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The hypothalamus may be viewed as the central piece of the survival circuits and is responsible for organizing endocrine, autonomic and behavioral responses to guarantee the survival of both the individual and the species. The hypothalamus is largely known to control the three basic classes of behavior required for animal survival, namely, ingestive, defensive, and reproductive behaviors. Over the years, a great deal has been learned regarding the hypothalamic circuits organizing these classes of behavior. In this review, we will focus on hypothalamic circuits involved in organizing anti-predatory and social defenses, noting putative interactions with other hypothalamic systems that mediate metabolic control and social responses, and exploring how the hypothalamic defensive circuits may influence emotional memory linked to predatory and social threats.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape from innate and conditioned threats. The hypothalamic dorsal premammillary nucleus (PMd) may control escape, as it is activated by escape-inducing threats and projects to the region most implicated in flight, the dorsolateral periaqueductal gray (dlPAG). We show that in mice cholecystokinin (cck)-expressing PMd cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Lastly, human fMRI data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd as a central node of the escape network.

Made available in DSpace on 2022-04-29T08:45:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-08-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. We investigated the role of orexin receptors type 1 (OX1R) and type 2 (OX2R) in the PL in such processes upon confrontation with an erratically moving robo-beetle in mice. The selective blockade of OX1R and OX2R in the PL with SB 334867 (3, 30, 300 nM) and TCS OX2 29 (3, 30, 300 nM), respectively, did not affect general exploratory behavior or reactive fear such as avoidance, jumping or freezing, but significantly enhances tolerance and approach behavior at the highest dose of each antagonist tested (300 nM). We interpret these findings as evidence for an altered cognitive appraisal of the potential threatening stimulus. Consequently, the orexin system seems to bias the perception of stimuli towards danger or threat via OX1R and OX2R in the PL. Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP) Neuronal Plasticity Research Group Max Planck Institute of Psychiatry Department of Pharmacology Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP) Department of Anatomy Biomedical Sciences Institute of the University of São Paulo (ICB-USP) Behavioural Neuroscience Institute (INeC) NAP-USP-Neurobiology of Emotions Research Centre (NuPNE) Ribeirão Preto Medical School of the University of São Paulo Central Nervous System Diseases Research Boehringer Ingelheim Pharmaceuticals Die Gesellschaft mit Beschränkter Haftung & Compagnie Kommanditgesellschaft Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP)

Predator exposure is a life-threatening experience and elicits learned fear responses to the context in which the predator was encountered. The anterior cingulate area (ACA) occupies a pivotal position in a cortical network responsive to predatory threats, and it exerts a critical role in processing fear memory. Ours results revealed that the ACA is involved in both the acquisition and expression of contextual fear to predatory threat. Overall, the ACA can provide predictive relationships between the context and the predator threat and influences fear memory acquisition through projections to the basolateral amygdala and perirhinal region and the expression of contextual fear through projections to the dorsolateral periaqueductal gray. Our results expand previous studies based on classical fear conditioning and open interesting perspectives for understanding how the ACA is involved in processing contextual fear memory to ethologic threatening conditions that entrain specific medial hypothalamic fear circuits (i.e., predator- and conspecific-responsive circuits).

Animals must balance needs to approach threats for risk assessment and to avoid danger. The dorsal periaqueductal gray (dPAG) controls defensive behaviors, but it is unknown how it represents states associated with threat approach and avoidance. We identified a dPAG threatavoidance ensemble in mice that showed higher activity farther from threats such as the open arms of the elevated plus maze and a predator. These cells were also more active during threat avoidance behaviors such as escape and freezing, even though these behaviors have antagonistic motor output. Conversely, the threat approach ensemble was more active during risk assessment behaviors and near threats. Furthermore, unsupervised methods showed that avoidance/approach states were encoded with shared activity patterns across threats. Lastly, the relative number of cells in each ensemble predicted threat avoidance across mice. Thus, dPAG ensembles dynamically encode threat approach and avoidance states, providing a flexible mechanism to balance risk assessment and danger avoidance.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.

Animals must balance needs to approach threats for risk-assessment and to avoid danger. The dorsal periaqueductal gray (dPAG) controls defensive behaviors, but it is unknown how it represents states associated with threat approach and avoidance. We identified a dPAG threat-avoidance ensemble in mice that showed higher activity far from threats such as the open arms of the elevated plus maze and a live predator. These cells were also more active during threat-avoidance behaviors such as escape and freezing, even though these behaviors have antagonistic motor output. Conversely, the threat-approach ensemble was more active during risk-assessment behaviors and near threats. Furthermore, unsupervised methods showed approach/avoidance states were encoded with shared activity patterns across threats. Lastly, the relative number of cells in each ensemble predicted threat-avoidance across mice. Thus, dPAG ensembles dynamically encode threat approach and avoidance states, providing a flexible mechanism to balance risk-assessment and danger avoidance.

Evasion from imminent threats and prey attack are opposite behavioral choices critical to survival. The lateral periaqueductal gray (LPAG) is a key player in these behaviors, it responds to social threats and prey hunting while also driving predatory attacks and active defense. Our results revealed that distinct neuronal populations in the LPAG drive prey hunting and evasion from social threats. We show that the LPAG provides a putative glutamatergic projection to the lateral hypothalamic area (LHA). LPAG > LHA pathway optogenetic inhibition impaired insect predation but did not alter escape/attack ratio during social defeat. The results suggest that the LPAG control over evasion to a social attack may be regarded as a stereotyped response depending probably on descending projections. Conversely, the LPAG control over predatory behavior involves an ascending pathway to the LHA that likely influences LHAGABA neurons driving predatory hunting and may provide an emotional drive for appetitive rewards.

The brainstem dorsal periaqueductal gray (dPAG) has been widely recognized as being a vital node orchestrating the responses to innate threats. Intriguingly, recent evidence also shows that the dPAG mediates defensive responses to fear conditioned contexts. However, it is unknown whether the dPAG displays independent or shared patterns of activation during exposure to innate and conditioned threats. It is also unclear how dPAG ensembles encode and predict diverse defensive behaviors. To address this question, we used miniaturized microscopes to obtain recordings of the same dPAG ensembles during exposure to a live predator and a fear conditioned context in male mice. dPAG ensembles encoded not only distance to threat, but also relevant features, such as predator speed and angular offset between mouse and threat. Furthermore, dPAG cells accurately encoded numerous defensive behaviors, including freezing, stretch-attend postures, and escape. Encoding of behaviors and of distance to threat occurred independently in dPAG cells. dPAG cells also displayed a shared representation to encode these behaviors and distance to threat across innate and conditioned threats. Last, we also show that escape could be predicted by dPAG activity several seconds in advance. Thus, dPAG activity dynamically tracks key kinematic and behavioral variables during exposure to threats, and exhibits similar patterns of activation during defensive behaviors elicited by innate or conditioned threats. These data indicate that a common pathway may be recruited by the dPAG during exposure to a wide variety of threat modalities. SIGNIFICANCE STATEMENT The dorsal periaqueductal gray (dPAG) is critical to generate defensive behaviors during encounters with threats of multiple modalities. Here we use longitudinal calcium transient recordings of dPAG ensembles in freely moving mice to show that this region uses shared patterns of activity to represent distance to an innate threat (a live predator) and a conditioned threat (a shock grid). We also show that dPAG neural activity can predict diverse defensive behaviors. These data indicate the dPAG uses conserved population-level activity patterns to encode and coordinate defensive behaviors during exposure to both innate and conditioned threats.

Evasion from imminent threats and prey attack are opposite behavioral choices critical to survival. Curiously, the lateral periaqueductal gray (LPAG) has been implicated in driving both responses. The LPAG responds to social threats and prey hunting while also drives predatory attacks and active defense. However, the LPAG neural mechanisms mediating these behaviors remain poorly defined. Here, we investigate how the LPAG mediates the choices of predatory hunting and evasion from a social threat. Pharmacogenetic inhibition in Fos DD-Cre mice of neurons responsive specifically to insect predation (IP) or social defeat (SD) revealed that distinct neuronal populations in the LPAG drive the prey hunting and evasion from social threats. We show that the LPAG provides massive glutamatergic projection to the lateral hypothalamic area (LHA). Optogenetic inhibition of the LPAG-LHA pathway impaired IP but did not alter escape/attack ratio during SD. We also found that pharmacogenetic inhibition of LHAGABA neurons impaired IP, but did not change evasion during SD. The results suggest that the LPAG control over evasion to a social attack may be regarded as a stereotyped response depending probably on glutamatergic descending projections. On the other hand, the LPAG control over predatory behavior involves an ascending glutamatergic pathway to the LHA that likely influences LHAGABA neurons driving predatory attack and prey consumption. The LPAG-LHA path supposedly provides an emotional drive for prey hunting and, of relevance, may conceivably have more widespread control on the motivational drive to seek other appetitive rewards.

How an animal responds to environmental stressors and threats is essential for survival. These responses are governed through an interconnected circuit in the brain dubbed the limbic system. Three main structures of the limbic system are the amygdala, bed nucleus of the stria terminalis (BNST), and hypothalamus. Together these structures define a central stress-threat circuit. This chapter describes the most up to date knowledge of how these structures function in regulating responses to stressors and how each of these structures is formed from embryonic development. This knowledge of the underlying biology of these regions is essential to design rational therapeutic approaches for conditions, such as post-traumatic stress disorder (PTSD) that are characterized by dysregulation of the stress-threat system. In this chapter, we also describe the critical unanswered questions in the field of stress-threat research and potential future research directions.

The basolateral amygdala complex, which includes the lateral, basolateral and basomedial nuclei, has been implicated in innate and contextual fear responses to predator threats. In the basolateral complex, the lateral and posterior basomedial nuclei are able to process predator odor information, and they project to the predator-responsive hypothalamic circuit; lesions in these amygdalar sites reduce innate responses and practically abolish contextual fear responses to predatory threats. In contrast to the lateral and posterior basomedial nuclei, the basolateral nucleus does not receive direct information from predator olfactory cues and has no direct link to the predator-responsive hypothalamic circuit. No attempt has previously been made to determine the specific role of the basolateral nucleus in fear responses to predatory threats, and we currently addressed this question by making bilateral N-methyl-D-aspartate lesions in the anterior basolateral nucleus of the amygdala (BLAa), which is often regarded as being contiguous with the lateral amygdalar nucleus, and tested both innate and contextual fear in response to cat exposure. Accordingly, BLAa lesions decreased both innate and contextual fear responses to predator exposure. Considering the targets of the BLAa, the nucleus accumbens appears to be a potential candidate to influence innate defensive responses to predator threats. The present findings also suggest that the BLAa has a role in fear memory of predator threat. The BLAa is likely involved in memory consolidation, which could potentially engage BLAa projection targets, opening interesting possibilities in the investigation of how these targets could be involved in the consolidation of predator-related fear memory.

Naturalistic escape requires versatile context-specific flight with rapid evaluation of local geometry to identify and use efficient escape routes. It is unknown how spatial navigation and escape circuits are recruited to produce context-specific flight. Using mice, we show that activity in cholecystokinin-expressing hypothalamic dorsal premammillary nucleus (PMd-cck) cells is sufficient and necessary for context-specific escape that adapts to each environment's layout. In contrast, numerous other nuclei implicated in flight only induced stereotyped panic-related escape. We reasoned the dorsal premammillary nucleus (PMd) can induce context-specific escape because it projects to escape and spatial navigation nuclei. Indeed, activity in PMd-cck projections to thalamic spatial navigation circuits is necessary for context-specific escape induced by moderate threats but not panic-related stereotyped escape caused by perceived asphyxiation. Conversely, the PMd projection to the escape-inducing dorsal periaqueductal gray projection is necessary for all tested escapes. Thus, PMd-cck cells control versatile flight, engaging spatial navigation and escape circuits.

Previous studies from our group have shown that risk assessment behaviors are the primary contextual fear responses to predatory and social threats, whereas freezing is the main contextual fear response to physically harmful events. To test contextual fear responses to a predator or aggressive conspecific threat, we developed a model that involves placing the animal in an apparatus where it can avoid the threat-associated environment. Conversely, in studies that use shock-based fear conditioning, the animals are usually confined inside the conditioning chamber during the contextual fear test. In the present study, we tested shock-based contextual fear responses using two different behavioral testing conditions: confining the animal in the conditioning chamber or placing the animal in an apparatus with free access to the conditioning compartment. Our results showed that during the contextual fear test, the animals confined to the shock chamber exhibited significantly more freezing. In contrast, the animals that could avoid the conditioning compartment displayed almost no freezing and exhibited risk assessment responses (i.e., crouch-sniff and stretch postures) and burying behavior. In addition, the animals that were able to avoid the shock chamber had increased Fos expression in the juxtadorsomedial lateral hypothalamic area, the dorsomedial part of the dorsal premammillary nucleus and the lateral and dorsomedial parts of the periaqueductal gray, which are elements of a septo/hippocampal-hypothalamic-brainstem circuit that is putatively involved in mediating contextual avoidance. Overall, the present findings show that testing conditions significantly influence both behavioral responses and the activation of circuits involved in contextual avoidance.

Exposure to stressful conditions induces long-lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. Moreover, the interaction of a stressful experience and the retrieval of an established fear memory trace enhance both fear expression and fear retention. Related to this, the stimulation of the dorsolateral part of the mesencephalic periaqueductal gray matter (dlPAG) prior to retrieval potentiates a fear memory trace previously acquired. Therefore, the question that arises is whether the dlPAG mediates the increased fear expression and fear retention after retrieval. Rats were subjected to a contextual fear conditioning paradigm using a single footshock, and 1 day later, rats were subjected to a stressful situation. As previously reported, there was an increase of freezing response only in those rodents that were re-exposed to the associated context at 1 and 5 days after stress exposure. Muscimol intra-dlPAG prior to the restraint event prevented such increase. Conversely, Muscimol intra-dlPAG infusion immediately after the stress experience had no effect on the resulting fear memory. When the neuroendocrine response to stress was explored, intra-dlPAG infusion of muscimol prior to stress decreased Fos expression in the paraventricular nucleus and serum corticosterone levels. Moreover, this treatment prevented the enhancement of the density of hippocampal "mature" spines associated with fear memory. In conclusion, the present results suggest that the dlPAG is a key neural site for the negative valence instruction necessary to modulate the promoting influence of stress on fear memory.

Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.

Melanin-concentrating hormone (MCH) is a hypothalamic peptide that plays a critical role in the regulation of food intake and energy metabolism. In this study, we investigated the potential role of dense hippocampal MCH innervation in the spatially oriented food-seeking component of feeding behavior. Rats were trained for eight sessions to seek food buried in an arena using the working memory version of the food-seeking behavior (FSB) task. The testing day involved a bilateral anti-MCH injection into the hippocampal formation followed by two trials. The anti-MCH injection did not interfere with the performance during the first trial on the testing day, which was similar to the training trials. However, during the second testing trial, when no food was presented in the arena, the control subjects exhibited a dramatic increase in the latency to initiate digging. Treatment with an anti-MCH antibody did not interfere with either the food-seeking behavior or the spatial orientation of the subjects, but the increase in the latency to start digging observed in the control subjects was prevented. These results are discussed in terms of a potential MCH-mediated hippocampal role in the integration of the sensory information necessary for decision-making in the pre-ingestive component of feeding behavior.

In the present study, we examined behavioral and brain regional activation changes of rats). To a nonmammalian predator, a wild rattler snake (Crotalus durissus terrificus). Accordingly, during snake threat, rat subjects showed a striking and highly significant behavioral response of freezing, stretch attend, and, especially, spatial avoidance of this threat. The brain regional activation patterns for these rats were in broad outline similar to those of rats encountering other predator threats, showing Fos activation of sites in the amygdala, hypothalamus, and periaqueductal gray matter. In the amygdala, only the lateral nucleus showed significant activation, although the medial nucleus, highly responsive to olfaction, also showed higher activation. Importantly, the hypothalamus, in particular, was somewhat different, with significant Fos increases in the anterior and central parts of the ventromedial hypothalamic nucleus (VMH), in contrast to patterns of enhanced Fos expression in the dorsomedial VMH to cat predators, and in the ventrolateral VMH to an attacking conspecific. In addition, the juxtodorsalmedial region of the lateral hypothalamus showed enhanced Fos activation, where inputs from the septo-hippocampal system may suggest the potential involvement of hippocampal boundary cells in the very strong spatial avoidance of the snake and the area it occupied. Notably, these two hypothalamic paths appear to merge into the dorsomedial part of the dorsal premammillary nucleus and dorsomedial and lateral parts of the periaqueductal gray, all of which present significant increases in Fos expression and are likely to be critical for the expression of defensive behaviors in responses to the snake threat.

The ventral part of the anteromedial thalamic nucleus (AMv) receives substantial inputs from hypothalamic sites that are highly responsive to a live predator or its odor trace and represents an important thalamic hub for conveying predatory threat information to the cerebral cortex. In the present study, we begin by examining the cortico-amygdalar-hippocampal projections of the main AMv cortical targets, namely, the caudal prelimbic, rostral anterior cingulate, and medial visual areas, as well as the rostral part of the ventral retrosplenial area, one of the main targets of the anterior cingulate area. We observed that these areas form a clear cortical network. Next, we revealed that in animals exposed to a live cat, all of the elements of this circuit presented a differential increase in Fos, supporting the idea of a predator threat-responsive cortical network. Finally, we showed that bilateral cytotoxic lesions in each element of this cortical network did not change innate fear responses but drastically reduced contextual conditioning to the predator-associated environment. Overall, the present findings suggest that predator threat has an extensive representation in the cerebral cortex and revealed a cortical network that is responsive to predatory threats and exerts a critical role in processing fear memory.

The ventral part of the anteromedial thalamic nucleus (AMv) is heavily targeted by the dorsal premammillary nucleus (PMd), which is the main hypothalamic site that is responsive to both predator and conspecific aggressor threats. This PMd-AMv pathway is likely involved in modulating memory processing, and previous findings from our group have shown that cytotoxic lesions or pharmacological inactivation of the AMv drastically reduced contextual fear responses to predator-associated environments. In the present study, we investigated the role of the AMv in both unconditioned (i.e., fear responses during social defeat) and contextual fear responses (i.e., during exposure to a social defeat-associated context). We addressed this question by placing N-methyl-d-aspartate (NMDA) lesions in the AMv and testing unconditioned fear responses during social defeat and contextual fear responses during exposure to a social defeat-associated context. Accordingly, bilateral AMv lesions did not change unconditioned responses, but decreased contextual conditioning related to social defeat. Notably, our bilateral AMv lesions also included, to a certain degree, the nucleus reuniens (RE), but single RE lesions did not affect innate or contextual fear responses. Overall, our results support the idea that the AMv works as a critical hub, receiving massive inputs from a hypothalamic site that is largely responsive to social threats and transferring social threat information to circuits involved in the processing of contextual fear memories.

The periaqueductal gray (PAG) has been commonly recognized as a downstream site in neural networks for the expression of a variety of behaviors and is thought to provide stereotyped responses. However, a growing body of evidence suggests that the PAG may exert more complex modulation of a number of behavioral responses and work as a unique hub supplying primal emotional tone to influence prosencephalic sites mediating complex aversive and appetitive responses. Of particular relevance, we review how the PAG is involved in influencing complex forms of defensive responses, such as circa-strike and risk assessment responses in animals. In addition, we discuss putative dorsal PAG ascending paths that are likely to convey information related to threatening events to cortico-hippocampal-amygdalar circuits involved in the processing of fear learning. Finally, we discuss the evidence supporting the role of the PAG in reward seeking and note that the lateral PAG is part of the circuitry related to goal-oriented responses mediating the motivation to hunt and perhaps drug seeking behavior.

The present review covers two independent approaches, a neuroanatomical and a pharmacological (focused on serotonergic transmission), which converge in highlighting the critical role of the hypothalamus and midbrain periaqueductal gray matter in the generation of panic attacks and in the mechanism of action of current antipanic medication. Accordingly, innate and learned fear responses to different threats (i.e., predator, aggressive members of the same species, interoceptive threats and painful stimuli) are processed by independent circuits involving corticolimbic regions (the amygdala, the hippocampus and the prefrontal and insular cortices) and downstream hypothalamic and brainstem circuits. As for the drug treatment, animal models of panic indicate that the drugs currently used for treating panic disorder should work by enhancing 5-HT inhibition of neural systems that command proximal defense in both the dorsal periaqueductal gray and in the medial hypothalamus. For the anticipatory anxiety, the reviewed evidence points to corticolimbic structures, such as the amygdala, the septo-hippocampus and the prefrontal cortex, as its main neural substrate, modulated by stimulation of 5-HT2C and 5-HT1A receptors.

Maternal aggression is under the control of a wide variety of factors that prime the females for aggression or trigger the aggressive event. Maternal attacks are triggered by the perception of sensory cues from the intruder, and here we have identified a site in the hypothalamus of lactating rats that is highly responsive to the male intruder—the ventral premammillary nucleus (PMv). The PMv is heavily targeted by the medial amygdalar nucleus, and we used lesion and immediate-early gene studies to test our working hypothesis that the PMv signals the presence of a male intruder and transfers this information to the network organizing maternal aggression. PMv-lesioned dams exhibit significantly reduced maternal aggression, without affecting maternal care. The Fos analysis revealed that PMv influences the activation of hypothalamic and septal sites shown to be mobilized during maternal aggression, including the medial preoptic nucleus (likely to represent an important locus to integrate priming stimuli critical for maternal aggression), the caudal two-thirds of the hypothalamic attack area (comprising the ventrolateral part of the ventromedial hypothalamic nucleus and the adjacent tuberal region of the lateral hypothalamic area, critical for the expression of maternal aggression), and the ventral part of the anterior bed nuclei of the stria terminalis (presently discussed as being involved in controlling neuroendocrine and autonomic responses accompanying maternal aggression). These findings reveal an important role for the PMv in detecting the male intruder and how this nucleus modulates the network controlling maternal aggression.

Melanin-concentrating hormone (MCH) and neuropeptide glutamic acid-isoleucine (NEI) are expressed in neurons that are located mainly in the hypothalamus and project widely throughout the rat central nervous system. One of the main targets of melanin-concentrating hormone is the hippocampal formation, although the exact origin of the projections is unknown. By using injections of the retrograde tracer True Blue into the hippocampus, together with immunohistochemical analysis, we observed retrogradely labeled melanin-concentrating hormone-containing neurons in the lateral hypothalamic area, incerto-hypothalamic area, perifornical area, the periventricular nucleus of the hypothalamus, and in the internuclear area (between the dorsomedial and ventromedial nuclei of the hypothalamus), as well as a few retrogradely labeled and melanin-concentrating hormone-immunoreactive cells in the supramammillary nucleus. The afferents from the lateral hypothalamic area were confirmed using injection of the anterograde tracer biotinylated dextran amine, which enabled us to use histochemical analysis in order to visualize fibers and terminals in the hippocampal formation. In the medial septal nucleus, we found cholinergic neurons that are also putatively innervated by melanin-concentrating hormone immunoreactive fibers and project to the hippocampal formation. Finally, using two different protocols for immunoperoxidase, we were able to show GABAergic basket cells presumably innervated by melanin-concentrating hormone-immunoreactive fibers in the hippocampal formation. On the basis of the data collected herein, we hypothesize that the MCH/NEI projections from hypothalamic nuclei participate in spatial memory and learning through direct and indirect pathways. These pathways would enable the animal to organize its exploratory behavior during foraging.

Our understanding of the extrinsic connections of the lateral hypothalamic area (LHA) has deepened in recent years. In particular, a series of studies using neural pathway-tracing methods to investigate the macroconnections of histologically differentiated LHA regions, have revealed that the neural connections of these regions are substantially distinct, and have robust connections with neural circuits controlling survival behaviors. To begin testing functional associations suggested by the distinct LHA region neural connections, the present study has investigated the role of the LHA juxtadorsomedial region (LHAjd) in the control of social defeat (a socially-relevant defensive behavior). Male rats received bilateral cytotoxic lesions targeted to the LHAjd. A resident-intruder paradigm was then employed to investigate the effect of these lesions on defensive behavioral responses. Behavioral data were collected during three phases of testing: (1) pre-encounter habituation to testing context; (2) encounter with a dominant conspecific in the testing context; and (3) post-encounter context. Statistical analysis of behavioral measures revealed a significant decrease in risk assessment behaviors during post-encounter context testing in lesioned intruders compared to sham-lesioned and intact rats. However, changes in defensive behavioral measures during the habituation, or during resident-intruder encounters, did not reach significance. We discuss these data in relation to LHAjd (and neighboring LHA region) neural connections, and in relation to current advances in understanding of the neural control of defensive behaviors. A refined model for the neural circuits that are central to the control of socially-relevant defensive behaviors is outlined. We also consider possible broader implications of these data for disorders of behavioral control.

Previous studies using morphine-treated dams reported a role for the rostral lateral periaqueductal gray (rlPAG) in the behavioral switching between nursing and insect hunting, likely to depend on an enhanced seeking response to the presence of an appetitive rewarding cue (i.e., the roach). To elucidate the neural mechanisms mediating such responses, in the present study, we first observed how the rlPAG influences predatory hunting in male rats. Our behavioral observations indicated that bilateral rlPAG NMDA lesions dramatically interfere with prey hunting, leaving the animal without chasing or attacking the prey, but do not seem to affect the general levels of arousal, locomotor activity and regular feeding. Next, using Phaseolus vulgaris-leucoagglutinin (PHA-L), we have reviewed the rlPAG connection pattern, and pointed out a particularly dense projection to the hypothalamic orexinergic cell group. Double labeled PHA-L and orexin sections showed an extensive overlap between PHA-L labeled fibers and orexin cells, revealing that both the medial/perifornical and lateral hypothalamic orexinergic cell groups receive a substantial innervation from the rlPAG. We have further observed that both the medial/perifornical and lateral hypothalamic orexinergic cell groups up-regulate Fos expression during prey hunting, and that rlPAG lesions blunted this Fos increase only in the lateral hypothalamic, but not in the medial/perifornical, orexinergic group, a finding supposedly associated with the lack of motivational drive to actively pursue the prey. Overall, the present results suggest that the rlPAG should exert a critical influence on reward seeking by activating the lateral hypothalamic orexinergic cell group.

The multiple memory systems theory proposes that the hippocampus and the dorsolateral striatum are the core structures of the spatial/relational and stimulus-response (S-R) memory systems, respectively. This theory is supported by double dissociation studies showing that the spatial and cue (S-R) versions of the Morris water maze are impaired by lesions in the dorsal hippocampus and dorsal striatum, respectively. In the present study we further investigated whether adult male Wistar rats bearing double and bilateral electrolytic lesions in the dorsal hippocampus and dorsolateral striatum were as impaired as rats bearing single lesions in just one of these structures in learning both versions of the water maze. Such a prediction, based on the multiple memory systems theory, was not confirmed. Compared to the controls, the animals with double lesions exhibited no improvement at all in the spatial version and learned the cued version very slowly. These results suggest that, instead of independent systems competing for holding control over navigational behaviour, the hippocampus and dorsal striatum both play critical roles in navigation based on spatial or cue-based strategies.

The retinohypothalamic tract is one component of the optic nerve that transmits information about environmental luminance levels through medial and lateral branches to four major terminal fields in the hypothalamus. The spatial distribution and organization of axonal projections from each of these four terminal fields were analyzed and compared systematically with the anterograde pathway tracer PHAL in rats where the terminal fields had been labeled with intravitreal injections of a different anterograde pathway tracer, CTb. First, the well-known projections of two medial retinohypothalamic tract targets (the ventrolateral suprachiasmatic nucleus and perisuprachiasmatic region) were confirmed and extended. They share qualitatively similar projections to a well-known set of brain regions thought to control circadian rhythms. Second, the projections of a third medial tract target, the ventromedial part of the anterior hypothalamic nucleus, were analyzed for the first time and shown to resemble qualitatively those from the suprachiasmatic nucleus and perisuprachiasmatic region. And third, projections from the major lateral retinohypothalamic tract target were analyzed for the first time and shown to be quite different from those associated with medial tract targets. This target is a distinct core part of the ventral zone of the anterior group of the lateral hypothalamic area that lies just dorsal to the caudal two-thirds of the supraoptic nucleus. Its axonal projections are to neural networks that control a range of specific goal-oriented behaviors (especially drinking, reproductive, and defensive) along with adaptively appropriate and complementary visceral responses and adjustments to behavioral state.

The amygdala plays a critical role in determining the emotional significance of sensory stimuli and the production of fear-related responses. Large amygdalar lesions have been shown to practically abolish innate defensiveness to a predator; however, it is not clear how the different amygdalar systems participate in the defensive response to a live predator. Our first aim was to provide a comprehensive analysis of the amygdalar activation pattern during exposure to a live cat and to a predator-associated context. Accordingly, exposure to a live predator up-regulated Fos expression in the medial amygdalar nucleus (MEA) and in the lateral and posterior basomedial nuclei, the former responding to predator-related pheromonal information and the latter two nuclei likely to integrate a wider array of predatory sensory information, ranging from olfactory to non-olfactory ones, such as visual and auditory sensory inputs. Next, we tested how the amygdalar nuclei most responsive to predator exposure (i.e. the medial, posterior basomedial and lateral amygdalar nuclei) and the central amygdalar nucleus (CEA) influence both unconditioned and contextual conditioned anti-predatory defensive behavior. Medial amygdalar nucleus lesions practically abolished defensive responses during cat exposure, whereas lesions of the posterior basomedial or lateral amygdalar nuclei reduced freezing and increased risk assessment displays (i.e. crouch sniff and stretch postures), a pattern of responses compatible with decreased defensiveness to predator stimuli. Moreover, the present findings suggest a role for the posterior basomedial and lateral amygdalar nuclei in the conditioning responses to a predator-related context. We have further shown that the CEA does not seem to be involved in either unconditioned or contextual conditioned anti-predatory responses. Overall, the present results help to clarify the amygdalar systems involved in processing predator-related sensory stimuli and how they influence the expression of unconditioned and contextual conditioned anti-predatory responses.

Combining the results of behavioral, neuronal immediate early gene activation, lesion and neuroanatomical experiments, we have presently investigated the role of the superior colliculus (SC) in predatory hunting. First, we have shown that insect hunting is associated with a characteristic large increase in Fos expression in the lateral part of the intermediate gray layer of the SC (SCig). Next, we have shown that animals with bilateral NMDA lesions of the lateral parts of the SC presented a significant delay in starting to chase the prey and longer periods engaged in other activities than predatory hunting. They also showed a clear deficit to orient themselves toward the moving prey and lost the stereotyped sequence of actions seen for capturing, holding and killing the prey. Our Phaseolus vulgaris-leucoagglutinin analysis revealed that the lateral SCig, besides providing the well-documented descending crossed pathway to premotor sites in brainstem and spinal cord, projects to a number of midbrain and diencephalic sites likely to influence key functions in the context of the predatory behavior, such as general levels of arousal, motivational level to hunt or forage, behavioral planning, appropriate selection of the basal ganglia motor plan to hunt, and motor output of the primary motor cortex. In contrast to the lateral SC lesions, medial SC lesions produced a small deficit in predatory hunting, and compared to what we have seen for the lateral SCig, the medial SCig has a very limited set of projections to thalamic sites related to the control of motor planning or motor output, and provides conspicuous inputs to brainstem sites involved in organizing a wide range of anti-predatory defensive responses. Overall, the present results served to clarify how the different functional domains in the SC may mediate the decision to pursue and hunt a prey or escape from a predator.

The hypothalamus plays especially important roles in various endocrine, autonomic, and behavioral responses that guarantee the survival of both the individual and the species. In the rat, a distinct hypothalamic defensive circuit has been defined as critical for integrating predatory threats, raising an important question as to whether this concept could be applied to other prey species. To start addressing this matter, in the present study, we investigated, in another prey species (the mouse), the pattern of hypothalamic Fos immunoreactivity in response to exposure to a predator (a rat, using the Rat Exposure Test). During rat exposure, mice remained concealed in the home chamber for a longer period of time and increased freezing and risk assessment activity. We were able to show that the mouse and the rat present a similar pattern of hypothalamic activation in response to a predator. Of particular note, similar to what has been described for the rat, we observed in the mouse that predator exposure induces a striking activation in the elements of the medial hypothalamic defensive system, namely, the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial hypothalamic nucleus and the dorsal premammillary nucleus. Moreover, as described for the rat, predator-exposed mice also presented increased Fos levels in the autonomic and parvicellular parts of the paraventricular hypothalamic nucleus, lateral preoptic area and subfornical region of the lateral hypothalamic area. In conclusion, the present data give further support to the concept that a specific hypothalamic defensive circuit should be preserved across different prey species.

In this study we provide a comprehensive analysis of the hypothalamic activation pattern during exposure to a live predator or an environment previously associated with a predator. Our results support the view that hypothalamic processing of the actual and the contextual predatory threats share the same circuit, in which the dorsal premammillary nucleus (PMd) plays a pivotal role in amplifying this processing. To further understand the role of the PMd in the circuit organizing antipredatory defensive behaviors, we studied rats with cytotoxic PMd lesions during cat exposure and examined the pattern of behavioral responses as well as how PMd lesions affect the neuronal activation of the systems engaged in predator detection, in contextual memory formation and in defensive behavioral responses. Next, we investigated how pharmacological blockade of the PMd interferes with the conditioned behavioral responses to a context previously associated with a predator, and how this blockade affects the activation pattern of periaqueductal gray (PAG) sites likely to organize the conditioned behavioral responses to the predatory context. Behavioral observations indicate that the PMd interferes with both unconditioned and conditioned antipredatory defensive behavior. Moreover, we have shown that the PMd influences the activation of its major projecting targets, i.e. the ventral part of the anteromedial thalamic nucleus which is likely to influence mnemonic processing, and PAG sites involved in the expression of antipredatory unconditioned and conditioned behavioral responses. Of particular relevance, this work provides evidence to elucidate the basic organization of the neural circuits integrating unconditioned and contextual conditioned responses to predatory threats.

The bilateral intranigral infusion of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult male Wistar rats caused a specific and partial loss of substantia nigra pars compacta (SNc) dopamine neurons, a partial depletion of striatal dopamine, and a deficit to learn the intra-maze cued version of the Morris water maze. Pre-training the SNc rats in the spatial version of the water maze or simply maintaining the animals on the water maze platform reversed this deficit. This improvement was even observed when the order of the extra-maze cues presented to the rats during pre-training of the spatial version was changed during training of the intra-maze cued version. However, this deficit was not reversed either by maintaining the animals on the platform if the spatial cues were surrounded and covered with a curtain or by swimming sessions in the maze without the escape platform and the curtain. These findings suggest that none of the following elements alone, learned during the spatial task pre-training, could help SNc rats learn the intra-maze cued task: improvement of swimming skills or knowledge of the existence of the escape platform; distance between the platform and the border of the pool; location of a particular extra-maze cue; relations among extra-maze cues. However, the simultaneous presence of the escape platform and extra-maze cues (irrespective of their relational configuration) during the pre-training sessions proved to be necessary for this improving effect to occur.

Previous studies from our laboratory have shown that insect hunting is associated with a distinct Fos up-regulation in the ventrolateral caudoputamen at intermediate rostro-caudal levels. It is largely known that ventrolateral striatum participates in the control of orofacial movements and forepaw usage accompanying feeding behavior, but there has been no study investigating its possible roles during predatory hunting. We have presently examined the role of the ventrolateral striatum during roach hunting by using the reversible blockade with lidocaine. Accordingly, non-treated and saline-treated animals performed the insect hunting quite well, displaying a rather stereotyped form of motor actions for chasing, capturing and killing the prey. During the bilateral blockade of the ventrolateral striatum, the animals showed a significantly longer latency to start hunting and to capture the first prey. The lidocaine-treated animals captured the prey by using mostly the mouth, with little forepaw assistance, and were less effective in capturing the roaches. Moreover, while handling the prey, animals with ventrolateral striatal inactivation kept biting several parts of the prey, but failed to deliver the killing bite to the head, leaving them alive and moving, more likely to escape. Overall, the present findings suggest that the ventrolateral striatum implements the stereotyped actions seen during prey capture and handling, and may influence the motivational drive to start attacking the roaches, as well.

Different types of predator odors engage elements of the hypothalamic predator-responsive circuit, which has been largely investigated in studies using cat odor exposure. Studies using cat odor have led to detailed mapping of the neural sites involved in innate and contextual fear responses. Here, we reviewed three lines of work examining the dynamics of the neural systems that organize innate and learned fear responses to cat odor. In the first section, we explored the neural systems involved in innate fear responses and in the acquisition and expression of fear conditioning to cat odor, with a particular emphasis on the role of the dorsal premammillary nucleus (PMd) and the dorsolateral periaqueductal gray (PAGdl), which are key sites that influence innate fear and contextual conditioning. In the second section, we reviewed how chemical stimulation of the PMd and PAGdl may serve as a useful unconditioned stimulus in an olfactory fear conditioning paradigm; these experiments provide an interesting perspective for the understanding of learned fear to predator odor. Finally, in the third section, we explored the fact that neutral odors that acquire an aversive valence in a shock-paired conditioning paradigm may mimic predator odor and mobilize elements of the hypothalamic predator-responsive circuit.

This study compares histological, neurochemical, behavioral, motor and cognitive alterations as well as mortality of two models of Parkinson's disease in which 100 microg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6 microg 6-hydroxydopamine (6-OHDA) was bilaterally infused into the central region of the substantia nigra, compact part, of adult male Wistar rats. Both neurotoxins caused a significant loss of nigral tyrosine hydroxylase-immunostained cells and striatal dopamine depletion, but 6-OHDA caused more widespread and intense cell loss, more intense body weight loss and more mortality than MPTP. Both 6-OHDA- and MPTP-lesioned rats presented similar deficits in performing a working memory and a cued version of the Morris water maze task and few exploratory/motor alterations in the open field and catalepsy tests. However, rats presented a significant and transitory increase in locomotor activity after the MPTP lesion and a hypolocomotor behavior tended to be present after the 6-OHDA lesion. The picture of mild motor effects and robust impairment of habit learning and spatial working memory observed in MPTP-lesioned rats models the early phase of Parkinson's disease.

In the present study, we introduce an experimental procedure to study, in rats, a wide range of natural defensive reactions. Animals were tested in an experimental apparatus that consisted of a home cage (25 x 25 x 25 cm) connected to another chamber (25 x 25 x 25 cm-the food compartment) by a hallway (12.5 cm wide and 100 cm long, with 25-cm high walls). During 10 days before the testing procedures, each animal was isolated in the home cage, and, at the beginning of the dark phase, allowed to explore the rest of the apparatus and obtain food pellets stored in the food compartment. The testing consisted of three phases: exploring a familiar and safe environment (phase 1, on the 10th day), cat exposure (phase 2, on the 11th day), and, on the following day, exposure to the environment where the predator had been previously encountered (phase 3). These three conditions thus provided a low-defense baseline; a high level of freezing during cat exposure; and a high level of risk assessment to the hostile environment condition. An important feature of the present experimental procedure was that the behavioral responses were very stable among the animals tested within each individual phase of the testing schedule. In each phase of the testing schedule, we have also examined the Fos immunoreactivity in pontine periventricular sites related to controlling behavioral activation (i.e. the nucleus incertus) or attentional status (i.e. the locus coeruleus). Animals actively exploring a safe and familiar environment presented an increased activation of the nucleus incertus; the locus coeruleus, in turn, was particularly activated during cat exposure, and also, to lesser degree, during exposure to the hostile environment. These results give further support to the view that the animals present quite distinct behavioral states during each one of the testing situations. Taken together, the evidence suggests the present experimental procedure as particularly suitable for analyzing the neural basis of a number of specific defensive responses.

The neural circuits mediating fear to naturalistic threats are poorly understood. Here we demonstrate that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region implicated in feeding, sex, and aggression, are essential for predator and social fear in mice. Our study establishes a critical role for VMH in fear and carries implications for the selective intervention in pathological fear in humans.

O nosso entendimento das bases neurofisiológicas da reação emocional do medo baseia-se em grande parte nos estudos que envolvem respostas condicionadas a estímulos fisicamente aversivos, como, por exemplo, o choque elétrico nas patas. Enquanto este paradigma parece ser útil para avaliarmos os sistemas neurais envolvidos na resposta do, assim chamado, medo condicionado (que tipicamente tem se limitado à observação da resposta de congelamento), este paradigma parece ter sérias limitações para investigarmos as bases neurais das respostas de medo em circunstancias naturais. Trabalhos recentes utilizando técnicas de lesões neurais bem como de mapeamento funcional em animais expostos a predadores naturais, ou somente ao odor destes predadores, revelam uma série de estruturas neurais como responsáveis pelas respostas de medo inato, bastante distintas daquelas previamente implicadas nas respostas de condicionamento aversivo. Como revisto no presente trabalho, entre estas estruturas temos distritos diferenciados da zona medial do hipotálamo; setores específicos da amídala e do sistema septo-hipocampal, envolvidos, respectivamente no processamento de pistas relacionadas à presença do predador e na análise contextual do ambiente; e setores da matéria cinzenta periaquedutal, já classicamente envolvidos na expressão de respostas de defesa. Estas informações podem ser potencialmente importantes para a análise e terapêutica de psicopatologias relacionadas aos distúrbios da reação emocional de medo.

The aim of the present study was to test if the nigrostriatal pathway is an essential component for a water maze cued task learning and if it works independently of the hippocampal memory system. This hypothesis was tested using an animal model of Parkinson's disease in which male Wistar rats were lesioned in the substantia nigra pars compacta (SNc) by the intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), thus causing a partial depletion of striatal dopamine. SNc-lesioned and sham-operated animals were implanted bilaterally with guide cannulae above the dorsal hippocampus in order to be tested after the administration of 0.4 microl 2% lidocaine or saline into this structure. The animals were tested in a spatial or in a cued version of the water maze, memory tasks previously reported to model hippocampal-dependent spatial/relational and striatal-dependent S-R learning, respectively. Hippocampal inactivation, but not SNc lesion, impaired learning and memory in the spatial version of the water maze. An opposite situation was observed with the cued version. No significant interaction was observed between the SNc lesion and hippocampal inactivation conditions affecting scores in the spatial or in the cued version of the water maze. These results suggest that the nigrostriatal pathway is an essential part of the memory system that processes S-R learning and that it works independently of the hippocampal memory system that processes spatial/relational memories.

Considering the periaqueductal gray's (PAG) general roles in mediating motivational responses, in the present study, we compared the Fos expression pattern in the PAG induced by innate behaviors underlain by opposite motivational drivers, in rats, namely, insect predation and defensive behavior evoked by the confrontation with a live predator (a cat). Exposure to the predator was associated with a striking Fos expression in the PAG, where, at rostral levels, an intense Fos expression was found largely distributed in the dorsomedial and dorsolateral regions, whereas, at caudal levels, Fos-labeled cells tended to be mostly found in the lateral and ventrolateral columns, as well as in the dorsal raphe nucleus. Quite the opposite, insect predation was associated with increased Fos expression predominantly in the rostral two thirds of the lateral PAG, where the majority of the Fos-immunoreactive cells were found at the oculomotor nucleus levels. Remarkably, both exposure to the cat and insect predation upregulated Fos expression in the supraoculomotor region and the laterodorsal tegmental nucleus. Overall, the present results clearly suggest that the PAG activation pattern appears to reflect, at least partly, the animal's motivational status. It is well established that the PAG is critical for the expression of defensive responses, and, considering the present findings, it will be important to investigate how the PAG contributes to the expression of the predatory behavior, as well.

1. In this article we review the studies of memory disabilities in a rat model of Parkinson's disease (PD). 2. Intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. 3. These animals present learning and memory deficits but no sensorimotor impairments, thus modeling the early phase of PD when cognitive impairments are observed but the motor symptoms of the disease are barely present. 4. The cognitive deficits observed in these animals affect memory tasks proposed to model habit learning (the cued version of the water maze task and the two-way active avoidance task) and working memory (a working memory version of the water maze), but spare long-term spatial memory (the spatial reference version of the Morris water maze). 5. The treatment of these animals with levodopa in a dose that restores the striatal level of dopamine does not reverse these memory impairments, probably because this treatment promotes a high level of dopamine in extrastriatal brain regions, such as the prefrontal cortex and the hippocampus. 6. On the other hand, the adenosine receptor antagonist, caffeine, partly reverse the memory impairment effect of SNc lesion in these rats. This effect may be due to caffeine action on nigrostriatal neurons, since it induces dopamine release and modulates the interaction between adenosine and dopamine receptor activity. 7. These results suggest that the MPTP SNc-lesioned rats are a good model to study memory disabilities related to PD and that caffeine and other selective A(2A) adenosine receptor antagonists are promising drugs to treat this symptoms in PD patients.

Superior predatory skills led to the evolutionary triumph of jawed vertebrates. However, the mechanisms by which the vertebrate brain controls predation remain largely unknown. Here, we reveal a critical role for the central nucleus of the amygdala in predatory hunting. Both optogenetic and chemogenetic stimulation of central amygdala of mice elicited predatory-like attacks upon both insect and artificial prey. Coordinated control of cervical and mandibular musculatures, which is necessary for accurately positioning lethal bites on prey, was mediated by a central amygdala projection to the reticular formation in the brainstem. In contrast, prey pursuit was mediated by projections to the midbrain periaqueductal gray matter. Targeted lesions to these two pathways separately disrupted biting attacks upon prey versus the initiation of prey pursuit. Our findings delineate a neural network that integrates distinct behavioral modules and suggest that central amygdala neurons instruct predatory hunting across jawed vertebrates.

The dorsal premammillary nucleus (PMd) is thought to play a critical role in the expression of fear responses to environmental threats. We have previously reported that, during an encounter with a predator, the PMd presents an impressive increase in Fos levels and cell body-specific chemical lesions therein virtually eliminated the expression of escape and freezing responses. Therefore, the PMd may be viewed as a strategic starting point to delineate prosencephalic circuits seemingly critical for the organization of innate fear responses. In the present review, we provide a comprehensive examination of the neural circuits putatively involved in influencing this hypothalamic site, and supplement this analysis with recent observations from our laboratory on the expression of Fos protein in the central nervous system of rats exposed to a live predator.