Rescue of Vasopressin Synthesis in Magnocellular Neurons of the Supraoptic Nucleus Normalises Acute Stress-Induced Adrenocorticotropin Secretion and Unmasks an Effect on Social Behaviour in Male Vasopressin-Deficient Brattleboro Rats.

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA), but not in the central and basolateral amygdala or lateral hypothalamus. In vitro electrophysiological recordings showed an AVP-induced inhibition of MeA neurons that was prevented by picrotoxin administration, supporting the possible regulatory role of AVP originating in the SON. A memory deficit in the novel object recognition test seen in di/di animals remained unaffected by AVP-AAV treatment. Interestingly, although di/di rats show intact social investigation and aggression, the SON AVP-AAV treatment resulted in an alteration of these social behaviours. AVP released from the magnocellular SON neurons may stimulate adrenocorticotropin secretion in response to defined stressors and might participate in the fine-tuning of social behaviour with a possible contribution from the MeA.

The role of central and medial amygdala in normal and abnormal aggression: A review of classical approaches.

The involvement of the amygdala in aggression is supported by overwhelming evidence. Frequently, however, the amygdala is studied as a whole, despite its complex internal organization. To reveal the role of various subdivisions, here we review the involvement of the central and medial amygdala in male rivalry aggression, maternal aggression, predatory aggression, and models of abnormal aggression where violent behavior is associated with increased or decreased arousal. We conclude that: (1) rivalry aggression is controlled by the medial amygdala; (2) predatory aggression is controlled by the central amygdala; (3) hypoarousal-associated violent aggression recruits both nuclei, (4) a specific upregulation of the medial amygdala was observed in hyperarousal-driven aggression. These patterns of amygdala activation were used to build four alternative models of the aggression circuitry, each being specific to particular forms of aggression. The separate study of the roles of amygdala subdivisions may not only improve our understanding of aggressive behavior, but also the differential control of aggression and violent behaviors of various types, including those associated with various psychopathologies.

Considerations for the use of virally delivered genetic tools for in-vivo circuit analysis and behavior in mutant mice: a practical guide to optogenetics.

Optogenetics was the method of the year in 2010 according to Nature Neuroscience. Since then, this method has become widespread, the use of virally delivered genetic tools has extended to other fields such as pharmacogenetics, and optogenetic techniques have become frequently applied in genetically manipulated animals for in-vivo circuit analysis and behavioral studies. However, several issues should be taken into consideration when planning such experiments. We aimed to summarize the critical points concerning optogenetic manipulation of a specific brain area in mutant mice. First, the appropriate vector should be chosen to allow optimal optogenetic manipulation. Adeno-associated viral vectors are the most common carriers with different available serotypes. Light-sensitive channels are available in many forms, and the expression of the delivered genetic material can be influenced in many ways. Second, selecting the adequate stimulation protocol is also essential. The pattern, intensity, and timing could be determinative parameters. Third, the mutant strain might have a phenotype that influences the observed behavior. In conclusion, detailed preliminary experiments and numerous control groups are required to choose the best vector and stimulation protocol and to ensure that the mutant animals do not have a specific phenotype that can influence the examined behavior.

Median raphe region stimulation alone generates remote, but not recent fear memory traces.

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex.

Structural and functional alterations in the prefrontal cortex after post-weaning social isolation: relationship with species-typical and deviant aggression.

Although the inhibitory control of aggression by the prefrontal cortex (PFC) is the cornerstone of current theories of aggression control, a number of human and laboratory studies showed that the execution of aggression increases PFC activity; moreover, enhanced activation was observed in aggression-related psychopathologies and laboratory models of abnormal aggression. Here, we investigated these apparently contradictory findings in the post-weaning social isolation paradigm (PWSI), an established laboratory model of abnormal aggression. When studied in the resident-intruder test as adults, rats submitted to PWSI showed increased attack counts, increased share of bites directed towards vulnerable body parts of opponents (head, throat, and belly) and reduced social signaling of attacks. These deviations from species-typical behavioral characteristics were associated with a specific reduction in the thickness of the right medial PFC (mPFC), a bilateral decrease in dendritic and glial density, and reduced vascularization on the right-hand side of the mPFC. Thus, the early stressor interfered with mPFC development. Despite these structural deficits, aggressive encounters enhanced the activation of the mPFC in PWSI rats as compared to controls. A voxel-like functional analysis revealed that overactivation was restricted to a circumscribed sub-region, which contributed to the activation of hypothalamic centers involved in the initiation of biting attacks as shown by structural equation modeling. These findings demonstrate that structural alterations and functional hyperactivity can coexist in the mPFC of rats exposed to early stressors, and suggest that the role of the mPFC in aggression control is more complex than suggested by the inhibitory control theory.

Neural mechanisms of predatory aggression in rats-implications for abnormal intraspecific aggression.

Our recent studies showed that brain areas that are activated in a model of escalated aggression overlap with those that promote predatory aggression in cats. This finding raised the interesting possibility that the brain mechanisms that control certain types of abnormal aggression include those involved in predation. However, the mechanisms of predatory aggression are poorly known in rats, a species that is in many respects different from cats. To get more insights into such mechanisms, here we studied the brain activation patterns associated with spontaneous muricide in rats. Subjects not exposed to mice, and those which did not show muricide were used as controls. We found that muricide increased the activation of the central and basolateral amygdala, and lateral hypothalamus as compared to both controls; in addition, a ventral shift in periaqueductal gray activation was observed. Interestingly, these are the brain regions from where predatory aggression can be elicited, or enhanced by electrical stimulation in cats. The analysis of more than 10 other brain regions showed that brain areas that inhibited (or were neutral to) cat predatory aggression were not affected by muricide. Brain activation patterns partly overlapped with those seen earlier in the cockroach hunting model of rat predatory aggression, and were highly similar with those observed in the glucocorticoid dysfunction model of escalated aggression. These findings show that the brain mechanisms underlying predation are evolutionarily conservative, and indirectly support our earlier assumption regarding the involvement of predation-related brain mechanisms in certain forms of escalated social aggression in rats.

The neural background of hyper-emotional aggression induced by post-weaning social isolation.

Post-weaning social isolation in rats is believed to model symptoms of early social neglect-induced externalizing problems including aggression-related problems. We showed earlier that rats reared in social isolation were hyper-aroused during aggressive contacts, delivered substantially more attacks that were poorly signaled and were preferentially aimed at vulnerable body parts of opponents (head, throat and belly). Here we studied the neural background of this type of aggression by assessing the expression of the activation marker c-Fos in 22 brain areas of male Wistar rats submitted to resident-intruder conflicts. Post-weaning social isolation readily produced the behavioral alterations noticed earlier. Social isolation significantly increased the activation of brain areas that are known to directly or indirectly control inter-male aggression. Particularly, the medial and lateral orbitofrontal cortices, anterior cingulate cortex, bed nucleus of the stria terminalis, medial and basolateral amygdala, hypothalamic attack area, hypothalamic paraventricular nucleus and locus coeruleus showed increased activations. This contrasts our earlier findings obtained in rats with experimentally induced hypoarousal, where abnormal attack patterns were associated with over-activated central amygdala, lateral hypothalamus, and ventrolateral periaqueductal gray that are believed to control predatory attacks. We have observed no similar activation patterns in rats socially isolated from weaning. In summary, these findings suggest that despite some phenotypic similarities, the neuronal background of hypo and hyperarousal-associated abnormal forms of aggression are markedly different. While the neuronal activation patterns induced by normal rivalry and hypoarousal-driven aggression are qualitative different, hyperarousal-associated aggression appears to be an exaggerated form of rivalry aggression.

Temporal changes in c-Fos activation patterns induced by conditioned fear.

Mechanisms underlying shock-induced conditioned fear - a paradigm frequently used to model posttraumatic stress disorder, PTSD - are usually studied shortly after shocks. Some of the brain regions relevant to conditioned fear were activated in all the c-Fos studies published so far, but the overlap between the activated regions was small across studies. We hypothesized that discrepant findings were due to dynamic neural changes that followed shocks, and a more consistent picture would emerge if consequences were studied after a longer interval. Therefore, we exposed rats to a single session of footshocks and studied their behavioral and neural responses one and 28 days later. The neuronal activation marker c-Fos was studied in 24 brain regions relevant for conditioned fear, e.g. in subdivisions of the prefrontal cortex, hippocampus, amygdala, hypothalamic defensive system, brainstem monoaminergic nuclei and periaqueductal gray. The intensity of conditioned fear (as shown by the duration of contextual freezing) was similar at the two time-points, but the associated neuronal changes were qualitatively different. Surprisingly, however, Multiple Regression Analyses suggested that conditioned fear-induced changes in neuronal activation patterns predicted the duration of freezing with high accuracy at both time points. We suggest that exposure to electric shocks is followed by a period of plasticity where the mechanisms that sustain conditioned fear undergo qualitative changes. Neuronal changes observed 28 days but not 1 day after shocks were consistent with those observed in human studies performed in PTSD patients.

Novel use of a lipid-lowering fibrate medication to prevent nicotine reward and relapse: preclinical findings.

Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

Activation patterns of cells in selected brain stem nuclei of more and less stress responsive rats in two animal models of PTSD - predator exposure and submersion stress.

This study had two purposes. First: compare predator and water submersion stress cFos activation patterns in dorsal raphe (DR), locus coeruleus (LC) and periaqueductal gray (PAG). Second: identify markers of vulnerability to stressors within these areas. Rats were either predator or submersion stressed and tested 1.75 h later for anxiety-like behavior. Immediately thereafter, rats were sacrificed and cFos expression examined. In DR, serotonergic cells expressing or not expressing cFos were also counted. Predator and submersion stress increased anxiety-like behavior (in the elevated plus maze- EPM) equally over controls. Moreover, stressed rats spent equally less time in the center of the hole board than handled controls, another indication of increased anxiety-like behavior. To examine vulnerability, rats which were less anxious (LA) and more (highly) anxious (MA) in the EPM were selected from among handled control and stressed animals. LA rats in the stressed groups were considered stress non-responsive and MA stressed rats were considered stress responsive. LA and MA rats did not differ in cFos expression in any brain area, though stressors did increase cFos cell counts in all areas over controls. Intriguingly, the number of serotonergic DR neurons not activated by stress predicted degree of anxiety response to submersion stress only. LA submersion stressed rats had more serotonergic cells than all other groups, and MA submersion stressed rats had fewer serotonergic cells than all other groups, which did not differ. Moreover, these cell counts correlated with EPM anxiety. We conclude that a surplus of such cells protects against anxiogenic effects of submersion, while a paucity of such cells enhances vulnerability to submersion stress. Other data suggest serotonergic cells may exert their effects via inhibition of dorsolateral PAG cells during submersion stress. Findings are discussed with respect to serotonergic transmission in vulnerability to predator stress and relevance of findings for post traumatic stress disorder (PTSD). This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

A comparison of activation patterns of cells in selected prefrontal cortical and amygdala areas of rats which are more or less anxious in response to predator exposure or submersion stress.

This study had two purposes. First: to compare predator and water submersion stress cFos activation in medial prefrontal cortices (mPFC) and the medial amygdala (MeA). Second: to identify markers of vulnerability to stressors within these areas. Rats were either predator or submersion stressed and tested 1.75 h later for anxiety. Immediately thereafter, rats were sacrificed and cFos expression was examined. Predator and submersion stress equally increased anxiety-like behavior in the elevated plus maze (EPM) and hole board. To examine vulnerability, rats which were less anxious (LA) and more (highly) anxious (MA) in the EPM were selected from among handled control and stressed animals. LA stressed rats were considered stress non-responsive while MA stressed rats were considered stress responsive. Predator stress, but not submersion stress, activated MeA cFos. CFos expression of mPFC cells was elevated in LA rats and reduced in MA rats in predator stressed animals only, correlating negatively with anxiety. These findings are consistent with data implicating greater mPFC excitability in protection against the effects on affect of traumatic stress. The findings also suggest that this conclusion is stressor specific, applying to predator stress but not submersion stress. Both stressors have been suggested to model hyperarousal and comorbid anxiety aspects of PTSD in humans. Hence the use of these paradigms to identify brain bases of vulnerability and resilience to traumatic stress in PTSD has translation potential. On the other hand, our evidence of stressor specificity of vulnerability/resilience markers raises a caution. The data suggest that preclinical markers of vulnerability/resilience in a given stress paradigm are at best suggestive, and translational value must ultimately be confirmed in humans.

Brain mechanisms involved in predatory aggression are activated in a laboratory model of violent intra-specific aggression.

Callous-unemotional violence associated with antisocial personality disorder is often called 'predatory' because it involves restricted intention signaling and low emotional/physiological arousal, including decreased glucocorticoid production. This epithet may be a mere metaphor, but may also cover a structural similarity at the level of the hypothalamus where the control of affective and predatory aggression diverges. We investigated this hypothesis in a laboratory model where glucocorticoid production is chronically limited by adrenalectomy with glucocorticoid replacement (ADXr). This procedure was proposed to model important aspects of antisocial violence. Sham and ADXr rats were submitted to resident/intruder conflicts, and the resulting neuronal activation patterns were investigated by c-Fos immunocytochemistry. In line with earlier findings, the share of attacks aimed at vulnerable targets (head, throat and belly) was dramatically increased by ADXr, while intention signaling by offensive threats was restricted. Aggressive encounters activated the mediobasal hypothalamus, a region involved in intra-specific aggression, but sham and ADXr rats did not differ in this respect. In contrast, the activation of the lateral hypothalamus that is tightly involved in predatory aggression was markedly larger in ADXr rats; moreover, c-Fos counts correlated positively with the share of vulnerable attacks and negatively with social signaling. Glucocorticoid deficiency increased c-Fos activation in the central amygdala, a region also involved in predatory aggression. In addition, activation patterns in the periaqueductal gray - involved in autonomic control - also resembled those seen in predatory aggression. These findings suggest that antisocial and predatory aggression are not only similar but are controlled by overlapping neural mechanisms.

Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats.

Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB(1) receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Delta(9)-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB(1) receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB(1) receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.

Lasting changes in social behavior and amygdala function following traumatic experience induced by a single series of foot-shocks.

Neuronal plasticity within the amygdala mediates many behavioral effects of traumatic experience, and this brain region also controls various aspects of social behavior. However, the specific involvement of the amygdala in trauma-induced social deficits has never been systematically investigated. We exposed rats to a single series of electric foot-shocks--a frequently used model of trauma--and studied their behavior in the social avoidance and psychosocial stimulation tests (non-contact versions of the social interaction test) at different time intervals. Social interaction-induced neuronal activation patterns were studied in the prefrontal cortex (orbitofrontal and medial), amygdala (central, medial, and basolateral), dorsal raphe and locus coeruleus. Shock exposure markedly inhibited social behavior in both tests. The effect lasted at least 4 weeks, and amplified over time. As shown by c-Fos immunocytochemistry, social interactions activated all the investigated brain areas. Traumatic experience exacerbated this activation in the central and basolateral amygdala, but not in other regions. The tight correlation between the social deficit and amygdala activation patterns suggest that the two phenomena were associated. A real-time PCR study showed that CRF mRNA expression in the amygdala was temporarily reduced 14, but not 1 and 28 days after shock exposure. In contrast, amygdalar NK1 receptor mRNA expression increased throughout. Thus, the trauma-induced social deficits appear to be associated with, and possibly caused by, plastic changes in fear-related amygdala subdivisions.

The effect of neurokinin1 receptor blockade on territorial aggression and in a model of violent aggression.

BACKGROUND: Neurokinin1 (NK1) receptor blockers were recently proposed for the treatment of anxiety and depression. Disparate data suggest that NK1 receptors are also involved in the control of aggressiveness, but their role is poorly known. METHODS: We evaluated the aggression-induced activation of NK1 neurons by double-labeling brain sections for NK1 receptors and c-Fos in two laboratory models of aggression. We also studied the effects of the NK1 antagonist L-703,606 in these models. RESULTS: Aggressive encounters activated a large number of NK1 receptor-expressing neurons in areas relevant for aggression control. The activation was aggression-specific, because the effects of psychosocial encounters (that allowed sensory but not physical contacts) were markedly weaker. In the medial amygdala, the activation of neurons expressing NK1 receptors showed a marked positive correlation with the occurrence of violent attacks. In resident/intruder conflicts, NK1 blockade lowered the number of hard bites, without affecting milder forms of attack. In the model of violent aggression, attacks on vulnerable body parts of opponents (the main indicators of violence in this model) were decreased to the levels seen in control subjects. Autonomic deficits seen in the model of violent aggression were also ameliorated. The effects of the compound were not secondary to changes in locomotion or in the behavior of intruders. CONCLUSIONS: Our data show that neurons expressing NK1 receptors are involved in the control of aggressiveness, especially in the expression of violent attacks. This suggests that NK1 antagonists-beyond anxiety and depression-might also be useful in the treatment of aggressiveness and violence.

The activation of prefrontal cortical neurons in aggression--a double labeling study.

Violence is associated with prefrontal deficits in humans, suggesting that this brain area inhibits aggressiveness. Its role, however, remains controversial, as certain subdivisions of the prefrontal cortex become activated by fights in rodents. Disparate human findings also show that this area is acutely activated by aggression under certain conditions. We explored prefrontal neuronal activation patterns in resident rats exposed to psychosocial (sensory contact with the intruder) and aggressive encounters. Both psychosocial and aggressive encounters increased c-Fos activation in the prelimbic (PrL), anterior cingular (Cg1), agranular insular (AI), ventral (VO) and lateral orbital (LO) cortices. The infralimbic (IL) and medial orbital (MO) cortices were activated significantly by aggressive encounters only. No other prefrontal regions were activated by psychosocial or aggressive encounters. The overwhelming majority of activated cells were pyramidal (glutamatergic) cells in the Cg1, IL, PrL, MO, and VO, whereas interneuron and pyramidal cell activation was similar in AI and LO. When rats showed violent aggression, the activation of GABAergic inhibitory cells decreased in these two, and two other areas (IL and MO). Notably, the latter two areas appeared to be specifically involved in aggressive behavior. The change occurred in a recently developed model of violent aggression. In this model, pyramidal cell activation in the above mentioned four areas (IL, MO, AI, and LO) predicted over 95% of variation in attack counts in general and violent attacks in particular. Based on these data, we present a tentative hypothesis on the involvement of the prefrontal cortex in the control of aggression.

The activation of raphe serotonergic neurons in normal and hypoarousal-driven aggression: a double labeling study in rats.

The serotonergic system is well known for its aggression lowering effects. It has been shown repeatedly, however, that the serotonergic system is activated during fights, and recent data suggested that it is necessary for the expression of aggressive behavior. We investigated the interaction between serotonergic activation and aggressive behavior by assessing the co-localization of the c-Fos signal (marker of neuronal activation) with tryptophan-hydroxylase activity (marker of serotonin secretion) in the raphe. Control rats were compared with rats exposed to visual and olfactory (but not physical) contacts with opponents (psychosocial stimulation) as well as with rats exposed to aggressive encounters. Fights were accompanied by the activation of the raphe; however, the effect was not aggression-specific, as a similar activation was induced by psychosocial contacts. The lack of behavioral specificity in activation suggests that it was related to social arousal rather than to the execution of fights. The activation of serotonergic raphe neurons showed a negative correlation with aggressive behavior, which is in line with the widespread view that serotonin neurotransmission downregulates aggressive behavior. The activation of serotonergic neurons did not show a correlation with measures of hypoarousal-driven abnormal aggression, which indicates that factors other than the raphe control this behavior. The latter finding may explain the low efficacy of serotonergic treatments in conduct and antisocial personality disorders, in which violence correlates with hypoarousal.

Hypothalamic attack area-mediated activation of the forebrain in aggression.

It is believed that aggressive attacks are activated by a downward stimulatory stream that includes the medial amygdala, hypothalamic attack area, and periaqueductal grey. However, the hypothalamic attack area (from which attacks can be induced by electrical stimulation) sends projections to the forebrain, the significance of which is unknown. Here we report that the unilateral stimulation of the hypothalamic attack area per se induced an unilateral c-Fos activation of most brain nuclei involved in attack, and that attacks occurred only when cortical regions were also activated, and the activation of the medial amygdala and hypothalamic attack area were bilateral. This suggests that the hypothalamic attack area not only transmits information to lower brain structures but also activates forebrain structures involved in attack.

Neural background of glucocorticoid dysfunction-induced abnormal aggression in rats: involvement of fear- and stress-related structures.

Glucocorticoid hypofunction is associated with persistent aggression in some psychologically disordered human subjects and, as reported recently, induces abnormal forms of aggression in rats. Here we report on the effects of glucocorticoid hypofunction on aggression-induced neural activation. Rats were adrenalectomized, and implanted with low-release glucocorticoid pellets. After one week recovery, they were challenged by an unfamiliar intruder in their home-cage. Neural activation was studied by c-Fos protein immunocytochemistry. Aggressive encounters in controls induced c-Fos activation in all brain areas relevant for the control of aggression (cortex, amygdala, septum, hypothalamus, periaqueductal grey and the locus coeruleus). Very intense c-Fos activation was observed in the medial amygdala, the hypothalamic attack area and the periaqueductal grey matter which constitute a downward stimulatory stream that activates attack behaviour. The experimentally induced glucocorticoid hypofunction dramatically increased attacks targeted towards vulnerable parts of the opponent's body (mainly the head). This abnormal behaviour was not associated with changes in the activation of brain centres involved in the control of aggression. However, the activation of brain centres involved in both the stress response (the parvocellular part of the hypothalamic paraventricular nucleus) and fear reactions (central amygdala) were markedly increased. An acute glucocorticoid treatment abolished both behavioural and neural consequences of glucocorticoid hypofunction. Our data suggest that glucocorticoid hypofunction-induced abnormal forms of aggressiveness are related to increased sensitivity to stressors and fear-eliciting stimuli. This assumption is supported by the finding that fearful situations induce attack patterns in intact rats that are similar to those induced by glucocorticoid hypofunction.