Innate Defensive Behaviors Research Articles

Age-associated alteration of innate defensive response to a looming stimulus and brain functional connectivity pattern in mice

Innate defensive behaviors are essential for species survival. While these behaviors start to develop early in an individual’s life, there is still much to be understood about how they evolve with advancing age. Considering that aging is often accompanied by various cognitive and physical declines, we tested the hypothesis that innate fear behaviors and underlying cerebral mechanisms are modified by aging. In our study we investigated this hypothesis by examining how aged mice respond to a looming visual threat compared to their younger counterparts. Our findings indicate that aged mice exhibit a different fear response than young mice when facing this imminent threat. Specifically, unlike young mice, aged mice tend to predominantly display freezing behavior without seeking shelter. Interestingly, this altered behavioral response in aged mice is linked to a distinct pattern of functional brain connectivity compared to young mice. Notably, our data highlights a lack of a consistent brain activation following the fear response in aged mice, suggesting that innate defensive behaviors undergo changes with aging.

Repeated presentation of visual threats drives innate fear habituation and is modulated by environmental and physiological factors.

To survive predation, animals must be able to detect and appropriately respond to predator threats in their environment. Such defensive behaviors are thought to utilize hard-wired neural circuits for threat detection, sensorimotor integration, and execution of ethologically relevant behaviors. Despite being hard-wired, defensive behaviors (i.e. fear responses) are not fixed, but rather show remarkable flexibility, suggesting that extrinsic factors such as threat history, environmental contexts, and physiological state may alter innate defensive behavioral responses. The goal of the present study was to examine how extrinsic and intrinsic factors influence innate defensive behaviors in response to visual threats. In the absence of a protective shelter, our results indicate that mice showed robust freezing behavior following both looming (proximal) and sweeping (distal) threats, with increased behavioral vigor in response to looming stimuli, which represent a higher threat imminence. Repeated presentation of looming or sweeping stimuli at short inter-trial intervals resulted in robust habituation of freezing, which was accelerated at longer inter-trial intervals, regardless of contextual cues. Finally, physiological factors such as acute stress further disrupted innate freezing habituation, resulting in a delayed habituation phenotype, consistent with a heightened fear state. Together, our results indicate that extrinsic factors such as threat history, environmental familiarity, and physiological stressors have robust and diverse effects on defensive behaviors, highlighting the behavioral flexibility in how mice respond to predator threats.

GABAergic Retinal Ganglion Cells Projecting to the Superior Colliculus Mediate the Looming-Evoked Flight Response.

The looming stimulus-evoked flight response to approaching predators is a defensive behavior in most animals. However, how looming stimuli are detected in the retina and transmitted to the brain remains unclear. Here, we report that a group of GABAergic retinal ganglion cells (RGCs) projecting to the superior colliculus (SC) transmit looming signals from the retina to the brain, mediating the looming-evoked flight behavior by releasing GABA. GAD2-Cre and vGAT-Cre transgenic mice were used in combination with Cre-activated anterograde or retrograde tracer viruses to map the inputs to specific GABAergic RGC circuits. Optogenetic technology was used to assess the function of SC-projecting GABAergic RGCs (scpgRGCs) in the SC. FDIO-DTA (Flp-dependent Double-Floxed Inverted Open reading frame-Diphtheria toxin) combined with the FLP (Florfenicol, Lincomycin & Prednisolone) approach was used to ablate or silence scpgRGCs. In the mouse retina, GABAergic RGCs project to different brain areas, including the SC. ScpgRGCs are monosynaptically connected to parvalbumin-positive SC neurons known to be required for the looming-evoked flight response. Optogenetic activation of scpgRGCs triggers GABA-mediated inhibition in SC neurons. Ablation or silencing of scpgRGCs compromises looming-evoked flight responses without affecting image-forming functions. Our study reveals that scpgRGCs control the looming-evoked flight response by regulating SC neurons via GABA, providing novel insight into the regulation of innate defensive behaviors.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice, as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Because persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we tested whether the LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors toward more passive action locking rather than escape behaviors in response to an aerial threat in both male and female mice, as well as prolonging the latency to escape responses in female mice. While this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI during late adolescence.

Modulation of TNF Release by the Innate Fear Odorant 2-Methylthiazoline Requires TRPA1-Mediated Signaling

The innate fear odorant 2-Methylthiazoline (2-MT) elicits highly robust innate fear and defensive behaviors, such as freezing, hypothermia and bradycardia via activation of transient receptor potential ankyrin 1 (TRPA1) channels. Activation of TRPA1-expressing vagus nerve fibers also regulates IL-1β induced hypothermia and reflex anti-inflammatory responses. However, it is unclear whether 2-MT can trigger an anti-inflammatory response via TRPA1 activation. Here, we demonstrate that 2-MT attenuates endotoxin-induced tumor necrosis factor (TNF) production in wild-type mice in TRPA1-dependent manner. Exposure to 2-MT induces a significant reduction in serum TNF in wild-type mice injected with endotoxin as compared to vehicle control mice (vehicle control vs. 2-MT; 1,123 ± 32.3 pg/mL vs. 714.1 ± 58.2 pg/mL; * p=0.02). However, 2-MT exposure fails to suppress endotoxin-induced TNF-release in TrpA1-knock out mice (vehicle control vs. 2-MT; 1,123 ± 32.3 vs. 948.7 ± 99.2 pg/mL; ns p=0.89). A single exposure to 2-MT during endotoxin injection also protects animals from lethal endotoxemia and significantly improves survival as compared to vehicle-exposed endotoxemic controls (vehicle control vs. single 2-MT Odor; 26.7% vs. 66.7% survival 120 hours post LPS injection). In addition, significant improvement in disease activity is observed in mice exposed to 2-MT odorant (vehicle control vs. single 2-MT Odor; disease activity: 0.5 ± 0.2 a.u. vs. 0.3 ± 0.1 a.u., * p=0.01). Collectively, these data characterize the anti-inflammatory effcacy of 2-MT and demonstrate that the modulation of TNF release by 2-MT requires TRPA1-mediated signaling. This work is supported in part by grants from NIH, NIGMS, 1R35 GM118182 to KJT and 1R01AR083159-01 to SSC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chemo- and optogenetic activation of hypothalamic Foxb1-expressing neurons and their terminal endings in the rostral-dorsolateral PAG leads to tachypnea, bradycardia, and immobility.

Foxb1 -expressing neurons occur in the dorsal premammillary nucleus (PMd) and further rostrally in the parvafox nucleus, a longitudinal cluster of neurons in the lateral hypothalamus of rodents. The descending projection of these Foxb1+ neurons end in the dorsolateral part of the periaqueductal gray (dlPAG). The functional role of the Foxb1+ neuronal subpopulation in the PMd and the parvafox nucleus remains elusive. In this study, the activity of the Foxb1+ neurons and of their terminal endings in the dlPAG in mice was selectively altered by employing chemo- and optogenetic tools. Our results show that in whole-body barometric plethysmography, hM3Dq-mediated, global Foxb1+ neuron excitation activates respiration. Time-resolved optogenetic gain-of-function manipulation of the terminal endings of Foxb1+ neurons in the rostral third of the dlPAG leads to abrupt immobility and bradycardia. Chemogenetic activation of Foxb1+ cell bodies and ChR2-mediated excitation of their axonal endings in the dlPAG led to a phenotypical presentation congruent with a 'freezing-like' situation during innate defensive behavior.

Chemo- and optogenetic activation of hypothalamic Foxb1-expressing neurons and their terminal endings in the rostral-dorsolateral PAG leads to tachypnea, bradycardia, and immobility

Foxb1 -expressing neurons occur in the dorsal premammillary nucleus (PMd) and further rostrally in the parvafox nucleus, a longitudinal cluster of neurons in the lateral hypothalamus of rodents. The descending projection of these Foxb1+ neurons end in the dorsolateral part of the periaqueductal gray (dlPAG). The functional role of the Foxb1+ neuronal subpopulation in the PMd and the parvafox nucleus remains elusive. In this study, the activity of the Foxb1+ neurons and of their terminal endings in the dlPAG in mice was selectively altered by employing chemo- and optogenetic tools. Our results show that in whole-body barometric plethysmography, hM3Dq-mediated, global Foxb1+ neuron excitation activates respiration. Time-resolved optogenetic gain-of-function manipulation of the terminal endings of Foxb1+ neurons in the rostral third of the dlPAG leads to abrupt immobility and bradycardia. Chemogenetic activation of Foxb1+ cell bodies and ChR2-mediated excitation of their axonal endings in the dlPAG led to a phenotypical presentation congruent with a ‘freezing-like’ situation during innate defensive behavior.

Lateral hypothalamic glutamatergic inputs to VTA glutamatergic neurons mediate prioritization of innate defensive behavior over feeding

The lateral hypothalamus (LH) is involved in feeding behavior and defense responses by interacting with different brain structures, including the Ventral Tegmental Area (VTA). Emerging evidence indicates that LH-glutamatergic neurons infrequently synapse on VTA-dopamine neurons but preferentially establish multiple synapses on VTA-glutamatergic neurons. Here, we demonstrated that LH-glutamatergic inputs to VTA promoted active avoidance, long-term aversion, and escape attempts. By testing feeding in the presence of a predator, we observed that ongoing feeding was decreased, and that this predator-induced decrease in feeding was abolished by photoinhibition of the LH-glutamatergic inputs to VTA. By VTA specific neuronal ablation, we established that predator-induced decreases in feeding were mediated by VTA-glutamatergic neurons but not by dopamine or GABA neurons. Thus, we provided evidence for an unanticipated neuronal circuitry between LH-glutamatergic inputs to VTA-glutamatergic neurons that plays a role in prioritizing escape, and in the switch from feeding to escape in mice.

Advances in neural circuits of innate fear defense behavior.

Fear, a negative emotion triggered by dangerous stimuli, can lead to psychiatric disorders such as phobias, anxiety disorders, and depression. Investigating the neural circuitry underlying congenital fear can offer insights into the pathophysiological mechanisms of related psychiatric conditions. Research on innate fear primarily centers on the response mechanisms to various sensory signals, including olfactory, visual, and auditory stimuli. Different types of fear signal inputs are regulated by distinct neural circuits. The neural circuits of the main and accessory olfactory systems receive and process olfactory stimuli, mediating defensive responses like freezing. Escape behaviors elicited by visual stimuli are primarily regulated through the superior colliculus and hypothalamic projection circuits. And auditory stimuli-induced responses, including escape, are mainly mediated through auditory cortex projection circuits. As for auditory stimuli, they are mainly triggered by the auditory cortical projection circuits, leading to escape and other responses. In this article, we review the research progress on the neural circuits of innate fear defensive behaviors in animals from different sensory systems, especially the projection circuits of olfactory, visual, and auditory systems, to provide references for the mechanistic study of related mental disorders.

Assessment of predation risk through conspecific cues by anuran larvae

Accurate assessment of predation risk is critical for prey survival during predator–prey interactions. Prey can assess predation risk by the presence of cues dropped by predators themselves, but they can also gather information about risk level through cues released by other prey, avoiding the hazard of being in close proximity to predators. In this study, we examine the ability of anuran larvae (Pelobates cultripes) to detect predation risk indirectly when they are in contact with conspecifics that have been recently exposed to chemical stimuli from natural predators (larvae of aquatic beetles). In a first experiment, we confirmed that larvae exposed to predator cues exhibited innate defensive behavior, indicating that they perceived the risk of predation and, thus, could potentially act as risk indicators for naïve conspecifics. In a second experiment, we observed that unexposed larvae paired with a startled conspecific adjusted their antipredator behavior, presumably by mirroring conspecifics’ behavior and/or using chemical cues from their partners as a risk information source. This cognitive ability of tadpoles to assess predation risk through conspecific cues might play an important role in their interaction with predators, facilitating the early detection of potential threats to elicit appropriate antipredator responses and increase the chances of survival.

Characterization of ventromedial hypothalamus activity during exposure to innate and conditioned threats.

In the face of imminent predatory danger, animals quickly detect the threat and mobilize key survival defensive actions, such as escape and freezing. The dorsomedial portion of the ventromedial hypothalamus (VMH) is a central node in innate and conditioned predator-induced defensive behaviours. Prior studies have shown that activity of steroidogenic factor 1 (sf1)-expressing VMH cells is necessary for such defensive behaviours. However, sf1-VMH neural activity during exposure to predatory threats has not been well characterized. Here, we use single-cell recordings of calcium transients from VMH cells in male and female mice. We show this region is activated by threat proximity and that it encodes future occurrence of escape but not freezing. Our data also show that VMH cells encoded proximity of an innate predatory threat but not a fear-conditioned shock grid. Furthermore, chemogenetic activation of the VMH increases avoidance of innate threats, such as open spaces and a live predator. This manipulation also increased freezing towards the predator, without altering defensive behaviours induced by a shock grid. Lastly, we show that optogenetic VMH activation recruited a broad swath of regions, suggestive of widespread changes in neural defensive state. Taken together, these data reveal the neural dynamics of the VMH during predator exposure and further highlight its role as a critical component of the hypothalamic predator defense system.

Neural Circuit Mechanisms Involved in Animals' Detection of and Response to Visual Threats.

Evading or escaping from predators is one of the most crucial issues for survival across the animal kingdom. The timely detection of predators and the initiation of appropriate fight-or-flight responses are innate capabilities of the nervous system. Here we review recent progress in our understanding of innate visually-triggered defensive behaviors and the underlying neural circuit mechanisms, and a comparison among vinegar flies, zebrafish, and mice is included. This overview covers the anatomical and functional aspects of the neural circuits involved in this process, including visual threat processing and identification, the selection of appropriate behavioral responses, and the initiation of these innate defensive behaviors. The emphasis of this review is on the early stages of this pathway, namely, threat identification from complex visual inputs and how behavioral choices are influenced by differences in visual threats. We also briefly cover how the innate defensive response is processed centrally. Based on these summaries, we discuss coding strategies for visual threats and propose a common prototypical pathway for rapid innate defensive responses.

Anatomical and functional study of the cuneiform nucleus: A critical site to organize innate defensive behaviors.

The cuneiform nucleus (CUN) is a midbrain structure located lateral to the caudal part of the periaqueductal gray. In the present investigation, we first performed a systematic analysis of the afferent and efferent projections of the CUN using FluoroGold and Phaseolus vulgaris leucoagglutinin as retrograde and anterograde neuronal tracers, respectively. Next, we examined the behavioral responses to optogenetic activation of the CUN and evaluated the impact of pharmacological inactivation of the CUN in both innate and contextual fear responses to a predatory threat (i.e., a live cat). The present hodologic evidence indicates that the CUN might be viewed as a caudal component of the periaqueductal gray. The CUN has strong bidirectional links with the dorsolateral periaqueductal gray (PAGdl). Our hodological findings revealed that the CUN and PAGdl share a similar source of inputs involved in integrating information related to life-threatening events and that the CUN provides particularly strong projections to brain sites influencing antipredatory defensive behaviors. Our functional studies revealed that the CUN mediates innate freezing and flight antipredatory responses but does not seem to influence the acquisition and expression of learned fear responses.

Male and female mice display consistent lifelong ability to address potential life-threatening cues using different post-threat coping strategies

BackgroundSex differences ranging from physiological functions to pathological disorders are developmentally hard-wired in a broad range of animals, from invertebrates to humans. These differences ensure that animals can display appropriate behaviors under a variety of circumstances, such as aggression, hunting, sleep, mating, and parental care, which are often thought to be important in the acquisition of resources, including territory, food, and mates. Although there are reports of an absence of sexual dimorphism in the context of innate fear, the question of whether there is sexual dimorphism of innate defensive behavior is still an open question. Therefore, an in-depth investigation to determine whether there are sex differences in developmentally hard-wired innate defensive behaviors in life-threatening circumstances is warranted.ResultsWe found that innate defensive behavioral responses to potentially life-threatening stimuli between males and females were indistinguishable over their lifespan. However, by using 3 dimensional (3D)-motion learning framework analysis, we found that males and females showed different behavioral patterns after escaping to the refuge. Specifically, the defensive “freezing” occurred primarily in males, whereas females were more likely to return directly to exploration. Moreover, there were also no estrous phase differences in innate defensive behavioral responses after looming stimuli.ConclusionsOur results demonstrate that visually-evoked innate fear behavior is highly conserved throughout the lifespan in both males and females, while specific post-threat coping strategies depend on sex. These findings indicate that innate fear behavior is essential to both sexes and as such, there are no evolutionary-driven sex differences in defensive ability.

Somatostatin-Positive Neurons in the Rostral Zona Incerta Modulate Innate Fear-Induced Defensive Response in Mice

Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival. The zona incerta (ZI) has been demonstrated to play important roles in fear learning and fear memory, as well as modulating auditory-induced innate defensive behavior. However, whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown. Here, we found that somatostatin (SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus. Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus. Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia. In addition, we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens (Re) mediated fear-like defensive behavior. Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus (SC) that projected to the Re-projecting SST-positive neurons in the rostral ZI (SC-ZIrSST-Re pathway). Together, our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.

Dopamine modulates visual threat processing in the superior colliculus via D2 receptors

SummaryInnate defensive responses, unlearned behaviors improving individuals’ chances of survival, have been found to involve the dopamine (DA) system. In the superior colliculus (SC), known for its role in defensive behaviors to visual threats, neurons expressing dopaminergic receptors of type 1 (Drd1+) and of type 2 (Drd2+) have been identified. We hypothesized that SC neurons expressing dopaminergic receptors may play a role in promoting innate defensive responses. Optogenetic activation of SC Drd2+ neurons, but not Drd1+ neurons, triggered defensive behaviors. Chemogenetic inhibition of SC Drd2+ neurons decreased looming-induced defensive behaviors, as well as pretreatment with the pharmacological Drd2+ agonist quinpirole, suggesting an essential role of Drd2 receptors in the regulation of innate defensive behavior. Input and output viral tracing revealed SC Drd2+ neurons mainly receive moderate inputs from the locus coeruleus (LC). Our results suggest a sophisticated regulatory role of DA and its receptor system in innate defensive behavior.

Hippocampal-hypothalamic circuit controls context-dependent innate defensive responses.

Preys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behavior is implemented at the circuit level. Here, using adult male mice, we show that the anterior hypothalamic nucleus (AHN) is best positioned to control this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system. Selective optogenetic stimulation and inhibition of hippocampal inputs to the AHN revealed that the HPC→AHN pathway not only mediates the contextual memory of predator threats but also controls the goal-directed escape by transmitting information about the surrounding environment. These results reveal a new mechanism for experience-dependent, top-down control of innate defensive behaviors.

Characterizing the effects of 2-phenylethylamine and coyote urine on unconditioned and conditioned defensive behaviors in adolescent male and female Long-Evans hooded rats

Predator odors provide critical information to prey species allowing them to gage potential threat via the detection of semiochemicals called kairomones. Recent reports indicate that the commercially available predator odor coyote urine (CU), and to a lesser extent 2-phenylethylamine (PEA), induce innate defensive behaviors in adult rats and mice. The aim of the present study was to see if the defense-inducing effects of CU and PEA would extend to adolescents. Specifically, we evaluated the ability of CU and PEA to induce unconditioned and conditioned defensive behavior in predator-odor naïve adolescent male and female Long-Evans hooded rats. An additional group of males were exposed to the non-predatory aversive odor formalin to control for potential general aversive properties of the odorants. The data revealed that in males, both CU and PEA, but not formalin induced measures of risk assessment, whereas CU and formalin produced avoidance of the odor source. In partial contrast, both CU and PEA produced avoidance of the odor source and increased measures of risk assessment in females. Surprisingly males failed to show any measures of defense during the cue+context conditioning test trial. In contrast, in females both odorants produced marginal effects during re-exposure to the conditioning context, with CU inducing conditioned avoidance and PEA inducing conditioned risk assessment. We conclude that commercially available CU and PEA elicit a moderate defensive profile compared to previous reports examining cat fur/skin odor in male and female adolescent rats. Future research needs to examine additional concentrations of the odorants to determine if a more robust unconditioned defensive profile (e.g., freezing) can be induced by these predator odors, and whether the defensive profile responds to standard anxiolytic drugs.

Cerebellum and Emotion Memory.

Fear is an important emotion for survival, and the cerebellum has been found to contribute not only to innate affective and defensive behavior, but also to learned fear responses. Acquisition and retention of fear conditioned bradycardia and freezing have been shown to depend on the integrity of the cerebellar vermis in rodents. There is a considerable number of brain imaging studies, which observe activation of the human cerebellum in fear conditioning paradigms. Different to what one may expect based on the initial cerebellar lesion studies, activations related to the learned prediction of threat go well beyond the vermis, and are most prominent in the lateral cerebellum. Different parts of the cerebellum likely contribute to learning of autonomic, motor, emotional and cognitive responses involved in classical fear conditioning. The neural operation which is performed in the various parts of the cerebellum is frequently assumed to be the same. One hypothesis is that the cerebellum acts as, or is part of, a predictive device. More recent findings will be discussed that thecerebellum may not only be involved in the processing of sensory prediction errors, but also in the processing of reward and reward prediction errors, which may play a central role in emotions and emotional learning. Current knowledge about the intrinsic learning mechanisms underlying fear memory in the cerebellum, and its connections with subcortical and cortical fear circuitry will be presented. The chapter will conclude with a discussion on how disordered cerebellar fear learning may contribute to affective disorders.

Mechanically evoked defensive attack is controlled by GABAergic neurons in the anterior hypothalamic nucleus.

Innate defensive behaviors triggered by environmental threats are important for animal survival. Among these behaviors, defensive attack toward threatening stimuli (for example, predators) is often the last line of defense. How the brain regulates defensive attack remains poorly understood. Here we show that noxious mechanical force in an inescapable context is a key stimulus for triggering defensive attack in laboratory mice. Mechanically evoked defensive attacks were abrogated by photoinhibition of vGAT+ neurons in the anterior hypothalamic nucleus (AHN). The vGAT+ AHN neurons encoded the intensity of mechanical force and were innervated by brain areas relevant to pain and attack. Activation of these neurons triggered biting attacks toward a predator while suppressing ongoing behaviors. The projection from vGAT+ AHN neurons to the periaqueductal gray might be one AHN pathway participating in mechanically evoked defensive attack. Together, these data reveal that vGAT+ AHN neurons encode noxious mechanical stimuli and regulate defensive attack in mice.