Aggression-driving circuits varies across species

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Aggression is a common behavior both among humans and other animals, which is known to be particularly important for defense, protection and survival.

While psychologists and neuroscientists have been investigating aggression for several decades, recent technological advances have enabled the collection of increasingly precise and insightful data that has helped to identify many of the neural mechanisms associated with aggressive behaviors in different species.

Researchers at New York University School of Medicine recently reviewed some of the most recent findings of studies investigating the neural underpinnings of aggression in order to delineate what the neuroscience research community has so far discovered about this crucial behavior.

In their paper, published in Nature Neuroscience, they delineate a ‘core aggression circuit’ composed of four subcortical brain regions that have been found to be linked to the manifestation of aggressive behaviors in multiple animal species.

“There have been significant advances in technology in the past 10 years, for instance, enabling the precise recording and manipulation of specific sets of cells in brain regions of interest,” Julieta E. Lischinsky and Dayu Lin, the two authors of the review paper, told Medical Xpress.

“These advances allowed neuroscientists to address a number of fundamental questions related to the study of aggression. In our article, we provide an overview of these advances and how they are paving the way towards a better understanding of the brain regions, cells and circuits responsible for aggression, as well as how it can be altered by the internal state of the animal.”

In their review paper, Lischinsky and Lin tried to identify the fundamental principles and neural mechanisms underlying aggressive behaviors across a wide range of animal species.

To do this, they analyzed past study findings and looked at the similarities and differences between how aggression manifests in three main types of animals, namely rodents, songbirds and primates.

Based on past observations, the researchers delineated what they refer to as a core aggression circuit (CAC); a set of four subcortical brain regions that are particularly active while animals are exhibiting aggressive behaviors.

Lischinsky and Lin also highlight the existence of two parallel circuits that appear to drive motor actions of aggression. These include a circuit that involves the medial hypothalamus and the midbrain, which has been linked with innate aggressive actions (e.g., biting in mice) and a circuit that contains the hypothalamus, dopamine cells in the ventral tegmental area and ventral striatum, which appears to drive aggressive behaviors that are acquired over time (e.g., specific types of singing in songbirds).

“The relative importance of these aggression-driving circuits varies across species,” Lischinsky and Lin explained. “In our paper, we also use past findings to describe the key circuits for controlling aggression.

The hippocampus-lateral septum circuit is considered the major top-down control for rodents and birds, while the prefrontal cortex plays a more important role in modulating aggression in primates potentially through its primate-specific direct projection to the medial hypothalamus and its dense connection to the midbrain.”

The recent paper authored by Lischinsky and Lin provides an overview of the main biological features of aggression across species and the neural substrates that are now known to play a key role in aggressive behaviors.

While it does not present any new evidence, it could prove to be highly valuable for neuroscientists who are conducting research related to aggression, as it offers a clear summary and representation of the neural circuits associated with this particular behavior based on what neuroscientists have discovered about it so far.

“Our paper summarizes past findings that show how the same subcortical regions in the core aggression circuit are implicated in aggressive behaviors across species, despite the differences in aggression observed in these species,” Lischinsky and Lin said.

“This highlights how understanding the circuitry in other species such as rodents and songbirds can be very informative for uncovering the complexity of human aggression.”

Although the majority of past studies investigating the neural underpinnings of aggression were carried out on animals, some of the findings could also apply to humans.

As aggressive outbursts are associated with numerous psychiatric conditions, including conduct disorder and schizophrenia, the evidence that Lischinsky and Lin review in their paper could ultimately contribute to the development of more effective pharmacological or psychological treatments for these conditions, which are specifically designed to reduce aggressive behavior.

“Our plans for future investigation are to better understand more precisely the connectivity among CAC regions and their top-down control at the neuronal population level that results in aggressive actions,” Lischinsky and Lin said.

“We are also interested in how the circuit we delineate in our paper is modified in the short- and long-term by the internal state of the animals such as by energy level, reproductive state and experience, among others.”


In humans, aggression has developed to become part of our defense and protection, but it may also be a symptom reflecting certain medical conditions. As a state of mind, it may be directed towards objects, animals, or human beings, without any obvious motive, and aggression could be a means of self-infliction or be a result from illegal use of drugs and anabolic steroids. It may be elicited by provocation (1, 2) and be detrimental to a person’s health through stress as in e.g. cardiovascular disorders (3, 4). As stress-related, aggression involves cortisol and activity in the hypothalamic–pituitary axis (HPA axis) (5).

In his theory of the general adaptation syndrome, Hans Selye emphasized the role of the immune system following the response to stress (6). Since then, we have learned that stress is a broad category including some aversive events which can elicit an aggressive response (1), and that the immune system interferes with normal and pathological brain functioning and behavior (7).

Pheromones and odors from the urine have been associated with aggressive behavior (8) and over the years, scientists have had several hypothesis such as the frustration-aggression hypothesis proposed as early as in 1941 (9). It is currently accepted that aggressive behavior can be viewed as a strategy by humans and animals to cope with stress, implying that neurobiological mechanisms involved in stress responses should underlie both physiological and pathological aggression (10–13).

Studies of the HPA axis, has later linked the brain’s control of cortisol secretion via pituitary release of the adrenocorticotropic hormone (ACTH) (14). Both deficient and increased activation of the HPA axis have been associated with aggressive behavior and Cortisol suppresses the activity of the HPA axis through a mechanism of negative feedback.

Cortisol also modulates behavioral modalities including anxiety and distress (15), and diminishes the production of testosterone (16). Berkowitz (17) was convinced that high aggressive drive together with personality factors could explain aggression displacement whereas hypo-arousal-associated aggressiveness, a proposed characteristic of antisocial personality disorder, has been linked to glucocorticoid deficiency (18).

In contrast, hyper-arousal-driven aggressiveness, which could be related to the acute exaggerated glucocorticoid response to stress, can be seen in conditions such as post-traumatic stress disorder (PTSD) and intermittent explosive disorder. In fact a study showed that more than twice the individuals with diagnosed intermittent explosive disorder (IED) met the PTSD criteria, compared to individuals without IED(19).

After the introduction of the neuropeptide concept (20, 21) further studies have revealed that peptide hormones are the key modulators of the homeostasis, stress response, and motivated behavior (22, 23). In this regard, not only the centrally produced, but also peripherally derived peptides can access the brain (24), including transport across the blood-brain barrier (25), and diffusion together with macromolecules via the perivascular spaces (26).

The circumventricular organs in the brain, with their extensive and highly permeable capillaries, represent important sites of action of peripheral peptide hormones, e.g. the median eminence located in the vicinity of the ventromedial hypothalamic nucleus involved in the regulation of aggressive behavior (27). Thus, aggressive behavior may involve specific brain circuitries and activation of the HPA axis as a mechanism of altered response to stress, however, the biological background is so far not fully understood (28–31).

Immunoglobulins (Ig) or autoantibodies (autoAbs) reactive with neuropeptides and peptide hormones have been identified in humans and rodents showing associations of their plasma levels with aggressive or antisocial behavior, anxiety, and depression. For instance, in 2002 Fetissov et al. described IgG reactive with melanocortin peptides alpha-melanocyte-stimulating hormone (α-MSH) and ACTH in patients with eating disorders (ED) (32), results which later were followed by data showing increased plasma levels of ACTH-reactive autoAbs in subjects with increased aggressive and antisocial behavior (33). Most recently, a modulatory role of ACTH-reactive IgG in ACTH-induced cortisol secretion was demonstrated (34).

Understanding the modulatory role of autoAbs reactive with stress-related peptide hormones represents a new approach to aggressive behavior. Few studies are published on this immuno-modulated behavior, and the purpose of this review is to present the most recent knowledge integrating such autoAbs in neurobiological mechanisms of aggression.

Subtypes of Aggressive Behavior

There are long traditions of claiming that aggression falls into proactive or reactive types and that the basis for aggressive behavior is to inflict harm (12). Human aggression varies from purely reactive cases with unplanned fighting and strong emotions, to purely proactive, premeditated, and deliberate efforts to harm (35).

Reactive aggression is a response to a threat or a frustrating event, with the goal being only to remove the provoking stimulus. Reactive aggression is always associated with anger, as well as with a sudden increase in sympathetic activation and a failure of cortical regulation. In animals, reactive aggression is typically a response by the defender without any proactive elements (35), such as when a fight concerns food, whereas proactive aggression is seen rarer in most species.

Proactive aggression may refer to a planned attack with a purpose driven by an external or internal reward, and the proactivity is characterized by attention to a consistent target, and often by a lack of emotional arousal. Psychologists often distinguish between two different types of aggression, impulsive and instrumental. Impulsive or affective aggression with strong anger is not planned and it usually occurs during the heat of the moment, whereas in instrumental or predatory aggression, the aggressive behavior is goal oriented and thus normally well planned.

In this review, focus is set on the type of aggression seen in criminals sentenced to imprisonment due to their impulsive violent and extreme antisocial actions, but also where there are elements of both proactivity and premeditation, as well as of impulsivity and other personality issues. Consequently, some forms of aggressive behavior can be difficult to classify as being either one or the other, since an analysis of the kind of aggression observed in practice, often contains elements from various defined categories.

Hypothalamic-Pituitary-Adrenal Axis

The HPA axis refers to the interaction between the hypothalamus, the pituitary gland and the adrenal cortex, and the secretion of hormones involved in the stress response. This interaction is important for the early development and later consolidation of human behavior.

Neuronal co-localization of functionally related peptides is important for an immediate physiological response in which more than one transmitter participates. Neuropeptides, normally involved as a part of long-term response to stress, e.g. a trauma or an allergic- or inflammatory reaction, need more time to upregulate than classical neurotransmitters (36). Corticotropin-releasing hormone (CRH) links the HPA axis (14) to the brain’s response with stress required behavior, and its activity may thus influence anxiety and stress reactions (15).

For human beings, the impact of stress already experienced during a child’s early rearing environment may influence the development of later psychopathology and possibly identify hormonal substrates related to behavioral changes as the child gets older (37).

Recent data have revealed that the HPA axis and associated stress-related behavior can be influenced by immunoglobulins or natural autoAbs reactive with peptide hormones involved in regulation of the HPA axis activity (34). Furthermore, experimental studies have shown enhanced activation of the hypothalamic paraventricular nucleus and amygdala in glucocorticoid-deficient rats after exposure to the resident intruder (RI) stress protocol (33, 38).

Corticotrophin-Releasing Hormone

Specific neurons of the paraventricular nucleus (PVN) of the hypothalamus secrete CRH in response to stress. Under physiological conditions, its secretion varies during the 24 h cycle of the day; being highest in the morning and lowest during the night. The stimulation of ACTH secretion into the blood stream leads to the release of cortisol from the adrenal cortex (39).

This is an automatic regulation based on negative feedback so that the blood levels of cortisol shuts down the relevant CRH release activity in the hypothalamus, thereby preventing CRH levels from becoming too high (40). It is related to aggressive behavior as part of the stress response (41).

Adrenocorticotrophic Hormone

ACTH consists of 39 amino acids and is a peptide originating from the precursor pro-opiomelanocortin (POMC) (42), synthetized mainly in the pituitary and in the brain. CRH stimulate the synthesis and secretion of ACTH and act in synergy with the central nervous modulatory effects of arginine vasopressin (AVP), releasing stored ACTH from corticotropic cells. ACTH binds to the melanocortin type 2 G protein-coupled receptor (MC2R) expressed in the fasciculate and reticular zones of the adrenal cortex (39, 43), and triggers intracellular signaling pathways regulating the adrenal cortisol production.

Acute administrations of ACTH fragments increase fighting in mice, independently of corticosterone secretion (44), but ACTH injections in isolated mice may also decrease their aggressiveness (45). It was shown that there is a link between ACTH and aggressive behavior (46), and recently this link has been strengthened through studies on ACTH autoAbs (34).

Cortisol

Cortisol is a steroid and the body’s main stress hormone, released from the adrenal cortex. One of the first studies described a model in which the HPA axis was linked to aggression (47) and later, cortisol and aggression were seen in wrestlers who after fighting showed an increased level in serum cortisol (48). Cortisol is known from general physiology to be released during stress (49), and it contributes positively to the hormonal balance throughout the body, and most of our cells have cortisol receptors. Examples of cortisol functions are control of blood sugar levels, regulation of metabolism, anti-inflammatory effects, help to forming our memory, and depression (50).

Melanocyte-Stimulating Hormone

The peptide hormone and neuropeptide melanocyte-stimulating hormone (MSH), is produced by the brain and pituitary and consists of α-MSH, β-MSH, and γ-MSH, which are in the family of melanocortin peptides. The sequence of α-MSH consists of the 13 first amino acids of the ACTH molecule with antibody cross-reactivity as a consequence since antibodies to ACTH and α-MSH are not specific and will detect POMC, but only to an unknown degree (51).

Experiments on male mice showed that when a dominant/subordinate pair was injected 15 min before the testing with α-MSH, the attacks on the α-MSH-treated animal were more frequent compared to when the MSH was administered 24 h before testing (52) indicating that α-MSH increases aggressive behavior.

In the context of externalizing behavior, α-MSH involvement in stress (32) and aggression has been associated with melanocortin peptides since injection of α-MSH or ACTH fractions (amino acids 4–10) (45) induced aggression in mice. In addition, the melanocortin peptide pharmacophore also seems necessary for the pro-aggressive ACTH effects.

Oxytocin

Oxytocin (OT) and AVP are both nine amino acid peptide hormones (53) and their sequences differ by two amino acids (54). OT is acting as a neuromodulator in the brain regulating social and sexual behavior. It is involved in anxiety and stress response, and in aggression (22, 55, 56).

OT has protective effects against stress and studies have shown that it modulates neural circuitry for social cognition and fear in humans (57), and may disrupt the common output from the amygdala to the rat brainstem effector sites of the autonomic nervous system (58).

Intracerebral OT modulation is known to inhibit stress-induced activity of the HPA axis (59, 60), causing behavioral and neural effects such as reduced anxiety (61). Administration of OT with concomitant social support during stress exposure provides the lowest cortisol response and an anxiolytic effect (62).

Arginine Vasopressin

AVP has several peripheral and central functions, but relevant to this review regarding aggressive behavior, AVP functions as a neuromodulator. Its role in the central nervous system (CNS) seems to depend on the region in which AVP is released, including modulation of aggressive behavior (22, 56, 63, 64). AVP and CRH are found to co-exist in CRH nerve terminals (65, 66), and together with CRH, AVP strongly potentiates its ACTH-releasing activity (67, 68). As to the regulation, the function of the HPA axis has shown that in acute stress, CRH is a major player causing increased ACTH secretion, whilst in chronic stress; AVP modulation takes over as the main stimulator of ACTH release (69).

During an RI test, release of AVP, specifically in the hypothalamic mediolateral septum, was found to regulate intermale aggression in laboratory rats specifically bred for low (LAB)- or high (HAB)- anxiety‐related behavior (63). During the test exposure, LAB residents showed more aggression than the HAB residents, and the septal AVP release was found decreased in high-aggressive LAB rats compared to HAB males.

Studying the patterns of AVP release within the hypothalamic mediolateral septum in the two respective groups of rats, revealed that changes in AVP release varied with intermale aggressive behavior. Thus, high levels of aggressive behavior, as seen in LAB residents, were associated with decreased release of AVP in the septum. On the other hand, the low levels of aggression found in HAB residents were associated with an increase in septal AVP release (63).

Furthermore, during exposure to a non-social stressor, LAB rats responded with a stronger rise in plasma ACTH compared with HAB rats (70–72), reflecting a generally lower stressor susceptibility in the latter group, and at the same time, presenting a low trait anxiety. These findings are somewhat in line with the evidence that innate anxiety is inversely related to the level of intermale aggressive behavior (46).

Immunoglobulins

Ig are natural antibodies produced by B1 cells, including the processes in germ-free animals after activation by both T cell-dependent and independent mechanisms (73). Ig’s are divided into five classes or isotypes of which IgG is the most common type of antibody.

An autoAb is an antibody directed against one or more of the individual’s own proteins. The natural autoAbs are part of normal physiology of the innate and adaptive immune defense, and may in addition be involved in several homeostatic functions (74), e.g. in removal of old erythrocytes (75), and fighting any invaders or toxins in the body, including e.g. bacteria and viruses. The various IgG autoAbs are relatively stable throughout life as opposed to IgG-reactive to bacterial antigens, demonstrating individual differences which in turn increase as we get older (76).

Natural autoAbs of immunoglobulin M (IgM), IgG and immunoglobulin A (IgA) classes are present in all human beings without health problems (74, 77), they are polyreactive, and bind with different affinities to a variety of unrelated antigens, including those from micro-organisms.

Although the functional role of peptide hormone-reactive autoabs still needs to be further clarified, it appears that autoabs play a role in the transportation of peptide hormones and cytokines (78–81), and they seem to protect these peptides from degradation by plasma enzymes, thereby preserving biological activity (82).

ACTH-Reactive Autoabs

The few studies on ACTH IgG autoAbs in human aggression shown in Table 1 are those we are left with after thorough research in available databases.

Table 1 – Selected studies on ACTH-reactive IgG autoAbs and human aggressive behavior.

YearTitleAuthorsConclusive comments
2018“Autoantibodies reactive to ACTH can alter cortisol secretion in both aggressive and non-aggressive humans”.Vaeroy, et al (34)“ACTH-reactive plasmatic IgGs exhibit differential epitope preference in controls and violently aggressive subjects. IgGs can modulate ACTH-induced cortisol secretion” and the stress response. There were different epitopes between non-aggressive and violent criminals
2013“Corticotrophin (ACTH)-reactive immunoglobulins in adolescents in relation to antisocial behavior and stress-induced cortisol response”.Schaefer, et al. (83)“High total and free ACTH IgG are associated with higher antisocial behavior scores in boys. In girls, antisocial behavior is associated with low free ACTH IgG levels. Stress-induced cortisol release is associated with free ACTH IgG in boys and with total ACTH IgG in girls. ACTH IgG levels are related to antisocial behavior and HPA axis response to stress in adolescents”.
2006“Aggressive behavior linked to corticotrophin-reactive autoantibodies”.Fetissov, et al. (33).“High levels of ACTH-reactive autoAbs and altered levels of oxytocin- and vasopressin-reactive autoAbs in aggressors may interfere with the neuroendocrine mechanisms of stress and motivated behavior. A new biological mechanism of human aggressive behavior” (33) is suggested.

Table 1 – Selected studies on ACTH-reactive IgG autoAbs and human aggressive behavior.

Year Title Authors Conclusive comments
2018 “Autoantibodies reactive to ACTH can alter cortisol secretion in both aggressive and non-aggressive humans”. Vaeroy, et al (34) “ACTH-reactive plasmatic IgGs exhibit differential epitope preference in controls and violently aggressive subjects. IgGs can modulate ACTH-induced cortisol secretion” and the stress response. There were different epitopes between non-aggressive and violent criminals
2013 “Corticotrophin (ACTH)-reactive immunoglobulins in adolescents in relation to antisocial behavior and stress-induced cortisol response”. Schaefer, et al. (83) “High total and free ACTH IgG are associated with higher antisocial behavior scores in boys. In girls, antisocial behavior is associated with low free ACTH IgG levels. Stress-induced cortisol release is associated with free ACTH IgG in boys and with total ACTH IgG in girls. ACTH IgG levels are related to antisocial behavior and HPA axis response to stress in adolescents”.
2006 “Aggressive behavior linked to corticotrophin-reactive autoantibodies”. Fetissov, et al. (33). “High levels of ACTH-reactive autoAbs and altered levels of oxytocin- and vasopressin-reactive autoAbs in aggressors may interfere with the neuroendocrine mechanisms of stress and motivated behavior. A new biological mechanism of human aggressive behavior” (33) is suggested.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904880/


More information: Neural mechanisms of aggression across species. Nature Neuroscience(2020). DOI: 10.1038/s41593-020-00715-2.

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