Action Sequence Learning Is Impaired in Genetically Modified Mice with the Suppressed GABAergic Transmission from the Thalamic Reticular Nucleus to the Thalamus.

The thalamic reticular nucleus (TRN) is a thin sheet of GABAergic neurons surrounding the thalamus, and it regulates the activity of thalamic relay neurons. The TRN has been reported to be involved in sensory gating, attentional regulation, and some other functions. However, little is known about the contribution of the TRN to sequence learning. In the present study, we examined whether the TRN is involved in reward-based learning of action sequence with no eliciting stimuli (operant conditioning), by analyzing the performance of male and female Avp-Vgat-/- mice (Vgatflox/flox mice crossed to an Avp-Cre driver line) on tasks conducted in an operant box having three levers. Our histological and electrophysiological data demonstrated that in adult Avp-Vgat-/- mice, vesicular GABA transporter (VGAT) was absent in most TRN neurons and the GABAergic transmission from the TRN to the thalamus was largely suppressed. The performance on a task in which mice needed to press an active lever for food reward showed that simple operant learning of lever pressing and learning of win-stay and lose-shift strategies are not affected in Avp-Vgat-/- mice. In contrast, the performance on a task in which mice needed to press three levers in a correct order for food reward showed that learning of the order of lever pressing (action sequence learning) was impaired in Avp-Vgat-/- mice. These results suggest that the TRN plays an important role in action sequence learning.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

Focused-attention mindfulness increases sensitivity to current schedules of reinforcement.

Four experiments explored the impact of focused-attention mindfulness training on human performance on free-operant schedules of reinforcement. In each experiment, human participants responded on a multiple random ratio (RR), random interval (RI) schedule. In all experiments, responding was higher on RR than RI schedules, despite equated rates of reinforcement. A 10-min focused-attention mindfulness intervention (focused attention) produced greater differentiation between schedules than relaxation training (Experiments 1, 2, and 4), or no intervention (Experiment 3). Focused-attention mindfulness improved learning when the schedules associated with components of the multiple schedule were reversed. This occurred irrespective of whether the focused-attention mindfulness was before (Experiment 2) or after (Experiments 3 and 4) initial training, or whether compared to relaxation (Experiments 2 and 4) or no intervention (Experiment 3). In Experiment 4, following multiple RR, RI training, focused-attention mindfulness increased sensitivity to contingency reversal and did not interfere with previous training in a group that did not receive a contingency reversal. In contrast, relaxation training did not facilitate reversal learning and interfered with previous learning. The results suggest that focused-attention mindfulness improves awareness of operative contingencies by focusing participants on the present, rather than reducing interference from previous learning. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The effect of brief mindfulness training on the micro-structure of human free-operant responding: Mindfulness affects stimulus-driven responding.

BACKGROUND AND OBJECTIVES: The current study examines the extent to which mindfulness impacts on operant conditioning processes, and explores the suggestion that mindfulness training serves to make humans more sensitive to the current reinforcement contingencies with which they are presented. In particular, the effect of mindfulness on the micro-structure of human schedule performance was explored. It was expected that mindfulness might impact bout-initiation responding to a greater degree than within-bout responding, premised on the assumption that bout-initiation responses are habitual and not under conscious control, but within-bout responses are goal-directed and conscious. METHODS: Nonclinical participants experienced one of three brief (15min) interventions: focused attention breathing exercise (mindfulness), an unfocused attention breathing exercises, or no intervention. They then responded on a multiple random ratio (RR) random interval (RI) schedule. RESULTS: In the no intervention and unfocused attention groups, overall and within-bout response rates were higher on the RR than the RI schedule, but bout-initiation rates were the same on the two schedules. However, for the mindfulness groups all forms of responding were higher for the RR than the RI schedule. Previous work has noted that habitual, and/or unconscious or fringe-conscious events, are impacted by mindfulness training. LIMITATIONS: A nonclinical sample may limit generality. CONCLUSIONS: The current pattern of results suggests that this is also true in schedule-controlled performance, and offers an insight into the manner in which mindfulness alongside conditioning-based interventions, to bring all responses under conscious control.

Involvement of GABAA receptors of lateral habenula in the acquisition and expression phases of morphine-induced place preference in male rats.

The lateral habenula (LHb) is a critical brain structure involved in the aversive response to drug abuse. It has been determined that the gamma-aminobutyric acid (GABA)-ergic system plays the main role in morphine dependency. The role of GABA type A receptors (GABAARs) in LHb on morphine-induced conditioned place preference (CPP) remains unknown. In this study, the effect of bilateral intra-LHb microinjection of GABAAR agonist and antagonist on the acquisition and expression phases of CPP, utilizing a 5-day CPP paradigm in male rats, was evaluated. Subcutaneous administration of different doses of morphine caused a dose-dependent CPP. Intra-LHb microinjection of the GABAAR agonist, muscimol, in combination with morphine (5 mg/kg; subcutaneously) enhanced CPP scores in the acquisition phase of morphine CPP, whereas the GABAAR antagonist, bicuculline, significantly reduced the conditioning scores in the acquisition phase. Furthermore, pretreatment with a high dose of bicuculline reversed the additive effect of muscimol during the acquisition phase, yet the low dose of antagonist had no significant effect on agonist-induced CPP scores. On the other hand, muscimol (3 µg/rat) significantly increased CPP scores in the expression phase but bicuculline did not induce a significant effect on CPP scores. Bicuculline and muscimol microinjections did not affect locomotor activity in the testing sessions. Our results confirm that GABAARs in LHb play an active role in morphine reward. In addition, microinjections of bicuculline/muscimol may alter the morphine response through the GABAergic system.

Frustrative nonreward and cannabinoid receptors: Chronic (but not acute) WIN 55,212-2 treatment increased resistance to change in two reward downshift tasks.

Assessing the role of cannabinoid (CB) receptors in behavior is relevant given the trend toward the legalization of medicinal and recreational marijuana. The present research aims at bridging a gap in our understanding of CB-receptor function in animal models of frustrative nonreward. These experiments were designed to (1) determine the effects of chronic administration of the nonselective CB1-receptor agonist WIN 55,212-2 (WIN) on reward downshift in rats and (2) determine whether the effects of chronic WIN were reducible to acute effects. In Experiment 1, chronic WIN (7 daily injections, 10 mg/kg, ip) accelerated the recovery of consummatory behavior after a 32-to-4% sucrose downshift relative to vehicle controls. In addition, chronic WIN eliminated the preference for an unshifted lever when the other lever was subject to a 12-to-2 pellet downshift in free-choice trials, but only in animals with previous experience with a sucrose downshift. In Experiment 2, acute WIN (1 mg/kg, ip) reduced consummatory behavior, but did not affect recovery from a 32-to-4% sucrose downshift. The antagonist SR 141716A (3 mg/kg, ip) also failed to interfere with recovery after the sucrose downshift. In Experiment 3, acute WIN administration (1 mg/kg, ip) did not affect free-choice behavior after a pellet downshift, although it reduced lever pressing and increased magazine entries relative to vehicle controls. The effects of chronic WIN on frustrative nonreward were not reducible to acute effects of the drug. Chronic WIN treatment in rats, like chronic marijuana use in humans, seems to increase resistance to the effects of frustrative nonreward.

Closed-loop auditory stimulation method to modulate sleep slow waves and motor learning performance in rats.

Slow waves and cognitive output have been modulated in humans by phase-targeted auditory stimulation. However, to advance its technical development and further our understanding, implementation of the method in animal models is indispensable. Here, we report the successful employment of slow waves' phase-targeted closed-loop auditory stimulation (CLAS) in rats. To validate this new tool both conceptually and functionally, we tested the effects of up- and down-phase CLAS on proportions and spectral characteristics of sleep, and on learning performance in the single-pellet reaching task, respectively. Without affecting 24 hr sleep-wake behavior, CLAS specifically altered delta (slow waves) and sigma (sleep spindles) power persistently over chronic periods of stimulation. While up-phase CLAS does not elicit a significant change in behavioral performance, down-phase CLAS exerted a detrimental effect on overall engagement and success rate in the behavioral test. Overall CLAS-dependent spectral changes were positively correlated with learning performance. Altogether, our results provide proof-of-principle evidence that phase-targeted CLAS of slow waves in rodents is efficient, safe, and stable over chronic experimental periods, enabling the use of this high-specificity tool for basic and preclinical translational sleep research.

Midbrain-Level Neural Correlates of Behavioral Tone-in-Noise Detection: Dependence on Energy and Envelope Cues.

Hearing in noise is a problem often assumed to depend on encoding of energy level by channels tuned to target frequencies, but few studies have tested this hypothesis. The present study examined neural correlates of behavioral tone-in-noise (TIN) detection in budgerigars (Melopsittacus undulatus, either sex), a parakeet species with human-like behavioral sensitivity to many simple and complex sounds. Behavioral sensitivity to tones in band-limited noise was assessed using operant-conditioning procedures. Neural recordings were made in awake animals from midbrain-level neurons in the inferior colliculus, the first processing stage of the ascending auditory pathway with pronounced rate-based encoding of stimulus amplitude modulation. Budgerigar TIN detection thresholds were similar to human thresholds across the full range of frequencies (0.5-4 kHz) and noise levels (45-85 dB SPL) tested. Also as in humans, thresholds were minimally affected by a challenging roving-level condition with random variation in background-noise level. Many midbrain neurons showed a decreasing response rate as TIN signal-to-noise ratio (SNR) was increased by elevating the tone level, a pattern attributable to amplitude-modulation tuning in these cells and the fact that higher SNR tone-plus-noise stimuli have flatter amplitude envelopes. TIN thresholds of individual neurons were as sensitive as behavioral thresholds under most conditions, perhaps surprisingly even when the unit's characteristic frequency was tuned an octave or more away from the test frequency. A model that combined responses of two cell types enhanced TIN sensitivity in the roving-level condition. These results highlight the importance of midbrain-level envelope encoding and off-frequency neural channels for hearing in noise.SIGNIFICANCE STATEMENT Detection of target sounds in noise is often assumed to depend on energy-level encoding by neural processing channels tuned to the target frequency. In contrast, we found that tone-in-noise sensitivity in budgerigars was often greatest in midbrain neurons not tuned to the test frequency, underscoring the potential importance of off-frequency channels for perception. Furthermore, the results highlight the importance of envelope processing for hearing in noise, especially under challenging conditions with random variation in background noise level over time.

Ninjin'yoeito, a traditional Japanese Kampo medicine, suppresses the onset of anhedonia induced by dysfunction in the striatal dopamine receptor type 2-expressing medium spiny neurons.

OBJECTIVE: Recent studies have suggested that ninjin'yoeito (NYT), a traditional Japanese Kampo medicine, improves diminished motivation in humans and animals, rendering it a novel therapeutic option for impaired motivation. To better characterize the effect of NYT on motivation, we examined its effect on motivated behaviors in mice. METHODS: Mouse models of neurodegeneration-related apathy, in which striatal dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) were progressively damaged by diphtheria toxin expression, were chosen. RESULTS: The decrease in effort-based operant responding for rewards (sucrose pellets), indicative of the mouse's motivated behavior, in the affected mice was not suppressed by chronic treatment with NYT suspended in drinking water at 1% (w/v). Mice were then subjected to a sucrose preference test, wherein they freely chose to ingest tap water and a sucrose solution without being required to exert effort. The affected mice showed a decline in preference for sucrose over tap water, relative to nonaffected controls, indicating anhedonia-like traits. In contrast to the diminished operant behavior, the anhedonic behavior in the affected mice was prevented by the NYT administration. Furthermore, NYT did not affect the size of Drd2 mRNA disappearance in the striatum of affected mice, suggesting that the NYT effect was unrelated to DTA-mediated neurodegeneration. CONCLUSION: These results demonstrate that the beneficial effect of NYT on motivation is mediated, at least in part, through the potentiation of hedonic capacity by certain neuromodulatory pathways.

An amygdala-to-hypothalamus circuit for social reward.

Social interactions and relationships are often rewarding, but the neural mechanisms through which social interaction drives positive experience remain poorly understood. In this study, we developed an automated operant conditioning system to measure social reward in mice and found that adult mice of both sexes display robust reinforcement of social interaction. Through cell-type-specific manipulations, we identified a crucial role for GABAergic neurons in the medial amygdala (MeA) in promoting the positive reinforcement of social interaction. Moreover, MeA GABAergic neurons mediate social reinforcement behavior through their projections to the medial preoptic area (MPOA) and promote dopamine release in the nucleus accumbens. Finally, activation of this MeA-to-MPOA circuit can robustly overcome avoidance behavior. Together, these findings establish the MeA as a key node for regulating social reward in both sexes, providing new insights into the regulation of social reward beyond the classic mesolimbic reward system.

Daidzein modulates cocaine-reinforcing effects and cue-induced cocaine reinstatement in CD-1 male mice.

RATIONALE: Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. OBJECTIVES: Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. RESULTS: Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. CONCLUSIONS: Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.

Stability of motor cortex network states during learning-associated neural reorganizations.

A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.NEW & NOTEWORTHY The neural activity reorganizes throughout motor learning, but how this reorganization impacts the stability of network states is unclear. We used two-photon calcium imaging to investigate how the network states in layer 2/3 and layer 5 of forelimb motor and premotor cortex are modulated by motor learning. We show that motor cortex network states are layer-specific and constant regarding criticality during neural activity reorganization, and suggests that layer-specific constraints could be motivated by different functions.

Corticocortical and Thalamocortical Changes in Functional Connectivity and White Matter Structural Integrity after Reward-Guided Learning of Visuospatial Discriminations in Rhesus Monkeys.

The frontal cortex and temporal lobes together regulate complex learning and memory capabilities. Here, we collected resting-state functional and diffusion-weighted MRI data before and after male rhesus macaque monkeys received extensive training to learn novel visuospatial discriminations (reward-guided learning). We found functional connectivity changes in orbitofrontal, ventromedial prefrontal, inferotemporal, entorhinal, retrosplenial, and anterior cingulate cortices, the subicular complex, and the dorsal, medial thalamus. These corticocortical and thalamocortical changes in functional connectivity were accompanied by related white matter structural alterations in the uncinate fasciculus, fornix, and ventral prefrontal tract: tracts that connect (sub)cortical networks and are implicated in learning and memory processes in monkeys and humans. After the well-trained monkeys received fornix transection, they were impaired in learning new visuospatial discriminations. In addition, the functional connectivity profile that was observed after the training was altered. These changes were accompanied by white matter changes in the ventral prefrontal tract, although the integrity of the uncinate fasciculus remained unchanged. Our experiments highlight the importance of different communication relayed among corticocortical and thalamocortical circuitry for the ability to learn new visuospatial associations (learning-to-learn) and to make reward-guided decisions.SIGNIFICANCE STATEMENT Frontal neural networks and the temporal lobes contribute to reward-guided learning in mammals. Here, we provide novel insight by showing that specific corticocortical and thalamocortical functional connectivity is altered after rhesus monkeys received extensive training to learn novel visuospatial discriminations. Contiguous white matter fiber pathways linking these gray matter structures, namely, the uncinate fasciculus, fornix, and ventral prefrontal tract, showed structural changes after completing training in the visuospatial task. Additionally, different patterns of functional and structural connectivity are reported after removal of subcortical connections within the extended hippocampal system, via fornix transection. These results highlight the importance of both corticocortical and thalamocortical interactions in reward-guided learning in the normal brain and identify brain structures important for memory capabilities after injury.

S-EQUOL: a neuroprotective therapeutic for chronic neurocognitive impairments in pediatric HIV.

Chronic neurocognitive impairments, commonly associated with pediatric human immunodeficiency virus type 1 (PHIV), are a detrimental consequence of early exposure to HIV-1 viral proteins. Strong evidence supports S-Equol (SE) as an efficacious adjunctive neuroprotective and/or neurorestorative therapeutic for neurocognitive impairments in adult ovariectomized female HIV-1 transgenic (Tg) rats. There remains, however, a critical need to assess the therapeutic efficacy of SE when treatment occurs at an earlier age (i.e., resembling a therapeutic for children with PHIV) and across the factor of biological sex. Utilization of a series of signal detection operant tasks revealed prominent, sex-dependent neurocognitive deficits in the HIV-1 Tg rat, characterized by alterations in stimulus-reinforcement learning, the response profile, and temporal processing. Early (i.e., postnatal day 28) initiation of SE treatment precluded the development of chronic neurocognitive impairments in all (i.e., 100%) HIV-1 Tg animals, albeit not for all neurocognitive domains. Most notably, the therapeutic effects of SE are generalized across the factor of biological sex, despite the presence of endogenous hormones. Results support, therefore, the efficacy of SE as a neuroprotective therapeutic for chronic neurocognitive impairments in the post-cART era; an adjunctive therapeutic that demonstrates high efficacy in both males and females. Optimizing treatment conditions by evaluating multiple factors (i.e., age, neurocognitive domains, and biological sex) associated with PHIV and HIV-1 associated neurocognitive disorders (HAND) affords a key opportunity to improve the therapeutic efficacy of SE.

Avoiding Based on Shades of Gray: Generalization of Pain-Related Avoidance Behavior to Novel Contexts.

Avoidance behavior is protective, yet in the absence of genuine bodily threat, it may become disabling. Therefore, we investigated whether avoidance generalizes to novel safe contexts based on the similarity with the acquisition context. Healthy participants performed arm movements using a robotic arm to reach a target. Three trajectories (T1-3) led to the target. During acquisition, a painful stimulus could be partly/completely prevented by performing more effortful trajectories (ie, longer and more force needed), T2/T3, in the pain-avoidance context (eg, black background); in the yoked context (eg, white background), the same reinforcement schedule was applied irrespective of the chosen trajectories. Generalization of avoidance was tested in 2 novel contexts (eg, shades of gray backgrounds). We assessed self-reported pain-expectancy and pain-related fear for all trajectories, and avoidance behavior (ie, maximal deviation from T1). Results confirm that fear and expectancy ratings reflect the response-outcome contingencies and differential learning selectively generalized to the novel context resembling the original pain-avoidance context. Furthermore, a linear trend in avoidance behavior across contexts emerged, which is indicative of a generalization gradient. Participants avoided more in the context resembling the original pain-avoidance context than in the one resembling the yoked context, but this effect was not statistically significant. PERSPECTIVE: Perspective: We demonstrated acquisition of pain-related avoidance behavior in a within-subjects design, showing modulation of pain-related fear and pain-expectancy by context and providing limited evidence that avoidance selectively generalizes to novel, similar contexts. These results provide insight regarding the underlying mechanisms of the spreading of protective behavior in chronic pain patients.

Once an Avoider Always an Avoider? Return of Pain-Related Avoidance After Extinction With Response Prevention.

In exposure for chronic pain, avoidance is often forbidden (extinction with response prevention; RPE) to prevent misattributions of safety. Although exposure is an effective treatment, relapse is common. Little is known about the underlying mechanisms of return of pain-related avoidance. We hypothesized that pain-related avoidance would recover when becoming available again after RPE and after unexpected pain episodes ("reinstatement"), especially when restricting avoidance during RPE (compared to instructing not to use it). In an operant pain-related avoidance conditioning paradigm, healthy volunteers used a robotic arm to perform various arm reaching movements differing in pain-effort trade-off. During acquisition, participants learned to avoid pain by performing more effortful movements. During RPE they only performed the formerly pain-associated movement under extinction, and were either forbidden (Restricted group) or merely instructed (Instructed group) not to perform other movements. One day later, we tested spontaneous recovery and reinstatement of pain-related fear and avoidance with availability of all movements. Results showed that pain-related fear and avoidance re-emerge after RPE, though not to pretreatment levels. The reinstatement manipulation had no additional effect. No group differences were observed. We discuss findings in the context of learning processes in (chronic) pain disability and relapse prevention in chronic pain treatment. Perspective: Using experimental models of relapse, we investigated the return of pain-related avoidance behavior after extinction with response prevention. Findings are potentially informative for clinicians performing exposure treatment with chronic pain patients.

A cognitively demanding working-memory intervention enhances extinction Research article.

Improving extinction learning has the potential to optimize psychotherapy for persistent anxiety-related disorders. Recent findings show that extinction learning can be improved with a cognitively demanding eye-movement intervention. It is, however, unclear whether [1] any cognitively-demanding task can enhance extinction, or whether it is limited to eye movements, and [2] the effectiveness of such an intervention can be enhanced by increasing cognitive load. Participants (n = 102, n = 75 included in the final sample) completed a Pavlovian threat conditioning paradigm across two days. One group underwent standard extinction (Control), a second group underwent extinction paired with a 1-back working memory task (Low-Load), and a third group underwent extinction paired with a 2-back working memory task (High-Load). We found that the conditioned response during extinction was reduced for both the Low-Load and the High-Load groups compared to the Control group. This reduction persisted during recovery the following day when no working memory task was executed. Finally, we found that within the High-Load group, participants with lower accuracy scores on the 2-back task (i.e., for who the task was more difficult) had a stronger reduction in the conditioned response. We did not observe this relationship within the Low-Load group. Our findings suggest that cognitive load induced by a working memory intervention embedded during extinction reduces persistent threat responses.

A psychophysical approach to measuring the threshold for acoustic stimulation in zebrafish (Danio rerio).

Zebrafish are a popular vertebrate animal model for biomedical research including investigations of the auditory system. Responses to acoustic stimulation have been a challenge to carefully measure in zebrafish. Here, the authors have developed a procedure for measuring hearing sensitivity in adult zebrafish using an appetitive automated Go/No Go task. In this task, a trial is initiated when a fish passes through an observing gate. In a sound trial, the fish is reinforced by an automated food delivery system when it enters the reinforcement compartment. If the fish enters the reinforcement compartment during a no-sound trial, a timeout is implemented. Zebrafish successfully learned this task in a median of about ten days of daily training. Zebrafish were most sensitive at a frequency of 800 Hz, which corresponds well with sensitivity reported from physiological methods. As far as the authors know, the present study is the first to provide hearing thresholds for zebrafish using a conventional combination of operant conditioning and psychophysical procedures. This could open the door to other kinds of tests using acoustic stimuli as are commonly conducted in many other laboratory animals.

Best sensitivity of temporal modulation transfer functions in laboratory mice matches the amplitude modulation embedded in vocalizations.

The perception of spectrotemporal changes is crucial for distinguishing between acoustic signals, including vocalizations. Temporal modulation transfer functions (TMTFs) have been measured in many species and reveal that the discrimination of amplitude modulation suffers at rapid modulation frequencies. TMTFs were measured in six CBA/CaJ mice in an operant conditioning procedure, where mice were trained to discriminate an 800 ms amplitude modulated white noise target from a continuous noise background. TMTFs of mice show a bandpass characteristic, with an upper limit cutoff frequency of around 567 Hz. Within the measured modulation frequencies ranging from 5 Hz to 1280 Hz, the mice show a best sensitivity for amplitude modulation at around 160 Hz. To look for a possible parallel evolution between sound perception and production in living organisms, we also analyzed the components of amplitude modulations embedded in natural ultrasonic vocalizations (USVs) emitted by this strain. We found that the cutoff frequency of amplitude modulation in most of the individual USVs is around their most sensitive range obtained from the psychoacoustic experiments. Further analyses of the duration and modulation frequency ranges of USVs indicated that the broader the frequency ranges of amplitude modulation in natural USVs, the shorter the durations of the USVs.