Foundational Work on “Emotions” in Fruit Flies

SUMMARY The neural circuit mechanisms underlying emotion states remain poorly understood. Drosophila offers powerful genetic approaches for dissecting neural circuit function, but whether flies exhibit emotion like behaviors has not been clear. We recently proposed that model organisms may express internal states displaying ‘‘emotion primitives,’’ which are general characteristics common to different emotions, rather than specific anthropomorphic emotions such as ‘‘fear’’ or ‘‘anxiety.’’

Repetitive stimuli promoted graded (scalable) and persistent increases in locomotor velocity and hopping, and occasional freezing. The stimulus also dispersed feeding flies from a food resource, suggesting both negative valence and context generalization. Strikingly, there was a significant delay before the flies returned to the food following stimulus-induced dispersal, suggestive of a slowly decaying internal defensive state.

The length of this delay was increased when more stimuli were delivered for initial dispersal. These responses can be mathematically modeled by assuming an internal state that behaves as a leaky integrator of stimulus exposure. Our results suggest that flies’ responses to repetitive visual threat stimuli express an internal state exhibiting canonical emotion primitives, possibly analogous to fear in mammals.

Emotions are internal states that are expressed by specific behaviors and that modulate perception, cognition, and communication…. An alternative approach to identifying instances of emotional expression, which does not depend on anthropocentric homologies, is to establish general features of emotion states, or ‘‘emotion primitives,’’ which apply both to different emotions in a species and to emotions across phylogeny.

One can then search for behaviors that exhibit evidence of such emotion primitives in model organisms. We have recently suggested that such emotion primitives may include the following features or dimensions: persistence following stimulus cessation, scalability (a graded nature of the response), valence, generalization to different contexts, and stimulus degeneracy (different stimuli can evoke the same behavior by induction of a common emotion state). Although these primitives are features of internal emotion states, they should be reflected in the properties of behaviors that express such states.

Evidence of some of these properties in Drosophila has been provided using different behavioral paradigms. For example, flies are capable of entering states of persistent arousal, as evidenced by sustained locomotor activity and/or neural activity. In some cases, these states exhibit ‘‘scalability’’: the strength of the behavioral response scales in proportion to the number of stimuli or intensity of the stimulus.

  • Drosophila can be conditioned using either appetitive or aversive stimuli (and both ethanol and sexual experience appear to be rewarding to them), demonstrating that these animals can represent valence internally.
  • Flies that have been rejected by mating partners consume more ethanol, suggesting that rejection induces a state that generalizes to promote ethanol reward seeking.
  • In addition, flies have been shown to exhibit a ‘‘learned helplessness’’ response to an uncontrollable stressor, similar to rodents.

..flies show a cumulative response to successive stimulus presentations, provided that the inter-stimulus interval is sufficiently short. This property can be modeled by an internal state that behaves as a ‘‘leaky’’ integrator…

DISCUSSION Defensive responses to threats involve both rapid, reflex reactions and (in higher organisms) more sustained, state-dependent ‘‘integrative’’ behavioral responses. The former are likely to have evolved before the latter, as they are exhibited even by unicellular organisms. The latter type of response can reflect an internal arousal or emotion state; humans subjectively experience and report such a threat state as ‘‘fear’’ or ‘‘anxiety’’.

When such integrative responses to threats first began to emerge in evolution and whether they involve neural circuits overlapping with, or distinct from, those mediating reflexive responses is not known. Flies are well known to exhibit rapid, reflexive jump responses to a single presentation of a looming shadow. However, whether they are also capable of exhibiting longer-term, integrated responses to repetitive shadow stimuli has not been investigated previously. Here, we describe a novel behavioral assay, called ReVSA, in which flies can be exposed to repeated presentations of an aversive shadow stimulus in an enclosed arena, preventing escape.

Under these conditions, we observe features of the behavioral response that are suggestive of an internal state exhibiting multiple emotion primitives [3]. First, the response exhibits persistence: flies exposed to repeated shadow stimuli remain active for tens of seconds after the stimulus has terminated. Second, the response exhibits a negative valence, in that it interferes with feeding and that flies avoid the moving shadow in a directional manner. Third, the response generalizes across multiple settings (freely moving flies on plastic; stationary feeding flies on a food patch). Fourth, the response exhibits ‘‘stimulus degeneracy’’: a similar persistent increase in locomotor hyperactivity can be elicited by repeated presentation of a mechanical startle stimulus [20]; moreover, flies habituated to the shadow stimulus can be dishabituated by a mechanical startle. Finally, and most importantly, the behavioral response scales with stimulus number and frequency. These behavioral responses suggest that the response to multiple shadows reflects an underlying causal internal state characterized by the emotion primitives described above.

This inferred state can be mathematically modeled by assuming a shadow-induced labile quantity that accumulates with repeated shadow stimuli—in other words, a leaky integrator of shadow exposure…First, in Lorenz’s metaphor the ‘‘drive’’- filled vessel did not leak; it simply discharged its contents when a given behavior was released. Second, the level of drive was internally generated, whereas in the present case, it is generated by an external sensory (visual) stimulus.

The circuit-level mechanisms underlying such a leaky integrator remain to be investigated; multiple implementations are possible, including both network-based and molecular instantiations. Neuromodulators, such as biogenic amines or neuropeptides, are attractive candidates for the latter class of mechanism because they could encode scalability by their concentration and persistence by their rate of clearance. Indeed, across phylogeny, some neuropeptides are strikingly well conserved in their behavioral roles. Biogenic amines such as dopamine also play a conserved role in arousal. Drosophila as a genetic system is particularly well suited to search for such molecular mechanisms. Leaky integrators can also be instantiated by a number of circuit-level mechanisms. Improvements in population measurements of neural activity in head-fixed flies may aid in their discovery. Visual stimuli are vastly preferable to mechanical (startle) stimuli for such studies because the stimulus itself does not physically perturb the flies. What is the adaptive value of a system that integrates multiple threat stimuli to produce a scalable defensive response? Isn’t it safer for the fly simply to jump away as soon as it sees an overhead shadow? That may be the case for a well-fed fly, but starved flies engaged in feeding must make a cost-benefit decision: premature flight from a resource deprives the animals of food and consumes energy; conversely, delayed escape renders the animals increasingly vulnerable to predation. The ability to encode an integrated, scalable internal representation of the history of recent threats (which may share some features with working memory) and to use that representation to select behavioral responses and to tune their intensity may be adaptive in uncertain environments…

The behavioral response of flies in the ReVSA assay exhibits multiple properties consistent with the expression of a persistent, internal defensive state, possibly an evolutionary precursor to the emotion that humans subjectively experience as ‘‘fear.’’ Interestingly, recent studies in mice have shown that optogenetic stimulation of the ventromedial hypothalamus can elicit defensive behaviors exhibiting a similar set of properties [43, 44]. The establishment of this paradigm in Drosophila opens the way to a mechanistic dissection of the molecular and circuit-level implementation of this state, in a genetically powerful invertebrate species. Such mechanistic studies should help to resolve the long-standing issue of the causal relationship between behavior and internal emotion states and may also shed light on the phylogenetic origins and continuity of emotion.

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