Nonassociative Learning Research Articles

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

Nonassociative learning implementation by a single memristor-based multi-terminal synaptic device.

Animals' survival is dependent on their abilities to adapt to the changing environment by adjusting their behaviours, which is related to the ubiquitous learning behaviour, nonassociative learning. Thus mimicking the indispensable learning behaviour in organisms based on electronic devices is vital to better achieve artificial neural networks and neuromorphic computing. Here a three terminal device consisting of an oxide-based memristor and a NMOS transistor is proposed. The memristor with gradual conductance tuning inherently functions as the synapse between sensor neurons and motor neurons and presents adjustable synaptic plasticity, while the NMOS transistor attached to the memristor is utilized to mimic the modulatory effect of the neuromodulator released by inter neurons. Such a memristor-based multi-terminal device allows the practical implementation of significant nonassociative learning based on a single electronic device. In this study, the experience-induced modification behaviour, both habituation and sensitization, was successfully achieved. The dependence of the nonassociative behavioural response on the strength and interval of presented stimuli was also discussed. The implementation of nonassociative learning offers feasible and experimental advantages for further study on neuromorphic systems based on electronic devices.

Strain-dependent effects of acute caffeine on anxiety-related behavior in PVG/c, Long–Evans and Wistar rats

To assess the possibility that acute caffeine's behavioral action might depend on rats' strain, effects of 50mg/kg of the drug were observed on activity, anxiety-related behavior and habituation learning in male and female rats from three different strains, namely PVG/c, Long–Evans and Wistar. All subjects were tested in an open field, an elevated plus maze and a light–dark box. For the three strains combined, increased occupancy of the center of the open field and entries of the open plus-maze arms with caffeine suggested caffeine-induced anxiolysis, whereas increased grooming in the open field, decreased rearing in the plus maze and increased risk assessment in the light–dark box were consistent with anxiogenesis. Caffeine also reduced open-field rearing only for PVG/c rats, and entries into and occupation of the light side of the light–dark box only for Long–Evans rats, and increased total defecation in the three types of apparatus for all three strains combined. Overall, caffeine appeared to be mainly anxiogenic. The drug also increased open-field ambulation for PVG/c rats and walking for all rats, but decreased open-field ambulation and entries into the plus maze closed arms for Wistar rats alone. In general, Wistar rats appeared to be the least and Long–Evans the most anxious of the three strains investigated. Caffeine also decreased within-session habituation of open-field ambulation for PVG/c rats alone, thereby suggesting strain-dependent interference with non-associative learning and short-term memory. Several overall sex differences were also observed that supported female rats being more active and less anxious than males.

Basal forebrain dynamics during nonassociative and associative olfactory learning.

Cholinergic and GABAergic projections from the horizontal diagonal band (HDB) and medial preoptic area (MCPO) of the basal forebrain to the olfactory system are associated with odor discrimination and odor learning, as well as modulation of neural responses in olfactory structures. Whereas pharmacological and lesion studies give insights into the functional role of these modulatory inputs on a slow timescale, the response dynamics of neurons in the HDB/MCPO during olfactory behaviors have not been investigated. In this study we examined how these neurons respond during two olfactory behaviors: spontaneous investigation of odorants and odor-reward association learning. We observe rich heterogeneity in the response dynamics of individual HDB/MCPO neurons, with a substantial fraction of neurons exhibiting task-related modulation. HDB/MCPO neurons show both rapid and transient responses during bouts of odor investigation and slow, long-lasting modulation of overall response rate based on behavioral demands. Specifically, baseline rates were higher during the acquisition phase of an odor-reward association than during spontaneous investigation or the recall phase of an odor reward association. Our results suggest that modulatory projections from the HDB/MCPO are poised to influence olfactory processing on multiple timescales, from hundreds of milliseconds to minutes, and are therefore capable of rapidly setting olfactory network dynamics during odor processing and learning.

O044. Frequency-dependent habituation deficit of the nociceptive blink reflex in migraine with and without aura.

Background The habituation phenomenon is a frequency-dependent form of non-associative learning which reflects the excitability level of both sensory and pain systems. We previously demonstrated a frequency-dependent deficit of habituation of the conventional blink reflex in migraine[1]. We investigated the habituation of the trigeminal nociceptive system by studying the habituation of the late component (R2) of the nociceptive blink reflex (nBR) in a wide range of stimulation frequencies in subjects with migraine without aura (MWoA) and with aura (MWA).

O043. Frequency-dependent habituation deficit of the nociceptive blink reflex in cluster headache and paroxysmal hemicrania.

Background The habituation phenomenon is a frequency-dependent form of non-associative learning which reflects the excitability level of both sensory and pain systems. We previously demonstrated a frequency-dependent deficit of habituation of the conventional blink reflex in cluster headache (CH) [1]. We investigated the habituation of the trigeminal nociceptive system by studying the habituation of the late component (R2) of the nociceptive blink reflex (nBR) in a wide range of stimulation frequencies in CH and paroxysmal hemicrania (PH).

Effects of BPA and BPS exposure limited to early embryogenesis persist to impair non-associative learning in adults.

BackgroundBisphenol-A (BPA) is a polymerizing agent used in plastic bottles and several routinely used consumer items. It is classified among endocrine disrupting chemicals suspected to cause adverse health effects in mammals ranging from infertility and cancer to behavioral disorders. Work with the invertebrate lab model Caenorhabditis elegans has shown that BPA affects germ cells by disrupting double-stranded DNA break repair mechanisms. The current study utilizes this model organism to provide insight into low-dose and long-term behavioral effects of BPA and bisphenol-S (BPS), a supposed safer replacement for BPA.FindingsExperiments presented in our report demonstrate that the effects of embryonic exposure to considerably low levels of BPA persist into adulthood, affecting neural functionality as assayed by measuring habituation to mechano-sensory stimuli in C. elegans. These results are noteworthy in that they are based on low-dose exposures, following the rationale that subtler effects that may not be morphologically apparent are likely to be discernible through behavioral changes. In addition, we report that embryonic exposure to BPS follows a pattern similar to BPA.ConclusionsBuilding upon previous observations using the C. elegans model, we have shown that exposure of embryos to BPA and BPS affects their behavior as adults. These long-term effects are in line with recommended alternate low-dose chemical safety testing approaches. Our observation that the effects of BPS are similar to BPA is not unexpected, considering their structural similarity. This, to our knowledge, is the first reported behavioral study on low-dose toxicity of any endocrine disrupting chemical in C. elegans.

Distorted estimates of implicit and explicit learning in applications of the process-dissociation procedure to the SRT task.

We investigated potential biases affecting the validity of the process-dissociation (PD) procedure when applied to sequence learning. Participants were or were not exposed to a serial reaction time task (SRTT) with two types of pseudo-random materials. Afterwards, participants worked on a free or cued generation task under inclusion and exclusion instructions. Results showed that pre-experimental response tendencies, non-associative learning of location frequencies, and the usage of cue locations introduced bias to PD estimates. These biases may lead to erroneous conclusions regarding the presence of implicit and explicit knowledge. Potential remedies for these problems are discussed.

Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms.

The role of adult hippocampal neurogenesis in fear learning is controversial, with some studies suggesting neurogenesis is needed for aspects of fear learning and others suggesting it is dispensable. We generated transgenic mice in which neural progenitors can be selectively and inducibly ablated. Our data suggest that adult neurogenesis supports fear learning through two distinct mechanisms: it supports the ability to learn associations between traumatic events (unconditioned stimuli) and predictors (conditioned stimuli) while also buffering against nonassociative, anxiogenic effects of a traumatic experience. As a result, arrest of neurogenesis can enhance or impair learned fear depending on intensity of the traumatic experience and the extent to which it recruits associative versus nonassociative learning.

Behavioral and thyroid effects of in utero and lactational exposure of Sprague–Dawley rats to the polybrominated diphenyl ether mixture DE71

Exposure of rodents during gestation and lactation to polybrominated diphenyl ethers (PBDEs) has been reported to disrupt neurobehavioral function in offspring, as well as to disrupt thyroid function. To assess this we evaluated development and behavior after gestational and lactational exposure to the technical PBDE mixture DE71. Pregnant Sprague–Dawley rats were exposed to 0, 0.3, 3.0 or 30mg/kg/day of DE71 from gestation day 1 to postnatal day (PND) 21 and were assessed on a wide range of behavioral functions from early postnatal period until old age (PND 450). DE71 exposure decreased thyroid hormone levels (T3 and T4) in mothers and offspring with offspring being more sensitive that mothers. Developmental landmarks, neuromotor function, anxiety, learning and memory were not affected by DE71 at any age. DE71 produced small changes in motor activity rearing only at PND 110 but not at any other age and no other activity measure was altered by DE71. Cholinergic sensitivity measured by nicotine-stimulated motor activity was not affected by perinatal DE71 exposure. Acoustic startle responses were potentiated by DE71 at PND 90 indicating delayed effects on sensory reactivity. Habituation was measured in motor activity tests at five ages but was not altered by DE71 at any age. Habituation measured in startle tests was also not affected by exposure to DE71. For thyroid hormone levels at PND 21, the lowest adverse effect level was 3.0mg/kg. Few behavioral effects were observed and the lowest adverse effect level was 30mg/kg. Our results confirm that DE71 produces transient effects on thyroid hormone levels but does not result in learning or motor impairment and does not alter non-associative learning (habituation).

Modulation of different behavioral components by neuropeptide and dopamine signalings in non-associative odor learning of Caenorhabditis elegans

An animal's behavior is modulated by learning; however, the behavioral component modulated by learning and the mechanisms of this modulation have not been fully understood. We show here that two types of neural signalings are required for the modulation of different behavioral components in non-associative odor learning in the nematode Caenorhabditis elegans. We have previously found that C. elegans avoid the repulsive odor 2-nonanone, and preexposure to the odor for 1h enhances the avoidance behavior as a type of non-associative learning. Systematic quantitative analyses of behavioral components revealed that the odor preexposure caused increases in average duration of straight migration (“runs”) only when the animals were migrating away from the odor source within a certain range of bearing, which likely corresponds to odor decrement. Further, genetic analyses revealed that the genes for neuropeptide or dopamine signalings are both required for the enhanced odor avoidance. Neuropeptide signaling genes were required for the preexposure-dependent increase in run duration. In contrast, dopamine signaling genes were required not for the increase in run duration but likely for maintenance of run direction. Our results suggests that multiple behavioral components are regulated by different neuromodulators even in non-associative learning in C. elegans.

Aging in Sensory and Motor Neurons Results in Learning Failure in Aplysia californica.

The physiological and molecular mechanisms of age-related memory loss are complicated by the complexity of vertebrate nervous systems. This study takes advantage of a simple neural model to investigate nervous system aging, focusing on changes in learning and memory in the form of behavioral sensitization in vivo and synaptic facilitation in vitro. The effect of aging on the tail withdrawal reflex (TWR) was studied in Aplysia californica at maturity and late in the annual lifecycle. We found that short-term sensitization in TWR was absent in aged Aplysia. This implied that the neuronal machinery governing nonassociative learning was compromised during aging. Synaptic plasticity in the form of short-term facilitation between tail sensory and motor neurons decreased during aging whether the sensitizing stimulus was tail shock or the heterosynaptic modulator serotonin (5-HT). Together, these results suggest that the cellular mechanisms governing behavioral sensitization are compromised during aging, thereby nearly eliminating sensitization in aged Aplysia.

Odor Memory and Discrimination Covary as a Function of Delay between Encoding and Recall in Rats.

Nonassociative odor learning paradigms are often used to assess memory, social recognition and neuromodulation of olfactory pathways. We here use a modified object recognition paradigm to investigate how an important task parameter, delay between encoding and recall trials, affects the properties of this memory. We show that both memory for a previously investigated odorant and discrimination of a novel odorant decay with delay time and that rats can remember an odorant for up to 45min after a single trial encoding event. The number of odorants that can be encoded, as well as the specificity of the encoded memory, decrease with increased delay and also depend on stimulus concentration. Memory for an odorant and discrimination of a novel odorant decay at approximately the same rate, whereas the specificity of the formed memory decays faster than the memory itself. These results have important implications for the interpretation of behavioral data obtained with this paradigm.

Learning to predict and control harmful events: chronic pain and conditioning.

Pain is a biologically relevant signal and response to bodily threat, associated with the urge to restore the integrity of the body. Immediate protective responses include increased arousal, selective attention, escape, and facial expressions, followed by recuperative avoidance and safety-seeking behaviors. To facilitate early and effective protection against future bodily threat or injury, learning takes place rapidly. Learning is the observable change in behavior due to events in the internal and external environmental and includes nonassociative (habituation and sensitization) and associative learning (Pavlovian and operant conditioning). Once acquired, these knowledge representations remain stored in memory and may generalize to perceptually or functionally similar events. Moreover, these processes are not just a consequence of pain; they may directly influence pain perception. In contrast to the rapid acquisition of learned responses, their extinction is slow, fragile, context dependent and only occurs through inhibitory processes. Here, we review features of associative forms of learning in humans that contribute to pain, pain-related distress, and disability and discuss promising future directions. Although conditioning has a long and honorable history, a conditioning perspective still might open new windows on novel treatment modalities that facilitate the well-being of individuals with chronic pain.

Nonassociative learning in invertebrates.

The simplicity and tractability of the neural circuits mediating behaviors in invertebrates have facilitated the cellular/molecular dissection of neural mechanisms underlying learning. The review has a particular focus on the general principles that have emerged from analyses of an example of nonassociative learning, sensitization in the marine mollusk Aplysia. Learning and memory rely on multiple mechanisms of plasticity at multiple sites of the neuronal circuits, with the relative contribution to memory of the different sites varying as a function of the extent of training and time after training. The same intracellular signaling cascades that induce short-term modifications in synaptic transmission can also be used to induce long-term changes. Although short-term memory relies on covalent modifications of preexisting proteins, long-term memory also requires regulated gene transcription and translation. Maintenance of long-term cellular memory involves both intracellular and extracellular feedback loops, which sustain the regulation of gene expression and the modification of targeted molecules.

Learning modifies odor mixture processing to improve detection of relevant components.

Honey bees have a rich repertoire of olfactory learning behaviors, and they therefore are an excellent model to study plasticity in olfactory circuits. Recent behavioral, physiological, and molecular evidence suggested that the antennal lobe, the first relay of the olfactory system in insects and analog to the olfactory bulb in vertebrates, is involved in associative and nonassociative olfactory learning. Here we use calcium imaging to reveal how responses across antennal lobe projection neurons change after association of an input odor with appetitive reinforcement. After appetitive conditioning to 1-hexanol, the representation of an odor mixture containing 1-hexanol becomes more similar to this odor and less similar to the background odor acetophenone. We then apply computational modeling to investigate how changes in synaptic connectivity can account for the observed plasticity. Our study suggests that experience-dependent modulation of inhibitory interactions in the antennal lobe aids perception of salient odor components mixed with behaviorally irrelevant background odors.

The role of associative and non-associative learning in the training of horses and implications for the welfare (a review).

Horses were domesticated 6000 years ago and since then different types of approaches have been developed to enhance the horse's wellbeing and the human-horse relationship. Even though horse training is an increasingly important research area and many articles have been published on the subject, equitation is still the sport with the highest rate of human injuries, and a significant percentage of horses are sold or slaughtered due to behavioral problems. One explanation for this data is that the human-horse relationship is complex and the communication between humans and horses has not yet been accurately developed. Thus, this review addresses correct horse training based on scientific knowledge in animal learning and psychology. Specifically, it starts from the basic communication between humans and horses and then focuses on associative and non-associative learning, with many practical outcomes in horse management from the ground and under saddle. Finally, it highlights the common mistakes in the use of negative reinforcement, as well as all the implications that improper training could have on horse welfare. Increased levels of competence in horse training could be useful for equine technicians, owners, breeders, veterinarians, and scientists, in order to safeguard horse welfare, and also to reduce the number of human injuries and economic loss for civil society and the public health system.

Prenatal learning in an Australian songbird: habituation and individual discrimination in superb fairy-wren embryos.

Embryos were traditionally considered to possess limited learning abilities because of the immaturity of their developing brains. By contrast, neonates from diverse species show behaviours dependent on prior embryonic experience. Stimulus discrimination is a key component of learning and has been shown by a handful of studies in non-human embryos. Superb fairy-wren embryos (Malurus cyaneus) learn a vocal password that has been taught to them by the attending female during incubation. The fairy-wren embryos use the learned element as their begging call after hatching to solicit more parental feeding. In this study, we test whether superb fairy-wren embryos have the capacity to discriminate between acoustical stimuli and whether they show non-associative learning. We measured embryonic heart rate response using a habituation/dishabituation paradigm with eggs sourced from nests in the wild. Fairy-wren embryos lowered their heart rate in response to the broadcasts of conspecific versus heterospecific calls, and in response to the calls of novel conspecific individuals. Thus, fairy-wrens join humans as vocal-learning species with known prenatal learning and individual discrimination.

Neuromimetic Circuits with Synaptic Devices Based on Strongly Correlated Electron Systems

A crucial feature of biological neural architectures is their ability to learn, and unlearn, in response to external stimulation. In this work the authors reproduce this feature in an electronic network composed of strongly correlated electron materials implemented as synaptic devices. This network responds to both excitatory and inhibitory excitations, exhibits associative as well as nonassociative learning, and even displays habituation-like behavior and other aspects of authentic neuronal systems. This opens avenues for both investigating biological behaviors and designing computers with the capacity to learn and remember based on hardware alone.

Transcription and protein synthesis inhibitors influence long-term effects of acetyl-l-carnitine on non-associative learning in the leech

Acetyl-l-carnitine (ALC) is the principal acetyl ester of L-carnitine and it plays an essential role in intermediary metabolism. ALC affects several targets in the nervous system. Along this line of investigation, we analyzed the long-term effects of ALC on elementary nonassociative learning in the swimming induction model of the leech Hirudo medicinalis, in which nociceptive stimulation of the dorsal skin produces a more rapid swim response to a test stimulus (sensitization). In this simplified model a single ALC administration blocked the sensitizing effects of nociceptive stimulation in swim induction showing increasingly long lasting effects. Herein, we have analyzed the long-term effects of ALC on sensitization and dishabituation. Leeches were treated with inhibitors of either transcription or protein synthesis 30 min after the administration of ALC and, subsequently, subjected to noxious stimuli: the animals exhibited a sensitized swimming response 6 days after ALC treatment but not after 2 hours indicating that the long-term suppressive effects of ALC on sensitization/dishabituation needed mRNA and protein synthesis.