Ominous odors: olfactory control of instinctive fear and aggression in mice

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Aggression and fear are often thought to be distinct behavioral states, yet they share several common output responses. In the mouse, both can be initiated by specialized odor cues. How these cues signal through the olfactory system to promote behavior is largely unknown. Recent experiments have started to uncover the relevant signaling ligands, chemosensory receptors, and responsive sensory neurons that together enable the precise manipulation of behaviorally relevant neural circuits. Moreover, the use of molecular genetics and new experimental strategies has begun to reveal how the central nervous system processes olfactory information to initiate aggression and fear. A sensory-initiated comparative study of these two fundamental threat reactions promises to offer new mechanistic insight.

Highlights

► Olfactory cues promote innate fear and aggression. ► Candidate aggression and fear promoting odorant receptors have been identified. ► Overlapping and distinct brain regions mediate innate threat behaviors. ► Genetics underlying innate threat responses may offer mechanistic insight.

Introduction

Animals constantly encounter threats. Whether the menace is a competitor of the same species or a hungry predator, initiating an appropriate aggressive or fearful response increases the individual's chance of survival and reproduction. These critical behaviors are displayed similarly across species, which suggests that they are generated by evolutionarily conserved neural mechanisms, as Darwin first recognized well over a century ago [1]. Decades later, Cannon summarized the intricate relationship between the two main threat response states, fear and aggression, as ‘fight or flight’ [2]. Even though both fear and aggression have been extensively studied [3], their underlying neural mechanisms remain largely unknown.

Fighting or fleeing may be promoted by stimuli that have been previously associated with threat or by specialized cues that have intrinsic meaning. Associative fear has been intensively studied [4]. This paradigm has two distinct facets: the generation and recall of a memory as well as the display of fear. Innate fear presents an alternate and simplified model to focus studies on behavioral output. Olfactory cues command instinctive behavior with especially high probability in a wide variety of animals [5, 6, 7, 8]. The mouse detects specialized odorants emitted by conspecifics and heterospecifics, termed pheromones and kairomones, respectively, which are sufficient to robustly trigger the release of innate fearful and aggressive behaviors [8, 9]. Thus, olfaction can be experimentally leveraged to control, manipulate, and investigate the downstream neural circuits and mechanisms that promote innate behavior.

Fear and aggression are each complex behavioral states that have proven difficult to ‘solve’ independently. However, when considered together, their similarities and differences may provide mechanistic understanding (Figure 1). At the circuit level, both require an intact amygdala and hypothalamus [10, 11]. Through neuroendocrine modulation, both tip the autonomic balance to sympathetic domination. At the level of motor output the two behavioral states may even seamlessly integrate, as when a cornered animal suddenly turns ‘fear into fury’ [2]. However, the study of fear and aggression is often approached separately because of numerous differences in output: aggression is offensive (but see [12] for a more detailed discussion), fear is defensive; aggression promotes piloerection and rearing to increase apparent size, fear results in freezing and huddling to dissuade attention. Furthermore, fear and aggression are under differential developmental control. For example, territorial aggression is not elicited before the onset of puberty, whereas predator odor induces fear in juveniles [13, 14]. These similarities and differences provide a comparative framework to identify the common neural correlates that enable mobilization to threats, as well as the particular mechanisms that distinguish their separate but related motor patterns.

Section snippets

Specialized odor cues promote fear and aggression in the mouse

Almost any odorant can be conditioned to elicit fear or aggression. In addition, the mouse detects a subset of specialized odors that elicit behavior without prior associative conditioning. While the sources of many of these odorants are known, such as male mouse urine or predator excretions, the identities of most of the bioactive ligands remain unidentified. The ability of these cues to evoke aggressive and fearful responses across individuals without previous experience and learning

Circuits mediating aggressive and fearful behaviors: overlapping and distinct

Aggressive and fearful behaviors are complex motor sequences that typically employ the coordination of multiple muscle groups, and yet they are highly stereotyped across mice [11, 29], implying the existence of ‘hard-wiring’ to tie the coordinated actions together. While recent work has revealed many of the details of associative fear circuits [4, 30, 31, 32, 33], the identification of the neurons in the central nervous system that are necessary and sufficient for instinctive fear and

Genetic and molecular control of fear and aggression

Many of the brain regions implicated in fear and aggression are functionally and molecularly heterogeneous. The absence of methods to disentangle them has impeded a mechanistic study of the microcircuits involved. However, knowledge of the developmental mechanisms and neuromodulatory influences underlying innate aggression and fear may be exploited to dissect and delineate the relevant neural circuits with genetic techniques. Indeed, this strategy has been elegantly demonstrated in studies of

Concluding remarks

Even in a simplified experimental environment, a mouse faces an uncertain and complicated world, and thus any behavior may be viewed as flexible, probabilistic, and dynamic. Although the abovementioned genetic approaches offer a clear entry point to deconstruct the relevant neural circuits, it is worth noting that a large body of work has suggested that additional molecular and neuromodulatory sources [10, 56, 57, 58, 59] and even the birth of new olfactory cells [60] contribute to the control

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank C. Dulac, F. Papes, and N. Shah for helpful comments on the text. LS is supported by grants from the NIH-NIDCD, Ellison Medical Foundation, and Skaggs Trust.

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