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The study of behaviour is dominated by two approaches. On the one hand, ethologists aim to understand how behaviour promotes adaptation to natural contexts. On the other, neuroscientists aim to understand the molecular, cellular, circuit and psychological origins of behaviour. These two complementary approaches must be combined to arrive at a full understanding of behaviour in its natural setting. However, methodological limitations have restricted most neuroscientific research to the study of how discrete sensory stimuli elicit simple behavioural responses under controlled laboratory conditions that are only distantly related to those encountered in real life. Fortunately, the recent advent of neural monitoring and manipulation tools adapted for use in freely behaving animals has enabled neuroscientists to incorporate naturalistic behaviours into their studies and to begin to consider ethological questions. Here, we examine the promises and pitfalls of this trend by describing how investigations of rodent fear, aggression and dominance behaviours are changing to take advantage of an ethological appreciation of behaviour. We lay out current impediments to this approach and propose a framework for the evolution of the field that will allow us to take maximal advantage of an ethological approach to neuroscience and to increase its relevance for understanding human behaviour., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. European Molecular Biology Laboratory, under exclusive licence to Springer Nature Limited.)

In rodents, innate and learned fear of predators depends on the medial hypothalamic defensive system, a conserved brain network that lies downstream of the amygdala and promotes avoidance via projections to the periaqueductal gray. Whether this network is involved in primate fear remains unknown. To address this, we provoked flight responses to a predator (moving snake) in the marmoset monkey under laboratory conditions. We combined c-Fos immunolabeling and anterograde/retrograde tracing to map the functional connectivity of the ventromedial hypothalamus, a core node in the medial hypothalamic defensive system. Our findings demonstrate that the ventromedial hypothalamus is recruited by predator exposure in primates and that anatomical connectivity of the rodent and primate medial hypothalamic defensive system are highly conserved.

The ventromedial hypothalamus is a central node of the mammalian predator defense network. Stimulation of this structure in rodents and primates elicits abrupt defensive responses, including flight, freezing, sympathetic activation, and panic, while inhibition reduces defensive responses to predators. The major efferent target of the ventromedial hypothalamus is the dorsal periaqueductal gray (dPAG), and stimulation of this structure also elicits flight, freezing, and sympathetic activation. However, reversible inhibition experiments suggest that the ventromedial hypothalamus and periaqueductal gray play distinct roles in the control of defensive behavior, with the former proposed to encode an internal state necessary for the motivation of defensive responses, while the latter serves as a motor pattern initiator. Here, we used electrophysiological recordings of single units in behaving male mice exposed to a rat to investigate the encoding of predator fear in the dorsomedial division of the ventromedial hypothalamus (VMHdm) and the dPAG. Distinct correlates of threat intensity and motor responses were found in both structures, suggesting a distributed encoding of sensory and motor features in the medial hypothalamic-brainstem instinctive network. SIGNIFICANCE STATEMENT Although behavioral responses to predatory threat are essential for survival, the underlying neuronal circuits remain undefined. Using single unit in vivo electrophysiological recordings in mice, we have identified neuronal populations in the medial hypothalamus and brainstem that encode defensive responses to a rat predator. We found that both structures encode both sensory as well as motor aspects of the behavior although with different kinetics. Our findings provide a framework for understanding how innate sensory cues are processed to elicit adaptive behavioral responses to threat and will help to identify targets for the pharmacological modulation of related pathologic behaviors., (Copyright © 2020 the authors.)

How fear is represented in the brain has generated a lot of research attention, not only because fear increases the chances for survival when appropriately expressed but also because it can lead to anxiety and stress-related disorders when inadequately processed. In this review, we summarize recent progress in the understanding of the neural circuits processing innate fear in rodents. We propose that these circuits are contained within three main functional units in the brain: a detection unit, responsible for gathering sensory information signaling the presence of a threat; an integration unit, responsible for incorporating the various sensory information and recruiting downstream effectors; and an output unit, in charge of initiating appropriate bodily and behavioral responses to the threatful stimulus. In parallel, the experience of innate fear also instructs a learning process leading to the memorization of the fearful event. Interestingly, while the detection, integration, and output units processing acute fear responses to different threats tend to be harbored in distinct brain circuits, memory encoding of these threats seems to rely on a shared learning system., (© 2016 Silva et al.; Published by Cold Spring Harbor Laboratory Press.)

The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ according to the nature of the threat, with separate pathways having been identified for predator, conspecific and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predators. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of the VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in the VMHdm is required for both the acquisition and recall of predator fear memory, whereas that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The neural circuits mediating fear to naturalistic threats are poorly understood. We found that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region that has been implicated in feeding, sex and aggression, are essential for predator and social fear in mice. Our results establish a critical role for VMH in fear and have implications for selective intervention in pathological fear in humans.

The central nucleus of the amygdala (CeA) serves as a major output of this structure and plays a critical role in the expression of conditioned fear. By combining cell- and tissue-specific pharmacogenetic inhibition with functional magnetic resonance imaging (fMRI), we identified circuits downstream of CeA that control fear expression in mice. Selective inhibition of a subset of neurons in CeA led to decreased conditioned freezing behavior and increased cortical arousal as visualized by fMRI. Correlation analysis of fMRI signals identified functional connectivity between CeA, cholinergic forebrain nuclei, and activated cortical structures, and cortical arousal was blocked by cholinergic antagonists. Importantly, inhibition of these neurons switched behavioral responses to the fear stimulus from passive to active responses. Our findings identify a neural circuit in CeA that biases fear responses toward either passive or active coping strategies., (2010 Elsevier Inc. All rights reserved.)

Serotonin 1A receptor knockout (5-HT1AR KO) mice exhibit increased behavioral inhibition in conflict tests. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests. First, we considered whether behavioral inhibition in these knockout mice is a consequence of reduced exploratory motivation. The knockout mice engage in normal exploration during a light-dark test and normal exploration of a novel object in a familiar environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Second, we tested whether these mice exhibit increased behavioral inhibition in response to any aversive cues, or whether this response depends on cue modality. Knockout mice respond normally to discrete aversive cues in the Vogel lick-suppression test, arguing that their phenotype is restricted to conflict tests based on complex or spatial aversive cues. Third, to probe the processing of spatial aversive cues, we assessed fear conditioning to contextual cues. After contextual fear conditioning, knockout and wild-type (WT) mice express freezing responses when exposed to the training environment. However, when placed in an ambiguous environment containing both conditioned and novel cues, the freezing response of knockout mice does not significantly decrease as it does in WT mice, suggesting that the knockout fear response is biased toward threatening cues. We hypothesize that this inappropriate generalization of fearful behavior to a context containing both fearful and neutral stimuli, a phenomenon that occurs in a subset of human anxiety disorders such as panic disorder and post-traumatic stress disorder, underlies the anxiety phenotype of 5-HT1AR KO mice., (Neuropsychopharmacology (2006) 31, 101-111. doi:10.1038/sj.npp.1300774; published online 25 May 2005.)