Interaction between neurons of the frontal cortex and hippocampus during the realization of choice of food reinforcement quality in cats

Six cats were subjected to the procedure of appetitive instrumental conditioning (with light as a conditioned stimuls) by the method of the "active choice" of reinforcement quality. Short-delay conditioned bar-press responses were rewarded with bread-meat mixture, and the delayed responses were reinforced by meat. The animals differed in behavior strategy: four animals preferred the bar-pressing with a long delay (the so-called "self-control" group), and two cats preferred the bar-pressing with a short delay (the so-called "impulsive" group). Multiunit activity in the frontal cortex and hippocampus (CA3) was recorded via chronically implanted nichrome wire semimicroelectrodes. An interaction between the neighboring neurons in the frontal cortex and hippocampus (within local neural networks) and between the neurons of the frontal cortex and hippocampus (distributed neural networks in frontal-hippocampal and hippocampal-frontal directions) was evaluated by means of statistical crosscorrelation analysis of spike trains. Crosscorrelations between neuronal spike trains in the delay range of 0-100 ms were explored. It was shown that the number of crosscorrelations between the neuronal discharges both in the local and distributed networks was significantly higher in the "self-control" cats. It was suggested that the local and distributed neural networks of the frontal cortex and hippocampus are involved in the system of brain structures which determine the behavioral strategy of animals in the "self-control" group.     

The individual organization of frontal-hippocampal networks during realization of different behavioral tasks

Four cats were subjected to appetitive instrumental conditioning with light as a conditioned stimulus by the method of "active choice" of the reinforcement quality: short-delay conditioned bar-press responses were followed by bread-meat mixture and the delayed responses--by meat. The animals differed in behavior strategy: four animals preferred bar-pressing with long delay (so called "self-control" group); two animal preferred bar-pressing with short-delay (so called "impulsive" group). Then all the animals were learned to short-delay (1 s) instrumental conditioned reflex to light (CS+) reinforced by meat. The multiunit activity in the frontal cortex and the hippocampus (CA3) was recorded through chronically implanted nichrome-wire semimicroelectrodes. The interactions among the neighboring neurons in the frontal cortex and hippocampus (within the local neuronal networks) and between the neurons of the frontal cortex and hippocampus (distributed neuronal networks of frontal-hippocampal and hippocampal-frontal directions) were evaluated by means of statistical crosscorrelation analysis of the spike trains. Crosscorrelation interneuronal connections in the delay range 0-100 ms were explored. It was shown that the functional organization of the frontal and hippocampal neuronal networks differed in choice behavior and was similar during realization of short-delayed conditioned reflex. We suggest that the local and distributed neural networks of the frontal cortex and hippocampus take part in the realization of cognitive behavior, in particularly in the processes of the decision making.     

Organization of neocortical neuronal networks

Multiple unit activity in deep layers of the frontal and motor cortices was recorded by chronically implanted semimicroelectrodes in waking cats with different levels of food motivation. From four to seven neuronal spike trains were selected from the recorded multiunit activity. Interactions between neighbouring neurons in the motor and frontal areas of the neocortex (within the local neuronal networks) and between the neurons of these areas (distributed neuronal networks) were estimated by means of statistical crosscorrelation analysis of spike trains within the range of delays from 0 to 100 ms. Neurons in the local networks were divided in two subgroups: the neurons with higher spike amplitudes with the dominance of divergent connections and neurons with lower spike amplitudes with the dominance of convergent connections. Strong monosynaptic connections (discharges with a delay of less than 2 ms) between the neurons with high- and low-amplitude spikes formed the background of the local networks. Connections between low-amplitude neurons in the frontal cortex and high-amplitude neurons in the motor cortex dominated in the distributed networks. A 24-hour food deprivation predominantly altered the late interneuronal crosscorrelations with time delays within the range of 2-100 ms in both local and distributed networks.     

Interrelations between neurons of the frontal cortex and hippocampus under cholinergic deficit in choice behavior of cats

Appetitive instrumental conditioned reflexes on light (CS+) were formed in six cats by the method of "active choice" of quality of reinforcement; bread-meat mixture was given after short-delay conditioned bar-press responses, and the delayed responses were rewarded by meat. The animals differed in choice behavior strategy: "self-control", "ambivalent", "impulsive". The multiunit activity in the frontal cortex and hippocampus (CA3) was recorded. Cross-correlation analysis was used for estimation of correlation of activities in neuronal pairs in the frontal cortex and hippocampus (distributed frontal-hippocampal networks) and pairs within the same structure (frontal and hippocampal local neuronal networks). It was shown that the number of cross-correlations between the discharges of neurons both in the local and distributed networks was significantly higher in "self-control" cats. Under conditions of systemic administration of antagonists of muscarinic central cholinoreceptors (trihexyphenidyl and scopolamine), the bar-press conditioning impaired, the number of direct interneuronal connections decreased, and the number of externally synchronized correlations ("common input") significantly increased. The results suggest that the local and distributed neural networks of the frontal cortex and hippocampus are involved in the system of brain structures that determine the behavioral strategy of "self control".     

Local and distributed neuronal networks and individuality

To estimate stable behavioural peculiarities, an individual varying choice of greater or better appetite reinforcement depending on the time of instrumental motor response was used with cats. A decisive role in realisation of the response choice is played by the influence of motivational structures of hypothalamus and amygdala on formal areas of neocortex typical for "impulsive" (fast reacting) cats, and interaction of the frontal cortex--hippocampus system for the animals with delayed pressing of the lever to obtain their preferred food, i.e. manifesting the ability of "self-control".     

The organization of the network characteristics of the cells in local and distributed neuronal networks of the cat brain]

In cats with elaborated alimentary instrumental reflexes to light net characteristics of neurones of visual, motor cortex and the hypothalamus lateral nucleus were studied on the basis of revealed interneuronal interactions by means of cross-correlation method of analysis. Different organization of net properties of the cortical neurones in organization of local and distributed neuronal networks was shown, namely: predominance of the divergent characteristics over the convergent ones for cells in local networks and levelling of these relations in distributed nets. Neurones of the lateral hypothalamus nucleus had equal presentation of divergent and convergent properties in organization of local and distributed networks. Net characteristics of neurones of the cortical and subcortical structures were manifested in the background after the elaboration and the extinction of conditioned reflexes. Only small cells of the visual cortex were functionally dependent and changed correlation of net characteristics in local networks at CR extinction.     

The typological characteristics of higher nervous activity in dogs and the maxima of the cross-correlation function between the electrical activities of the frontal cortex and the brain limbic systems]

Electrical activity of the frontal cortex, dorsal hippocampus, basolateral amygdala and lateral hypothalamus was recorded in eight dogs with chronically implanted electrodes. Mean values of the maxima of crosscorrelation function (MCCF) between electrical potentials in the theta, alpha and beta-2 ranges were used as a basis for assessment of conditions for interaction between these structures. Typological features of the higher nervous activity were assessed by the animal performance under conditions of free choice of the reinforcement mode of a conditioned stimulus: either high probable but of low alimentary quality or with low probability but more valuable. The mean MCCF values in the theta range were higher than in the other ranges. The brain structure which had the high MCCF in the theta-range, at least, with two of the structures under study was considered as "dominant". It was shown that hippocampus was the dominant structure for melancholic dogs, the frontal cortex was in phlegmatics. The hypothalamus was shown to be the "dominant structure" in both sanguine and choleric animals, but, for the most part, its activity was correlated with different structures. Thus, conditions for interaction between the frontal cortex, hippocampus, amygdala and hypothalamus seem to be an important factor, which determines typological features of the higher nervous activity of dogs.     

The organization of instrumental food-procuring movements in rats]

The roles of the lateral hypothalamus, basolateral nucleus of the amygdalar complex, the second field of the frontal cortex, and ventromedial thalamic nucleus in organization of the fast ballistic food-procuring movements were studied in albino rats. Sequences of uni- and bilateral destruction of the brain structures were assessed by photorecording. Movement-related neuronal activity in these structures was recorded in freely moving animals. A specific involvement of each of the above listed structures in organization of food-procuring movements was shown. The lateral hypothalamus seems to participate in initiation of the motor program and its efficient realization, the basolateral amygdala appears to produce activatory, training, and stabilizing effects. The second field of the motor cortex leads in movement acquisition (i.e., in memorizing) and decision making about triggering the program. The idea about the relay role of the thalamic motor nucleus is supplemented by understanding of its more complex integrative function.     

The model of the reward choice basing on the theory of reinforcement learning

We developed the model of alimentary instrumental conditioned bar-pressing reflex for cats making a choice between either immediate small reinforcement ("impulsive behavior") or delayed more valuable reinforcement ("self-control behavior"). Our model is based on the reinforcement learning theory. We emulated dopamine contribution by discount coefficient of this theory (a subjective decrease in the value of a delayed reinforcement). The results of computer simulation showed that "cats" with large discount coefficient demonstrated "self-control behavior"; small discount coefficient was associated with "impulsive behavior". This data are in agreement with the experimental data indicating that the impulsive behavior is due to a decreased amount of dopamine in striatum.     

Impulsation of hypothalamic and amygdalar neurons in bilateral derivations in the state of food motivation

The character of impulsation of single neurons in the lateral hypothalamic and amygdalar central nucleus of rabbits recorded in bilateral derivations during quiet wakefulness, after 24-h food deprivation, and after satiation was studied by plotting autocorrelation histograms and by counting the mean frequency of discharges. During the transition from hunger to satiation, the character of impulsation of neurons in hypothalamus and amygdala changed in different ways: (1) a greater number of hypothalamic than amygdalar neurons changed their mean discharge frequency (85 versus 56%, respectively); (2) in hunger, the number of hypothalamic neurons with delta-frequency oscillations decreased as compared to quiet wakefulness and satiation, and in the amyglala the number of neurons with beta2-frequency oscillations increased; (3) in hunger, the number of hypothalamic neurons with bursting and periodic discharges decreased and the number of amygdalar neurons with equiprobabilistic discharges increased. During state alternation (according to the autocorrelation histograms) the strongest changes in the character of neuronal discharges took place in the left hypothalamus and left amygdala. The maximum differences in neuronal impulsation between the left and right hypothalamus were observed in the state of hunger and between the left and right amygdala, after satiation.     

Neuronal interactions between neuropeptide W- and orexin- or melanin-concentrating hormone-containing neurons in the rat hypothalamus

Neuropeptide W (NPW) was recently discovered as the endogenous ligand for GPR7 and GPR8, which are orphan G protein-coupled receptors isolated from the porcine brain. These receptors are assumed to be involved in feeding regulation and/or energy homeostasis. Recent anatomical studies have revealed that high levels of GPR7 mRNA are distributed in the brain, including the hypothalamus and amygdala. However immunohistochemical studies on the distribution and localization of NPW have revealed differing results concerning whether or not NPW-containing cell bodies and their processes are present in the hypothalamus. Only a few immunohistochemical reports have been published concerning the presence of NPW-containing neurons in the brains of rodents, while there have been no anatomical studies of the co-localization of this neuropeptide with other transmitters. On this basis, we used a specific antiserum against NPW to determine immunohistochemically the presence of NPW-containing neurons in the rat hypothalamus. Many NPW-like immunoreactive cell bodies and their processes could be detected in the caudal region of the lateral hypothalamus but not in its anterior or middle regions. Given this positive identification of NPW-containing neurons in the lateral hypothalamus, we further studied the nature of interaction between NPW-containing neurons and neurons containing feeding regulating peptides such as orexin- and melanin-concentrating hormone (MCH). Very close interactions between NPW-containing nerve processes and orexin- and MCH-containing neuronal cell bodies and processes could be observed. These morphological findings strongly suggest that NPW is involved in the regulation of feeding and/or sleep/arousal behavior through orexin- and/or MCH-mediated neuronal pathways.     

Automated Food-Procuring Movement-Related Neuronal Activity in the Basolateral Amygdala of the Rat

We studied the impulse activity of neurons of the basal and lateral amygdalar nuclei generated when experimental animals (rats) performed fast stereotyped food-procuring movements by the forelimb. Within the basolateral amygdala, there are neurons whose activity is related to different stages of getting off the food, and according to the characteristics of their spiking these neurons should be divided into a number of subpopulations. Activation forestalling the movement initiation by 0.5-1.0 sec was observed in most neurons of the basolateral amygdala; this is considered a manifestation of excitation related to a motivation component of the food-procuring behavior. Activation of amygdalar neurons following movement initiation can result from generation in this structure of additional excitation necessary for successful performance of a complete food-procuring motor cycle.     

Molecular annotation of integrative feeding neural circuits

The identity of higher-order neurons and circuits playing an associative role to control feeding is unknown. We injected pseudorabies virus, a retrograde tracer, into masseter muscle, salivary gland, and tongue of BAC-transgenic mice expressing GFP in specific neural populations and identified several CNS regions that project multisynaptically to the periphery. MCH and orexin neurons were identified in the lateral hypothalamus, and Nurr1 and Cnr1 in the amygdala and insular/rhinal cortices. Cholera toxin β tracing showed that insular Nurr1(+) and Cnr1(+) neurons project to the amygdala or lateral hypothalamus, respectively. Finally, we show that cortical Cnr1(+) neurons show increased Cnr1 mRNA and c-Fos expression after fasting, consistent with a possible role for Cnr1(+) neurons in feeding. Overall, these studies define a general approach for identifying specific molecular markers for neurons in complex neural circuits. These markers now provide a means for functional studies of specific neuronal populations in feeding or other complex behaviors.     

Reactions of neurons of orbitofrontal cortex to stimulation of limbic system formations

The reactions of 164 neurons of the orbitofrontal cortex (OFC) to stimulation of the mediodorsal nucleus of the thalamus (MD), the amygdaloid complex, and various sections of the hypothalamus, were investigated in acute experiments on cats. Stimulation of the MD led to the development in OFC neurons of reactions with a short (sometimes less than 6 msec) and stable latent period. Similar reactions were observed upon stimulation of the lateral amygdaloid nuclei. Stimulation of the basal and central nuclei of the amygdala evoked synchronization of the discharges in OFC neurons. Stable responses of OFC neurons developed from nuclei of the hypothalamus only in the lateral region. Stimulation of the other nuclei of the hypothalamus was accompanied by irregular responses or synchronization of the discharges. In an analysis of the material obtained, the functional characteristics of the connections between the structures investigated and OFC neurons were examined.State Medical Institute, Kemerovo. Translated from Neirofiziologiya, Vol. 3, No. 5, pp. 484–490, September–October, 1971.     

Electrophysiological effects of MCH on neurons in the hypothalamus

Melanin concentrating hormone (MCH) has been implicated in many brain functions and behaviors essential to the survival of animals. The hypothalamus is one of the primary targets where MCH-containing nerve fibers and MCH receptors are extensively expressed and its actions in the brain are exerted. Since the identification of MCH receptors as orphan G protein coupled receptors, the cellular effects of MCH have been revealed in many non-neuronal expression systems (including Xenopus oocytes and cell lines), however, the mechanism by which MCH modulates the activity in the neuronal circuitry of the brain is still under investigation. This review summarizes our current knowledge of electrophysiological effects of MCH on neurons in the hypothalamus, particularly in the lateral hypothalamus. Generally, MCH exerts inhibitory effects on neurons in this structure and may serve as a homeostatic regulator in the lateral hypothalamic area. Given the contrast between the limited data on cellular functions of MCH in the hypothalamus versus a fast growing body of evidence on the vital role of MCH in animal behavior, further investigations of the former are warranted.     

The choice of reinforcement quality depending on the delay time of the instrumental reaction in cats]

In experiments on seven cats instrumental delayed reflexes with different quality reinforcement were elaborated by method of "active choice", where the time of delay of the motor reaction served as a signal of quality of the reinforcement. Five cats used a strategy with long delay high-quality reinforcement (meat), and two cats preferred short delay and low-quality reinforcement (bread-meat mixture). In special experiments with the change of alimentary motivation (24-hour alimentary deprivation and saturation of animals) it was established that the level of alimentary motivation within the studied limits did not change the strategy of behaviour preferred by the given animal. Individually varying ability to choice of reaction determining more valuable reinforcement it is possible to consider as an experimental analogue of the mechanisms of will. The question is discussed about the role of typological properties of cats in choice of behaviour strategy.     

Individual typological characteristics of higher nervous performance and asymmetry of hippocampus and amygdala electrical activity in dogs

Electrical activity of the frontal cortex, dorsal hippocampus, basolateral amygdala and lateral hypothalamus of both hemispheres was recorded in nine dogs in the state of quiet wakefulness without any stimulation. Individual typological features of higher nervous activity were assessed by the animal performance under conditions of free choice of the reinforcement mode: either high probable but of low alimentary quality, or with low probability but more valuable. Mean values of the maxima of crosscorrelation function between electrical activity of the investigated structures of two hemispheres were used as a basis for assessment of conditions for interaction between left and right formations. For the hippocampus and amygdala, in some dogs these conditions were the best in the theta and beta 2 ranges, in other animals--in the theta and alpha bands. In phlegmatic dogs, spectral densities in the theta range were higher in the left hippocampus than in the symmetrical structure, in sanguine animals spectral densities in the theta and beta 2 ranges in the hippocampus and amygdala were higher in the right hemisphere than in the left one. Thus, the hemispheric asymmetry of electrical activity of the limbic formations seems to be an important factor, which determines the individual typological features of the higher nervous activity in dogs.     

Increased anxiety-like behavior and enhanced synaptic efficacy in the amygdala of GluR5 knockout mice

GABAergic transmission in the amygdala modulates the expression of anxiety. Understanding the interplay between GABAergic transmission and excitatory circuits in the amygdala is, therefore, critical for understanding the neurobiological basis of anxiety. Here, we used a multi-disciplinary approach to demonstrate that GluR5-containing kainate receptors regulate local inhibitory circuits, modulate the excitatory transmission from the basolateral amygdala to the central amygdala, and control behavioral anxiety. Genetic deletion of GluR5 or local injection of a GluR5 antagonist into the basolateral amygdala increases anxiety-like behavior. Activation of GluR5 selectively depolarized inhibitory neurons, thereby increasing GABA release and contributing to tonic GABA current in the basolateral amygdala. The enhanced GABAergic transmission leads to reduced excitatory inputs in the central amygdala. Our results suggest that GluR5 is a key regulator of inhibitory circuits in the amygdala and highlight the potential use of GluR5-specific drugs in the treatment of pathological anxiety.     

Influence of the medial raphe nucleus damage on discharge activity of the central and bazolateral nuclei of the amygdala

It has been revealed pronounced differences between neuronal discharge activity of central and basolateral nuclei of amygdala. After midbrain raphe medial nucleus damage discharge activity of amygdalar nuclei markedly changes, mainly by reciprocal manner. It is suggest that serotonergic afferentations from nucleus raphe to show various influence upon discharge activity of central and lateral nuclei of amygdala.