Research project Anger Management: Neuronal Network Organization, Plasticity and Sex-Specificity in Aggression
No man (or woman) is an island. We cooperate, we fight, we make friends and we raise our young; all selected from a repertoire of social behaviours that afford us opportunities for learning, access to food and possibilities to reproduce. To understand how social behavior is organized constitutes a critical step towards understanding ourselves.
Aggression offers an instructive and experimentally tractable example of social behaviour, prevalent among humans and near-ubiquitous across animal species, which can have serious consequences for both individuals and society. Like all behaviours, aggression emerges from the brain, where information about the world around us and the internal state of our body are integrated to trigger appropriate autonomic and muscle movement responses. Early clini- cal observations (see McEllistream, 2004) described the development of rage in patients with tumours in the hypothalamus, the evolutionarily conserved region that drives most instinctive behaviours.
Project description
Systematic experimental studies mimicking these lesions identified a diffuse rostrocaudal hypothalamic column, named the hypothalamic attack area (HAA), which upon stimulation caused cats to plunge into attack (Chi & Flynn, 1971; Kruk et al., 1983). While ethological studies made great strides in elucidating the behavioural expression of aggression (e.g. Tinbergen, 1968), the HAA remained a largely nebulous concept, and a brain circuit- based model of aggression stayed out of reach. Following the introduction of genetically driven tools in neuroscience, the field has undergone a revolution, including the demonstration that specific neurons in the ventrolateral sector of the mouse ventromedial hypothalamic nucleus (VMHvl) can drive aggression (Lin et al., 2011; Lee et al., 2014) in a manner that is scalable and can induce a switch from reproductive mounting. Subsequent studies by other investigators have refined our understanding of these cells, implicating them also in social control and sex- specific aggression (Yang et al., 2013; Hashikawa et al., 2017), but few have expanded beyond this particular subnucleus. The greater functional network that the VMHvl ties into has largely remained unknown, including its up-stream source of stimulation.
Recently, we identified a key entry node in the central network for aggression, formed by glutamatergic dopamine-transporter-expressing neurons in the mouse hypothalamic ventral premammillary nucleus (PMvDAT neurons; Stagkourakis et al., 2018; Fig. 1), located within the classical HAA. These cells can be optogenetically activated to drive intermale aggression (and inhibited or ablated with the opposite result). Through regenerative membrane currents and intra- and internuclear recurrent excitatory connections, PMvD A T neurons convert a brief stimulation into long-lasting discharge, providing an explanation for so-called behavioural “hysteresis” in aggression. By parallel projections to downstream nuclei PMvDAT neurons con- stitute an early organizing hub that can coordinately recruit separate brain targets to generate both attack behaviour and the reward that reinforces aggression, respectively. Finally, we have shown that brief manipulation of PMvDAT activity causes an enduring shift in the hierarchical relationship between a dominant and a subordinate male, implicating for the first time an “aggression nucleus” in determining social rank.
The establishment of this anatomical framework is a key step towards understanding social behaviour, but is in itself insufficient to explain the dynamic features of e.g. aggression. Indeed, while commonly discussed in terms of stereotyped, innate behaviour and the expression of a largely fixed personality, we also know that aggressive attacks have their own internal dynamics; they are triggered by context, and they start and stop at some point. The probability of aggression varies greatly across individuals, and even in a given individual across lifetime. These aspects of instinctive behaviours are crucially important, and have significant implications for the management of pathological aggression. Yet, the brain mechanisms that structure aggres- sion are still poorly understood.
Project members
Project managers
Christian Broberger
Professor of Neurochemistry
