Aversive Cues Research Articles

BitterMatch: recommendation systems for matching molecules with bitter taste receptors

Bitterness is an aversive cue elicited by thousands of chemically diverse compounds. Bitter taste may prevent consumption of foods and jeopardize drug compliance. The G protein-coupled receptors for bitter taste, TAS2Rs, have species-dependent number of subtypes and varying expression levels in extraoral tissues. Molecular recognition by TAS2R subtypes is physiologically important, and presents a challenging case study for ligand-receptor matchmaking. Inspired by hybrid recommendation systems, we developed a new set of similarity features, and created the BitterMatch algorithm that predicts associations of ligands to receptors with ~ 80% precision at ~ 50% recall. Associations for several compounds were tested in-vitro, resulting in 80% precision and 42% recall. The encouraging performance was achieved by including receptor properties and integrating experimentally determined ligand-receptor associations with chemical ligand-to-ligand similarities.BitterMatch can predict off-targets for bitter drugs, identify novel ligands and guide flavor design. The novel features capture information regarding the molecules and their receptors, which could inform various chemoinformatic tasks. Inclusion of neighbor-informed similarities improves as experimental data mounts, and provides a generalizable framework for molecule-biotarget matching.Graphical

Sex Differences in the Activity of Basolateral Amygdalar Neurons That Project to the Bed Nucleus of the Stria Terminalis and Their Role in Anticipatory Anxiety.

Abnormal fear and anxiety can manifest as psychiatric disorders. The bed nucleus of the stria terminalis (BNST) is implicated in sustained responding to, or anticipation of, an aversive event which can be expressed as anticipatory anxiety. The BLA is also active during anticipatory anxiety and sends projections to the BNST. However, little is known about the role for BLA neurons that project to BNST (BLA-BNST) in anticipatory anxiety in rodents. To address this, we tested whether chemogenetic inactivation of the BLA-BNST pathway attenuates sustained conditioned responses produced by anticipation of an aversive stimulus. For comparison, we also assessed BLA-BNST inactivation during social interaction, which is sensitive to unlearned anxiety. We found that BLA-BNST inactivation reduced conditioned sustained freezing and increased social behaviors, but surprisingly, only in males. To determine whether sex differences in BLA-BNST neuronal activity contribute to the differences in behavior, we used in vivo and ex vivo electrophysiological approaches. In males, BLA-BNST projection neurons were more active and excitable, which coincided with a smaller after-hyperpolarization current (I AHP) compared with other BLA neurons; whereas in females, BLA-BNST neurons were less excitable and had larger I AHP compared with other BLA neurons. These findings demonstrate that activity of BLA-BNST neurons mediates conditioned anticipatory anxiety-like behavior in males. The lack of a role of BLA-BNST in females in this behavior, possibly because of low excitability of these neurons, also highlights the need for caution when generalizing the role of specific neurocircuits in fear and anxiety.SIGNIFICANCE STATEMENT Anxiety disorders disproportionately affect women. This hints toward sex differences within anxiety neurocircuitry, yet most of our understanding is derived from male rodents. Furthermore, debilitating anticipation of adverse events is among the most severe anxiety symptoms, but little is known about anticipatory anxiety neurocircuitry. Here we demonstrated that BLA-BNST activity is required for anticipatory anxiety to a prolonged aversive cue, but only in males. Moreover, BLA-BNST neurons are hypoactive and less excitable in females. These results uncover BLA-BNST as a key component of anticipatory anxiety circuitry, and cellular differences may explain the sex-dependent role of this circuit. Uncovering this disparity provides evidence that the assumed basic circuitry of an anxiety behavior might not readily transpose from males to females.

Cortico-Striatal Control over Adaptive Goal-Directed Responding Elicited by Cues Signaling Sucrose Reward or Punishment.

The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been associated with the expression of adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, reported effects of mPFC manipulations on cue-elicited natural reward-seeking and inhibition thereof have been varied, with few studies examining cortico-striatal contributions in tasks that require adaptive responding to cues signaling reward and punishment within the same session. The current study aimed to better elucidate the role of mPFC and NAc subdivisions, and their functional connectivity in cue-elicited adaptive responding using a novel discriminative cue responding task. Male Long-Evans rats learned to lever-press on a VR5 schedule for a discriminative cue signaling reward, and to avoid pressing the same lever in the presence of another cue signaling punishment. Postacquisition, prelimbic (PL) and infralimbic (IL) areas of the mPFC, NAc core, shell, PL-core, or IL-shell circuits were pharmacologically or chemogenetically inhibited while animals performed under (1) nonreinforced (extinction) conditions, where the appetitive and aversive cues were presented in alternating trials alone or as a compound stimulus; and (2) reinforced conditions, whereby cued responding was accompanied by associated outcomes. PL and IL inactivation attenuated nonreinforced and reinforced goal-directed cue responding, whereas NAc core and shell inactivation impaired nonreinforced responding for the appetitive, but not aversive cue. Furthermore, PL-core and IL-shell inhibition disinhibited nonreinforced but not reinforced cue responding. Our findings implicate the mPFC as a site of confluence of motivationally significant cues and outcomes, and in the regulation of nonreinforced cue responding via downstream NAc targets.SIGNIFICANCE STATEMENT The ability to discriminate and respond appropriately to environmental cues that signal availability of reward or punishment is essential for survival. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been implicated in adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, less is known about the role they play in orchestrating adaptive responses to natural reward and punishment cues within the same behavioral task. Here, using a novel discriminative cue responding task combined with pharmacological or chemogenetic inhibition of mPFC, NAc and mPFC-NAc circuits, we report that mPFC is critically involved in responding to changing cued response-outcomes, both when the responses are reinforced, and nonreinforced. Furthermore, the mPFC coordinates nonreinforced discriminative cue responding by suppressing inappropriate responding via downstream NAc targets.

In young women, a link between childhood abuse and subliminal processing of aversive cues is moderated by impulsivity

BackgroundChildhood maltreatment is a serious public health concern. The association between child maltreatment, adverse behaviors, mental health outcomes, and alterations to brain function and structure have begun to be characterized. Less is known about the specific associations of maltreatment subtypes with cue-response to evocative cues and the moderating effects of confounding mental health/behavioral variables.MethodsFifty-four emerging adult women (aged 18–24) completed assessments for behaviors, mental health, and childhood maltreatment. They participated in a fMRI task featuring passive viewing of evocative (33 ms) cues presented by “backward masking” to prevent conscious processing. Correlations of abuse/neglect scores, behavioral/mental health factors, and brain function were assessed. Follow-up analyses investigated the moderating effects of behavioral/mental health factors on maltreatment and brain relationships.ResultsGreater frequency of childhood abuse and neglect were correlated with higher scores of impulsivity, depressive symptoms, and anxious attachment. Childhood abuse was positively associated with increased medial orbitofrontal cortical (mOFC) response to aversive (vs. neutral) cues. Among the behavioral/mental health variables, only impulsivity appeared to have a moderating effect on the relationship between childhood abuse and brain response to aversive cues.ConclusionsThe link between childhood abuse and a heightened mOFC response to “unseen” aversive stimuli, moderated by impulsivity, adds to the growing literature on the impact of prior adversity on brain function. These findings offer further understanding for the way in which childhood maltreatment affects the brain processing of negative stimuli, helping to explain the well-documented link between childhood maltreatment and a variety of adverse outcomes in adulthood.

The anterior cingulate cortex directly enhances auditory cortical responses in air-puffing-facilitated flight behavior.

For survival, animals encode prominent events in complex environments, which modulates their defense behavior. Here, we design a paradigm that assesses how a mild aversive cue (i.e., mild air puff) interacts with sound-evoked flight behavior in mice. We find that air puffing facilitates sound-evoked flight behavior by enhancing the auditory responses of auditory cortical neurons. We then find that the anterior part of the anterior cingulate cortex (ACC) encodes the valence of air puffing and modulates the auditory cortex through anatomical examination, physiological recordings, and optogenetic/chemogenetic manipulations. Activating ACC projections to the auditory cortex simulates the facilitating effect of air puffing, whereas inhibiting the ACC or its projections to the auditory cortex neutralizes this facilitating effect. These findings show that the ACC regulates sound-evoked flight behavior by potentiating neuronal responses in the auditory cortex.

Social Regulation of Negative Valence Systems During Development.

The ability to sense, perceive, and respond appropriately to aversive cues is critical for survival. Conversely, dysfunction in any of these pathway components can lead to heightened avoidance of neutral or rewarding cues, such as social partners. The underlying circuitry mediating both negative valence processing and social behavior is particularly sensitive to early life experience, but mechanisms linking experience to pathology remain elusive. Previous research in humans, rodents, and non-human primates has highlighted the unique neurobiology of the developing infant and the role of the caregiver in mediating the infant’s negative valence circuitry, and the importance of this early social relationship for scaffolding lasting social behavior. In this review, we summarize the current literature on the development of negative valence circuits in the infant and their social regulation by the caregiver following both typical and adversity-rearing. We focus on clinically-relevant research using infant rodents which highlights the amygdala and its interface with the mesolimbic dopamine system through innervation from the ventral tegmental area (VTA) as a locus of dysfunction following early-life adversity. We then describe how these circuits are recruited to perturb life-long social behavior following adversity and propose additional therapeutic targets in these circuits with an eye toward developing age-appropriate interventions.

Trial-wise exposure to visual emotional cues increases physiological arousal but not temporal discounting.

Humans and many animals devalue future rewards as a function of time (temporal discounting). Increased discounting has been linked to various psychiatric conditions, including substance-use-disorders, behavioral addictions, and obesity. Despite its high intra-individual stability, temporal discounting is partly under contextual control. One prominent manipulation that has been linked to increases in discounting is the exposure to highly arousing appetitive cues. However, results from trial-wise cue exposure studies appear highly mixed, and changes in physiological arousal were not adequately controlled. Here we tested the effects of appetitive (erotic), aversive, and neutral visual cues on temporal discounting in 35 healthy male participants. The contribution of single-trial physiological arousal was assessed using comprehensive monitoring of autonomic activity (pupil size, heart rate, electrodermal activity). Physiological arousal was elevated following aversive and in particular erotic cues. In contrast to our pre-registered hypothesis, steepness of temporal discounting was not significantly affected by emotional cues of either valence. Aversive cues tended to increase decision noise. Computational modeling revealed that trial-wise arousal only accounted for minor variance over and above aversive and erotic condition effects, arguing against a general effect of physiological arousal on temporal discounting.

A lexical approach for identifying behavioural action sequences.

Animals display characteristic behavioural patterns when performing a task, such as the spiraling of a soaring bird or the surge-and-cast of a male moth searching for a female. Identifying such recurring sequences occurring rarely in noisy behavioural data is key to understanding the behavioural response to a distributed stimulus in unrestrained animals. Existing models seek to describe the dynamics of behaviour or segment individual locomotor episodes rather than to identify the rare and transient sequences of locomotor episodes that make up the behavioural response. To fill this gap, we develop a lexical, hierarchical model of behaviour. We designed an unsupervised algorithm called "BASS" to efficiently identify and segment recurring behavioural action sequences transiently occurring in long behavioural recordings. When applied to navigating larval zebrafish, BASS extracts a dictionary of remarkably long, non-Markovian sequences consisting of repeats and mixtures of slow forward and turn bouts. Applied to a novel chemotaxis assay, BASS uncovers chemotactic strategies deployed by zebrafish to avoid aversive cues consisting of sequences of fast large-angle turns and burst swims. In a simulated dataset of soaring gliders climbing thermals, BASS finds the spiraling patterns characteristic of soaring behaviour. In both cases, BASS succeeds in identifying rare action sequences in the behaviour deployed by freely moving animals. BASS can be easily incorporated into the pipelines of existing behavioural analyses across diverse species, and even more broadly used as a generic algorithm for pattern recognition in low-dimensional sequential data.

The role of early attachment and parental presence in adolescent behavioral and neurobiological regulation

Early attachment shapes brain development underlying emotion regulation. Given that sensitivity to affective cues is heightened during adolescence and effective emotion regulation strategies continue to develop, it is imperative to examine the role of early attachment and parental influence on adolescent regulation. Fifty-one children (M age=32.61 months) participated in a modified Strange Situation with their mother and approximately 10 years later (M age =13.2 years) completed an fMRI scan during which they were presented with appetitive and aversive affective cues (images of adolescent interactions) during a Go-Nogo task. They completed the task alone and in the presence of a parent. Behavioral multilevel models and whole-brain analyses showed attachment-related patterns, such that affective cues elicited greater behavioral and neural dysregulation in insecure (versus secure) adolescents.Furthermore, parental presence buffered behavioral and neural dysregulation toward socially aversive cues for adolescents with early insecure attachment, underscoring the salience of caregivers across development in promoting regulation in their offspring

Specialized neurons in the right habenula mediate response to aversive olfactory cues.

Hemispheric specializations are well studied at the functional level but less is known about the underlying neural mechanisms. We identified a small cluster of cholinergic neurons in the dorsal habenula (dHb) of zebrafish, defined by their expression of the lecithin retinol acyltransferase domain containing 2 a (lratd2a) gene and their efferent connections with a subregion of the ventral interpeduncular nucleus (vIPN). The lratd2a-expressing neurons in the right dHb are innervated by a subset of mitral cells from both the left and right olfactory bulb and are activated upon exposure to the odorant cadaverine that is repellent to adult zebrafish. Using an intersectional strategy to drive expression of the botulinum neurotoxin specifically in these neurons, we find that adults no longer show aversion to cadaverine. Mutants with left-isomerized dHb that lack these neurons are also less repelled by cadaverine and their behavioral response to alarm substance, a potent aversive cue, is diminished. However, mutants in which both dHb have right identity appear more reactive to alarm substance. The results implicate an asymmetric dHb-vIPN neural circuit in the processing of repulsive olfactory cues and in modulating the resultant behavioral response.

Emotional reactivity to binge food and erotic cues in women with bulimia nervosa symptoms

BackgroundStudies on food cue reactivity have documented that altered responses to high-calorie food are associated with bulimic symptomatology, however, alterations in sexual motivations and behaviors are also associated clinical features in this population, which justify their inclusion as a research target. Here, we study responses to erotic cues—alongside food, neutral and aversive cues—to gain an understanding of specificity to food versus a generalized sensitivity to primary reinforcers.MethodsWe recorded peripheral psychophysiological indices –the startle reflex, zygomaticus, and corrugator responses—and self-reported emotional responses (valence, arousal, and dominance) in 75 women completing the Bulimia Test-Revised (BULIT-R). Multiple regression analysis tested whether BULIT-R symptoms were predicted by self-reported and psychophysiological responses to food versus neutral and erotic versus neutral images.ResultsThe results showed that individuals with higher bulimic symptoms were characterized by potentiated eye blink startle response during binge food (vs. neutral images) and more positive valence ratings during erotic (vs. neutral) cues.ConclusionsThe results highlight the negative emotional reactivity of individuals with elevated bulimic symptoms toward food cues, which could be related to the risk of progression to full bulimia nervosa and thereby addressed in prevention efforts. Results also point to the potential role of reactivity to erotic content, at least on a subjective level. Theoretical models of eating disorders should widen their conceptual scope to consider reactivity to a broader spectrum of primary reinforcers, which would have implications for cue exposure-based treatments.Plain English summaryWe examined appetitive and aversive cue responses in college women to investigate how bulimic symptoms relate to primary reinforcers such as food and erotic images. We recorded peripheral psychophysiological indices (the startle reflex, zygomaticus, and corrugator responses) and self-reported emotional responses (valence, arousal, and dominance) in 75 college women that were presented with the Spanish version of the Bulimia Test-Revised. The results showed that bulimic symptoms increase both psychophysiological defensiveness toward food cues and subjective pleasure toward erotic cues. The findings suggest a generalized sensitivity to primary reinforcers in the presence of bulimic symptoms, and emphasize the relevance of adopting a wider framework in research and treatment on bulimia nervosa.

Avoidance of the Plant Hormone Cis-Jasmone by Aedes aegypti Depends On Mosquito Age in Both Plant and Human Odor Backgrounds

Adults of many mosquito species feed on plants to obtain metabolic energy and to enhance reproduction. Mosquitoes primarily rely on olfaction to locate plants and are known to respond to a range of plant volatiles. We studied the olfactory response of the yellow fever mosquito Aedes aegypti to methyl jasmonate (MeJA) and cis-jasmone (CiJA), volatile compounds originating from the octadecanoid signaling pathway that plays a key role in plant defense against herbivores. Specifically, we investigated how Ae. aegypti of different ages responded to elevated levels of CiJA in two attractive odor contexts, either derived from Lima bean plants or human skin. Aedes aegypti females landed significantly less often on a surface with CiJA and MeJA compared to the solvent control, CiJA exerting a stronger reduction in landing than MeJA. Odor context (plant or human) had no significant main effect on the olfactory responses of Ae. aegypti females to CiJA. Mosquito age significantly affected the olfactory response, older females (7–9 d) responding more strongly to elevated levels of CiJA than young females (1–3 d) in either odor context. Our results show that avoidance of CiJA by Ae. aegypti is independent of odor background, suggesting that jasmonates are inherently aversive cues to these mosquitoes. We propose that avoidance of plants with elevated levels of jasmonates is adaptive to mosquitoes to reduce the risk of encountering predators that is higher on these plants, i.e. by avoiding ‘enemy-dense-space’.

Npas4a expression in the teleost forebrain is associated with stress coping style differences in fear learning

Learning to anticipate potentially dangerous contexts is an adaptive behavioral response to coping with stressors. An animal’s stress coping style (e.g. proactive–reactive axis) is known to influence how it encodes salient events. However, the neural and molecular mechanisms underlying these stress coping style differences in learning are unknown. Further, while a number of neuroplasticity-related genes have been associated with alternative stress coping styles, it is unclear if these genes may bias the development of conditioned behavioral responses to stressful stimuli, and if so, which brain regions are involved. Here, we trained adult zebrafish to associate a naturally aversive olfactory cue with a given context. Next, we investigated if expression of two neural plasticity and neurotransmission-related genes (npas4a and gabbr1a) were associated with the contextual fear conditioning differences between proactive and reactive stress coping styles. Reactive zebrafish developed a stronger conditioned fear response and showed significantly higher npas4a expression in the medial and lateral zones of the dorsal telencephalon (Dm, Dl), and the supracommissural nucleus of the ventral telencephalon (Vs). Our findings suggest that the expression of activity-dependent genes like npas4a may be differentially expressed across several interconnected forebrain regions in response to fearful stimuli and promote biases in fear learning among different stress coping styles.

Acquiring favorable attitudes based on aversive affective cues: Examining the spontaneity and efficiency of propositional evaluative conditioning

Most research in evaluative conditioning (EC) documents that a target object (conditioned stimulus, CS) acquires the same valence as a co-occurring affective cue (unconditioned stimulus, US). Some recent studies in EC have found that a CS may acquire the opposite valence as a US when people process a negational relation between the CS and the US, supporting a propositional learning mechanism for EC. However, these prior studies involved explicitly instructing respondents to assume that the CS opposes (e.g., “prevents”) the presented US. The present studies investigate whether and when people will spontaneously process an implied negational relation between co-occurring stimuli (e.g., CS = a flu-vaccine brand, US = sickness cue) in the absence of instructions. Across four studies examining the effects of aversive cues in ads promoting vaccine products, we find that using aversive cues can enhance attitudes towards a co-occurring vaccine brand even when there is no explicit instruction that directs people to assume a negational relation between co-occurring stimuli, reflecting the spontaneity of propositional evaluative learning. However, these positive effects of aversive cues on brand attitudes occurred only when people were under a low attentional load. When load was high, aversive cues were ineffective for enhancing (and even showed a more negative impact than neutral cues on) attitudes towards a vaccine brand, indicating the relative inefficiency of propositional learning of a negational relation.

Stress during Commercial Hatchery Processing Induces Long-Time Negative Cognitive Judgement Bias in Chickens.

Simple SummaryWorldwide, billions of laying hen chicks are incubated, hatched and processed in industrial hatcheries every year. When exposed to stress, hormones are incorporated in the feathers of the birds. Here, we measured levels of the stress hormone corticosterone to investigate possible stress during the incubation. Further, animals can perceive their environment either in a positive (optimistic) or a negative (pessimistic) way. We investigated how the early hatchery experiences affects “optimism” and “pessimism”. Commercially hatched chicks were exposed to a positive cue, an aversive cue, and ambiguous cues, in order to evaluate the cognitive welfare state of the animals. These chicks were compared to a group of non-stressed animals. Commercially incubated chicks did not have elevated levels of feather corticosterone, which implies that the main part of the stress effects from the hatchery originates from the period around hatch. Latencies to approach ambiguous cues were longer for the stressed chicks, i.e., these showed a more pessimistic-like behaviour. We conclude that the main part of the stress effects in commercially hatched chicks originates in the period around hatch, and further, that these birds show lasting levels of increased pessimism. This strongly indicates a long-time poorer welfare state for the animals.Worldwide, billions of laying hen chicks are incubated and processed under highly industrialised circumstances every year, which, as we have previously shown, has long-lasting effects. Here, we measured corticosterone incorporated in down feathers to investigate possible stress during the incubation and showed that commercially incubated chicks did not have elevated levels of feather corticosterone, which implies that the main part of the stress effects from hatchery originates from the perinatal period and the handling immediately post-hatch. Further, we investigated how the early hatchery stress affects the chicks’ cognitive welfare state, i.e., “optimism” and “pessimism”. We exposed commercially hatched chickens to a positive cue, an aversive cue and ambiguous cues. The birds were tested at 1 and 10 w of age and the behaviour was compared with that of non-stressed chicks. Latencies to approach ambiguous cues were longer for the stressed chicks, both at 1 (p = 0.008) and at 10 (p = 0.020) weeks of age, i.e., these showed a more pessimistic-like behaviour. We conclude that the main part of the stress effects in commercially hatched chicks originates in the perinatal period, and further, that these birds show lasting levels of increased pessimism. This strongly indicates a long-time poorer welfare state for the animals.

Contributions of aversive environmental stress to migraine chronification: Research update of migraine pathophysiology.

Clinical studies have suggested that internal and/or external aversive cues may produce a negative affective-motivational component whereby maladaptive responses (plasticity) of dural afferent neurons are initiated contributing to migraine chronification. However, pathophysiological processes and neural circuitry involved in aversion (unpleasantness)-producing migraine chronification are still evolving. An interdisciplinary team conducted this narrative review aimed at reviewing neuronal plasticity for developing migraine chronicity and its relevant neurocircuits and providing the most cutting-edge information on neuronal mechanisms involved in the processing of affective aspects of pain and the role of unpleasantness evoked by internal and/or external cues in facilitating the chronification process of migraine headache. Thus, information presented in this review promotes the understanding of the pathophysiology of chronic migraine and contribution of unpleasantness (aversion) to migraine chronification. We hope that it will bring clinicians’ attention to how the maladaptive neuroplasticity of the emotion brain in the aversive environment produces a significant impact on the chronification of migraine headache, which will in turn lead to new therapeutic strategies for this type of pain.

Dorsal Raphe Dopamine Neurons Signal Motivational Salience Dependent on Internal State, Expectation, and Behavioral Context.

The ability to recognize motivationally salient events and adaptively respond to them is critical for survival. Here, we tested whether dopamine (DA) neurons in the dorsal raphe nucleus (DRN) contribute to this process in both male and female mice. Population recordings of DRNDA neurons during associative learning tasks showed that their activity dynamically tracks the motivational salience, developing excitation to both reward-paired and shock-paired cues. The DRNDA response to reward-predicting cues was diminished after satiety, suggesting modulation by internal states. DRNDA activity was also greater for unexpected outcomes than for expected outcomes. Two-photon imaging of DRNDA neurons demonstrated that the majority of individual neurons developed activation to reward-predicting cues and reward but not to shock-predicting cues, which was surprising and qualitatively distinct from the population results. Performing the same fear learning procedures in freely-moving and head-fixed groups revealed that head-fixation itself abolished the neural response to aversive cues, indicating its modulation by behavioral context. Overall, these results suggest that DRNDA neurons encode motivational salience, dependent on internal and external factors.SIGNIFICANCE STATEMENT Dopamine (DA) contributes to motivational control, composed of at least two functional cell types, one signaling for motivational value and another for motivational salience. Here, we demonstrate that DA neurons in the dorsal raphe nucleus (DRN) encode the motivational salience in associative learning tasks. Neural responses were dynamic and modulated by the animal's internal state. The majority of single-cells developed responses to reward or paired cues, but not to shock-predicting cues. Additional experiments with freely-moving and head-fixed mice showed that head-fixation abolished the development of cue responses during fear learning. This work provides further characterization on the functional roles of overlooked DRNDA populations and an example that neural responses can be altered by head-fixation, which is commonly used in neuroscience.

Ventral pallidum neurons dynamically signal relative threat

The ventral pallidum (VP) is anatomically poised to contribute to threat behavior. Recent studies report a VP population that scales firing increases to reward but decreases firing to aversive cues. Here, we tested whether firing decreases in VP neurons serve as a neural signal for relative threat. Single-unit activity was recorded while male rats discriminated cues predicting unique foot shock probabilities. Rats’ behavior and VP single-unit firing discriminated danger, uncertainty, and safety cues. Two populations of VP neurons dynamically signaled relative threat, decreasing firing according to foot shock probability during early cue presentation, but disproportionately decreasing firing to uncertain threat as foot shock drew near. One relative threat population increased firing to reward, consistent with a bi-directional signal for general value. The second population was unresponsive to reward, revealing a specific signal for relative threat. The results reinforce anatomy to reveal the VP as a neural source of a dynamic, relative threat signal.

Response Processes to Looming Appetitive and Aversive Cues in Euthymic Bipolar Patients and Their First-Degree Relatives: An Exploratory Study.

Background:Patients with bipolar disorder demonstrate increased sensitivity to appetitive/rewarding stimuli even during euthymia. On presentation of arousing pictures, they show a peculiar response, suggesting heightened vigilance. While responding to looming arousing cues, studies show subjects with anxiety spectrum disorders exhibit increased reaction time (RT), explained by the “looming-vulnerability model.” This study aimed to investigate the responses to looming arousing cues in euthymic bipolar patients and their first-degree relatives, as compared to healthy controls.Method:A looming appetitive and aversive cue paradigm was designed for assessing the RT of patients to process appetitive and aversive cues. The behavioral inhibition/activation and sensitivity to reward/punishment amongst the groups were also assessed.Results:The bipolar group showed significantly longer RT to process appetitive cues irrespective of the looming condition. Aversive cues elicited significantly longer RT in both the bipolar group and in first-degree relatives, but only when presented with the looming condition. Significant looming bias was elicited in the bipolar group which suggested a particular cognitive style to looming cues. A composite measure of RT along with sensitivity to reward/punishment distinguishes the bipolar group and their first-degree relatives from the healthy controls.Conclusion:The looming vulnerability model may provide important insights for future exploration of cognitive endophenotypes in bipolar disorder.

Signal Decoding for Glutamate Modulating Egg Laying Oppositely in Caenorhabditis elegans under Varied Environmental Conditions.

SummaryAnimals' ability to sense environmental cues and to integrate this information to control fecundity is vital for continuing the species lineage. In this study, we observed that the sensory neurons Amphid neuron (ASHs and ADLs) differentially regulate egg-laying behavior in Caenorhabditis elegans under varied environmental conditions via distinct neuronal circuits. Under standard culture conditions, ASHs tonically release a small amount of glutamate and inhibit Hermaphrodite specific motor neuron (HSN) activities and egg laying via a highly sensitive Glutamate receptor (GLR)-5 receptor. In contrast, under Cu2+ stimulation, ASHs and ADLs may release a large amount of glutamate and inhibit Amphid interneuron (AIA) interneurons via low-sensitivity Glutamate-gated chloride channel (GLC)-3 receptor, thus removing the inhibitory roles of AIAs on HSN activity and egg laying. However, directly measuring the amount of glutamate released by sensory neurons under different conditions and assaying the binding kinetics of receptors with the neurotransmitter are still required to support this study directly.