The characterization and modelling of antipredator defensive behavior

The mammalian behavioral antipredator defense systems have been characterized in terms of reactions to present, localizable, threat stimuli: Analysis of the relationship between features of the predator and the environment, and specific defensive behaviors indicates that the latter can be predicted with a high degree of accuracy. A different set of defensive behaviors are seen when rats living in burrow systems are confronted by a predator outside the burrow. Flight to the burrow and immobility inside the burrow are followed by active investigation of the surface where the cat was seen (risk assessment), with all of these accompanied by inhibition of nondefensive behaviors such as eating, drinking, sexual behavior and aggression. Two additional behaviors are described in this context, ultrasonic cries made at a high initial rate (50% time) by animals inside the burrow systems, and declining over 1-2 hours following predator exposure, and, a specific modification of eating patterns when the subjects return to the surface and begin to eat. Eating bouts are shortened, with fewer episodes of continuous eating, interspersed with intervals of scanning of the environment, a vigilance activity previously reported in field research. This analysis of a broad spectrum of defensive behaviors is being used to develop test batteries providing simplified models of these phenomena.     

Sex differences and phase of light cycle modify chronic stress effects on anxiety and depressive-like behavior

The experiment examined whether sex differences and the phase of the light cycle modified how chronic restraint stress influenced anxiety and depressive-like behavior. Rats were restrained (6 h/d/21 d) and tested on the open field (OF), elevated plus maze (EPM), forced swim test (FST), and sucrose preference (SP) test. Chronic stress increased anxiety in both males and females in different tasks during the dark phase, but not in the light phase. When tested during the dark, chronic stress decreased time and grid crossings in the center arena of the OF in males, whereas chronic stress decreased open arm entries and time in the EPM in females. For OF and EPM, an anxiety index calculation confirmed that chronic stress increased anxiety measures when taking into consideration locomotion metrics. For the FST and SP, chronic stress had a tendency to alter the immobility index and sucrose preference in both sexes, but did not reach statistical significance alone. Therefore, a separate z-score was computed for each task and summed to represent a combined z-score of depressive-like behavior. In the light phase, chronic stress increased depressive-like behavior in males, but decreased depressive-like behavior in females. Chronic stress had no statistically significant effects on depressive-like behavior in the dark phase, although the pattern of chronic stress effects on depressive-like behavior in females was similar for both light cycle phases. The results indicate that chronic restraint stress effects on anxiety and depressive-like behavior depend upon the type of task, phase of the light cycle and sex of the individual.     

Serotoninergic activation of the basolateral amygdala and modulation of tonic immobility in guinea pig

Tonic immobility (TI), also known as death feigning or animal hypnosis, is a reversible state of motor inhibition that is not only triggered by postural inversion and/or movement restraining maneuvers but also by repetitive stimulation and pressure on body parts. Evidence has demonstrated that the basolateral nucleus of the amygdala (BLA) is particularly associated with defensive behavior that involves the emotional states of fear and anxiety. In addition, some reports have demonstrated that serotonin (5-HT) released in the amygdala is increased during states of stress and anxiety, principally in the BLA. In the present study, we investigated the effects of serotonergic activation of the BLA on the duration of TI. The results showed that the microinjection of 5-HT (3.0 microg) into the BLA decreased the duration of TI. Similarly, the administration of a 5-HT1A agonist (0.1 microg of 8-hydroxy-dipropylaminotretalin) or 5-HT2 agonist (0.1 microg of alpha-methyl-5-HT) into the BLA reduced the TI duration. The effect of 5-HT2 agonist was reversed by pretreatment with a dose that had no effect per se (0.01 microg) of ketanserin (5-HT2 receptor antagonists) into the BLA. Moreover, the activation of 5-HT1A and 5-HT2 receptors in the BLA did not alter the spontaneous motor activity in the open field test. The results of the present study indicate that the serotonergic system of the BLA possibly produces a reduction in fear and/or anxiety that reduces the TI duration in guinea pigs, but this is not due to increased spontaneous motor activity induced by serotonergic activation, which might affect TI duration non-specifically.     

Sex differences in drug addiction and response to exercise intervention: From human to animal studies

Accumulated research supports the idea that exercise could be an option of potential prevention and treatment for drug addiction. During the past few years, there has been increased interest in investigating of sex differences in exercise and drug addiction. This demonstrates that sex-specific exercise intervention strategies may be important for preventing and treating drug addiction in men and women. However, little is known about how and why sex differences are found when doing exercise-induced interventions for drug addiction. In this review, we included both animal and human that pulled subjects from a varied age demographic, as well as neurobiological mechanisms that may highlight the sex-related differences in these potential to assess the impact of sex-specific roles in drug addiction and exercise therapies.     

Sex differences in amphetamine-elicited rotational behavior and the lateralization of striatal dopamine in rats

Sex differences are described in both a lateralized behavior (amphetamine-elicited rotation) and in the lateralization of striatal dopamine (DA) content. Amphetamine (AMPH) elicited significantly more partial turns, total rotations and lateralized (net) rotations in female, than in male rats. The two sexes also differed in their pattern of net rotations over time. In females, but not males, the striatum containing higher DA levels after amphetamine was consistently found to be contralateral to the dominant direction of rotation observed in the first 5 min interval after AMPH. No relationship was found between rotational behavior and medial frontal cortex DA or norepinephrine. The results are discussed in reference to cerebral lateralization in humans, and to possible sex differences in the modulatory effects of gonadal steroid hormones on striatal function.     

Sex differences in anxiety and depression: Role of testosterone

Compelling evidence exists for pervasive sex differences in pathological conditions, including anxiety and depressive disorders, with females more than twice as likely to be afflicted. Gonadal hormones may be a major factor in this disparity, given that women are more likely to experience mood disturbances during times of hormonal flux, and testosterone may have protective benefits against anxiety and depression. In this review we focus on the effects of testosterone in males and females, revealed in both human and animal studies. We also present possible neurobiological mechanisms underlying testosterone’s mostly protective benefits, including the brain regions, neural circuits, and cellular and molecular pathways involved. While the precise underlying mechanisms remain unclear, both activational and organizational effects of testosterone appear to contribute to these effects. Future clinical studies are necessary in order to better understand when and how testosterone therapy may be effective in both sexes.     

Mechanisms of Sex Differences in Fear and Posttraumatic Stress Disorder

Following sexual maturity, females disproportionately have higher rates of posttraumatic stress disorder (PTSD) and experience greater symptom severity and chronicity as compared with males. This observation has led many to examine sex differences in PTSD risk factors. Though relatively few, these studies reveal that the root causes of PTSD sex differences are complex, and partly represent interactions between sex-specific nonbiological and biological risk factors, which differentially shape PTSD vulnerability. Moreover, these studies suggest that sex-specific PTSD vulnerability is partly regulated by sex differences in fear systems. Fear, which represents a highly conserved adaptive response to threatening environmental stimuli, becomes pathological in trauma- and stress-based psychiatric syndromes, such as PTSD. Over the last 30 years, considerable progress has been made in understanding normal and pathological molecular and behavioral fear processes in humans and animal models. Thus, fear mechanisms represent a tractable PTSD biomarker in the study of sex differences in fear. In this review, we discuss studies that examine nonbiological and biological sex differences that contribute to normal and pathological fear behaviors in humans and animal models. This, we hope, will shed greater light on the potential mechanisms that contribute to increased PTSD vulnerability in females.     

Sex differences in medial prefrontal and parietal cortex structure in children with disruptive behavior

Sex differences in brain structure in children with disruptive behavior disorders (DBD) remain poorly understood. This study examined sex differences in gray matter volume in children with DBD in a priori regions-of-interest implicated in the pathophysiology of disruptive behavior. We then conducted a whole-brain analysis of cortical thickness to examine sex differences in regions not included in our hypothesis. Exploratory analyses investigated unique associations between structure, and dimensional measures of severity of disruptive behavior and callous-unemotional traits. This cross-sectional study included 88 children with DBD (30 females) aged 8–16 years and 50 healthy controls (20 females). Structural MRI data were analyzed using surface-based morphometry to test for interactions between sex and group. Multiple-regression analyses tested for sex-specific associations between structure, callous-unemotional traits, and disruptive behavior severity. Boys with DBD showed reduced gray matter volume in the left ventromedial prefrontal cortex (vmPFC) and reduced cortical thickness in the supramarginal gyrus, but not girls compared to respective controls. Dimensional analyses revealed associations between sex, callous-unemotional traits, and disruptive behavior for amygdala and vmPFC volume, and ventrolateral prefrontal cortex cortical thickness. Sex-specific differences in prefrontal structures involved in emotion regulation may support identification of neural biomarkers of disruptive behavior to inform target-based treatments.     

Die hard: a blend of freezing and fleeing as a dynamic defense--implications for the control of defensive behavior

Freezing, fleeing or fighting back are general defensive responses in many taxa. These defenses are mutually exclusive, since a prey cannot simultaneously flee and fight, or freeze and flee. Each of these defenses by itself is rudimentary and probably cannot provide a completely effective means to elude predation. Freezing is efficient only if employed before the prey is spotted by the predator, otherwise the prey becomes a stationary, easy to catch target. In fleeing, the prey can move directly away and maximize its distance from the predator, move toward the predator to confine it to a single clashing point, or dodge sideways to evade the attack. Prey can also run in a straight path that is efficient against slow or distant predators, or in a zigzag path that is efficient when a raptor is close or fast. In all, freezing and fleeing constitute together a complex and flexible defensive response, and are probably controlled by different motor systems that are inter-connected to allow fast switching between these behaviors, as required for an effective and versatile response.     

Changes in defensive behaviors following olfactory bulbectomy in male and female rats

The present study examined if olfactory bulbectomy (OBX) altered defensive behaviors on the elevated plus-maze and the open-field differently in male and female rats. Similar increases in defensive behaviors in male and female rats were observed in both tests following OBX. No significant correlations were detected between defensive behaviors and activity, supporting the hypothesis that some behavioral changes following OBX may be due to decreased defensive behaviors and not increased activity.     

Sex and strain differences in morphine-induced temperature effects in WKYs and SHRs

Male and female normotensive Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) all responded to morphine treatment with biphasic dose-response curves, exhibiting hyperthermia at low doses and hypothermia at higher doses. However the direction and magnitude of temperature changes induced by different doses of morphine varied significantly depending upon the sex and strain (WKY vs. SHR) of the test animals. Both WKY and SHR males responded with little change in temperature at 1.0 mg/kg and hyperthermia at 5.0 mg/kg. Hypothermia appeared in SHR males at 10 mg/kg, while hypothermia in WKY males was not seen until 20 mg/kg was administered. Both WKY and SHR females demonstrated a greater sensitivity than their male counterparts to the thermotropic effects of morphine, exhibiting hyperthermia at 1.0 mg/kg, which was greater than the hyperthermia exhibited by male rats, and progressively greater hypothermia at 2.0, 5.0 and 10 mg/kg. SHR females demonstrated hypothermia at lower doses of morphine than did WKY females but were otherwise not different. These findings indicate that (1) morphine-induced temperature effects in SHRs and WKYs are dependent upon dose; (2) SHRs seem more sensitive than WKYs to the hypothermic effects of morphine; and (3) female rats seem more sensitive than male rats to the thermotropic effects of morphine in general.     

Risk assessment as an evolved threat detection and analysis process

Risk assessment is a pattern of activities involved in detection and analysis of threat stimuli and the situations in which the threat is encountered. It is a core process in the choice of specific defenses, such as flight, freezing, defensive threat and defensive attack, that counter the threat and minimize the danger it poses. This highly adaptive process takes into account important characteristics, such as type and location (including distance from the subject) of the threat, as well as those (e.g. presence of an escape route or hiding place) of the situation, combining them to predict which specific defense is optimal with that particular combination of threat and situation. Risk assessment is particularly associated with ambiguity either of the threat stimulus or of the outcome of available defensive behaviors. It is also crucial in determining that threat is no longer present, permitting a return to normal, nondefensive behavior. Although risk assessment has been described in detail in rodents, it is also a feature of human defensive behavior, particularly in association with ambiguity. Rumination may be a specifically human form of risk assessment, more often expressed by women, and highly associated with anxiety.Risk assessment behaviors respond to drugs effective against generalized anxiety disorder; however, flight, a dominant specific defense in many common situations, shows a pharmacological response profile closer to that of panic disorder. Risk assessment and flight also appear to show some consistent differences in terms of brain regional activation patterns, suggesting a potential biological differentiation of anxiety and fear/panic systems. An especially intriguing possibility is that mirror neurons may respond to some of the same types of situational differences that are analyzed during risk assessment, suggesting an additional functional role for these neurons.     

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.     

Behavioral correlates of chronic dominance-subordination relationships of male rats in a seminatural situation

Detailed characterization and analysis of intraspecific aggressive and defensive behaviors of rats in mixed sex groups is beginning to provide an understanding of the complex pattern of behavioral and physiological change associated with variation in dominance status. These findings indicate that male subordination dramatically reduces longevity and produces a pattern of behavior changes very similar to the defenses elicited by predatory exposure. In addition, many of these changes are, in detail, isomorphic to important behavioral features of clinical depression.     

Sex differences in anxiety and depression clinical perspectives

Sex differences are prominent in mood and anxiety disorders and may provide a window into mechanisms of onset and maintenance of affective disturbances in both men and women. With the plethora of sex differences in brain structure, function, and stress responsivity, as well as differences in exposure to reproductive hormones, social expectations and experiences, the challenge is to understand which sex differences are relevant to affective illness. This review will focus on clinical aspects of sex differences in affective disorders including the emergence of sex differences across developmental stages and the impact of reproductive events. Biological, cultural, and experiential factors that may underlie sex differences in the phenomenology of mood and anxiety disorders are discussed.     

Antipredator responses and defensive behavior: ecological and ethological approaches for the neurosciences

In nature, animals are exposed to a wide range of threats and dangers with predators being amongst the more prominent and intensely studied of these. The responses of prey to predators and various predator avoidance and antipredator behaviors have been extensively evaluated from ecological and ethological perspectives and more recent ethopharmacological and neuroscience approaches. Unfortunately, there has been relatively little interchange between the ecological–ethological and neuroscience areas with the latter often using responses to predators just simply as another ‘model’ system. There is, however, now a growing realization that integrative approaches incorporating ecological, evolutionary and neurobiological explanations are required for the understanding of behavior and its functions. This necessitates an incorporation of ecological and ethological concepts and validity with neuroscience approaches to the analysis of antipredator responses and defensive behavior. A number of selected ecological approaches that are used for the investigation of predator avoidance mechanisms and antipredator defensive behavior patterns are briefly reviewed here. These include examinations of how predation risk and its variation affect decision making in animals and how learning affects these responses. The trade-offs that are involved, how the risk of predation affects decisions concerning foraging behavior, mating and reproduction, as well as how varying levels of risk affect decisions relative to the type of defensive mechanisms utilized are briefly outlined. The utility of these approaches and their relevance to the design and interpretation of various neuroscience studies is addressed here.     

Modulation of defensive behavior by periaqueductal gray NMDA/glycine-B receptor

Glutamate (GLU) associated with glycine, act as co-transmitter at the N-methyl-D-aspartate/glycine-B (NMDA/GLY(B)) receptor. Dorsal periaqueductal gray (dPAG) neurons express NMDA/GLY(B) receptors suggesting a GLU physiological role in mediating the responses elicited by stimulation of this area. Immunohistochemical data provided evidence of a possible correlation among elevated plus-maze (EPM), fear-like defensive behavior, and dPAG activity. The present data show that whereas the NMDA/GLY(B) receptor agonists increased the open-arm avoidance responses in the EPM, the antagonists had the opposite effects. Microinjection of NMDA/GLY(B) receptor agonists within the dPAG during test sessions in the EPM resulted in an enduring learned fear response detected in the retest. Therefore, in addition to the proposed role for the dPAG in panic attacks (escape), these findings suggest that the dPAG can also participate in more subtle anxiety-like behaviors.