Conditioned reflex reproduction of evoked potentials during reinforcement by electrostimulation of the hypothalamus]

Conditioned evoked potentials to stimulation of a limb, a light flash or a short tone were studied on rats in acute experiments with nembutal anaesthesia and in chronic experiments. Electrical stimulation of the hypothalamus was used as reinforcement. Following the pairings of conditioned and hypothalamic stimulation, the appearance of conditioned EP was recorded, as manifest in the period of the previously applied unconditioned signal after its omission. Their emergence was facilitated after high-frequency stimulation of the hypothalamus or administration of galantamine, an anticholinesteraze drug. Coagulation of the hypothalamus did not prevent any manifestation of conditioned evoked potentials.     

M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation

Mesopontine cholinergic neurons (Ch5 and Ch6 cell groups) activate the cerebral cortex via thalamic projections, and activate locomotion and reward via dopamine neurons in the substantia nigra and ventral tegmental area (VTA). Nicotinic receptors in VTA activate dopamine neurons quickly, and are needed for the stimulant and rewarding effects of nicotine in rats. Muscarinic receptors in VTA activate dopamine neurons slowly, and are needed for the rewarding effects of hypothalamic stimulation, but do not increase locomotion. Antisense oligonucleotides targetting M5 mRNA, when infused into the VTA, inhibited M5 receptor binding and rewarding hypothalamic stimulation. Mutant mice with truncated M5 muscarinic receptor genes drank more water than wild-type controls. Spontaneous locomotion and locomotor responses to amphetamine and scopolamine were unchanged. Electrical stimulation near Ch6 induced dopamine release in the nucleus accumbens in two phases, an early phase (0-2 min after stimulation) dependent on nicotinic and gluatamatergic receptors in VTA, and a late phase (8-50 min after stimulation) dependent on muscarinic receptors in VTA. The late phase was lost in M5 mutant mice, while the early phase was unchanged. M5 muscarinic receptors bind slowly to muscarinic ligands, and appear to mediate slow secretions.     

Feeding,drug abuse,and the sensitization of reward by metabolic need

The incentive-motivating effects of external stimuli are dependent, in part, upon the internal need state of the organism. The increased rewarding efficacy of food as a function of energy deficit, for example, has obvious adaptive value. The enhancement of food reward extends, however, to drugs of abuse and electrical brain stimulation, probably due to a shared neural substrate. Research reviewed in this paper uses lateral hypothalamic electrical stimulation to probe the sensitivity of the brain reward system and investigate mechanisms through which metabolic need, induced by chronic food restriction and streptozotocin-induced diabetes, sensitizes this system. Results indicate that sensitivity to rewarding brain stimulation varies inversely with declining body weight. The effect is not mimicked by pharmacological glucoprivation or lipoprivation in ad libitum fed animals; sensitization appears to depend on persistent metabolic need or adipose depletion. While the literature suggests elevated plasma corticosterone as a peripheral trigger of reward sensitization, sensitization was not reversed by meal-induced or pharmacological suppression of plasma corticosterone. Centrally, reward sensitization is mediated by opioid receptors, since the effect is reversed by intracerebroventricular (i.c.v.) infusion of naltrexone, TCTAP (μ antagonist) and nor-binaltorphimine (κ antagonist). The fact that these same treatments, as well as i.c.v. infusion of dynorphin A antiserum, block the feeding response to lateral hypothalamic stimulation suggests that feeding and reward sensitization are mediated by a common opioid mechanism. Using in vitro autoradiography, radioimmunoassays and a solution hybridization mRNA assay, brain regional μ and κ opioid receptor binding, levels of prodynorphin-derived peptides, and prodynorphin mRNA, respectively, were measured in food-restricted and diabetic rats. Changes that could plausibly be involved in reward sensitization are discussed, with emphasis on the increased dynorphin A_1–8 and prodynorphin mRNA levels in lateral hypothalamic neurons that innervate the pontine parabrachial nucleus, where μ binding decreased and κ binding increased. Finally, the possible linkage between metabolic need and activation of a brain opioid mechanism is discussed, as is evidence supporting the relevance of these findings to drug abuse. Special issue dedicated to Dr. Eric J. Simon.     

Similar effect of caerulein on intracranial self-stimulation in vagotomized and non-vagotomized rats

Electrical stimulation eliciting self-stimulation behavior from postero-lateral hypothalamic implanted electrode was controlled by factors that control normal feeding. In this idea, lateral hypothalamic stimulation possessed an appetite whetting property and this is experienced as rewarding. The octapeptide cholecystokinin, a gut hormone, has been experimented upon to produce the complete behavioral sequence of satiety in rats. We observed that an i.p. injection of caerulein (an analog of cholecystokinin) did decrease, in a dose-related manner, the rate for brain self-stimulation. However, a similar effect on the rate of ICSS was measured after a bilateral cut of the vagus nerve at a subdiaphragmatic level. This result suggests that the decreasing effect on ICSS after an i.p. injection of caerulein is not strictly related to feeding. We interpret the decrease of reinforcement induced by caerulein as the action of a general satiety for any object presenting a rewarding value for behavior.     

Investigation of pallidofugal influences on hypothalamic activity

In chronic experiments on nine cats electrical stimulation of the posterior zones of the lateral hypothalamus led to reproduction of a conditioned food-getting reflex produced previously in response to clicks. During stimulation of the globus pallidus a food-getting reflex also appeared in 3 of 10 zones studied, but it did so only irregularly. In response to combined stimulation of the hypothalamus and these three zones of the globus pallidus facilitation of this reflex was observed: its intensity was increased and its latent period shortened. Stimulation of other areas of the globus pallidus inhibited the food getting reflex of hypothalamic origin on account of the intensification of purposeless motor responses. Stimulation of the globus pallidus evoked desynchronization of spontaneous hypothalamic electrical activity. After bilateral electrolytic destruction of the globus pallidus and its principal efferent pathway (the ansa lenticularis) no conditioned food-getting reflex was reproduced during hypothalamic stimulation. After pallidectomy the amplitude of the spontaneous waves and evoked potentials was reduced by a statistically significant degree in the hypothalamic zones tested. The results are evidence of the existence of regulatory functional influences of the globus pallidus on the lateral hypothalamus.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 6, No. 6, pp. 592–601, November–December, 1974.     

Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis

Dopamine was measured by microdialysis in the nucleus accumbens of freely moving rats while they experienced rewarding food, brain stimulation and drugs. Extracellular dopamine increased 37% when the animals pressed a lever for food reward. Electrical stimulation of a lateral hypothalamic feeding-reward (self-stimulation) site caused a similar increase in dopamine, with or without food. At the site in the nucleus accumbens where rats will administer amphetamine to themselves, injections of amphetamine or cocaine increased extracellular dopamine five-fold. Thus amphetamine and cocaine increase dopamine in a behavior reinforcement system which is normally activated by eating. Conversely, the release of dopamine by eating could be a factor in addiction to food.     

Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex.

Neural stimuli associated with traumatic events can readily become conditioned so as to reinstate the memory of the original trauma. These conditioned fear responses can last a lifetime and may be especially resistant to extinction. A large amount of data from many different laboratories indicate that the amygdala plays a crucial role in conditioned fear. The amygdala receives information from all sensory modalities and projects to a variety of hypothalamic and brainstem target areas known to be critically involved in specific signs that are used to define fear and anxiety. Electrical stimulation of the amygdala elicits a pattern of behaviours that mimic natural or conditioned states of fear. Lesions of the amygdala block innate or conditioned fear and local infusion of drugs into the amygdala have anxiolytic effects in several behavioural tests. Excitatory amino acid receptors in the amygdala are critical for the acquisition, expression and extinction of conditioned fear.     

Reinforcing stimulation of the postero-lateral hypothalamus and mating behaviour in the rat.

Male rats implanted with chronic electrodes into the postero-lateral hypothalamic site were tested for self-stimulation behaviour. Rats exhibiting steady self-stimulation behaviour were observed during mating tests with an oestrus female. During these tests the hypothalamus of male rats was stimulated. Results show that no stimulus-bound sexual behaviour was observed. Nevertheless, correlations were found between the rewarding value of the cerebral stimulation and the specific sexual components of mating behaviour. These results are interpreted with the hypothesis of a balancing effect between the reward elicited by direct stimulation of the brain and reward acquired by the presence of an oestrus female.     

The escape reactions in cats during electrical stimulation of the hypothalamus leading to the occurrence of aggressive behavior]

The influence of brain electrical stimulation, which induced some elements of agonistic behavior, on the preference of an animal of one of two compartments of the experimental chamber was studied in 7 male cats with implanted hypothalamic electrodes. The animals avoided the compartment in which they were stimulated. Self-stimulation reaction could not be formed on the basis of the electrical brain stimulation inducing certain elements of agonistic behavior. Passage latencies were shorter when an animal left the less preferential compartment that in the case when in started from the more preferential one. The obtained evidence suggests that hypothalamic stimulation producing certain elements of agonistic behavior evokes in an animal a negative internal state.     

Generalization of an instrumental defensive conditioned reflex elaborated to electric stimulation of the hypothalamus in dogs

Generalization of defensive conditioned reflexes elaborated to electrical stimulation of the lateral hypothalamus (LH) was studied in four dogs with electrodes implanted in various structures of the limbic system. Electrocutaneous stimulation was switched off when the dog lifted the foreleg to a definite level. Generalization of the conditioned reflex was manifested in different degrees when testing different formations of the limbic system, or testing one and the same structure, but at different stages of conditioning. Two types of generalization were found: the first one--a well pronounced motor reaction, by its latency, level and duration of lifting the foreleg similar to movements appearing in response to the conditioned stimulus; and the second one--low amplitude or short-term movements differing from conditioned ones. The first type of generalization was observed in response to stimulation of LH, contralateral to the point of signal stimulation, of the ventromedial hypothalamic nucleus, the mammillary bodies and the basal, lateral and to a lesser degree, the central nucleus of the amygdaloid complex; the second type--in response to stimulation of the ventral hippocampus, the medial and lateral septum nuclei.     

Role of licking and concomitant changes in the excitability of nerve centers in the elaboration of gustatory information in rats

The mechanism of nervous control of licking was studied in the frame work of the electrophysiological analysis of conditioned taste aversion. The licking rhythm is so stable that the rats are unable to slow it down by 20 percent. If the solution which was previously used for establishing the conditioned taste aversion, appears in the drinking spout, the rat stops drinking after one or two licks. Analysis of temporal relationships between afferent and efferent impulse activity of licking shows that the comparison of gustatory signals with memory traces and the corresponding decision occurs within 80 to 120 ms after lick onset. Electrical stimulation of the hypothalamic centres through implanted electrodes has shown that the amplitude of evoked responses and the impairment of licking increases, in proportion to the delay between lick onset and stimulus application. Isolated discharges of epileptic foci in the frontal cortex and the hypothalamus cause an omission of one or several licks, without interfering with the activity of the licking generator.     

Social and physical environments as a source of individual variation in the rewarding effects of testosterone in male California mice (Peromyscus californicus)

Despite extensive research revealing the occurrence of testosterone (T) pulses following social encounters, it is unclear how they lead to varied behavioral responses. We investigated the influence of residency (home versus unfamiliar environment) and social/sexual experience (pair-bonded, isolated or housed with siblings) on the plasticity of T's rewarding effects by measuring the development of conditioned place preferences (CPPs), a classical paradigm used to measure the rewarding properties of drugs. For pair-bonded males, T-induced CPPs were only produced in the environment wherein the social/sexual experience was accrued and residency status had been achieved. For isolated males, the T-induced CPPs only occurred when the environment was unfamiliar. For males housed with a male sibling, the T-induced CPPs were prevented in both the home and unfamiliar chambers. Our results reveal the plasticity of T's rewarding effects, and suggest that the behavioral functions of T-pulses can vary based on social/sexual experience and the environment in which residency was established. The formation of CPPs or reward-like properties of drugs and natural compounds can therefore exhibit malleability based on past experience and the current environment.     

不同背景的同伴强化及催产素处理对雌性棕色田鼠可卡因条件位置偏爱的影响

同伴间的社会互作是一种天然奖赏,能够影响成瘾药物使用的敏感性。催产素（Oxytocin,OT)能够调节社会行为,并提高社会互作的奖赏价值。然而不同背景的同伴互作以及与OT合并使用是否对可卡因的奖赏效应有不同的影响尚不清楚。棕色田鼠(Microtus mandarinus)是一种单配制田鼠,个体间具有较复杂的社会行为。利用雌性棕色田鼠,我们首先检测了可卡因(20 mg/kg)单独强化以及与不同背景关系的同伴（熟性雌性、陌生雌性和陌生雄性）同时强化诱导的条件位置偏爱（conditioned place preference, CPP）及持续时间;其次检测了实验鼠外周注射OT (1 mg /kg)并给予不同背景同伴强化对可卡因CPP的影响。结果表明,可卡因单独强化时,实验鼠能够形成可卡因CPP并能持续至3周;用熟悉的雌性同伴强化时,实验鼠对可卡因CPP的维持时间缩短;用陌生的雌性或雄性同伴强化时可抑制可卡因CPP的形成。实验鼠注射OT后,用熟悉雌性或陌生雄性同伴分别强化时会抑制或反转可卡因CPP。这些结果表明不同背景关系的同伴强化对可卡因奖赏效应的影响不同。OT可促进同伴强化的奖赏价值,降低动物对可卡因的偏爱,且该效应因强化同伴的背景而不同。     

Electroencephalographic studies on classically conditioned defensive reflex and avoidance lever-pressing in the dog (author's transl)]

Six dogs with implanted cortical and subcortical electrodes were trained to press a lever to avoid electroshock to a hind leg. Intracerebral stimulation at low frequency was delivered as an "indifferent" or a "CD" tracer. Changes of EEG responses to the tracers prior to the voluntary lever-pressing or the conditioned avoidance lever-pressing were prior to the voluntary lever-pressing or the conditioned avoidance lever-pressing were examined by continuous frequency analysis. (1) Evoked potentials to the tracer stimulation were changed just before the conditioned defensive reflex, the voluntary lever-pressing and the conditioned avoidance lever-pressing, regardless of the site of the tracer stimulation. (2) The cortical and subcortical structures (Hippo, RF) seemed to be involved in the neural circuit responsible for the avoidance lever-pressing, whereas the sensorimotor cortex may be essential in the circuit for the alimentary lever-pressing. (3) The avoidance lever-pressing and the EEG response to the "CS" tracer were influenced by the internal inhibition (experimental extinction, inhibitory mechanism was discussed.     

Retrieval of delayed evoked potentials after amygdaloid stimulation

The effect of amygdaloid stimulation on retrieval of delayed evoked potentials recorded in the cortex, mesencephalic reticular formation, lateral geniculate body, and hippocampus was investigated in unanesthetized curarized cats. Delayed evoked potentials were produced to 10–400 combinations of flashes and hypothalamic stimulation and consisted of potentials arising in response to a conditioned stimulus after a delay equal to the interval between it and the unconditioned stimulus. Amygdaloid stimulation facilitated the retrieval of these potentials if they had first been extinguished or had not appeared during initial testing.Institute of Physiology, Academy of Medical Sciences of the USSR, Siberian Branch, Novosibirsk. Translated from Neirofiziologiya, Vol. 8, No. 3, pp. 300–304, May–June, 1976.     

Context alters the ability of clitoral stimulation to induce a sexually-conditioned partner preference in the rat

We have shown previously that clitoral stimulation (CLS) of female rats induces significant conditioned place preference (CPP), indicating that it is rewarding. The present study asked whether CLS could induce a conditioned partner preference. In the first experiment, sexually naïve females received 10 alternating trials of CLS and No-CLS in the presence of a male rat behind a wire-mesh screen. For one group, CLS was made in the presence of the male scented with almond extract. On alternating trials, those females received sham CLS in the presence of an unscented male behind the screen. The order was reversed for the other group. After 5 trials in each condition, females were placed into an open field with two sexually vigorous males, one scented and the other unscented. Contrary to expectation, females displayed a preference for the male associated with sham CLS. The second experiment examined whether a partner preference could be conditioned by associating CLS with the almond odor alone. A new group of sexually naive females received the same CLS-odor, No-CLS-No Odor pairings as above, but with the odor presented on cotton gauze in the chamber. During the final open field test, those females selectively solicited the scented male. We conclude that CLS that induces CPP also induces conditioned partner preference. However, we propose that CLS in the presence of an inaccessible male created a sexual inhibitory state for female rats.     

Pavlovian Conditioned Approach Training in Rats

Cues that are contingently paired with unconditioned, rewarding stimuli can acquire rewarding properties themselves through a process known as the attribution of incentive salience, or the transformation of neutral stimuli into attractive, "wanted'' stimuli capable of motivating behavior. Pavlovian conditioned approach (PCA) develops after the response-independent presentation of a conditioned stimulus (CS; e.g., a lever) that predicts the delivery of an unconditioned stimulus (US; e.g., a food pellet) and can be used to measure incentive salience. During training, three patterns of conditioned responses (CRs) can develop: sign-tracking behavior (CS-directed CR), goal-tracking behavior (US-directed CR), and an intermediate response (both CRs). Sign-trackers attribute incentive salience to reward-related cues and are more vulnerable to cue-induced reinstatement of drug-seeking as well as other addiction-related behaviors, making PCA a potentially valuable procedure for studying addiction vulnerability. Here, we describe materials and methods used to elicit PCA behavior from rats as well as analyze and interpret PCA behavior in individual experiments.     

Acute High Fat Diet Consumption Activates the Mesolimbic Circuit and Requires Orexin Signaling in a Mouse Model

Overconsumption of palatable energy-dense foods has negative health implications and it is associated with obesity and several eating disorders. Currently, little is known about the neuronal circuitries activated by the acute ingestion of a rewarding stimulus. Here, we used a combination of immunohistochemistry, pharmacology and neuronal tracing analyses to examine the role of the mesolimbic system in general, and the orexin neurons in particular, in a simple experimental test in which naïve mice are allowed to spontaneously eat a pellet of a high fat diet (HFD) for 2 h. We found that acute HFD activates c-Fos expression in several reward-related brain areas, including the ventral tegmental area (VTA), nucleus accumbens, central amygdala and lateral hypothalamic area. We also found that: i- HFD-mediated orosensory stimulation was required for the mesolimbic pathway activation, ii- acute HFD differentially activates dopamine neurons of the paranigral, parabrachial pigmented and interfascicular sub-regions of the VTA, and iii- orexin neurons of the lateral hypothalamic area are responsive to acute HFD. Moreover, orexin signaling blockade, with the orexin 1 receptor antagonist SB-334867, reduces acute HFD consumption and c-Fos induction in the VTA but not in the other mesolimbic nuclei under study. Finally, we found that most orexin neurons responsive to acute HFD innervate the VTA. Our results show that acute HFD consumption recruits the mesolimbic system and that the full manifestation of this eating behavior requires the activation of orexin signaling.     

Mechanism of hypothalamic control of cardiac component of sinus nerve reflex.

The modulatory influence of hypothalamic structures on sinus nerve induced bradycardia was investigated in anaesthetized cats. Stimulation of the hypothalamic defence area inhibits the bradycardia produced by sinus nerve stimulation both in intact animals and also in animals with the spinal cord sectioned at C1 or C6. This inhibition was accompanied in the normal animal by an increased sympathetic discharge and by a sustained inspiration or tachypnoea. The same respiratory effects were noted in a spontaneously breathing C6 spinal animal, while an artificially ventilated C1 spinal animal still displayed a powerful central inspiratory drive in its recurrent laryngeal electroneurogram. The presence of central inspiratory activity was found to be an absolute impediment to the development of bradycardia. If this activity was eliminated by simultaneous stimulation of the superior laryngeal nerve, it was possible to obtain bradycardia during combined sinus nerve and hypothalamic defence area stimulation, though this bradycardia was modified by the presence of sympathetic discharge. The level of sympathetic neural discharge affects the magnitude of the bradycardia produced by sinus nerve stimulation. The bradycardia was less with normal or augmented level of sympathetic activity and was greater if this activity was reduced or absent. A lesion just caudal to the mammillary bodies disclosed a tonic hypothalamic influence both on respiration and on sympathetic discharge; stimulation of the sinus nerve produced a much more powerful bradycardia after the lesion. The existence of a respiratory "gate" through which afferent stimuli pass on their way to the nucleus ambiguus, and which can be operated by the hypothalamic defence and depressor areas, is postulated and discussed.     

Sexual reward in male rats: effects of sexual experience on conditioned place preferences associated with ejaculation and intromissions

Various behavioral models and studies have provided evidence suggesting that male rat sexual behavior has rewarding and reinforcing properties. However, there is little information regarding the rewarding values of the different components of sexual behavior. Therefore, this study used a conditioned place preference (CPP) paradigm to address whether ejaculation and intromissions differ in their rewarding incentive values. We also addressed whether the differential rewarding values were dependent on prior sexual experience. Sexually naïve and experienced males received one pairing of either intromissions or ejaculation with one of the chambers in the CPP box. The amount of time spent in each chamber of the CPP apparatus after conditioning was then measured. Both sexually naïve and sexually experienced males formed a CPP for ejaculation, while only sexually naïve, and not sexually experienced, males formed a CPP for intromissions. Moreover, in sexually naïve males, multiple pairings of ejaculation with the designated chamber resulted in a CPP relative to the control chamber paired with display of intromissions. These data support the hypothesis that there is a hierarchy of rewarding sexual behavior, with ejaculation being the most rewarding component, and that the rewarding incentive value of other components of sexual behavior is dependent upon prior sexual experience.