Faculty Bibliography

In many vertebrate species, certain individuals will seek out opportunities for aggression, even in the absence of threat-provoking cues. Although several brain areas have been implicated in the generation of attack in response to social threat, little is known about the neural mechanisms that promote self-initiated or 'voluntary' aggression-seeking when no threat is present. To explore this directly, we utilized an aggression-seeking task in which male mice self-initiated aggression trials to gain brief and repeated access to a weaker male that they could attack. In males that exhibited rapid task learning, we found that the ventrolateral part of the ventromedial hypothalamus (VMHvl), an area with a known role in attack, was essential for aggression-seeking. Using both single-unit electrophysiology and population optical recording, we found that VMHvl neurons became active during aggression-seeking and that their activity tracked changes in task learning and extinction. Inactivation of the VMHvl reduced aggression-seeking behavior, whereas optogenetic stimulation of the VMHvl accelerated moment-to-moment aggression-seeking and intensified future attack. These data demonstrate that the VMHvl can mediate both acute attack and flexible seeking actions that precede attack.

Aggression is a prevalent behavior in the animal kingdom that is used to settle competition for limited resources. Given the high risk associated with fighting, the central nervous system has evolved an active mechanism to modulate its expression. Lesioning the lateral septum (LS) is known to cause "septal rage," a phenotype characterized by a dramatic increase in the frequency of attacks. To understand the circuit mechanism of LS-mediated modulation of aggression, we examined the influence of LS input on the cells in and around the ventrolateral part of the ventromedial hypothalamus (VMHvl)-a region required for male mouse aggression. We found that the inputs from the LS inhibited the attack-excited cells but surprisingly increased the overall activity of attack-inhibited cells. Furthermore, optogenetic activation of the projection from LS cells to the VMHvl terminated ongoing attacks immediately but had little effect on mounting. Thus, LS projection to the ventromedial hypothalamic area represents an effective pathway for suppressing male aggression.

The ventromedial hypothalamus (VMH) was thought to be essential for coping with threat, although its circuit mechanism remains unclear. To investigate this, we optogenetically activated steroidogenic factor 1 (SF1)-expressing neurons in the dorsomedial and central parts of the VMH (VMHdm/c), and observed a range of context-dependent somatomotor and autonomic responses resembling animals' natural defensive behaviors. By activating independent pathways emanating from the VMHdm/c, we demonstrated that VMHdm/c projection to the dorsolateral periaqueductal gray (dlPAG) induces inflexible immobility, while the VMHdm/c to anterior hypothalamic nucleus (AHN) pathway promotes avoidance. Consistent with the behavior changes induced by VMH to AHN pathway activation, direct activation of the AHN elicited avoidance and escape jumping, but not immobility. Retrograde tracing studies revealed that nearly 50% of PAG-projecting VMHdm/c neurons send collateral projection to the AHN and vice versa. Thus, VMHdm/c neurons employ a one-to-many wiring configuration to orchestrate multiple aspects of defensive behaviors.

The ventromedial hypothalamus, ventrolateral area (VMHvl) was identified recently as a critical locus for inter-male aggression. Optogenetic stimulation of VMHvl in male mice evokes attack toward conspecifics and inactivation of the region inhibits natural aggression, yet very little is known about its underlying neural activity. To understand its role in promoting aggression, we recorded and analyzed neural activity in the VMHvl in response to a wide range of social and nonsocial stimuli. Although response profiles of VMHvl neurons are complex and heterogeneous, we identified a subpopulation of neurons that respond maximally during investigation and attack of male conspecific mice and during investigation of a source of male mouse urine. These "male responsive" neurons in the VMHvl are tuned to both the inter-male distance and the animal's velocity during attack. Additionally, VMHvl activity predicts several parameters of future aggressive action, including the latency and duration of the next attack. Linear regression analysis further demonstrates that aggression-specific parameters, such as distance, movement velocity, and attack latency, can model ongoing VMHvl activity fluctuation during inter-male encounters. These results represent the first effort to understand the hypothalamic neural activity during social behaviors using quantitative tools and suggest an important role for the VMHvl in encoding movement, sensory, and motivation-related signals.

The hypothalamus was first implicated in the classic "fight or flight" response nearly a century ago, and since then, many important strides have been made in understanding both the circuitry and the neural dynamics underlying the generation of these behaviors. In this review, we will focus on the role of the hypothalamus in aggression, paying particular attention to recent advances in the field that have allowed for functional identification of relevant hypothalamic subnuclei. Recent progress in this field has been aided by the development of new techniques for functional manipulation including optogenetics and pharmacogenetics, as well as advances in technology used for chronic in vivo recordings during complex social behaviors. We will examine the role of the hypothalamus through the complimentary lenses of (1) loss of function studies, including pharmacology and pharmacogenetics; (2) gain of function studies, including specific comparisons between results from classic electrical stimulation studies and more recent work using optogenetics; and (3) neural activity, including both immediate early gene and awake-behaving recordings. Lastly, we will outline current approaches to identifying the precise role of the hypothalamus in promoting aggressive motivation and aggressive action.

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.

Natural odorants are complex mixtures of diverse chemical compounds. Monomolecular odorants are represented in the main olfactory bulb by distinct spatial patterns of activated glomeruli. However, it remains unclear how individual compounds contribute to population representations of natural stimuli, which appear to be unexpectedly sparse. We combined gas chromatography and intrinsic signal imaging to visualize glomerular responses to natural stimuli and their fractionated components. While whole stimuli activated up to 20 visible glomeruli, each fractionated component activated only one or few glomeruli, and most glomeruli were activated by only one component. Thus, responses to complex mixtures reflected activation by multiple components, with each contributing only a small part of the overall representation. We conclude that the population response to a complex stimulus is largely the sum of the responses to its individual components, and activation of an individual glomerulus independently signals the presence of a specific component.

Mammalian urine releases complex mixtures of volatile compounds that are used in reproduction, territoriality and conspecific recognition. To understand how such complex mixtures are represented in the main olfactory bulb, we analysed the electrophysiological responses of individual mitral cells to volatile compounds in mouse urine. In both males and females, urine volatile compounds evoke robust responses in a small subset of mitral cells. Fractionation of the volatile compounds using gas chromatography showed that out of the hundreds of compounds present, mitral cells are activated by single compounds. One cohort of mitral cells responded exclusively to male urine; these neurons were activated by (methylthio)methanethiol, a potent, previously unknown semiochemical present only in male urine. When added to urine, synthetic (methylthio)methanethiol significantly enhances urine attractiveness to female mice. We conclude that mitral cells represent natural odorant stimuli by acting as selective feature detectors, and that their activation is largely independent of the presence of other components in the olfactory stimulus.