Midbrain-hypothalamic interrelationships in the control of aggressive behavior

Previous studies have suggested an involvement of the midbrain ventral tegmental area in the biting attack upon a rat elicited by electrical stimulation of the lateral hypothalamus in cats. In order assess further the relationship between these two regions, 12 cats were implanted with attack-eliciting electrodes in both the lateral hypothalamus and the midbrain ventral tegmental area. Following a lesion of the midbrain attack site, attack previously elicited from hypothalamic electrodes ipsilateral to the lesion was eliminated or significantly reduced in frequency. The attack elicited from electrodes in the hypothalamus contralateral to the lesion was unaffected. Midbrain lesions made at sites from which attack was never elicited had no effect on hypothalamically elicited attack. The midbrain lesion in some cases eliminated only certain components of the total attack pattern; for example, the approach of a cat to the rat frequently remained present while the bite was absent. Additionally, it was found that the attack elicited from rostral hypothalamic electrodes was disrupted to a greater degree by a single midbrain lesion than the attack elicited from more caudal hypothalamic electrodes. These finding are discussed in terms of the neural system mediating this form of aggressive behavior in cats.     

Visual aspects of centrally elicited attack behavior in the cat: “Patterned reflexes” associated with selection of and approach to a rat

It has been previously suggested that the electrical brain stimulation which elicits quiet-biting attack in the cat actively affects the way the central nervous system processes visual and tactile information concerned with the reflexes involved in the terminal aspects of attack. In order to examine the effects of brain stimulation on a nonterminal aspect of attack – the stimulated cat's selection of and approach to a rat – cats were implanted with attack-eliciting electrodes in both the lateral hypothalamus and the midbrain ventral tegmental area. These cats were then tested in an 8-ft-long cage, one end of which was divided into three, 2-ft-long parallel compartments, whose openings faced the end of the cage from which the cat commenced its approach. An anesthetized rat was placed at the back of one compartment, a bowl of food at the back of another compartment, and the third compartment contained no object. It was found in the first experiment that the attack elicited by nearly all electrodes was selectively directed at the rat. However, the success of the cat in finding the compartment containing the rat varied dramatically for different electrodes in the same cat. Further, these differences were stable and did not change as the cat gained experience with the task. The results suggested that the stimulation of different brain sites in the same cat differentially affected the visual neural mechanisms involved in guiding a cat to a rat. Previous studies have also suggested that the effects of brain stimulation which elicits quiet-biting attack are largely lateralized to the side of the brain stimulated. In order to determine if the effects of stimulation on the neural mechanisms mediating the visually guided approach of a cat to a rat were also lateralized, attempts were made in a second experiment to disrupt the visual input to one side of the brain by unilaterally transecting the optic tract. It was found that this manipulation interfered with the visually guided selective approach to a rat, if the cat was stimulated through hypothalamic or mid-brain electrodes ipsilateral to the optic tract transection, but not if the hypothalamic or midbrain stimulation was on the contralateral (visually intact) side of the brain. However, any final interpretation of the results was confounded by the finding in all of these cats of a complex syndrome of neglect of all contralateral sensory information.     

Motivated behaviors elicited from hypothalamus, midbrain, and pons of the guinea pig (Cavia porcellus).

Eating, drinking, biting attack, male mating behavior, and gnawing were elicited by electrical stimulation through electrodes located predominantly in a region extending from the preoptic area through the lateral hypothalamus into the ventral midbrain. Escape and digging were elicited from a parallel but more medial region that overlapped the lateral zone only in the preoptic-anterior hypothalamic area. Several differentiable vocalizations were produced from sites distributed through most, although not all, areas explored. Sites yielding painlike responses were located principally in the vicinity of the presumed pain pathway traced after anterolateral cordotomy in other species. Reward was obtained from widespread sites that were generally congruent with catecholaminergic systems as described in the rat. Although there was considerable overlap of the effective zones for many responses, their underlying mechanisms were differentiated anatomically by localized differences in their distribution or functionally by the elicitation of pure responses from some electrodes. Response mechanisms localized in the brain stem of the guinea pig generally resembled those in the rat, although there were differences in details, especially in the posterior midbrain and pons.     

Predatory aggression: Midbrain-pontine junction rather than hypothalamus as the critical structure?

Electrical stimulation of sites in the region of the ventromedial periaqueductal gray substance at the level of the midbrain–pontine junction was found to elicit a predatory attack by a cat upon a rat. The intensity of stimulation required to elicit the attack was three to four times less than that required to elicit similar behavior by hypothalamic stimulation. The results suggest that anatomically distinct regions of the periaqueductal gray substance are concerned with the regulation of predatory and affective forms of aggressive behavior. The difficulty in reconciling these results with the preeminent role assigned the hypothalamus in the organization of predatory behavior is also discussed.     

Phenylpropanolamine inhibits feeding, but not drinking, induced by hypothalamic stimulation.

In rats bearing lateral hypothalamic electrodes that elicited both feeding and drinking, intraperitoneal injection of the appetite suppressant drug phenylpropanolamine (Propadrine) inhibited only feeding. This occurred whether feeding and drinking were tested simultaneously or separately. Selective inhibition of lateral hypothalamic feeding also followed injection of this drug through lateral, but not medial, hypothalamic electrode cannulas. We conclude that hypothalamically induced feeding is under some of the same pharmacological controls as spontaneous feeding, that this control may be exerted, in part, in or near the lateral hypothalamus, and that the neural systems which induce feeding and drinking during hypothalamic stimulation can be pharmacologically separated.     

Transfer of an escape response from tail shock to brain-stimulated attack behavior

Nine cats, each with two hypothalamic electrodes in sites which when stimulated produced either quiet attack or attack accompanied by certain forms of vocalization, were trained to escape from tail shock by jumping onto a stool. They were then tested for transfer of the escape response to brain stimulation. Stimulation of the seven sites that yielded quiet biting attack did not elicit the learned response of jumping onto the stool. Stimulation of eight of the 11 sites that yielded attack accompanied by vocalization did elicit the learned response. It was concluded that attack behavior elicited by brain stimulation should not be considered a special case of the response to aversive stimulation, but that attack and response to aversive stimulation involve independent but overlapping systems.     

Aggressive behavior induced by electrical stimulation in the midbrain central gray of male rats

Electrical stimulation via electrodes implanted in the lateral hypothalamus may induce intraspecific aggressive behavior. Small electrolytic lesions placed via these electrodes resulted in a five– to tenfold increase in the current threshold for aggression. Degenerating fibers were stained by means of the Fink-Heimer method and could be followed caudally to the dorsal midbrain central gray and to the mammillary bodies. A few axons could be traced rostrally to the medial septum. Aggression could be induced from 10 of 112 electrodes implanted in the central gray; the other electrodes elicited either locomotion, vocalization, jump, or “alarm-like reactions.” The morphology of the induced aggression was similar to the morphology of the hypothalamically induced aggression, though it was often accompanied with motor disturbances and was less intense. Hypothalamic stimulation was combined with simultaneous central gray stimulation in rats with electrodes both in the hypothalamus and in the central gray. Hypothalamic thresholds for aggression could be lowered by this stimulation of the central gray, even when no aggressive responses were observed during central gray stimulation alone. This suggests that, although aggression is not manifest, electrical stimulation may activate neural tissue involved in aggressive behavior. It is concluded that in rats central gray and hypothalamus are part of the same neural network mediating intraspecific aggression.     

Neurochemical mechanisms underlying amygdaloid modulation of aggressive behavior in the cat

Studies designed to determine the respective roles of substance P, excitatory amino acids, and enkephalins in amygdaloid modulation of defensive rage behavior in the cat are presented. The basic design of these studies involved three stages. In stage I, cannula electrodes for stimulation and drug infusion were implanted into medial hypothalamic or midbrain periaqueductal gray (PAG) sites from which defensive rage behavior could be elicited. Then, a stimulating electrode was implanted into a site within the medial, basal, or central nuclear complex from which modulation of the defensive rage response could be obtained. Amygdaloid modulation of defensive rage was determined in the following manner: it employed the paradigm of dual stimulation in which comparisons were made of response latencies between alternate trials of dual (i. e., amygdala = medial hypothalamus [or PAG]) and single stimulation of the hypothalamus or PAG alone. Thus, stage I established the baseline level ofmodulation (i. e., facilitation or suppression of defensive rage) in the predrug stimulation period. In stage II, a selective or nonselective receptor antagonist for a given transmitter system was administered either peripherally or intracerebrally at the defensive rage site, after which time the same dual stimulation paradigm was then repeated over the ensuing 180 min postinjection period in order to determine the effects of drug delivery upon amygdaloid modulation of defensive rage. Stage III of the study took place at the completion of the pharmacological testing phase. The retrograde axonal tracer, Fluoro-Gold, was microinjected into the defensive rage site within the medial hypothalamus or PAG, and following a 6-14 day survival period, animals were sacrificed and brains were processed for histological and immunocytochemical analyses for the neurotransmitters noted above. This procedure thus permitted identification of cells within the amygdala which were labeled retrogradely and which were also immunostained positively for substance P, excitatory amino acids, or enkephalin. For studies involving substance P, defensive rage was elicited from the medial hypothalamus and for studies examining the roles of excitatory amino acids and enkephalin, defensive rage was elicited from the PAG. In the first study, facilitation of hypothalamically elicited defensive rage was obtained with dual stimulation of the medial nucleus of the amygdala. In separate experiments, the selective NK₁ non-peptide antagonist, CP 96,345, was administered both peripherally as well as intracerebrally into the hypothalamic defensive rage sites in doses of 0.5-4.0 mg/kg (i. p.) and 0.5-2.5 nmol (i. c.). Following drug delivery, the facilitatory effects of medial amygdaloid stimulation were blocked in a dose- and time-dependent manner in which the effects were noted as early as 5 min postinjection. The maximum drug dose (4.0 mg/kg) employed for peripheral administration resulted in a 42% reduction in the facilitatory effects of the medical amygdala (P < 0.002). This drug, when microinjected directly into medial hypothalamic defensive rage sites at the maximum dose level of 2.5 nmol, resulted in an 84% reduction of the suppressive effects of amygdaloid stimulation (P < 0.5) at 5 min postinjection. In the next study, an N-methyl-D-aspartate (NMDA) antagonist, DL-α-amino-7-phosphonoheptanoic acid (AP-7), was administered either peripherally (0.1-1.0 mg/kg) or intracerebrally (0.2 and 2.0 nmol) into PAG defensive rage sites. Facilitation of defensive rage behavior, which was observed following dual stimulation of the basal amygdala and PAG, was significantly reduced by either route of drug administration in a dose- and time-dependent manner. At the maximum dose level of peripheral administration, AP-7 reduced amygdaloid facilitation of defensive rage by 63% (P < 0.001) for 60 min, postinjection. A smaller (i. e., 19%) but still significant (P < 0.05) reduction in facilitation was obtained following intracerebral administration of the drug. In a third study, the non-selective opioid receptor antagonist, naloxone (27.5 nmol), infused directly into PAG defensive rage sites, totally blocked the suppressive effects of central amygdaloid stimulation for a period of 30 min (P < 0.05) in a dose- and time-dependent manner. The anatomical phase of this study revealed the following relationships: 1) that large numbers of neurons projecting to the medial hypothalamus from the medial amygdala immunoreact positively for substance P; 2) that neurons projecting to the PAG from the basal complex of amygdala immunoreact positively for glutamate and aspartate; and 3) that neurons located within the central nucleus of the amygdala which project to the PAG immunoreact positively for met-enkephalin. Collectively, these observations provide new evidence which characterizes the likely neurotransmitters linked with specific amygdaloid pathways subserving the modulation of defensive rage behavior in the cat.     

Approach and withdrawal analysis of the effects of hypothalamic stimulation and lesions in rats.

In a paradigm in which rats would both initiate and terminate hypothalamic stimulation, "purely" rewarding lateral hypothalamic and "purely" aversive medial hypothalamic electrodes were identified. Subjects were then given a series of tests designed to assess the effects of brain stimulation on approach and withdrawal behaviors. Lateral hypothalamic stimulation facilitated approach behavior and suppressed withdrawal behaviors, whereas medial hypothalamic stimulation produced largely the opposite effects. No serious motor deficits due to stimulation were detected with either type of electrode. In a second experiment, the approach-withdrawal effects of bilateral lateral hypothalamic lesions were tested and found to suppress approach behaviors and facilitate withdrawal behaviors. Other neurological examinations revealed motor deficits, but these deficits do not account for the specific pattern of results observed on the approach-withdrawal tests. These approach-withdrawal phenomena are interpreted in terms of altering a natural balance between approach and withdrawl behavior facilitating systems in the lateral and medial hypothalamus, respectively.     

Stress-induced Fos-like Immunoreactivity in the Pons and the Medulla Oblongata of Rats

Immunoreactivity of the immediate early gene c-fos was used to investigate changes in the activity of brainstem neurons in response to acute stressors like immobilization, formalin-induced pain, cold exposure, hemorrhage and insulin-induced hypoglycemia. Different stressors induced Fos-like immunoreactivity in different pontine and medullary neurons. A single, 3 hour immobilization was found to be a very strong stimulus that activated brainstem catecholaminergic (tyrosine hydroxylase-immunopositive) neurons and cells in the raphe and certain pontine tegmental nuclei, as well as in the reticular formation. Pain, induced by a subcutaneous injection of formalin was also effective on catecholamine-synthesizing neurons and on others cells in the nucleus of the solitary tract. Cold exposure activated cells mainly in the sensory spinal trigeminal and parabrachial nuclei and in the so-called "pontine thermoregulatory area". Moderate Fos-like immunoreactivity was induced by a hypotonic (25%) hemorrhage in medullary catecholaminergic neurons, the nucleus of the solitary tract and the Barrington nucleus. Among stressful stimuli used, insulin-induced hypoglycemia elicited the smallest Fos activation in the lower brainstem. The present observations indicate that different stressors may use different neuronal pathways in the central organization of the stress response.     

Adrenergic stimulation of the rat diencephalon and its effect on food intake and hoarding activity

The diencephalic area most sensitive to microinjections of noradrenaline lay outside the area of the lateral hypothalamus in which feeding can be produced by electrical stimulation. Injection of either area, including injections that caused increased feeding, failed to have any effect on hoarding activity. Since hoarding can be elicited both by food deprivation and by electrical stimulation of the lateral hypothalamus, these findings indicate biochemical, anatomical and motivational differences between the central feeding mechanism sensitive to adrenergic stimulation, and that responding to electrical stimulation or nutritional depletion. The former mechanism may be disinhibitory; the latter, excitatory.     

Attack, eating, drinking, and gnawing elicited by electrical stimulation of rat mesencephalon and pons.

Eating, drinking, and gnawing were electrically elicited from the rat mesencephalon in the vicinity of the lateral branch of the descending medial forebrain bundle, but attack was evoked from the dorsomedial tegmentum adjacent to the central gray. The effective zones continued further caudally to the dorsal posterior pons. Unlike hypothalamically elicited behavior, eating, drinking, and gnawing often persisted 5-40 sec after termination of stimulation. Vocalization and escape activity were obtained principally from the vicinity of central pain pathways originating from the anterolateral cord. Other electrodes produced eating, drinking, gnawing, and grooming, which began only after termination of stimulation.     

Control of-treadmill exercise of rats with hypothalamic stimulation

Running and resting behavior of rats was measured during treadmill exercise under conditions involving (1) rear-shock avoidance, (2) continuous electrical stimulation of the hypothalamus, or (3) no rear-shock and no hypothalamic stimulation. Hypothalamic stimulation was superior for eliciting consistent running with a minimum of resting. A second experiment demonstrated that decreases in hypothalamically elicited treadmill running resulting from prolonged exercise could be counteracted by increasing the intensity of the hypothalamic stimulus. A third experiment suggested that very little training was needed to induce a high and consistent level of running performance using hypothalamic stimulation.     

Effects of lesions of the amygdala, preoptic area, and hypothalamus on estradiol-induced activity in the female rat.

Lesions of the anterior hypothalamic nucleus and the medial preoptic area sharply attenuated enhancement of wheel running by estradiol benzoate in ovariectomized female rats. Lesions of the corticomedial amygdala had no effect on this behavior. The hormonal effects on activity were largely independent of any changes in body weight. Results of this first experiment indicated that the anterior hypothalamic and medial preoptic areas are critically involved in the induction of activity by estradiol. However, this experiment provided no support for suggestions that the corticomedial amygdala inhibits those structures that mediate the estrogenic induction of activity. In the second experiment, food deprivation was used to stimulate activity. Results of this experiment suggested that the reduction in the ability of estradiol to induce activity following anterior hypothalamic and medial preoptic lesions does not reflect a general inability to become more active.     

Gallbladder distention and the effects of several drugs on heart rate,respiratory movements and cortical potentials in cats with hypothalamic lesions

The effects of chronic hypothalamic lesions and various drugs on the viscero-visceral reflexes of cats have been investigated, utilizing measurement of the bioelectrical activity of the cerebral cortex. After coagulation of the posterolateral hypothalamus the heart rate decreased by 40–60 beats per minute, but eventually it regained its initial value. The viscero-visceral reflexes from the gallbladder to the heart were preserved after the operative procedure. Chlorpromazine and atropine blocked both arousal and the cardiorespiratory response to stimulation of the gallbladder. Similar effects were produced by novocaine and pantocaine.     

Projection of the Magnocellular Red Nucleus to the Region of the Accessory Abducens Nucleus in the Rabbit

The projection of the magnocellular red nucleus (RNm) to the region of the accessory abducens nucleus (AABD) was traced in rabbit using the bidirectional tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP). In one set of animals, recordings of antidromic responses from RNm neurons elicited by electrical stimulation of the rubrospinal tract were used to localize injections of WGA-HRP for orthograde labeling of RNm terminals. In a different set of animals, horseradish peroxidase was injected into the retractor bulbi muscle to retrogradely label motoneurons of the AABD. The positions of RNm fibers and terminals were examined and compared to the locations and distribution of AABD cell bodies and labeled dendrites. Analyses revealed that along the entire rostrocaudal extent of the AABD, RNm efferents terminate primarily lateral to, or in the lateral aspects of, labeled motoneurons. For the rostral AABD, RNm efferents terminate only lateral to the nucleus. Although the terminals are not positioned to contact cell bodies of the AABD, they could overlap with dendrites that extend in the lateral direction. RNm efferents terminate more extensively within the posterior AABD, overlapping within both dendritic and cell body regions of the nucleus. Even in this posterior region, however, RNm efferents were distributed primarily over the lateral half of the nucleus. These data show that RNm can monosynaptically influence the AABD, through primarily its lateral and posterior aspects. Our findings also show that a major target of RNm efferents is the reticular cell population located lateral to the AABD, suggesting that the RNm also may affect AABD motoneuronal output indirectly through its projection to reticular cells.     

Hyperreactivity, muricide, and intraspecific aggression in the rat produced by infusion of local anesthetic into the lateral septum or surrounding areas

Intracranial infusions of a local anesthetic (lidocaine, 2%) were made bilaterally (4 microliter over 20 min) through permanently implanted cannulas ending in the lateral septum or adjacent areas. Increases in irritability and reactivity to the experimenter, muricide, and intermale aggression were produced by injections into the lateral septum and the region ventral to it. The increases in reactivity and interanimal aggresion occurred in varying degrees and were independent of one another, but intermale aggression occurred only in animals showing muricide. The most effective site for eliciting the entire spectrum of aggressive behaviors was the region ventral to the anterior septum. The region ventral to the posterior septum (medial preoptic area, anterior hypothalamic area, straia terminalis) was unique in that it tended to produce a high incidence of muricide, with only modest increases in reactivity. The lateral septum was moderately effective in producing the entire range of aggressive behaviors. No changes in behavior were noted with infusions into the medial septum or th medial forebrain bundle/lateral preoptic area ventrolateral to the septum. It is suggested that the hyperreactivity and irritability may be relat to hyperdefensiveness and that muricide and intermale aggression are points on a continuum of interanimal aggressiveness.     

Acute homeostatic imbalances reinstate sensorimotor dysfunctions in rats with lateral hypothalamic lesions

It has previously been demonstrated that rats recovered from aphagia and adipsia after large bilateral electrolytic lesions of the lateral hypothalamic area do not show the normal feeding response to 2-deoxyglucose or drinking response to polyethylene glyol. The present work reveals that such homeostatic imbalances reinstate the profound sensorimotor impairments that are seen in the immediate postoperative period but abate in parallel with the gradual recovery of ingestive behaviors. Administration of alpha-methyltyrosine or spiroperidol produced sensory and motor dysfunctions in rats with lateral hypothalamic lesions that were similar to those observed after 2-deoxyglucose. These results suggest that the residual feeding and drinking deficits of rats with lateral hypothalamic lesions after apparent recovery of function do not reflect specific loss of putative gluco- and volume-regulatory contributions to ingestive behavior. Instead, they may indicate continued impairments in nonspecific activational components of motivation that normally are mediated, in part, by central dopaminergic neurons.     

Possible conditioned stimulus pathway for classical eyelid conditioning in rabbits. I. Anatomical evidence for direct projections from the pontine nuclei to the cerebellar interpositus nucleus.

Wheat germ agglutinin and cholera toxin-conjugated horseradish peroxidase (HRP) were used to retrogradely and anterogradely trace connectivity between the lateral regions of the pontine nuclei and the anterior interpositus nucleus of the cerebellum in rabbits. Projections from the pontine nuclei were found to terminate in the anterior interpositus nucleus and the interpositus was found to send projections to the pontine nuclei. Projections from the nucleus reticularis tegmenti pontis, dorsal accessory inferior olive, and Larsell's lobule HVI of the cerebellum were also found to terminate in the interpositus nucleus and projections from the interpositus nucleus to the inferior olivary complex were observed. The projections from brain stem regions to the interpositus nucleus are discussed as possible pathways that are involved in classical eyelid conditioning.     

Classical discrimination conditioning of the rabbit's eyelid response using pontine stimulation as a conditioned stimulus

Classical discrimination conditioning of the nictitating membrane/eyelid response was performed on seven rabbits using stimulation of the pontine nuclei or middle cerebellar peduncle as the conditioned stimulus (CS) and an air puff as the unconditioned stimulus (US). The rabbits learned to discriminate between a CS paired with a US and delivered to one pontine nucleus (the CS+) and a CS presented alone and delivered to the contralateral pontine nucleus (the CS-). Subsequent reversal of the discrimination was also achieved when the CS+ and CS- stimulation sites were interchanged. The results are interpreted as support for the idea that essential plasticity for classical eyelid conditioning occurs efferent to the pontine nuclei, possibly in regions of the cerebellum.