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Biomedical subjects

M R Kruk

Publications and source records attributed to M R Kruk.

At least 19 recordsLinked to original sources

Neuronal substrate of electrically induced grooming in the PVH of the rat: involvement of oxytocinergic systems?

Electrical stimulation of the paraventricular (PVH) and adjacent hypothalamic area evokes self-grooming behaviour. Current intensity thresholds for grooming can be obtained depending on the exact localization of the electrode site. Sites localized at greater distance of the center of the grooming area evoke grooming at greater latencies and higher current intensity, or no grooming at all. Results are compared with injections of neuroactive substances into the PVH from previous studies, which showed a similar site specificity for grooming. We found similarity in the distribution of electrode sites in the paraventricular and anterior hypothalamic areas at which grooming is induced, and hypothalamic immunoreactive oxytocinergic neurons and fibres. In addition, we reported earlier that oxytocin infusions into the PVH in resting animals induce grooming, in contrast to other grooming-related peptides, such as alpha-melanocyte-stimulating hormone. We hypothesize that electrical stimulation may induce grooming by activation of oxytocinergic systems originating from the PVH.

Animals

PVH lesions do not inhibit stressor-induced grooming in the rat.

Electrical and chemical stimulation of specific parts of the paraventricular hypothalamus (PVH) and the adjacent hypothalamus induce self-grooming responses in the rat. The function of this hypothalamic grooming area (HGA) is not understood. The localization of the HGA in the hypothalamus suggests that grooming, a behavioural response to stressors, is somehow linked to the neuroendocrine response to stressors. In this study it is shown that grooming induced by the stressors, mild restraint and moistening of the fur of the rat, is not inhibited by complete, bilateral radiofrequency lesions of the HGA. The changes in grooming patterns observed following lesions suggest that the HGA may have a function in the timing of different grooming elements.

Animals

Effect of environmental stressors on time course, variability and form of self-grooming in the rat: handling, social contact, defeat, novelty, restraint and fur moistening.

Grooming is often related to dearousal following stressors. Interestingly, electrical and chemical stimulation of the paraventricular nucleus of the hypothalamus (PVH), at levels that are known to activate the hypothalamus-pituitary adrenal axis (HPA), also elicits grooming. At the level of the PVH, the neuroendocrine stress response is apparently still linked to the behavioural response to stressors. However the precise nature of this relation is not fully understood. Here we report on grooming in rats following exposure to different stressors which are known to activate the HPA axis. Stressors such as handling, restraint, novelty, encounters with aggressive or non-aggressive conspecifics, or moistening the fur, change the amount and time course of grooming upon return in the home cage, as compared with controls that are just handled. However, the amount of grooming is not directly related to the strength of the stressor. Defeated intruders groom less upon return in their home cage. Novelty and non-aggressive encounters with conspecifics reduce the variation in the amount of grooming between rats. The time course of grooming over the 20-min observation period also differs between treatments. Following restraint, or exposure to non-aggressive conspecifics, grooming first increases and then decreases. Moistened rats immediately start grooming which subsequently decreases. Rats used as intruders in the territory of another rat maintain a constant low level of grooming. Rats placed in a novel cage steadily increase grooming during the 20-min observation period. These results suggest that grooming cannot be simply understood as an immediate response necessary to reduce arousal following stressors. Following exposure to a stressor, grooming rather seems temporary suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression

Efferent connections of the hypothalamic "aggression area" in the rat.

The efferent connections of the hypothalamic area of the rat, where attack behaviour can be elicited by electrical stimulation, were studied using iontophoretic injections of Phaseolus vulgaris-leucoagglutinin. Specificity for the hypothalamic "attack area" was investigated by comparison with efferents of hypothalamic sites outside the attack area. The hypothalamic attack area consists of the intermediate hypothalamic area and the ventrolateral pole of the ventromedial hypothalamic nucleus. Fibres from the hypothalamic attack area, as well as fibres from several other hypothalamic sites, form diffuse fibre "streams" running rostrally or caudally. Many varicosities that are found on the fibres suggest, that these fibres are capable of influencing many brain sites along their way. Projection sites were found throughout the brain. In the comparison between attack area efferents and controls, many overlapping brain sites were found. Hypothalamic efferents preferentially originating in the largest part of the attack area, i.e. the intermediate hypothalamic area, were found in the mediodorsal and parataenial thalamic nuclei. Within the septum, a spatial organization of hypothalamic innervation was found. Fibres from the attack area formed specialized "pericellular baskets" in the dorsolateral aspect of the intermediate part of the lateral septal nucleus. Fibres from other hypothalamic sites were found in other septal areas and did not form these septal baskets. Within the mesencephalic central gray, fibres from the attack area were found specifically in the dorsal part and dorsal aspect of the lateral part of the central gray. Physiological and pharmacological studies have shown that several brain sites are involved in different aspects of aggressive behaviour. Some of these areas, as for instance the dorsomedial thalamic nucleus, septum and central gray, are innervated by efferents from the hypothalamic attack area, whereas other sites, like ventral premammillary nucleus and ventral tegmental area, are not. It is concluded from the present findings, that a number of brain sites, that are known to be involved in agonistic behaviour, receive hypothalamic information preferentially from the hypothalamic attack area through diffusely arranged varicose fibres. The function of each connection in the regulation of specific behaviours remains to be further investigated.

Agonistic Behavior

Periaqueductal gray lesions do not affect grooming, induced electrically in the hypothalamic paraventricular area in the rat.

Electrical stimulation inducing behavioral responses from the hypothalamus seems to activate systems involved in the execution phase of the behaviour rather than in the introductory or decision-making phase. However, the pathways involved are not fully understood. Projections originating from hypothalamic areas involved in specific behavioral responses are rather complex. The periaqueductal gray (PAG) has been proposed to be an essential output station of hypothalamic behavioral mechanisms. Here we report that lesions of the periaqueductal gray area have no effect on grooming responses evoked by electrical stimulation of the hypothalamic paraventricular area. Neither threshold current intensities needed to evoke grooming, nor latencies were affected 7 or 14 days after lesioning. The lesions caused severe behavioural deficits. Animals did not drink or eat spontaneously, had problems with motor coordination and sometimes showed strong defensive reactions upon touch. However, their grooming responses induced by hypothalamic stimulation were not changed. The PAG may have a modulatory role on grooming behaviour; however, this modulatory effect apparently is overruled during electrical stimulation of the hypothalamus.

Animals

Behavioural responses of bicucculline methiodide injections into the ventral hypothalamus of freely moving, socially interacting rats.

Several studies, using electrical stimulation of parts of the hypothalamus, have shown, that different parts of the hypothalamus yield different behavioural responses upon stimulation. In order to differentiate between stimulation of neuronal cell bodies and passing fibres and to investigate the role of GABA in hypothalamically elicited behaviour, 25 local injections with bicucculline methiodide, a GABA antagonist, (35 ng/0.2 microliter) were performed in the ventral parts of the hypothalamus of 16 freely moving rats in a social environment. A cannula system was used that allowed injection without interruption of the ongoing social interactions. Digging, gnawing, drinking and attack behaviour were elicited in different animals. By plotting the behavioural responses of the animals into a detailed hypothalamic atlas, we assessed the hypothalamic distribution of the elicited behavioural responses. A number of injections elicited a combination of two or three different responses, probably due to diffusion of the substance, thus disinhibiting more than one behavioural system. Our results are in general agreement with previous electrical stimulation data and show that, in an overlapping pattern, different populations of neurons are involved in the elicitation of digging, gnawing, drinking and attack behaviour. In the hypothalamus, a tonic GABAergic inhibition of neurons involved in the display of these types of behaviour appears to exist.

Aggression

Initiation of self-grooming in resting rats by local PVH infusion of oxytocin but not alpha-MSH.

The present study was designed to discriminate between factors that initiate and/or prolong self-grooming. The study of factors initiating the grooming response is complicated by the fact that rats may groom already as a consequence of the injection procedure, due to release of endogenous substances after needle insertion or just handling of the animal. Therefore we used an infusion technique that allowed the rats to settle down quietly after they had been connected to an infusion pump, before the actual infusion of the peptide took place. In a previous report, we showed that direct injections of ACTH1-24 and alpha-melanocyte-stimulating hormone (alpha-MSH) into the paraventricular nucleus of the hypothalamus (PVH) prolong self-grooming caused by the injection procedure. Whether these peptides can also initiate grooming, however, is not yet clear. In this report, we compare the effects of alpha-MSH and oxytocin after infusion into the PVH in resting animals. Oxytocin is abundantly present in the PVH and is known to be involved in the regulation of grooming behavior. Slow infusions of oxytocin (0.1 microgram) do initiate grooming, but alpha-MSH (0.1 microgram) is without any behavioral effect. This suggests that oxytocin in the PVH is involved in the initiation of self-grooming, whereas alpha-MSH and probably ACTH do maintain grooming initiated otherwise, either by mechanical activation of the PVH and/or by the handling procedures. Infusion of substances in resting animals apparently is a way to avoid interactions between ongoing overt behavior and peptide-induced effects.

Animals

Induction of grooming in resting rats by intracerebroventricular oxytocin but not by adrenocorticotropic hormone-(1-24) and alpha-melanocyte-stimulating hormone.

Adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) injected i.c.v. induce so called 'excessive grooming'. Whether these peptides play a role in the initiation of grooming is not clear, since rats will groom even as a consequence of a particular environmental stimulation, such as handling and/or a novel environment. In most studies, therefore, the first 15 min after i.c.v. injection are not examined. Here we report on the effects of slow i.c.v. infusions of ACTH-(1-24), alpha-MSH and oxytocin in resting rats in their home cages. Interestingly, i.c.v. infusions of oxytocin did initiate grooming in a dose-related way. In contrast, i.c.v. infusions of both ACTH-(1-24) and alpha-MSH in resting rats were without effect on grooming. Oxytocin is apparently involved in the initiation of self-grooming in rats, whereas ACTH and alpha-MSH prolonged grooming initiated by other means, e.g. handling procedures and/or a novel environment. We conclude that the effects of alpha-MSH and ACTH on grooming are conditional, depending on the behavioural state (active or resting) of the animal.

Animals

Differential effect of ACTH1-24 and alpha-MSH induced grooming in the paraventricular nucleus of the hypothalamus.

Injection of ACTH1-24 as well as alpha-MSH in the paraventricular nucleus of the hypothalamus (PVH) induces intense grooming in the rat. While comparing the details of MSH, ACTH and control grooming, we found that the induction of grooming was highly site specific. Even injection of saline in that specific area produced some grooming, possibly due to the release of endogenous substances. To distinguish between effects caused by the peptides and the effects caused by the injection procedure, we compared the behavioural effects of saline and peptide injections in sites with exactly the same location in the PVH, in a post-hoc matched pairs design. Using this design we found that the grooming response induced by saline is of a limited duration. ACTH1-24 and alpha-MSH prolong grooming beyond that period. Interestingly, rats receiving alpha-MSH continued to groom, while rats receiving ACTH1-24 changed to scratching. This confirms earlier findings suggesting that grooming and scratching have a differential organization at the level of the PVH. Whether the peptides also have a role in the initiation of the grooming response, or just prolong a response caused by other local factors requires another experimental approach.

Animals

Behavioural effects of NMDA injected into the hypothalamic paraventricular nucleus of the rat.

Electrical stimulation of the hypothalamic paraventricular nucleus (PVH) and of the adjacent dorsal hypothalamic area (DHA) evokes grooming behaviour. Microinjections of low doses of kainic acid, an agonist of the kainate type of glutamate receptors, into the same area evokes the same behaviour. To test whether other glutamate receptors are involved, microinjections with N-methyl-D-aspartic acid (NMDA) were made into the PVH/DHA area and the behaviour was observed. From the total observation time (30 min) up to 73% was spent on grooming, accompanied by yawning. Pronounced feeding behaviour was also noticed at 3 injection sites but not until 23 min after injection. Conclusions are that neurones within the PVH/DHA area are involved in grooming behaviour, possibly via glutamatergic innervation. The interaction between grooming and feeding behaviour at the level of the PVH is discussed.

Animals

Grooming induced by intrahypothalamic injection of ACTH in the rat: comparison with grooming induced by intrahypothalamic electrical stimulation and i.c.v. injection of ACTH.

Intracerebroventricular (i.c.v.) injection of adrenocorticotropic hormone (ACTH) elicits grooming in the rat, but the neural organization of this response is still obscure. Electrical stimulation (EHS) in an area around the hypothalamic paraventricular nucleus (PVH) also elicits grooming. This hypothalamic area contains many ACTH-immunoreactive fibres. Injection of ACTH1-24 (0.3 microgram/0.3 microliters) in the same area elicits intense grooming responses in the rat. Latency, intensity and precise patterning of the grooming response are dependent upon the exact site of injection. Comparison of grooming responses elicited by EHS, ACTH injected i.c.v. and ACTH injected in the PVH reveals that these are slightly dissimilar. This may provide clues as to the brain mechanisms involved in the organization of the different components of grooming. EHS does not elicits scratching and even reduces 'spontaneous' scratching. Also, EHS-elicited grooming is characterized by short pauses. The time-course of appearance of yawning differs between ACTH-PVH and ACTH-i.c.v. injections. Excited locomotion elicited only by ACTH-i.c.v. is apparently caused by ACTH-sensitive systems outside the PVH. The results suggest that the ACTH-containing part of the hypothalamus around the PVH is crucially involved in the organization of grooming behaviour. We believe that at this level in the brain, the subroutines of grooming, scratching and yawning are integrated into one skin maintenance behaviour.

Adrenocorticotropic Hormone

Ethology and pharmacology of hypothalamic aggression in the rat.

Stimulation of a restricted area of the rat's hypothalamus elicits unprovoked violent attacks of a species-specific and strain-specific nature. Serotonergic drugs affecting 5HT1 receptors, propranolol, the 5HT re-uptake inhibitor fluvoxamine, and the anxiolytic oxazepam, inhibit hypothalamic attack selectively. However, hypothalamic attack is extremely unsensitive for many drugs that do affect attack provoked by natural stimuli. The pharmacology, the form, the impulsive nature, the absence of preliminaries, the insensitivity for contexts and ultimate aims of aggressive behaviour, suggest that a mechanism with the limited function of damaging adversaries of any kind is activated in the hypothalamus. This hypothalamic attack release mechanism (harm) requires specific sensory input for the expression of specific motor components, such as biting and kicking. The back and dorsal part of the opponent's head are the important attack releasing and directing stimuli. Attacks of this nature are part of the "aggressive" repertoire of the rat in natural settings. "Lateral" or "sideways" postures, specific for intermale fighting cannot be induced by hypothalamic stimulation. Drug, lesion, and stimulation studies suggest that attack and "sideways" postures are under the control of different central mechanisms. These results suggest new ways to describe the patterning of aggressive behaviour. There are interesting ethopharmacological similarities between hypothalamic responses and obsessive compulsive disorders (OCD) in man. It is suggested that further study of the ethopharmacology of hypothalamic responses may shed light on the pathophysiology of impulsive behavioural symptoms which in man seem to be beyond the control of appraisal or context.

Aggression

Interactions between simultaneously activated behavioral systems in the rat.

Interactions between electrically induced attack and teeth-chattering from 1 electrode and grooming from another were examined in male albino rats. The interaction between electrically induced attack and deprivation-induced feeding, as well as the effect of food deprivation on attack, was also studied. Results indicate that attack appears to be a dominant response, for it suppressed grooming and feeding at a low level of activation. On the other hand, it was not affected by simultaneously induced grooming or feeding. However, food deprivation decreased the threshold for attack, leaving attack latency, attack form, or bite targets unaffected. Teeth-chattering, suggested to be related to attack and flight, was also a dominant response. Results suggest that interactions between behavioral systems are in favor of the systems that must act acutely on activation in order to survive. Apparently, the regulations governing these interactions are represented in the functional organization of the brain.

Aggression

Hypothalamic substrates for brain stimulation-induced patterns of locomotion and escape jumps in the rat.

The hypothalamic response area for electrically induced locomotion was determined using moveable electrodes and discriminant analysis as an appropriate statistical technique. At 241 out of 641 stimulated sites locomotion was induced. The distribution of locomotion sites is relatively diffuse. Discriminant analysis of both positive and negative electrode localizations yields areas with high, intermediate or low probability of inducing the response. The response is considered to be mediated by fibres of the subpallido-pedunculopontine system, which includes the mesencephalic locomotor region. Different categories of exploratory and flight-directed locomotion were distinguished, and response areas for both categories were determined. In addition the response area for escape jumps was delimited. Exploratory locomotion is mainly induced from the lateral hypothalamus, while flight-directed locomotion and escape jumps are evoked from the medial hypothalamus. The response area for exploratory locomotion reflects the lateral hypothalamic distribution of the subpallidal projection to the mesencephalic locomotor region. A diffuse substrate for flight behavior seems to occupy almost the entire medial hypothalamus. It is concluded that a locomotor subroutine subserving different behavioural mechanisms can be activated at many hypothalamic sites.

Animals

Hypothalamic substrates for brain stimulation-induced attack, teeth-chattering and social grooming in the rat.

In this paper the boundaries of the hypothalamic response areas for brain stimulation-induced attack, social grooming and teeth-chattering were delimited. A total of 641 hypothalamic sites in 71 male CPW/WU Wistar rats were electrically stimulated. Positive sites for any behavioural response cluster into restricted hypothalamic areas. Discriminant analysis of both positive and negative electrode localizations yields areas with high, intermediate and low probabilities of inducing the behavioural response concerned. Each response has its own response area where probabilities are high. Neuroanatomical correlates of these response areas are discussed. The response area of attack is suggested to be an integrative processing area, stimulation of which overrules some aspects of integration and directly activates the behavioural program of attack. Although some authors consider all three responses to be part of the behavioural repertoire of aggression, the response areas are not identical. Social grooming and attack are considered to be induced from different neural systems. Similarly, attack and teeth-chattering have been shown to derive from different neural mechanisms, despite substantial overlap of both response areas. It is suggested that teeth-chattering derives from the simultaneous activation of both attack and flight tendencies. No further distinctions with respect to threshold current intensities can be made within responses areas. However, the underlying neural substrates are not homogeneous, for thresholds vary along the course of individual electrodes.

Aggression

Hypothalamic substrates for brain stimulation-induced grooming, digging and circling in the rat.

Despite a great number of studies concerned with the induction of specific behavioural responses from the rat hypothalamus by electrical brain stimulation, hypothalamic response areas and underlying neural substrates have never been determined accurately. In this study the boundaries of the hypothalamic response areas for grooming, digging and circling were delimited using moveable electrodes, an enriched environment containing a variety of goal objects, and an appropriate statistical technique. A total of 641 hypothalamic sites in 71 male CPB/WU Wistar rats were electrically stimulated. Results are plotted on a detailed stereotaxic brain atlas of the rat hypothalamus. Positive sites for any behavioural response cluster into restricted hypothalamic areas. Discriminant analysis of both positive and negative electrode localizations yields areas with high, intermediate or low probabilities of inducing the behavioural response concerned. Each response has its own response area where probabilities are high, although there may be overlap. Even within response areas a distinction can be made between areas in which the response can be induced at relatively high or low threshold current intensities. Lowest threshold sites within electrode tracks are often clustered. In search of neuroanatomical correlates, grooming is related to the distribution of ACTH-immunoreactive neural elements, digging is related to the distribution of efferent fibres from the bed nucleus of the stria terminalis, and circling is related to the distribution of dopaminergic fibres of the nigrostriatal pathway. The results clearly point to the stimulation site being the most important determinant of the evoked behavioural response. Evidently behavioural specificity does exist within the hypothalamus.

Animals

Postpartum aggression in rats does not influence threshold currents for EBS-induced aggression.

Female Wistar rats were tested for aggressive behaviour induced by electrical brain stimulation (EBS) in the lateral hypothalamus. Threshold currents for the induction of aggression were determined on several days before the females were paired with experienced breeder males. Beginning in the second week of pregnancy threshold current values were measured once or twice weekly. No change in thresholds was observed either during pregnancy, the early postpartum period or after weaning. Lactation was the only period during which the females were spontaneously aggressive towards male intruders in their home cage, but not in the EBS cage. Analysis of bite targets revealed no difference between the bite patterns in the postpartum maternal aggression test and the EBS-induced attacks. The results demonstrate that the change in physiological and hormonal status in pregnant and lactating females has no influence on the propensity to attack during EBS. The similarity in wound patterns does not advocate a major difference in the types of aggression studied. We speculate upon the nature of EBS-induced attacks as the activation of a rigid, final pathway of aggression which is rather insensitive to mild modulations.

Aggression