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Abstract

Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this ‘survival circuit’ has been implicated in anxiety-related disorders.
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... The importance of the periaqueductal grey (PAG) in regulating the execution of fear responses has been well demonstrated, both by seminal studies from the 1980s and 1990s [4, 5, 23, 24,, 60, 67, 86], and by more recent work investigating fear circuitry [2,18,22,36,41,59,56,57,74,68,75]. The PAG receives and integrates inputs from many brain regions, including the hypothalamus [74], amygdala [39,68], medial-prefrontal cortex [59], and superior colliculus [22], resulting in the expression of flight-or-freeze fear responses. ...
... The importance of the periaqueductal grey (PAG) in regulating the execution of fear responses has been well demonstrated, both by seminal studies from the 1980s and 1990s [4, 5, 23, 24,, 60, 67, 86], and by more recent work investigating fear circuitry [2,18,22,36,41,59,56,57,74,68,75]. The PAG receives and integrates inputs from many brain regions, including the hypothalamus [74], amygdala [39,68], medial-prefrontal cortex [59], and superior colliculus [22], resulting in the expression of flight-or-freeze fear responses. The role of the PAG in contributing to the pathophysiology of ASD has not yet been elucidated. ...
... We hypothesised that the increase in shock-elicited flight response in Nlgn3 −/y rats is due to altered physiological properties in the periaqueductal grey (PAG), a midbrain region previously shown to control fear expression [2,18,22,36,39,41,56,57,68,75]. ...
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Abstract Background: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however diferences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cel- lular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods: This study uses a range of behavioural tests to understand diferences in fear response behaviour in Nlgn3−/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in fight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-feld potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3−/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results: We observed that, unlike the wildtype, Nlgn3−/y rats are more likely to response with fight rather than freez- ing in threatening situations. Electrophysiological fndings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3−/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability com- pared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufced to evoke fight behav- iour in Nlgn3−/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations: Our fndings do not examine what specifc cell type in the PAG is likely responsible for these pheno- types. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the frst few years of life.
... The importance of the periaqueductal grey (PAG) in regulating the execution of fear responses has been well demonstrated, both by seminal studies from the 1980s and 1990s [4, 5, 23, 24,, 60, 67, 86], and by more recent work investigating fear circuitry [2,18,22,36,41,59,56,57,74,68,75]. The PAG receives and integrates inputs from many brain regions, including the hypothalamus [74], amygdala [39,68], medial-prefrontal cortex [59], and superior colliculus [22], resulting in the expression of flight-or-freeze fear responses. ...
... The importance of the periaqueductal grey (PAG) in regulating the execution of fear responses has been well demonstrated, both by seminal studies from the 1980s and 1990s [4, 5, 23, 24,, 60, 67, 86], and by more recent work investigating fear circuitry [2,18,22,36,41,59,56,57,74,68,75]. The PAG receives and integrates inputs from many brain regions, including the hypothalamus [74], amygdala [39,68], medial-prefrontal cortex [59], and superior colliculus [22], resulting in the expression of flight-or-freeze fear responses. The role of the PAG in contributing to the pathophysiology of ASD has not yet been elucidated. ...
... We hypothesised that the increase in shock-elicited flight response in Nlgn3 −/y rats is due to altered physiological properties in the periaqueductal grey (PAG), a midbrain region previously shown to control fear expression [2,18,22,36,39,41,56,57,68,75]. ...
Article
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Background Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3 . Methods This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3 −/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3 −/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results We observed that, unlike the wildtype, Nlgn3 −/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3 −/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3 −/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions We describe altered fear responses in Nlgn3 −/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD.
... Alterations in CPM reflect an imbalance between facilitatory and inhibitory descending pain pathways to the DHSC, but the underlying neural circuits remain largely unknown (3,12). Recent studies have identified specific neural circuits in the PAG and the RVM promoting either pain inhibition or pain facilitation (13)(14)(15)(16)(17). These circuits involve monoaminergic neurons that are also the target of the more efficient current medication against chronic pain, namely, the serotonin-noradrenaline reuptake inhibitors (SNRIs). ...
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Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.
... However, another hypothesis for how deimatic behaviours work is that they elicit fear responses because a stimulus is recognised and misclassified as a potential threat (Skelhorn et al., 2016). Phasic fear is a state of apprehension elicited by a specific and imminent perceived threat, that dissipates once the danger is removed (Davis et al., 2010;Miles, Davis & Walker, 2011;Sato & Yamawaki, 2014;Tovote et al., 2016). It produces responses that can be rapid, occurring within 100 ms of stimulus onset, and could mediate observers' responses to deimatic behaviour (Pomeroy & Heppner, 1977;Åsli & Flaten, 2012). ...
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Deimatic behaviours, also referred to as startle behaviours, are used against predators and rivals. Although many are spectacular, their proximate and ultimate causes remain unclear. In this review we aim to synthesise what is known about deimatic behaviour and identify knowledge gaps. We propose a working hypothesis for deimatic behaviour, and discuss the available evidence for the evolution, ontogeny, causation, and survival value of deimatic behaviour using Tinbergen's Four Questions as a framework. Our overarching aim is to direct future research by suggesting ways to address the most pressing questions in this field.
... Those structures included the mPFC, the lateral septum, the preoptic area, the ventromedial hypothalamic nucleus, and the zona incerta. This is in line with previous findings (Beart et al., 1994;Beitz, 1989;Tovote et al., 2016, for review see Silva and McNaughton, 2019). Electrical stimulation of the prelimbic cortex in rats has been shown to trigger vocalizations (Bennett et al., 2019). ...
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Although mice mostly communicate in the ultrasonic range, they also emit audible calls. We demonstrate that mice selectively bred for high anxiety-related behavior (HAB) have a high disposition for emitting sonic calls when caught by the tail. The vocalization was unrelated to pain but sensitive to anxiolytics. As revealed by manganese-enhanced MRI, HAB mice displayed an increased tonic activity of the periaqueductal gray (PAG). Selective inhibition of the dorsolateral PAG not only reduced anxiety-like behavior but also completely abolished sonic vocalization. Calls were emitted at a fundamental frequency of 3.8 kHz, which falls into the hearing range of numerous predators. Indeed, playback of sonic vocalization attracted rats if associated with a stimulus mouse. If played back to HAB mice, sonic calls were repellent in the absence of a conspecific but attractive in their presence. Our data demonstrate that sonic vocalization attracts both predators and conspecifics depending on the context.
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Chapter
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