predicts the threat before onset of avoidance movement. PPT neurons activate further during the succeeding CS-driven avoidance movement, or during the faster US-driven escape movement. PPT neuron activation was weak during slow spontaneous movements but correlated sharply with movement speed and, therefore, with the urgency of the behavior. Moreover, using optogenetics, we found that these neurons must discharge during the signaled avoidance interval for naive mice to effectively learn the active avoidance behavior. As an essential hub for signaled active avoidance, neurons in the midbrain tegmentum process the conditioned cue that predicts the threat and discharge sharply relative to the speed or apparent urgency of the avoidance (learned) and escape (innate) responses.SIGNIFICANCE STATEMENTDuring signaled active avoidance behavior, subjects move away to avoid a threat when directed by an innocuous sensory stimulus. Using imaging methods in freely behaving mice, we found that the activity of neurons in a part of the midbrain, known as the pedunculopontime tegmentum, increases during the presentation of the innocuous sensory stimulus that predicts the threat and also during the expression of the learned behavior as mice move away to avoid the threat. In addition, inhibiting these neurons abolishes the ability of mice to learn the behavior. Thus, neurons in this part of the midbrain code and are essential for signaled active avoidance behavior.