Involvement of mesencephalic reticular formation neurons in cat conditioned reflexes

Traditional defensive and operant food reflexes were used to investigate neuronal responses of the mesencephalic reticular formation. It was found that these neurons may be divided into different groups according to function, depending on how they respond to positive conditioning stimuli. Of the two main groups of neurons with sustained tonic reactions one is activated in response to positive acoustic conditioning stimulation; it no longer reacts to the same stimulus after extinction of the reflex, while the other only becomes involved in response to positive stimulation accompanying the initiation of movement. Neurons belonging to the second group begin to respond directly to acoustic stimulation after extinction of the conditioned reflex. Neurons of the mesencephalic reticular formation can thus exercise additional tonic ascending effects both in the production and inner inhibition of the conditioned reflex. The group of neurons with a phasic reaction, i.e., a double response (a direct response to sound and another produced by movement) displayed a drop in spontaneous activity during the shaping of inhibition of differentiation and of extinction in particular. It was found that the initial changes in the spike response of reticular formation neurons during conditioning and pseudo-conditioning are similar. There are thus grounds for stating that neurons of the mesencephalic reticular formation participate in the shaping, production, and inner inhibition of traditional and operant conditioned reflexes in a differentiated capacity rather than as a population reacting identically.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 2, pp. 161–171, March–April, 1986.     

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement.In N = 21 healthy humans, visual conditioned stimuli (CS⁺) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS⁻) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness.Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS⁺. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS⁻ was observed. In the reinstatement phase, a tendency for parahippocampal activation was found.Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.     

Features of the formation of conditioned secretory reflexes in response to the stimulation of different areas of the caudate nucleus of the dog

Properties were studied of elaboration of conditioned alimentary secretory reflexes to threshold electric stimulation of the caudate nucleus in dogs. The rate of formation of such a reflex and its magnitude were considerably lower than in reflexes elaborated to distant stimuli. Latencies were longer; dynamics of conditioned and unconditioned secretory reactions was similar to that of reflexes to a weak stimulus--light. The motor component of the conditioned alimentary reaction, as a rule, was absent. Characteristics were revealed of formation of alimentary reflexes to stimulation of the dorsal and ventral parts of the head and body of the caudate nucleus.     

Does heart rate differentiate neurotic from normal people in a conditional reflex test?

This study is to compare heart reactivity between normals and anxiety neurotic patients. Five male and five female patients with anxiety neurosis and four male and five female normal persons were submitted to classic delayed conditional reflexes with different probabilities of reinforcement (shock), to a defensive instrumental conditional reflex, and to a neutral nonreinforced stimulus. The basal heart frequency was higher in neurotics and in women than in normals and men. The conditional stimulus (CS) associated with a shock generally produced a bradycardia in normal individuals and in neurotic men, but a tachycardia in neurotic women (effects most pronounced in cases with 100% shock probability). The instrumental CS caused a tachycardia in all of the groups, with highest values in neurotic women. The neutral stimulus produced bradycardia in all persons. The aftereffect of the light stimulus depended on whether a shock was administered and on the CS. The differences between neurotics and normals are explained as caused by the heightened excitatory level of the CNS of the neurotic group, produced by the unspecific activating effect of chronic anxiety, and differences of plastic processes in both groups, resulting in different effects of phasic anxiety on the heart. Complex inhibitory-excitatory interactions of the sympathetic and the vagal system underlying the heart rate changes may be assumed. Possible mechanisms leading to sex differences are discussed.     

Changes in the cholinosensitivity of sensomotor cortex neurons during conditioned reflex extinction]

Characteristics of neuronal responses of the sensorimotor cortex to ionophoretically administered neuromediators (acetylcholine, L-glutamate) were studied in rabbit in the course of extinction of conditioned defensive reflex. In the majority of neurones the extinction of the conditioned reflex is accompanied by a drop of cholinosensitivity. In a number of neurones the extinction of reflexes either does not change the reaction to acetylcholine, or enhances it. The analysis of these reactions permits to assume the existence of a group of neurones directly involved in the formation, fixation and storage of the temporary connection.     

Changes in trace reactions of sensorimotor cortex and putamen neurons as affected by haloperidol

Experiments on conscious rabbits were made to elaborate motor conditioned reflexes through pairing stimuli with electrocutaneous reinforcement applied every 30 s. Neuronal activity in the sensorimotor cortex and putamen was recorded during formation and reproduction of the conditioned reflexes before and after haloperidol injection (0.2 mg/kg i. v.). In the putamen, haloperidol increased the number of neurons exhibiting trace conditioned activity and made the intensity and duration of these processes rise. The changes seen in the sensorimotor cortex were opposite in nature. Inhibition of trace conditioned activity in the sensorimotor cortex depended mainly on the decreased amplitude of the reaction conditioned component. The role of the dopaminergic system in the interaction of the neostriatum and sensorimotor cortex and in formation and reproduction of trace conditioned activity of both the structures is discussed.     

Simple discrete-time metapopulation models of patch occupancy

Simple models in theoretical ecology have a long-standing history of being used to understand how specific processes influence population dynamics as well as providing a foundation for future endeavors. The Levins model is the seminal example of this for continuous-time metapopulation dynamics. However, many natural populations have a distinct separation between processes and data is not collected continuously leading to the need for using a discrete-time model. Our goal is to develop a simple discrete-time metapopulation model of patch occupancy using difference equations. In our formulation, we consider the two fundamental processes of colonization and extinction that will be treated as sequential events and will only consider patch occupancy. To achieve this, we use a composition of two functions where one will reflect the extinction process and the other for the colonization process. Under some mild assumptions, we are able determine the dynamic behavior of the metapopulation. In addition, we provide numerous examples for the functions used to emulate the colonization and extinction processes. Our results illustrate that the dynamics of the model are tied to properties such as convexity and monotonicity of the colonization and extinction functions. In particular, if the model is non-monotone, then complex dynamics can arise such as cyclic and even chaotic behavior. Overall, our approach shows how certain properties of the colonization and extinction functions can influence metapopulation dynamics.     

The Markovian binary tree applied to demography

We apply matrix analytic methods and branching processes theory to a comparison of female populations in different countries. We show how the same mathematical model allows us to determine characteristics about individual women, such as the distribution of her lifetime, the time until her first and her last daughter, and the number of daughters, as well as to analyze properties of the whole female family generated by a first woman, such as the extinction probability of the family, the distributions of the time until extinction, of the family size at any given time and of the total progeny.     

Interdependence of learning and paradoxical sleep in the cat

The effect of learning sessions on the structure of the sleep-wakefulness cycle, as well as the effect of paradoxical sleep (PS) deprivation (PSD) following learning sessions, on the acquisition and extinction of instrumental alimentary reflexes to two feeders with sound discrimination, were studied on cats. The analysis of the data obtained led to following conclusions: The above learning sessions have no marked effect on the structure of the sleep-wakefulness cycle in the post-learning period, i.e. the percentage ratio of its phases is not altered by the increase of one of them. When PSD by non-emotional awakening is used, the number of PS onsets is not affected by learning sessions. This indicates that learning does not produce any considerable effect on the formation of PS need. PSD by non-emotional awakening following learning sessions does not retard the acquisition and extinction of the instrumental alimentary reflexes. The above data are interpreted as indicating that PS has no specific significance in memory trace consolidation during formation of long-term memory.     

Correlation of the neuronal impulse activity of different areas of the neocortex in rabbits in the switching of positive and inhibitory conditioned reflexes

By cross-correlation method conjugation in impulse activity of pairs of simultaneously recorded units in the visual and sensorimotor areas of the neocortex (representations of the conditioned and unconditioned stimuli) was studied during the switching of defensive positive and inhibitory reflexes in rabbits. 30-second fragments of impulse activity were analyzed in intervals before and after three presentations of positive and inhibitory conditioned stimuli (CS). The activity of single pairs of units in the process of stimuli presentation was characterized by instability. Only in 29% of 51 units' pairs the presence or absence of correlation between their discharges was stable. Analysis of activity of 75 pairs of units showed differences in impulse activity in inhibitory and positive tonic reflexes. The number of pairs of correlated units in about 30 s after inhibitory CS decreased (27%) in comparison with the interval before its action (52%). In the inhibitory tonic conditioned reflex, temporal intervals of discharges of one unit correlated with discharges of the second unit undergo changes. The obtained results testify that such parameter as the number of pairs of units with correlated activity in intersignal time interval is very important for the realization of motor reaction to conditioned stimuli.     

The role of the pallidum in regulating cortical activity]

Bilateral ablation of the pallidum halves the duration of extinction of conditioned motor food reflexes and contributes to 30 to 50% extinction of the electro-defensive reflexes. Pallidum functional depression by potassium chloride or novacaine leads to a temporary total depression of conditioned motor food reflexes. Depending on the frequency of pallidum stimulation, synchronization or desynchronization of the cortical bioelectrical activity is observed. Ablation of the pallidum in anaesthetized cats results in a high amplitude and low-frequency cortical activity. Injection of large doses of potassium chloride into the pallidum results in a forced running forward which lasts 30 to 40 min. The pallidum is considreed as a structure controlling the cortex activity, which takes part in the mechanisms of sensory information processes in the course of adaptive behaviour.     

Conditioned reflex: detector and command neuron

Conditioned reflex is characterized by plasticity resulting in a bilateral selective input-output linking. In simple nervous systems, input stimuli are represented by selective detectors connected with command neurons through plastic synapses strengthened during associative learning and weakened during extinction. The process of associative learning is due to temporal coincidence of excitation in both detector and command neurons. Short-term memory within a plastic synapses is mediated by phosphorilation of postsynaptic receptor molecules not requiring protein synthesis. Long-term synaptic memory parallels expression of immediate early genes that mediates structural gene expression and protein synthesis. A simple detector-command neuron association becomes more complex in the course of evolution. Input mechanism is supplemented with predetector interneurons preceding detectors. Detector selectively tuned to specific input stimulus is converging on a command neuron constitute selectivity mechanism for conditioned reflexes to complex stimuli. The complication also concerns the output mechanisms. Command neurons become more specialized, and an additional link of premotor interneurons is incorporated between command neurons and motor neurons. Via synapses, the command neurons can produce excitation in a particular set of premotor neurons controlling a specific set of motor neurons responsible for behavioral act configuration. Specialization of command neurons in combination with premotor neuron structures increases the variability of outputs. Conditioned reflexes with more complex inputs and more flexible outputs determine the diversity of acquired behaviors.     

The response of generalized motor activation in man

The effect of short acoustic and photic stimuli on the magnitude of the T- and H-reflexes was investigated in man. Two periods of increase in the amplitude and dispersion of the two test reflexes, disappearing during repetition of the stimulation, were found. Its first component differs from the second in the greater change in the T-reflex and the smaller extinction. The pattern of changes after photic and acoustic stimulation was the same but acoustic evoked a stronger response. The changes discovered are a subthreshold manifestation of the generalized response of motor activation evoked by a wide range of stimuli. It is postulated that its first component is determined by interaction between pyramidal impulses and the motor cortex and the second is due to the efferent volley from the primary cortical projection zones through the reticulo-spinal tract.     

Vector representation of associative learning

I. P. Pavlov [12] has shown that conditioned reflexes are selective both with respect to conditioned stimuli and to conditioned reflexes elicited by those conditioned stimuli. At the neuronal level selective aspects of conditioned stimuli are based on detectors selectively tuned to respective stimuli. The selective aspects of conditioned reflexes are due to command neurons representing specific unconditioned reflexes. It can be assumed that conditioned reflexes result from association between selective detectors and specific command neurons. The detectors activated by a conditioned stimulus constitute a combination of excitations--a detector excitation vector. The detector excitation vector acts on a command neuron via a set of plastic synapses--a synaptic weight vector. Plastic synapses are modified in the process of learning making command neuron selectively tuned to a specific conditioned stimulus. The selective tuning of a particular command neuron to a specific excitation vector referred to a conditioned stimulus is a basis of associative learning. The probabilities of conditioned reflexes elicited by conditioned and differential stimuli implicitly contain information concerning excitation vectors that encode respective stimuli. Contribution of the vector code to associative learning was explored combining differential color conditioning with intracellular recording from color-coding neurons. It was shown that colors in carps and monkeys are represented on a hypersphere in the four-dimensional space similar to human color space. The basis of the color space is constituted by red-green, blue-yellow, brightness and darkness neurons.     

Spontaneous decisions and operant conditioning in fruit flies

Already in the 1930s Skinner, Konorskiand colleagues debated the commonalities, differences and interactions among the processes underlying what was then known as “conditioned reflexes type I and II”, but which is today more well-known as classical (Pavlovian) and operant (instrumental) conditioning. Subsequent decades of research have confirmed that the interactions between the various learning systems engaged during operant conditioning are complex and difficult to disentangle. Today, modern neurobiological tools allow us to dissect the biological processes underlying operant conditioning and study their interactions. These processes include initiating spontaneous behavioral variability, world-learning and self-learning. The data suggest that behavioral variability is generated actively by the brain, rather than as a by-product of a complex, noisy input-output system. The function of this variability, in part, is to detect how the environment responds to such actions. World-learning denotes the biological process by which value is assigned to environmental stimuli. Self-learning is the biological process which assigns value to a specific action or movement. In an operant learning situation using visual stimuli for flies, world-learning inhibits self-learning via a prominent neuropil region, the mushroom-bodies. Only extended training can overcome this inhibition and lead to habit formation by engaging the self-learning mechanism. Self-learning transforms spontaneous, flexible actions into stereotyped, habitual responses.     

In vivo catechol activity in the rat locus coeruleus following different nociceptive stimuli and naloxone.

The nucleus locus coeruleus (LC) has been implicated in the processing of spinal reflexes following noxious stimuli. It has been demonstrated that noxious stimuli activate LC neuronal firing, but little is known about the neurochemical changes that might occur following such activation. To determine the effects of different noxious stimuli on LC neuronal activity, anaesthetized rats were exposed to mechanical (tail pinch), thermal (55 degrees C water), and chemical (5% Formalin injected in the hind paw) stimuli; the catechol oxidation current (CA.OC), an index of noradrenergic neuronal activity, in the locus coeruleus was monitored using differential normal pulse voltammetry. In addition, the effect of the opioid antagonist naloxone on the CA.OC in the LC was examined. Exposure to both mechanical and chemical stimuli significantly increased CA.OC indicating an increase in LC noradrenergic neuronal activity, while the thermal stimulus had no effect. Treatment with naloxone (1 mg/kg i.v.) had no effect on CA.OC in the LC. The results show a differential responsiveness of LC noradrenergic neurons to different modes of noxious stimuli and fail to demonstrate a tonic opioid regulation of these neurons in the anaesthetized rat.     

Rapid Plasticity in the Prefrontal Cortex during Affective Associative Learning

MultiCS conditioning is an affective associative learning paradigm, in which affective categories consist of many similar and complex stimuli. Comparing visual processing before and after learning, recent MultiCS conditioning studies using time-sensitive magnetoencephalography (MEG) revealed enhanced activation of prefrontal cortex (PFC) regions towards emotionally paired versus neutral stimuli already during short-latency processing stages (i.e., 50 to 80 ms after stimulus onset). The present study aimed at showing that this rapid differential activation develops as a function of the acquisition and not the extinction of the emotional meaning associated with affectively paired stimuli. MEG data of a MultiCS conditioning study were analyzed with respect to rapid changes in PFC activation towards aversively (electric shock) paired and unpaired faces that occurred during the learning of stimulus-reinforcer contingencies. Analyses revealed an increased PFC activation towards paired stimuli during 50 to 80 ms already during the acquisition of contingencies, which emerged after a single pairing with the electric shock. Corresponding changes in stimulus valence could be observed in ratings of hedonic valence, although participants did not seem to be aware of contingencies. These results suggest rapid formation and access of emotional stimulus meaning in the PFC as well as a great capacity for adaptive and highly resolving learning in the brain under challenging circumstances.     

The human tyrosine kinase Kit and its gatekeeper mutant T670I,show different kinetic properties: Implications for drug design

The tyrosine kinase Kit, a receptor for Stem Cell Factor, is involved, among others, in processes associated to cell survival, proliferation and migration. Upon physiological conditions, the activity of Kit is tightly regulated. However, primary mutations that lead to its constitutive activation are the causal oncogenic driver of gastrointestinal stromal tumours (GISTs). GISTs are known to be refractory to conventional therapies but the introduction of Imatinib, a selective inhibitor of tyrosine kinases Abl and Kit, significantly ameliorated the treatment options of GISTs patients. However, the acquisition of secondary mutations renders Kit resistant towards all available drugs. Mutation involving gatekeeper residues (such as V654a and T670I) influence both the structure and the catalytic activity of the enzyme. Therefore, detailed knowledge of the enzymatic properties of the mutant forms, in comparison with the wild type enzyme, is an important pre-requisite for the rational development of specific inhibitors. In this paper we report a thorough kinetic analysis of the reaction catalyzed by the Kit kinase and its gatekeeper mutated form T670I. Our results revealed the different mechanisms of action of these two enzymes and may open a new avenue for the future design of specific Kit inhibitors.     

Dynamics of the formation, reproduction and recognition of trace conditioned reflexes to positive and negative stimuli

The dynamics of formation, reproduction, and recognition of trace conditioned reflexes to positive and differentiation stimuli was studied on subjects of 15-17 years old. Formation and reproduction of such reflexes was found to occur under a close interaction of both levels of the higher nervous activity--recognized and unrecognized levels. Recognized reactions prevailed on unrecognized ones in cases of involvement of active attention. On the basis of this fact, the formation and reproduction of trace conditioned reflexes to positive stimuli has been supposed to occur with an active participation of the left hemisphere. The right hemisphere apparently plays a leading role in formation and reproduction of trace conditioned reflexes to differention stimuli to which the attention of the subjects was not fixed.