Are reactions to frustrative nonreward in other animals a model for human anger? Neurobehavioral implications and therapeutic applications.

Anger is a powerful and mostly deleterious emotion that can impair an individual's health and social relationships and that imposes considerable costs on society at large. It is a constituent of multiple psychopathologies, most notably intermittent explosive disorder. Excessive anger can drive injurious and even lethal reactive aggression. To understand its biobehavioral origins and develop appropriate therapeutic interventions, an animal model of human anger would be quite useful. The phenomena of aggression provoked by frustrative nonreward (FNR) in other animals, including species of fish, birds, and mammals, resemble those in people in whom it elicits subjectively experienced anger. The brief history presented here traces the original, overgeneralized frustration-aggression hypothesis for humans through to the discovery of operant schedule-induced attack in birds, rodents, and ourselves to the current status of FNR as a cross-species, transdiagnostic construct within the National Institute of Health Research Domain Criteria. Brain circuitry that is activated by frustration, generates felt anger and motivates reactive aggression includes discomfort reactions likely instantiated in the insula and cingulate gyrus of the salience network and reward expectancy/prediction error mediated by the ventral striatum and other structures. Caveats in establishing a paradigm for other animals that most closely matches FNR-induced anger in people include avoiding confounds with other aggression-provoking stimuli and situations, providing evidence for aggressive motivation, as well as behavior, and demonstrating activation of homologous brain structures. With appropriate regard for these caveats, developing such paradigms appears to be the best route to advancing psychopharmacological and deep brain stimulation treatments for excessive anger. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Molecular mechanisms of group I metabotropic glutamate receptor mediated LTP and LTD in basolateral amygdala in vitro.

The roles of group I metabotropic glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) and mGluR5, in regulating synaptic plasticity and metaplasticity in the basolateral amygdala (BLA) remain unclear. The present study examined mGluR1- and mGluR5-mediated synaptic plasticity in the BLA and their respective signaling mechanisms. Bath application of the group I mGluR agonist, 3,5-dihydroxyphenylglycine (DHPG) (20 µM), directly suppressed basal fEPSPs (84.5 ± 6.3% of the baseline). The suppressive effect persisted for at least 30 min after washout; it was abolished by the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) but was unaffected by the mGluR5 antagonist 2-methyl-6- (phenylethynyl)-pyridine (MPEP). Interestingly, application of DHPG (at both 2 and 20 µM), regardless of the presence of CPCCOEt, could transform single theta burst stimulation (TBS)-induced short-term synaptic potentiation into a long-term potentiation (LTP). Such a facilitating effect could be blocked by the mGluR5 antagonist MPEP. Blockade of phospholipase C (PLC), the downstream enzyme of group I mGluR, with U73122, prevented both mGluR1- and mGluR5-mediated effects on synaptic plasticity. Nevertheless, blockade of protein kinase C (PKC), the downstream enzyme of PLC, with chelerythrine (5 µM) only prevented the transforming effect of DHPG on TBS-induced LTP and did not affect DHPG-induced long-term depression (LTD). These results suggest that mGluR1 activation induced LTD via a PLC-dependent and PKC-independent mechanism, while the priming action of mGluR5 receptor on the BLA LTP is both PLC and PKC dependent. The BLA metaplasticity mediated by mGluR1 and mGluR5 may provide signal switching mechanisms mediating learning and memory with emotional significance.

The Neurobehavioral Phenotype in Mucopolysaccharidosis Type IIIB: an Exploratory Study.

OBJECTIVES: Our goal was to describe the neurobehavioral phenotype in mucopolysaccharidosis Type IIIB (MPS IIIB). Parents report that behavioral abnormalities are a major problem in MPS III posing serious challenges to parenting and quality-of-life for both patient and parent. Our previous research on MPS IIIA identified autistic symptoms, and a Klüver-Bucy-type syndrome as indicated by reduced startle and loss of fear associated with amygdala atrophy. We hypothesized that MPS IIIB would manifest similar attributes when assessed with the same neurobehavioral protocol. METHODS: Ten patients with MPS IIIB were compared with 9 MPS IIIA patients, all older than 6. 8 younger children with Hurler syndrome (1H) were chosen as a comparison group for the Risk Room procedure; MPS IH does not directly affect social/emotional function and these younger children were closer to the developmental level of the MPS IIIB group. To examine disease severity, cognitive ability was assessed. Four evaluations were used: the Risk Room procedure (to measure social-emotional characteristics, especially fear and startle responses), the Autism Diagnostic Observation Schedule (ADOS), the Sanfilippo Behavior Rating Scale (SBRS), and amygdala brain volumes calculated from manually-traced MRI images. RESULTS: The two groups are equivalent in severity and show severe cognitive impairment. On the ADOS, the MPS IIIB patients exhibited the same autistic features as IIIA. The IIIB means differed from MPS IH means on most measures. However, the IIIB group did not approach the Risk Room stranger, like the MPS IH group who kept their distance, but unlike the IIIA group who showed no fear of the stranger. On the SBRS, the MPS IIIB patients were described as more inattentive and more fearful, especially of new people than the MPS IIIA. Onsets of some disease characteristics appeared more closely spaced and slightly earlier in MPS IIIB than IIIA. CONCLUSIONS: On most behavioral measures, MPS IIIB patients did not differ substantially from MPS IIIA patients over age six, demonstrating autistic features and a Klüver Bucy-like syndrome including lack of fear and poor attention. Delay in onset of behavioral symptoms was associated with later diagnosis in two patients. Lack of fear, poor attention, and autistic-like symptomatology are as characteristic of MPS IIIB as they are of MPS IIIA. A possible difference is that the some behavioral abnormalities develop more quickly in MPS IIIB, If this is so, these patients may become at risk for harm and present a challenge for parenting even earlier than do those with MPS IIIA. .In future clinical trials of new treatments, especially with respect to quality of life and patient management, improvement of these behaviors will be an essential goal. Because very young patients were not studied, prospective natural history documentation of the early development of abnormal behaviors in MPS IIIB is needed.

Evidence for a functional and anatomical relationship between the lateral septum and the hypothalamus in the control of flank marking behavior in Golden hamsters.

Golden hamsters with established dominant/subordinate relationships communicate their social status by rubbing pheromone-producing flank glands against objects in the environment. This behavior, called flank marking, is controlled by vasopressin-sensitive neurons localized to the anterior hypothalamus. Vasopressinergic magnocellular neurons in the nucleus circularis and medial aspect of the supraoptic nucleus are thought to be a source of neurotransmitter for the initiation of flank marking. The present study was undertaken to examine the extrahypothalamic control of flank marking. The anatomical and functional connections between the lateral septum and the vasopressin-containing nuclear groups in and around the anterior hypothalamus were examined by: (1) tracing afferent and efferent connections following microinjection of horseradish peroxidase and Phaseolus vulgaris-leucoagglutinin into the lateral septum, and (2) recording odor-induced flank marking prior to and following ibotenate lesions in the septum. The greatest number of perikarya retrogradely labeled with horseradish peroxidase were found lateral to the anterior hypothalamus and ventral to the fornix in the area of the lateral hypothalamus. The vasopressin-containing nuclear groups, e.g., paraventricular, supraoptic, suprachiasmatic nuclei, and the nucleus circularis, were devoid of labeled perikarya. Nerve terminals anterogradely labeled with Phaseolus vulgaris-leucoagglutinin were primarily localized to the anterior hypothalamus, in and around the nucleus circularis, and the medial aspect of the supraoptic nucleus. The lateral aspect of the supraoptic nucleus was devoid of nerve terminals as were the paraventricular and suprachiasmatic nuclei. The anatomical connections between the lateral septum and the hypothalamus appear to be necessary for the control of flank marking, since the microinjection of ibotenate into this limbic site significantly reduced odor-induced flank marking as compared to control microinjections of 0.9% NaCl.

Attack priming in female Syrian golden hamsters is associated with a c-fos-coupled process within the corticomedial amygdala.

Allowing a resident hamster a single "priming" attack on a conspecific induces a transient aggressive arousal as indicated by a reduction in the latency and increase in the probability of attack on a second intruder presented within the next 30 min. We present two lines of evidence identifying the corticomedial amygdala as an important locus mediating this effect. (1) Attack priming significantly increases the number of neurons expressing immunocytochemically identified Fos protein in the corticomedial amygdala, but not elsewhere. Pursuit and biting of an inanimate object does not induce corticomedial amygdala c-fos expression of the same pattern or magnitude. The corticomedial amygdala contribution to the priming effect involves more than a non-specific arousal, since corticomedial amygdala c-fos expression does not correlate with locomotor activity, a standard indicator of such arousal. (2) Radiofrequency lesions of the corticomedial amygdala reduce aggression, the greatest reduction occurring with the more anterior lesions. Other behaviors, including a priming-like locomotor practice effect in a running wheel, are unaffected by corticomedial amygdala lesions. These findings suggest that attack priming is an aggression-specific effect resulting from a Fos-coupled change within neural circuitry of which the corticomedial amygdala is a part. From a theoretical point of view, these experiments suggest a new approach to the analysis of the mechanisms underlying aggressive behavior and the persistence of aggressive arousal. We present a sketch of a quantitative neurobehavioral model which relates attack probability to neural activation within the corticomedial amygdala. From a methodological viewpoint, these experiments extend the utility of mapping c-fos expression as a technique for localizing endogenous, behavior-specific processes within the central nervous system.

Kainic Acid lesion of vasopressinergic neurons in the hypothalamus disrupts flank marking behavior in golden hamsters.

Abstract It is well established that flank marking behavior in the Golden hamster is controlled by vasopressin-sensitive neurons localized to the anterior hypothalamus; however, the source(s) of vasopressinergic innervation to this area is unknown. Previous analysis by immunocytochemistry showed distinct populations of vasopressinergic magnocellular neurons localized to the supraoptic nucleus, paraventricular nucleus and the nucleus circularis that did not project to the neurohypophysis. In the present study, these same hypothalamic nuclei were lesioned by microinjection of kainic acid to determine which, if any, of these populations of vasopressin neurons are involved in the control of flank marking. Unilateral lesions in the areas of the nucleus circularis and supraoptic nucleus at the rostro-caudal plane of the anterior hypothalamus abolished odor-induced flank marking behavior. Lesions in the paraventricular nucleus at the level of the anterior hypothalamus did not consistently inhibit flank marking, while lesions of magnocellular neurons rostral or caudal to the anterior hypothalamus were ineffective. The microinjection of vasopressin into the anterior hypothalamus following lesion of the paraventricular and supraoptic nuclei stimulated flank marking, evidence that treatment with kainic acid did not damage the efferent component of this behavior. However, animals with lesions in the nucleus circularis did not respond to the microinjection of vasopressin; hence, it is uncertain whether lesions in this area disrupt vasopressinergic innervation to the anterior hypothalamus or simply destroy the motor neurons controlling flank marking. In summary, the data clearly demonstrate that vasopressin neurons localized primarily to the medial aspect of the supraoptic nucleus are necessary for sensory integration of odor-induced flank marking, and as such, may be one possible source of neurotransmitter controlling this behavior.

Brief, high-frequency stimulation of the corticomedial amygdala induces a delayed and prolonged increase of aggressiveness in male Syrian golden hamsters.

Brief 200-Hz stimulation of the corticomedial amygdala (CMA) increases the aggressiveness of male Syrian golden hamsters for about 30 min; the effect peaks 10-15 min after stimulation. This effect is sensitive to stimulation amplitude and frequency. Stimulation at the parameters that reduce attack latency increases flank marking but does not affect copulation latency or general activity. Immunocytochemical analysis suggests that stimulation effects may be coupled to c-fos expression and that unilateral stimulation has bilateral effects. CMA stimulation effects appear to mimic part of the time course of behaviorally induced attack priming. The temporal persistence of aggression may result from long-term potentiation-like changes within CMA-related neural circuitry.

Differential effects of ethyl (R,S)-nipecotate on the behaviors of highly and minimally aggressive female golden hamsters.

The GABA uptake inhibitor ethyl (R,S)-nipecotate produces a dose-dependent suppression of aggression in highly aggressive hamsters but not in minimally aggressive ones. This suppression occurs at doses below those producing peripheral cholinergic effects; at the highest dose used it persists after these effects have dissipated. Doses sufficient to suppress aggression have no significant effect on grooming, locomotor activity and other behaviors but do affect sunflower seed acceptance. The differential effects of the drug on highly and minimally aggressive animals may indicate that their differences in aggression are due to differences in endogenous GABAergic activity. These results, together with previous evidence for parallel circadian variation in GABA uptake and aggressive behavior, suggest that GABA uptake may be an important endogenous regulator of aggression.

Plasma levels of human neurotensin: methodological and physiological considerations.

The ingestion of a meal high in fat content is known to increase circulating levels of neurotensin (NT) in humans. However, the magnitude of the postprandial rise of NT in the general circulation and its physiological significance have been subject of much debate. The present study examines circulating levels of NT in male volunteers prior to and following each of their three daily meals (ca. 31 g fat/meal). The response observed are also compared to that elicited by the direct instillation of intralipid (ca. 44 g fat) into the duodenum. NT levels were determined by radioimmunoassay of acid/acetone extracted plasma fractionated by high pressure liquid chromatography. Meals caused a significant but modest increase in NT levels, with the largest increment (ca. 4 fmol/ml) occurring after breakfast. In contrast, NT levels increased ca. 20 fmol/ml with intraduodenal instillation of lipid. The meal-stimulated increases in circulating NT measured here are 4- to 5-fold less than those reported by others, the difference most likely reflecting the lesser amount of lipid ingested. Previous studies provided subjects with single meals containing in excess of 120 g of fat; the 30 g of fat ingested by our subjects, ca. 33% of total caloric intake, is near that recommended by the U.S. Senate, Select Committee on Nutritional and Human Needs. These data show that diets with a reasonable fat content have only a modest effect on circulating levels of NT.

Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters.

Although the anterior hypothalamus has been implicated in the control of aggression in various rodent species, little is known about the neurochemical mechanisms mediating this control. It has been established that flank marking, which occurs with high frequency during agonistic encounters in hamsters, is dependent upon vasopressin-sensitive neurons in the anterior hypothalamus. The present study was undertaken to determine whether intraspecific aggression in this species is similarly influenced by vasopressin in this area of the hypothalamus. Adult male hamsters, surgically implanted with guide cannulae aimed at the anterior hypothalamus, were microinjected with three different concentrations of the V1-receptor antagonist d(CH2)5Tyr(Me)AVP or a vehicle control of 0.9% NaCl. Sixty minutes after each microinjection a smaller male hamster was introduced into the home cage of the treated hamster. The resident hamsters showed a significant dose-dependent reduction in the number of biting attacks on the intruders over the 10 minute test period. The V1-receptor antagonist also caused a significant increase in the resident hamster's latencies to attack the intruder. However, the resident hamsters' total contact time with the intruder was unaffected by drug treatment suggesting that the reduction of aggression was not due to a generalized effect upon social behavior. The specificity of the drug treatment was further supported by the observation that it did not affect resident hamsters' sexual motivation or ability to mount a receptive female. These data suggest that vasopressin-sensitive neurons in the anterior hypothalamus are involved in the control of intraspecific aggression in male hamsters.

Flight-elicited attack and priming of aggression in nonaggressive hamsters.

We report a technique for inducing attack in apparently nonaggressive hamsters that takes advantage of several behavioral effects: (a) the vigorous flight that repeatedly defeated hamsters display in the presence of conspecifics, (b) the potent, attack-eliciting properties of such flight, and (c) attack priming (i.e., aggressive arousal from exposure to an initial stimulus animal carries over to exposure to a second one). Resident hamsters that had consistently failed to attack nonfleeing intruders were found to readily attack intruders that did flee. But repeated exposure to the fleeing intruders alone did not induce long-term changes in aggressiveness. However, flight-elicited attack did successfully prime attack onto nonfleeing intruders presented immediately after the fleeing intruder was removed. Repeating such priming transfer trials induced long-term changes in the formerly nonaggressive subjects. We conclude that this is an effective procedure for inducing aggression that would be preferred when it is important to avoid exposing subjects to aversive stimuli. The changes in behavior that we observed seem to reflect heightened motivational levels.

Technique for vestibular neurotomy in the rat.

A technique for vestibular neurotomy in the rat has been developed. Removal of the tympanic membrane and ossicles through the external auditory meatus permits access to the auditory bulla. After the pterygopalatine artery has been cauterized, and the electrode may be introduced through the oval widow. The vestibular branch of the VIII nerve can then be cauterized with the electrode without direct visualization.

Septo-hypothalamic organization of a stereotyped behavior controlled by vasopressin in golden hamsters.

In golden hamsters, microinjections of arginine vasopressin (AVP) within the anterior hypothalamus (AH) and lateral septum (LS) elicit the display of a stereotyped behavior: flank marking. As these areas are reciprocally connected, we tested whether AVP-sensitive sites constitute an organized network. Flank marking was recorded in animals with ibotenic acid lesions within the AH or LS after AVP injections within the LS or AH. While AVP injections in the AH and LS induced high flank-marking scores, certain lesions blocked the behavior. Lesions of the LS failed to affect flank marking induced by injections within the AH. In contrast, unilateral AH lesions blocked flank marking induced either by LS injections or AH injections in the contralateral side. These results suggest that the bilateral integrity of the AH is critical for the activation of flank-marking behavior by AVP. Together, these data suggest that the AH is an important relay of the neural network controlling flank-marking behavior.

Bandage backfall: labyrinthine and non-labyrinthine components.

A cataleptic animal clings in a vertical position, unmoving, for abnormally long periods by supporting some of its weight on its hindlegs, grasping with the forepaws, flexing its forelimbs, and holding the head horizontal. When the head is snugly wrapped with a bandage, the head slowly falls backward, the neck hyperextends, the forelimbs extend and the grasp is released, resulting in the animal falling backward to the ground. It was earlier suggested that in cataleptic animals, the bandage inhibits vestibular and kinesthetic mechanisms of head support, yielding the backfall sequence [35]. However, preliminary experiments showed that labyrinthectomized rats made cataleptic by haloperidol fall backwards when placed in a vertical clinging position, even without a bandage, suggesting that in the rat the bandage-backfall reaction depends only on the vestibular system. In the present paper, this result is verified but, by additional experiments, the latter conclusion is shown to be incorrect. In labyrinthectomized rats made cataleptic by other means (lateral hypothalamic damage, or bulbocapnine), backfall from clinging did not occur unless a bandage was applied. Therefore, the bandage does indeed appear to inhibit the kinesthetic mechanisms that maintain head support in labyrinthectomized cataleptic rats. Haloperidol, particularly in high doses, greatly weakens postural support in labyrinthectomized rats (causing the animal to sag down and fall back when clinging), although the effect is not detectable in rats with labyrinths intact. However, labyrinthectomy reveals that the bandage can trigger an active dorsiflexion of the neck which in itself appears to inhibit clinging and righting. Bandage-induced dorsiflexion is present to a much lesser degree in intact animals, indicating that labyrinthine mechanisms inhibit the dorsiflexion reflex. Therefore, in the intact, cataleptic rat the bandage backfall reaction appears to be produced by the combined effects of a passive component (inhibition of kinesthetic support mechanisms), and an active component (elicitation of dorsiflexion of the neck).

Vasopressin in the septal area of the golden hamster controls scent marking and grooming.

Microinjection of arginine vasopressin into the lateral septum and bed nucleus of the stria terminalis of male hamsters stimulates intense flank marking and flank gland grooming, while microinjections of vasopressin in sites immediately adjacent to these areas or in the lateral ventricle are ineffective. Microinjections of oxytocin, angiotensin II and the behaviorally active C-terminal fragment of vasopressin, metabolite neuropeptide, by comparison, do not stimulate flank marking. Effective sites for vasopressin injection are clearly superimposable upon autoradiographically defined sites of high V1-receptor density. Furthermore, vasopressin-sensitive neurons in the lateral septum and bed nucleus of the stria terminalis are necessary for the expression of naturally elicited flank marking since the microinjection of a V1-receptor antagonist into these sites was able to temporarily block flank marking triggered by odors from conspecifics.

Disinhibition of muricide and irritability by intraseptal muscimol.

In two experiments we have found and replicated the observation that intraseptal muscimol profoundly facilitates muricide. It also increases irritability (response to handling). These effects are specific to aggressive behaviors in that the drug affects neither activity nor chocolate chip acceptance. The effects of the GABA synthesis inhibitor thiosemicarbazide depend upon the site of injection within the septum; in more anterior loci the drug produces the expected increase in muricide latency; in more posterior sites it produces an anomalous facilitation of muricide. The serotonergic agents quipazine and metergoline have no significant effect when injected into any of these sites. These results suggest that the septal neurons mediating the muricide-inhibitory effect of electrical stimulation [29] are subject to local, GABAergic, control. Inhibition of these neurons by muscimol produces a net disinhibition of muricide.

Facilitation of muricide in rats by cholinergic stimulation of the lateral hypothalamus.

The effect of cholinergic stimulation of the lateral hypothalamus on muricide in rats was evaluated in two experiments. In Experiment 1, injections of the cholinergic agonist carbachol (5.0-20.0 micrograms) were found to facilitate muricide in rats that spontaneously killed mice. In Experiment 2, rats were induced to kill mice by food deprivation and then stimulated with carbachol (2.5-5.0 micrograms). Facilitation of muricide was found to be coincident with increased scores on a handling difficulty (irritability) scale for the majority of rats. These results suggest that facilitation of muricide by cholinergic stimulation of lateral hypothalamic areas may be related to increases in irritable aggression.

Diazepam enhances conditioned defeat in hamsters (Mesocricetus auratus).

Male hamsters that have been repeatedly defeated by larger, aggressive males subsequently flee from, rather than attack, nonaggressive male intruders that are introduced into their home cages. We have referred to this generalization of flight in response to nonaggressive intruders as "conditioned defeat" (CD). In an attempt to reverse CD pharmacologically, diazepam (DZP) was administered to hamsters at two different time points relative to CD acquisition and subsequent response generalization tests, which involved the exposure of subjects to nonaggressive intruders (NAIs). In Experiment 1, subjects were given a single injection of one of 4 doses of DZP (0, 2, 6, or 20 mg/kg) immediately following CD acquisition. Twenty-four hours later, contrary to expectations, subjects that had received the 6 mg/kg dose displayed elevated flight responses in the presence of an NAI. Flight responding declined over days except in subjects that received the highest dose. In the second experiment, hamsters were administered a single injection of either 0, 2, or 6 mg/kg DZP just prior to a response generalization test occurring 24 h following CD training. Flight responses to the NAIs were again exaggerated in subjects that were given the 6 mg/kg dose, an effect that persisted several days without further drug administration. The present findings suggest the possibility that benzodiazepines can potentiate fear responses under certain stressful conditions.

The time course of attack priming effects in female golden hamsters.

In two experiments using different procedures we have found that attack latency, having been reduced by a previous priming attack, returns to baseline levels over a 24 hr period. In both experiments an unexpected, transient increase in attack latency occured 2 hr postpriming. The procedure of the second experiment precludes the possibility that this is a circadian effect. There were no cumulative effects of successive priming attacks suggesting that, under the conditions of these experiments, each attack "resets" the animals' aggressive state. The effects of a single brief agonistic encounter are substantial and persistent enough to be involved in such phenomena as the escalation and redirection of aggression observed in field studies.

The caudate nucleus egocentric localization system.

It is hypothesized that the motor and spatial functions ascribed to the caudate nucleus are actually different aspects of a single system for spatial localization. Within this system movement programs are the code for spatial locations, i.e. the position of any point in space is defined by the head/eye movement necessary to bring that point into focus. This is an egocentric system; points in space are defined solely in terms of their distance and direction from the observer. The experimental finding that caudate lesions in rats impair their performance in an egocentric localization task, but not in another, equally difficult spatial task, demonstrates a caudate role in this system. Since, in an egocentric system, positions in space are defined relative to the observer, every movement of the observer must be accompanied by a compensatory updating of the internal representation of any given point. Studies with Huntington's Chorea patients are consistent with a caudate involvement in this feature of the system also. Electrophysiological experiments with cats indicate that vestibular information, which can be used in the compensatory updating process, is available to the caudate. It is suggested that this system is used by normal animals in delayed response performance.