An analysis of reinstatement after extinction of a conditioned taste aversion.

Taste aversion learning has sometimes been considered a specialized form of learning. In several other conditioning preparations, after a conditioned stimulus (CS) is conditioned and extinguished, reexposure to the unconditioned stimulus (US) by itself can reinstate the extinguished conditioned response. Reinstatement has been widely studied in fear and appetitive Pavlovian conditioning, as well as operant conditioning, but its status in taste aversion learning is more controversial. Six taste-aversion experiments with rats therefore sought to discover conditions that might encourage it there. The results often yielded little to no evidence of reinstatement, and we also found no evidence of concurrent recovery, a related phenomenon in which responding to a CS that has been conditioned and extinguished is restored if a second CS is separately conditioned. However, a key result was that reinstatement occurred when the conditioning procedure involved multiple closely spaced conditioning trials that could have allowed the animal to learn that a US presentation signaled or set the occasion for another trial with a US. Such a mechanism is precluded in many taste aversion experiments because they often use very few conditioning trials. Overall, the results suggest that taste aversion learning is experimentally unique, though not necessarily biologically or evolutionarily unique. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Social neuroscience: How we learn to avoid the bully.

During social interactions, individuals evaluate relationships with their peers and switch from approach to avoidance, particularly in response to aggressive encounters. A new study in mice investigated the underlying brain mechanisms and identified oxytocin as a key regulator of social avoidance learning.

The Neural Correlates of Individual Differences in Reinforcement Learning during Pain Avoidance and Reward Seeking.

Organisms learn to gain reward and avoid punishment through action-outcome associations. Reinforcement learning (RL) offers a critical framework to understand individual differences in this associative learning by assessing learning rate, action bias, pavlovian factor (i.e., the extent to which action values are influenced by stimulus values), and subjective impact of outcomes (i.e., motivation to seek reward and avoid punishment). Nevertheless, how these individual-level metrics are represented in the brain remains unclear. The current study leveraged fMRI in healthy humans and a probabilistic learning go/no-go task to characterize the neural correlates involved in learning to seek reward and avoid pain. Behaviorally, participants showed a higher learning rate during pain avoidance relative to reward seeking. Additionally, the subjective impact of outcomes was greater for reward trials and associated with lower response randomness. Our imaging findings showed that individual differences in learning rate and performance accuracy during avoidance learning were positively associated with activities of the dorsal anterior cingulate cortex, midcingulate cortex, and postcentral gyrus. In contrast, the pavlovian factor was represented in the precentral gyrus and superior frontal gyrus (SFG) during pain avoidance and reward seeking, respectively. Individual variation of the subjective impact of outcomes was positively predicted by activation of the left posterior cingulate cortex. Finally, action bias was represented by the supplementary motor area (SMA) and pre-SMA whereas the SFG played a role in restraining this action tendency. Together, these findings highlight for the first time the neural substrates of individual differences in the computational processes during RL.

Nucleus accumbens neurons dynamically respond to appetitive and aversive associative learning.

To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined. Here, we investigated the relevance of D1- and D2-neurons in associative learning, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks in mice. Sucrose was used as a positive valence unconditioned stimulus (US) and foot shock was used as a negative valence US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general increase in activity in response to the conditioned stimuli (CS). Interestingly, D1- and D2-neurons present distinct changes in activity after sucrose consumption that dynamically evolve throughout learning. During the aversive Pavlovian conditioning, D1- and D2-neurons present an increase in the activity in response to the CS and to the US (shock). Our data support a model in which D1- and D2-neurons are concurrently activated during appetitive and aversive conditioning.

Top-down control of flight by a non-canonical cortico-amygdala pathway.

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder1. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.

Persistent avoidance of virtual food in anorexia nervosa-restrictive type: Results from motion tracking in a virtual stopping task.

OBJECTIVE: Food avoidance is central to patients with anorexia nervosa-restrictive type (AN-R). Competing accounts in experimental psychopathology research suggest that food avoidance may result from automatic, habitual responses or from elevated inhibitory control abilities. This study investigated behavioral trajectories of food avoidance in a novel virtual reality stopping task. METHOD: Sixty patients with AN-R and 29 healthy controls with normal weight were investigated using a novel, kinematic task in virtual reality. We recorded spatial displacement in stop- and go-trials to virtual food and control objects. Inhibitory control abilities were operationalized by the VR task in stopping performance (i.e., interrupted movement in stop-trials), whereas we also measured habitual avoidance of virtual food across both go- and stop-trials (i.e., delayed movement relative to nonfood objects). RESULTS: In patients with AN-R, hand displacements were shorter to food versus nonfood across stop- and go-trials, reflected in a Stimulus × Group interaction. Healthy controls showed no differences. Importantly, the food-specific effect in AN-R was identical across stop- and go-trials, indicating habitual food avoidance. Moreover, stop error rates (i.e., stop-trials with response) were lower in patients with AN-R. DISCUSSION: The findings suggest food-specific habitual avoidance and heightened generalized inhibitory control in AN-R. The continuously delayed displacements during active hand movements across stop- and go-trials indicated the persistence of patients' avoidance of food. PUBLIC SIGNIFICANCE: Experimental research investigates the mechanisms underlying mental disorders such as anorexia nervosa. In this study, we measured interrupted hand movements in response to food pictures or neutral pictures (shoes) in patients with anorexia nervosa and healthy controls. A virtual reality scenario was used. Findings indicated that patients were slower at approaching food, interrupted or not. Key mechanisms of food avoidance can be translated into habit-based treatment options in future research.

A dedicated hypothalamic oxytocin circuit controls aversive social learning.

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.

Prefrontal Regulation of Safety Learning during Ethologically Relevant Thermal Threat.

Learning and adaptation during sources of threat and safety are critical mechanisms for survival. The prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) have been broadly implicated in the processing of threat and safety. However, how these regions regulate threat and safety during naturalistic conditions involving thermal challenge still remains elusive. To examine this issue, we developed a novel paradigm in which adult mice learned that a particular zone that was identified with visuospatial cues was associated with either a noxious cold temperature ("threat zone") or a pleasant warm temperature ("safety zone"). This led to the rapid development of avoidance behavior when the zone was paired with cold threat or approach behavior when the zone was paired with warm safety. During a long-term test without further thermal reinforcement, mice continued to exhibit robust avoidance or approach to the zone of interest, indicating that enduring spatial-based memories were formed to represent the thermal threat and thermal safety zones. Optogenetic experiments revealed that neural activity in PL and IL was not essential for establishing the memory for the threat zone. However, PL and IL activity bidirectionally regulated memory formation for the safety zone. While IL activity promoted safety memory during normal conditions, PL activity suppressed safety memory especially after a stress pretreatment. Therefore, a working model is proposed in which balanced activity between PL and IL is favorable for safety memory formation, whereas unbalanced activity between these brain regions is detrimental for safety memory after stress.

Characterization of taste sensitivities to amino acids and sugars by conditioned taste aversion learning in chickens.

Taste plays an essential role in regulating the feeding behaviors of animals. The present study aimed to characterize the taste sensory profiles of amino acids and sugars in chickens. To achieve this, we employed a conditioned taste aversion learning method, which is characterized by a specific pairing of gastrointestinal malaise and taste perception. Our findings revealed that chickens were able to learn to avoid L-Val, L-Lys, and L-His through conditioned taste aversion learning, and exhibited a strong aversion to L-Arg. These results suggest that chickens are primarily sensitive to basic amino acids, including L-Lys, which is a crucial limiting amino acid in feeds. Interstingly, this sensitivity to basic amino acids in chickens contrasts with humans, who are mainly sensitive to acidic amino acids as umami taste. Furthermore, despite the absence of a mammalian sweet taste receptor gene in the chicken genome, we demonstrated that chickens learned to avoid glucose, galactose, sucrose, and maltose by conditioned taste aversion learning. Taken together, the present study provides the idea that chickens possess a gustatory perception toward specific amino acids and sugars for the detection of beneficial nutrients in their feeds.

Schizophrenia-relevant social, attentional and cognitive traits in female RHA vs. RLA rats: Effects of neonatal handling.

The Roman high- (RHA) and low-avoidance (RLA) rats were bidirectionally selected and bred for, respectively, their rapid vs. extremely poor acquisition in the two-way active avoidance task. Consistent between-strain neurobehavioural differences have been found in anxiety- and stress-linked traits, as well as in schizophrenia-related phenotypes. RLAs display enhanced anxious- and stress-related phenotypes, whereas RHA rats show impulsivity, hyperactivity and attention/cognition-related impairments. Many of these typical behavioural phenotypes have been reported to be positively modulated by environmental treatments such as neonatal handling (NH). However, most studies on the Roman rat strains have been carried out in males. Thus, the present study for the first time focused on the joint evaluation of differences in novel object exploration (NOE), social interaction (SI), prepulse inhibition of the startle response (PPI), and cognitive performance and flexibility in various spatial tasks (using the Morris water maze, MWM) in females of both Roman rat strains. We also aimed at evaluating the long-lasting effects of NH treatment on the RHA vs. RLA profiles in these tests/tasks. Results show that anxiety-related behavior, as measured by the NOE test and self-grooming in the SI test, was increased in RLA rats, and dramatically reduced by NH. In the SI test RLA rats displayed diminished social interaction, which was rescued by NH. RHA females exhibited a deficit of PPI, which was not affected by NH. Spatial tasks in the MWM showed impairments of working memory, reference learning/memory and spatial reversal learning (i.e., cognitive flexibility) in RHA females. Spatial reference learning and cognitive flexibility (i.e., reversal task) showed some improvement in rats (mainly in RHAs) that had received NH during the first three weeks of life. With the exception of the SI test, the pattern of differences between female RHA vs. RLA profiles was overall consistent with what has previously been found in males of both strains, and NH treatment was able to enduringly improve some emotion-related and (spatial) cognitive outcomes in both strains.

High-Anxious People Generalize Costly Pain-Related Avoidance Behavior More to Novel Safe Contexts Compared to Low-Anxious People.

Pain-related avoidance is adaptive when there is a bodily threat, but when it generalizes to safe movements/situations, it may become disabling. Both subclinical anxiety-a vulnerability marker for chronic pain-and chronic pain are associated with excessive fear generalization to safe stimuli/situations. Previous research focused mainly on passive fear correlates (psychophysiological arousal and self-reports) leaving avoidance behavior poorly understood. Therefore, we tested whether high-anxious individuals generalize their pain-related avoidance behavior more to novel, safe contexts than low-anxious people. In a robotic-arm-reaching task, both groups (low vs high trait anxiety) performed 1 of 3 movements to reach a target. In the threat context (black background), a painful stimulus could be partly/completely prevented by performing more effortful trajectories (longer and more force needed); in the safe context (white background), no pain occurred. Generalization of avoidance was tested in 2 novel contexts (light/dark gray backgrounds). We assessed pain expectancy, pain-related fear, startle eyeblink responses for all trajectories, and avoidance behavior (ie, maximal deviation from shortest trajectory). Results indicated that differential fear and expectancy selectively generalized to the novel context resembling the original threat context in both groups. Interestingly and in contrast with the verbal reports, high-anxious participants avoided more in the novel context resembling the original safe context, but not in the 1 resembling the threat context. No generalization emerged in the startle data. Because excessive pain-related avoidance specifically may cause withdrawal from daily life activities, these findings suggest that high-anxious individuals may be vulnerable to developing chronic pain disability. PERSPECTIVE: This paper shows that high-anxious people do not overgeneralize pain-related fear and pain expectancy learned in a threat context more to novel, safe contexts than low-anxious individuals, but that they do avoid more in those contexts. These findings suggest that high-anxious individuals may be vulnerable to developing chronic pain disability.

Itsy bitsy spider: Fear and avoidance (generalization) in a free-exploratory virtual reality paradigm.

Most experimental avoidance paradigms lack either control over the experimental situation or simplify real-life avoidance behavior to a great extent, making it difficult to generalize the results to the complex approach-avoidance situations that anxious individuals face in daily life. The current study aimed to examine the usability of our recently developed free-exploratory avoidance paradigm in Virtual Reality (VR) that allows for the assessment of subjective as well as behavioral avoidance in participants with varying levels of spider fear. In a VR escape room, participants searched for cues to decipher a code-locked door. Opening a wooden box marked with a post-it note (conditioned stimulus, CS) resulted in exposure to a virtual crawling spider (unconditioned stimulus, US). Avoidance of the original CS and other objects marked with the CS (generalization stimuli, GSs; EXPgen condition) or non-marked (CONT condition) objects was measured via questionnaires and relative manipulation times in a novel room. We expected a positive linear relationship between US aversiveness (levels of spider fear) and (generalization of) fear and avoidance behaviors. Avoidance learning and generalization was demonstrated on both a subjective and behavioral level. Higher levels of spider fear were, overall, related to more negative emotions in response to the encounter with the spider, higher US expectancies for the GSs, and more self-reported and behavioral avoidance of the original CS and the GSs. Finally, we explored relationships between trait anxiety and intolerance of uncertainty and fear and avoidance (generalization), but no robust associations were observed. In conclusion, we confirmed the expected positive linear relationship between spider fear and (generalization of) fear and avoidance behaviors. Our results suggest that our free-exploratory VR avoidance paradigm is well-suited to investigate avoidance behaviors and the generalization of avoidance.

Sex divergent behavioral responses in platform-mediated avoidance and glucocorticoid receptor blockade.

Women are more likely than men to develop anxiety or stress-related disorders. A core behavioral symptom of all anxiety disorders is avoidance of fear or anxiety eliciting cues. Recent rodent models of avoidance show reliable reproduction of this behavioral phenomenon in response to learned aversive associations. Here, a modified version of platform-mediated avoidance that lacked an appetitive task was utilized to investigate the learning and extinction of avoidance in male and female C57BL6/J mice. Here, we found a robust sex difference in the acquisition and extinction of platform-mediated avoidance. Across three experiments, 63.7% of female mice acquired avoidance according to our criterion, whereas 83.8% of males acquired it successfully. Of those females that acquired avoidance, they displayed persistent avoidance after extinction compared to males. Given their role in regulating stress responses and habitual behaviors, we investigated if glucocorticoid receptors (GR) mediated avoidance learning in males and females. We found that a subcutaneous injection (25 mg/kg) of the GR antagonist, RU486 (Mifepristone), significantly reduced persistent avoidance in females but did not further reduce avoidance in males after extinction. These data suggest that GR activation during avoidance learning may contribute to persistent avoidance in females that is resistant to extinction.

Activation of multiple neuromodulatory systems in alert rats acquiring conditioned taste aversion revealed by positron emission tomography.

Conditioned taste aversion (CTA) is an essential ability for animals to consume food safely and is regulated by neuromodulatory systems including the dopamine, noradrenaline, serotonin, and acetylcholine systems. However, because few studies focused on a comprehensive understanding of whole-brain activities, how these neuromodulators contribute to the process of CTA remains an open issue. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can visualize activated regions within the whole brain simultaneously and noninvasively. This study aimed to understand the mechanisms of CTA, especially focusing on the retrieval process after CTA acquisition by FDG-PET imaging. CTA was established in rats who received an intraoral application of saccharin solution (IOAS) on the first day (Day 1), a LiCl i.p. injection after an IOAS on Day 2, and an IOAS on Day 3 (CTA group). The subtraction images of Day 3 of the SHAM group, which received a 0.9 % NaCl (saline) injection instead of a LiCl on Day 2, from those of Day 3 of the CTA group revealed increases in FDG signals in multiple brain regions including the substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and nucleus basalis magnocellularis, in addition to the hippocampus and nociception-related regions, including the parabrachial nucleus and solitary nucleus. On the other hand, the visceral pain induced by the LiCl injection increased FDG signals in the primary and secondary somatosensory and insular cortices in addition to the parabrachial nucleus and solitary nucleus. These results suggest that the retrieval process of CTA induces brain regions producing neuromodulators and pain-related brainstem.

Lateral Habenula Neurons Signal Cold Aversion and Participate in Cold Aversion.

The aversion to cold is a fundamental motivated behavior that contributes to the body temperature homeostasis. However, the involvement of the lateral habenula (LHb) as a regulatory hub for negative emotions in this physiological process remains uninvestigated. In this study, we demonstrate an elevation in the population activity of LHb neurons following exposure to cold stimuli. Additionally, we establish the necessity of Vglut2-expressing neurons within the LHb for the encoding of cold aversion behaviors. Furthermore, we have elucidated a neural circuit from excitatory neurons of the dorsomedial hypothalamus (DMH) to LHb that plays a crucial role in this progress. Manipulation of the DMH-LHb circuit has a significant impact on cold aversion behavior in mice. It is worth noting that this circuit does not exhibit any noticeable effects on autonomic thermoregulation or depression-like behavior. The identification of these neural mechanisms involved in behavioral thermoregulation provides a promising avenue for future research.

State-dependent modulation of positive and negative affective valences by a parabrachial nucleus-to-ventral tegmental area pathway in mice.

Appropriately responding to various sensory signals in the environment is essential for animal survival. Accordingly, animal behaviors are closely related to external and internal states, which include the positive and negative emotional values of sensory signals triggered by environmental factors. While the lateral parabrachial nucleus (LPB) plays a key role in nociception and supports negative valences, it also transmits signals including positive valences. However, the downstream neuronal mechanisms of positive and negative valences have not been fully explored. In the present study, we investigated the ventral tegmental area (VTA) as a projection target for LPB neurons. Optogenetic activation of LPB-VTA terminals in male mice elicits positive reinforcement in an operant task and induces both avoidance and attraction in a place-conditioning task. Inhibition of glutamic acid decarboxylase (GAD) 65-expressing cells in the VTA promotes avoidance behavior induced by photoactivation of the LPB-VTA pathway. These findings indicate that the LPB-VTA pathway is one of the LPB outputs for the transmission of positive and negative valence signals, at least in part, with GABAergic modification in VTA.

Comparison of two reaction-time-based and one foraging-based behavioral approach-avoidance tasks in relation to interindividual differences and their reliability.

Approaching rewards and avoiding punishments is a fundamental aspect of behavior, yet individuals differ in the extent of these behavioral tendencies. One popular method to assess differences in approach-avoidance tendencies and even modify them, is using behavioral tasks in which spontaneous responses to differently valenced stimuli are assessed (e.g., the visual joystick and the manikin task). Understanding whether these reaction-time-based tasks map onto the same underlying constructs, how they predict interindividual differences in theoretically related constructs and how reliable they are, seems vital to make informed judgements about current findings and future studies. In this preregistered study, 168 participants (81 self-identified men, 87 women) completed emotional face versions of these tasks as well as an alternative, foraging-based paradigm, the approach-avoidance-conflict task, and answered self-report questionnaires regarding anxiety, aggression, depressive symptoms, behavioral inhibition and activation. Importantly, approach-avoidance outcome measures of the two reaction-time-based tasks were unrelated with each other, showed little relation to self-reported interindividual differences and had subpar internal consistencies. In contrast, the approach-avoidance-conflict task was related to behavioral inhibition and aggression, and had good internal consistencies. Our study highlights the need for more research into optimizing behavioral approach-avoidance measures when using task-based approach-avoidance measures to assess interindividual differences.

Distinct spatiotemporal brainstem pathways of outcome valence during reward- and punishment-based learning.

Learning to seek rewards and avoid punishments, based on positive and negative choice outcomes, is essential for human survival. Yet, the neural underpinnings of outcome valence in the human brainstem and the extent to which they differ in reward and punishment learning contexts remain largely elusive. Here, using simultaneously acquired electroencephalography and functional magnetic resonance imaging data, we show that during reward learning the substantia nigra (SN)/ventral tegmental area (VTA) and locus coeruleus are initially activated following negative outcomes, while the VTA subsequently re-engages exhibiting greater responses for positive than negative outcomes, consistent with an early arousal/avoidance response and a later value-updating process, respectively. During punishment learning, we show that distinct raphe nucleus and SN subregions are activated only by negative outcomes with a sustained post-outcome activity across time, supporting the involvement of these brainstem subregions in avoidance behavior. Finally, we demonstrate that the coupling of these brainstem structures with other subcortical and cortical areas helps to shape participants' serial choice behavior in each context.

Glia transmit negative valence information during aversive learning in Drosophila.

During Drosophila aversive olfactory conditioning, aversive shock information needs to be transmitted to the mushroom bodies (MBs) to associate with odor information. We report that aversive information is transmitted by ensheathing glia (EG) that surround the MBs. Shock induces vesicular exocytosis of glutamate from EG. Blocking exocytosis impairs aversive learning, whereas activation of EG can replace aversive stimuli during conditioning. Glutamate released from EG binds to N-methyl-d-aspartate receptors in the MBs, but because of Mg2+ block, Ca2+ influx occurs only when flies are simultaneously exposed to an odor. Vesicular exocytosis from EG also induces shock-associated dopamine release, which plays a role in preventing formation of inappropriate associations. These results demonstrate that vesicular glutamate released from EG transmits negative valence information required for associative learning.

An evaluation of hedonic responses in taste-potentiated odor aversion using the analysis of licking microstructure and orofacial reactivity.

Two experiments examined the hedonic responses conditioned to odor cues in the phenomenon of taste-potentiated odor aversion. Experiment 1 analyzed the microstructure of licking behavior during voluntary consumption. A tasteless odor (amyl acetate) was delivered to rats either diluted in water or mixed with saccharin before being injected with LiCl. At test, subjects which had received the odor-taste compound during conditioning showed both lower odor consumption and lick cluster size, a result indicating an increased negative evaluation of the odor. Experiment 2 examined the orofacial reactions elicited by the odor as index of its hedonic impact. During conditioning, the rats were intraorally infused with either the odor alone or the odor-saccharin compound before being injected with LiCl. At test, they were infused with the odor and their orofacial responses video recorded. More aversive orofacial responses were elicited by the odor cue in rats that had compound conditioning, again a result indicating a strengthened negative hedonic reactivity compared to animals experiencing odor aversion conditioning alone. Taken together, these results indicate that taste-mediated potentiation of odor aversion conditioning impacts on the acquisition of conditioned hedonic reactions as well as consumption.