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Neural Systems Involved in Fear‐Potentiated Startle
Abstract
The acoustic startle reflex offers a number of advantages for analyzing the neural bases of behavior. Startle apparently is mediated by excitatory amino acids at several of the synapses that comprise the short-latency startle pathway. The reflex is modulated by a variety of neurotransmitters at both the spinal and the supraspinal levels. In addition to showing habituation and sensitization, startle is increased in the presence of a fear stimulus. This may result from activation of the central nucleus of the amygdala which projects directly tot he acoustic startle pathway. A major challenge for future studies will be to determine what neurotransmitters, which are known to modulate startle, are involved in habituation, sensitization, and fear conditioning and to begin to analyze these processes at a cellular level.
... There is no single circuit in the brain responsible for the termination of movement. Instead, multiple neural systems appear to carry out the process depending on the specific set of circumstances that require it [1][2][3][4][5][6][7][8]. ...
... When an animal is surprised by a bright light or loud noise, it activates the startle reflex, which causes a strong increase in muscle tone and termination of ongoing behaviour. This is an unconscious action that occurs prior to cognitive assessment of a situation, but which can be modulated by conditions such as fear or experience [7,[69][70][71]. Most studies have focused on the jump-like reflex that occurs during presentation of the surprising stimulus, but recent work has looked at the arresting effects of startle in ongoing behaviour. ...
... In agreement with this role, the superficial SC was shown to contain a population of parvalbumin-positive excitatory neurons that could drive defensive behaviours including freezing and escape [79]. This population projects to the parabigeminal nucleus of the brainstem, which neighbours the MLR and PRF and has been implicated in the startle response [7]. In both these neighbouring regions, GABAergic neuron activity has been shown to halt ongoing behaviour and locomotion [25,65], suggesting a generalized role for GABAergic activity in this area. ...
The ability to stop ongoing movement is fundamental to animal survival. Behavioural arrest involves the hierarchical integration of information throughout the forebrain, which ultimately leads to the coordinated inhibition and activation of specific brainstem motor centres. Recent advances have shed light on multiple regions and pathways involved in this critical behavioural process. Here, we synthesize these new findings together with previous work to build a more complete understanding of the circuit mechanisms underlying suppression of ongoing action. We focus on three specific conditions leading to behavioural arrest: goal completion, fear and startle. We outline the circuitry responsible for the production of these behaviours and discuss their dysfunction in neurological disease.
This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’.
... Davis, 1980;Hoffman and Fleshler, 1963;Leaton, 1976). The unconditional startle response to the loud noise can be potentiated if the loud noise is delivered in the presence of a cue or a context that has been associated with shock/fear (Brown et al., 1951;Davis, 1989). While our 75 dB noise stimulus is less intense than the 98-120 dB noise used in typical acoustic startle studies, we observed an unconditional noise-elicited response that also decreased with habituation (Experiment 4). ...
... Furthermore, our data and those of Totty et al., 2021 indicate that these responses require a fearful context in order to occur. Fear is well known to potentiate startle responses (Brown et al., 1951;Davis, 1989). Perhaps the low intensity noise is below threshold to elicit a startle response on its own, but a fearful context potentiates this unconditional startle response and brings it above threshold. ...
Fear conditioning is one of the most frequently used laboratory procedures for modeling learning and memory generally, and anxiety disorders in particular. The conditional response (CR) used in the majority of fear conditioning studies in rodents is freezing. Recently, it has been reported that under certain conditions, running, jumping or darting replaces freezing as the dominant CR. These findings raise both a critical methodological problem and an important theoretical issue. If only freezing is measured but rodents express their learning with a different response, then significant instances of learning, memory, or fear may be missed. In terms of theory, whatever conditions lead to these different behaviors may be a key to how animals transition between different defensive responses and different emotional states. In mice, we replicated these past results but along with several novel control conditions. Contrary to the prior conclusions, running and darting were primarily a result of nonassociative processes and were actually suppressed by associative learning. Darting and flight were taken to be analogous to nonassociative startle or alpha responses that are potentiated by fear. Additionally, associative processes had some impact on the topography of flight behavior. On the other hand, freezing was the purest reflection of associative learning. We also uncovered a rule that describes when these movements replace freezing: When afraid, freeze until there is a sudden novel change in stimulation, then burst into vigorous flight attempts. This rule may also govern the change from fear to panic.
... The fear potentiated startle (FPS) is a potentiation of this response towards threatening stimuli (e.g. a CS+) as compared to stimuli that are neutral or safe (e.g. ITI or CS-) [64] . In animals, FPS reflects a basic brainstem reflex modulated by the amygdala [64] and the neural basis of FPS in humans has more recently begun to be explored [65]. ...
... ITI or CS-) [64] . In animals, FPS reflects a basic brainstem reflex modulated by the amygdala [64] and the neural basis of FPS in humans has more recently begun to be explored [65]. FPS has been used as a dependent variable in several experiments employing Pavlovian fear conditioning [62,66,67]. ...
Across the human life span, fear is often acquired indirectly by observation of the emotional expressions of others. The observational fear conditioning protocol was previously developed as a laboratory model for investigating socially acquired threat responses. This protocol serves as a suitable alternative to the widely used Pavlovian fear conditioning, in which threat responses are acquired through direct experiences. In the observational fear conditioning protocol, the participant (observer) watches a demonstrator being presented with a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US). The expression of threat learning is measured as the conditioned response (CR) expressed by the observer in the absence of the demonstrator. CRs are commonly measured as skin conductance responses, but behavioral and neural measures have also been implemented. The experimental procedure is suitable for divergent populations, can be administered by a graduate student and takes ~40 min. Similar protocols are used in animals, emphasizing its value as a translational tool for studying socioemotional learning.
... The well-established phenomenon of fear-potentiated startle (FPS; Davis, 1989) provides a noninvasive methodology for examining the effects of drugs on subcortical emotion systems in humans. Numerous studies have shown that the startle response to an abrupt, intense stimulus (e.g., loud noise) increases above baseline when elicited in the presence of a cue that has been paired with shock. ...
... The subcortical amygdala is recognized as central to fear processing because it projects directly to defensive action systems (including the startle reflex circuit; Davis, 1989;Fanselow, 1994). However, the amygdala receives afferent input from various brain regions, including primary sensory structures (i.e., thalamus, sensory cortex) and also higher associative systems such as the hippocampus. ...
... In animals and humans, startle increases during threat, and this effect is blocked by anxiolytic drugs (Davis, 1979(Davis, , 1986Patrick, Berthot, & Moore, 1996). In animals, Davis (1989) showed that fear-potentiated startle is mediated by the amygdala, a cornerstone of the aversive system (Fanselow, 1994;LeDoux, 1995). The absence of normal startle potentiation in psychopaths signifies a weakness in the capacity of aversive cues to prime defen-sive actions: in this case, to intensify a protective reflex but perhaps more broadly to interrupt goal seeking and promote avoidance of danger. ...
... Therefore, consistent with most prior research involving the startle probe paradigm (cf. Anthony, 1985;Davis, 1989;Lang, 1995), present analyses focused on patterns of startle modulation, in particular, blink inhibition or potentiation for pleasant and unpleasant pictures in relation to the neutral reference condition. A distributional analysis of the standard score data revealed few (<0.6%) outlying scores greater than + 3 standard deviations); these scores were corrected by "fencing in." ...
This study extended prior work showing abnormal affect–startle modulation in psychopaths. Male prisoners viewed specific categories of pleasant (erotic or thrilling) and unpleasant (victim or direct threat) slide pictures, along with neutral pictures. Acoustic startle probes were presented early (300 and 800 ms) and late (1,800, 3,000, and 4,500 ms) in the viewing interval. At later times, nonpsychopaths showed moderate and strong reflex potentiation for victim and threat scenes, respectively. For psychopaths, startle was inhibited during victim scenes and only weakly potentiated during threat. Psychopaths also showed more reliable blink inhibition across pleasant contents than nonpsychopaths and greater heart rate orienting to affective pictures overall. These results indicate a heightened aversion threshold in psychopaths. In addition, deficient reflex modulation at early times suggested a weakness in initial stimulus evaluation among psychopaths. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
... similar to fear-potentiated startle (Brown et al., 1951;Davis, 1989). In humans, freezing behavior to threatening cues predicts subsequent startle magnitude to unexpected stimuli (van Ast et al., 2022). ...
We describe the close correspondence between predatory imminence continuum theory (PICT) and the National Institute of Mental Health’s Research Domain Criteria (RDoC) for negative valence. RDoC’s negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. PICT divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat. While there is a close correspondence between PICT modes and negative valence threat constructs, based on PICT, we describe some potential elaborations of RDoC constructs. Both have consonant views of fear and anxiety and provide explicit distinctions between these emotional states, relating them to specific defensive behaviors and functions. We describe recent data that causally implicate human subjective emotional states with amygdala activity, which is also critical for defensive behavior. We conclude that attention to neuroethological views of defense can advance our understanding of the etiology and treatment of anxiety and stress disorders.
... These models assume the causal role of interoceptive information in the development of affective experience thus they are called peripheral theories of emotion. Central theories do not suppose such a causal link (Cannon, 1927(Cannon, , 1931Panksepp, 1982Panksepp, , 1991Oatley and Johnson-laird, 1987;Davis, 1989;LeDoux, 1990); still, they accept that emotions are typically characterized by peripheral changes that prepare the organism for the behavioral response. As a proportion of these changes, both visceral and somatosensory, may reach conscious awareness, an association between the emotional experience and the perception of body changes can be explained by central theories too. ...
Interoception in the broader sense refers to the perception of internal states, including the perception of the actual state of the internal organs (visceroception) and the motor system (proprioception). Dimensions of interoception include (1) interoceptive accuracy, i.e., the ability to sense internal changes assessed with behavioral tests, (2) confidence rating with respect to perceived performance in an actual behavioral test, and (3) interoceptive sensibility, i.e., the self-reported generalized ability to perceive body changes. The relationship between dimension of cardioceptive and proprioceptive modalities and their association with affect are scarcely studied. In the present study, undergraduate students (N = 105, 53 males, age: 21.0 ± 1.87 years) filled out questionnaires assessing positive and negative affect (Positive and Negative Affect Schedule), interoceptive sensibility (Body Awareness Questionnaire), and body competence (Body Competence Scale of the Body Consciousness Questionnaire). Following this, they completed a behavioral task assessing cardioceptive accuracy (the mental heartbeat tracking task by Schandry) and two tasks assessing proprioceptive accuracy with respect to the tension of arm flexor muscles (weight discrimination task) and the angular position of the elbow joint (joint position reproduction task). Confidence ratings were measured with visual analog scales after the tasks. With the exception of a weak association between cardioceptive accuracy and the respective confidence rating, no associations between and within modalities were found with respect to various dimensions of interoception. Further, the interoceptive dimensions were not associated with state and trait positive and negative affect and perceived body competence. In summary, interoceptive accuracy scores do not substantially contribute to conscious representations of cardioceptive and proprioceptive ability. Within our data, non-pathological affective states (PANAS) are not associated with the major dimensions of interoception for the cardiac and proprioceptive modalities.
... Specifically, we aim to distinguish between three hypothetical response profiles with distinct functional interpretation: a) emotional visual stimuli produce an immediate displacement leading to a maximum deviation from postural equilibrium, which is then immediately restored by a compensatory adjustment, b) stimuli produce a displacement followed by a short period of immobility and a return to baseline while the stimulus is still visible, c) stimuli evoke a postural displacement that persists throughout the stimulus presentation period. The first hypothet-ical response profile portrays the postural component of the locomotor startle reflex, which serves as an interruption of ongoing activity in order to evaluate a potentially harmful situation 32 Our investigation is the first to demonstrate that humans respond to briefly-presented affective pictures with phasic postural displacements directly associated with individual stimuli. Specifically, we find an identical postural response pattern for pictures from all affective categories, while the amplitude of postural deviations from equilibrium varies as a function of the induced emotion (stimulus significance). ...
Erotic scenes and images of mutilated bodies are emotional stimuli that have repeatedly shown to evoke specific neurophysiological responses associated with enhanced attention and perceptual processing. Remarkably however, only a handful of studies have investigated human motor reactions to emotional activation as a direct index of physical approximation or withdrawal. Given the inconclusive results of these studies, the approach-avoidance distinction, one of the most salient concepts in human motivational research, remains a broadly exploited hypothesis that has never been empirically demonstrated. Here, we investigate postural responses elicited by discrete emotional stimuli in healthy young adults. We discover that both positive and negative affective pictures induce a significant posterior deviation from postural baseline equilibrium. Further, we find that neutral pictures also evoke posterior deviation, although with a less pronounced amplitude. Exploring the dynamical evolution of postural responses to emotional pictures at high temporal resolution, we uncover a characteristic profile that remains stable for stimuli from all three affective categories. In contrast, the postural response amplitude is modulated by the emotional content of the stimulus. Our observations do not support the interpretation of postural responses to affective picture-viewing as approach-avoidance behavior. Instead, our findings indicate the involvement of a previously unrecognized motor component of the physiological mechanism underlying human orienting responses.
... The magnitude of the acoustic startle reflex increases when aversive cues, such as Pavlovian conditioned stimuli (conditional stimulus (CS)), are presented with the startle stimulus (Davis, 1989). Fear-potentiated startle then refers to an increase in the magnitude of the acoustic startle reflex when the CS is presented versus startle trials in the absence of the CS. ...
Prior studies suggest that levels of ovarian hormones may affect learning and memory in rats, including studies of fear conditioning and extinction. We previously showed that female rats show reduced retention of extinction compared to males when measuring fear-potentiated startle, but not when measuring freezing behavior. One commonly reported observation in studies of freezing behavior is that rats with increased levels of estradiol during extinction learning show better retention of extinction than rats given extinction training when levels of estradiol are low. Here, we tested the hypothesis that fear extinction retention in a fear-potentiated startle paradigm in females is influenced by levels gonadal hormones, which we had not accounted for in our original report. We used the fear-potentiated startle paradigm to test if extinction learning was affected by estrous phase, ovariectomy, or acute systemic injections of estradiol in ovariectomized rats. We report that neither the expression nor extinction of fear-potentiated startle differed in rats given extinction training in proestrus compared to those in metestrus. Removal of the ovaries had no effect on fear acquisition or extinction learning as assessed by fear-potentiated startle. Finally, systemic injections of estradiol given to ovariectomized rats before extinction training had no effect on the expression of fear or the retention of extinction. Our findings suggest that the effect of female gonadal hormones on fear conditioning and extinction may depend on the measure of fear employed or by the parameters used to study fear learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
... (b) Basic circuitry of the startle reflex. The nc gigantocellularis in the caudal and ventral part of the nucleus pontis caudalis receives input from various sensory sources and is involved in producing startle [121,122]. Adapted from [123]. CC BY 2.0. ...
This paper provides an update on the neural control of bipedal walking in relation to bioinspired models and robots. It is argued that most current models or robots are based on the construct of a symmetrical CPG (central pattern generator). However, new evidence suggests that CPG functioning is basically asymmetrical with its flexor half linked more tightly to the rhythm generator. The stability of bipedal gait, which is an important problem for robots and biological systems, is also addressed. While it is not possible to determine how biological biped systems guarantee stability, robot solutions can be useful to propose new hypothesis for biology. In the second part of this review, the focus is on gait perturbations, which is an important topic in robotics in view of the frequent falls of robots when faced with perturbations. From the human physiology it is known that the initial reaction often consists of a brief interruption followed by an adequate response. For instance, the successful recovery from a trip is achieved using some basic reactions (termed elevating and lowering strategies), that depend on the phase of the step cycle of the trip occurrence. Reactions to stepping unexpectedly in a hole depend on comparing expected and real feedback. Implementation of these ideas in models and robotics starts to emerge, with the most advanced robots being able to learn how to fall safely and how to deal with complicated disturbances such as provided by walking on a split-belt.
... Much work on the output of amygdala activation has led to a greater understanding of many of the downstream neural pathways that mediate the enhanced startle response, hyperarousal, increased heart rate, and other core aspects of response to fear and threats. [26][27][28][29][30] From this perspective, a wide range of treatments for PTSD may share a central therapeutic mechanism of restoring balance between PFC and amygdala function. Selective serotonin reuptake inhibitors may exert their benefit by decreasing hyperreactivity in the amygdala. ...
Importance:
Posttraumatic stress disorder (PTSD) is a common psychiatric illness, increasingly in the public spotlight in the United States due its prevalence in the soldiers returning from combat in Iraq and Afghanistan. This educational review presents a contemporary approach for how to incorporate a modern neuroscience perspective into an integrative case formulation. The article is organized around key neuroscience "themes" most relevant for PTSD. Within each theme, the article highlights how seemingly diverse biological, psychological, and social perspectives all intersect with our current understanding of neuroscience.
Observations:
Any contemporary neuroscience formulation of PTSD should include an understanding of fear conditioning, dysregulated circuits, memory reconsolidation, epigenetics, and genetic factors. Fear conditioning and other elements of basic learning theory offer a framework for understanding how traumatic events can lead to a range of behaviors associated with PTSD. A circuit dysregulation framework focuses more broadly on aberrant network connectivity, including between the prefrontal cortex and limbic structures. In the process of memory reconsolidation, it is now clear that every time a memory is reactivated it becomes momentarily labile-with implications for the genesis, maintenance, and treatment of PTSD. Epigenetic changes secondary to various experiences, especially early in life, can have long-term effects, including on the regulation of the hypothalamic-pituitary-adrenal axis, thereby affecting an individual's ability to regulate the stress response. Genetic factors are surprisingly relevant: PTSD has been shown to be highly heritable despite being definitionally linked to specific experiences. The relevance of each of these themes to current clinical practice and its potential to transform future care are discussed.
Conclusions and relevance:
Together, these perspectives contribute to an integrative, neuroscience-informed approach to case formulation and treatment planning. This may help to bridge the gap between the traditionally distinct viewpoints of clinicians and researchers.
... In contrast, some previous SocAnh research did not find any alteration of blink magnitude in a startle probe response paradigm using both positive and negative stimuli (Gooding et al., 2002). Importantly, blink magnitude reflects a defensive reflex (Lang, Bradley, & Cuthbert, 1990) that is mediated by direct projections from the amygdala to the nucleus reticularis pontis caudalis, a structure in the brainstem (e.g., Davis, 1989;Hitchcock & Davis, 1987;Miserendino & Davis, 1993). Thus, the startle probe is thought to reflect the influence of primarily subcortical brain regions. ...
Both extreme levels of social anhedonia (SocAnh) and perceptual aberration/magical ideation (PerMag) are associated with risk for schizophrenia-spectrum disorders and with emotional abnormalities. Yet, the nature of any psychophysiological-measured affective abnormality, including the role of automatic/controlled processes, is unclear. We examined the late positive potential (LPP) during passive viewing (to assess automatic processing) and during cognitive reappraisal (to assess controlled processing) in three groups: SocAnh, PerMag, and controls. The SocAnh group exhibited an increased LPP when viewing negative images. Further, SocAnh exhibited greater reductions in the LPP for negative images when told to use strategies to alter negative emotion. Similar to SocAnh, PerMag exhibited an increased LPP when viewing negative images. However, PerMag also exhibited an increased LPP when viewing positive images as well as an atypical decreased LPP when increasing positive emotion. Overall, these results suggest that at-risk groups are associated with shared and unique automatic and controlled abnormalities.
... There is a rich literature on startle potentiation as an index of defensive reactivity in animals and humans. Davis and colleagues (e.g., Davis, 1989 ;Davis, Falls, Campeau, & Kim, 1993 ) mapped the neural circuitry of fear -potentiated startle, defined as increased magnitude of the whole -body reaction to an abrupt noise probe in the presence of a fear cue, in animals. These investigators showed that the mecha- nism for this effect is a pathway from the central nucleus of the amygdala to the pontine reticular node of the basic startle circuit. ...
... As suggested by Matthys et al. (2013), before adequate cognitive control of emotions generated by the prefrontal cortex can occur, external stimuli associated with reward and punishment need to be processed by the Autonomic Nervous System (ANS) that regulates HR and SC responses. Established evidence also suggest that the amygdala, which are associated with emotional processing, controls psychophysiological components of defensive responding, such as autonomic and startle reactivity to fear stimuli (Davis, 1989;Patrick, 1994). ...
... Empirically, fearlessness in individuals with psychopathic traits has been documented by the absence or restricted display of startle potentiation during exposure to fearful or aversive stimuli. It is important to note that the absence of aversive startle potentiation may reflect diminished amygdala activity, which is theoretically and empirically linked to fear (e.g., Davis, 1989;Kramer, Patrick, Krueger, & Gasperi, 2012;Patrick, 1994). Aversive startle potentiation is reduced among fearless individuals or persons scoring high on the PCL-R's affective-interpersonal or the Psychopathic Personality Inventory's fearless dominance dimensions of psychopathy but not the impulsive-antisocial dimension (Benning et al., 2005;Fanti, Panayiotou, Kyranides, & Avramides, 2016;Vaidyanathan, Patrick, & Bernat, 2009;Vanman, Mejia, Dawson, Schell, & Raine, 2003). ...
This study examined associations of psychopathy facets of boldness, meanness, and disinhibition with clinically relevant variables and physiological reactivity to affective stimuli. These associations were examined after accounting for developmental associations with adolescent psychopathic traits, namely callous-unemotional traits, narcissism, and impulsivity. Psychopathic traits were assessed during adolescence using the Antisocial Process Screening Device and the Inventory of Callous Unemotional traits and during young adulthood via the Triarchic Psychopathy Measure. Clinical variables (N = 99, Mage = 15.91, 53% female), as well as affective and physiological responses (heart rate, skin conductance, startle modulation) to violent and erotic videos (N = 88, Mage = 19.92, 50% female) were also assessed during adulthood. After accounting for adolescent psychopathic traits, boldness was associated with high cognitive reappraisal and low anxiety, fear, and hostility, and meanness was related to callous-unemotional traits, hostility, less sympathy to victims, and less use of cognitive reappraisal. Disinhibition, by contrast, was associated with impulsivity, increased anxiety, and hostile and aggressive tendencies, as well as conduct disorder, antisocial personality disorder symptoms, and cognitive suppression. In addition, evidence was found for different physiological measures operating as biological indicators of these distinctive dimensions, with reduced resting heart rate and cardiac reactivity to violent stimuli indicative of boldness, above and beyond adolescent psychopathic traits, and low startle potentiation for violent stimuli indicative of callous-unemotional traits and meanness. These findings provide evidence for the value of a multidomain approach for clarifying neurobiological mechanisms of psychopathic tendencies that can inform prevention and treatment efforts. (PsycINFO Database Record
... Fear-potentiated startle refers to a phenomenon that the magnitude of the acoustic startle reflex is augmented in the presence of a cue (e.g., a light) that has previously been paired with a shock [2]. In the test, a neutral stimulus (termed conditioned stimulus, CS) is first paired with a shock, and then the animal's startle reflex is compared in either the presence or the absence of the CS. ...
Fear-potentiated startle (FPS) and prepulse inhibition (PPI) of acoustic startle are two widely used paradigms specifically designed to capture the impact of negative emotion (e.g. fear) and preattentive function on startle response. Currently, there is no single paradigm that incorporates both FPS and PPI, making it impossible to examine the potential interactions between fear and attention in the regulation of startle response. In this study, we developed an integrated FPS and PPI test protocol and validated it with psychoactive drugs. In Experiment 1, male Sprague-Dawley rats were randomly assigned to one of five groups, receiving either Light -Shock conditioning trials, non-overlapping Lights and Shocks, Light alone, Shock alone, or no Light and Shock. They were then tested for startle response and PPI concurrently, under the Light or No Light. FPS was observed only in rats subjected to fear conditioning, whereas all rats showed PPI and startle habituation. Experiment 2 used this paradigm and demonstrated a dissociative effect between diazepam (an anxiolytic drug) and phencyclidine (a nonselective NMDA receptor antagonist) on FPS and PPI. Diazepam suppressed both FPS and PPI, while PCP selectively disrupted PPI but not FPS. The diazepam's anxiolytic effect on FPS was further confirmed in the elevated plus maze test. Together, our findings indicate that our paradigm combines FPS and PPI into a single paradigm, and that is useful to examine potential interactions between multiple psychological processes, to identify the common neural substrates and to screen new drugs with multiple psychoactive effects.
... The medial portion of the CeN sends GABAergic projections to the regions responsible for individual fear behaviors, such as the periaqueductal gray (vPAG) (freezing, analgesia, vocalization), hypothalamus (hormonal responses and hypertension), dorsal motor nucleus of the vagus (heart rate), and nucleus reticularis pontis caudalis ( potentiated startle) (Davis 1989). GABAergic circuitry within the CeN regulates this output (Haubensak et al. 2010). ...
Pavlovian conditioning is the process by which we learn relationships between stimuli and thus constitutes a basic building block for how the brain constructs representations of the world. We first review the major concepts of Pavlovian conditioning and point out many of the pervasive misunderstandings about just what conditioning is. This brings us to a modern redefinition of conditioning as the process whereby experience with a conditional relationship between stimuli bestows these stimuli with the ability to promote adaptive behavior patterns that did not occur before the experience. Working from this framework, we provide an in-depth analysis of two examples, fear conditioning and food-based appetitive conditioning, which include a description of the only partially overlapping neural circuitry of each. We also describe how these circuits promote the basic characteristics that define Pavlovian conditioning, such as error-correction-driven regulation of learning.
... The amygdala is closely tied to emotional processing and control of fear, and is directly involved in orienting attention, perception, and action toward motivated goals (Davis & Whalen, 2001;Lang et al., 1997;Lang & Davis, 2006;LeDoux, 2000). A significant body of research has identified three main pathways stemming from the amygdala that control aspects of defensive responding: (1) projections from the central nucleus of the amygdala to the lateral hypothalamus, which underlie autonomic responding; (2) afferents from the amygdala to the midbrain central gray, which mediate freezing and other behavioral coping strategies; and (3) direct projections from the amygdala to the reticularis pon caudalis, which modulate fear-conditioned startle responses (Davis, 1989). Normative functioning across these pathways is necessary for effective emotional expression and regulation, emotional learning and memory, and motivated behavior (Thompson, Lewis, & Calkins, 2008). ...
Child maltreatment is associated with disruptions in physiological arousal, emotion regulation, and defensive responses to cues of threat and distress, as well as increased risk for callous unemotional (CU) traits and externalizing behavior. Developmental models of CU traits have focused on biological and genetic risk factors that contribute to hypoarousal and antisocial behavior, but have focused less on environmental influences (Blair, 2004; Daversa, 2010; Hare, Frazell, & Cox, 1978; Krueger, 2000; Shirtcliff et al., 2009; Viding, Fontaine, & McCrory, 2012). The aim of the present investigation was to measure the independent and combined effects of child maltreatment and high CU traits on emotion-modulated startle response in children. Participants consisted of 132 low-income maltreated (
n
= 60) and nonmaltreated (
n
= 72) children between 8 and 12 years old who attended a summer camp program. Acoustic startle response (ASR) was elicited in response to a 110-dB 50-ms probe while children viewed a slideshow of pleasant, neutral, and unpleasant IAPS images. Maltreatment status was assessed through examination of Department of Human Services records. CU traits were measured using counselor reports from the Inventory of Callous and Unemotional Traits (Frick, 2004), and conduct problems were measured using counselor and child self-report. We found no significant differences in emotion-modulated startle in the overall sample. However, significant differences in ASR by maltreatment status, maltreatment subtype, and level of CU traits were apparent. Results indicated differential physiological responses for maltreated and nonmaltreated children based on CU traits, including a pathway of hypoarousal for nonmaltreated/high CU children that differed markedly from a more normative physiological trajectory for maltreated/high CU children. Further, we found heightened ASR for emotionally and physically neglected children with high CU and elevated antisocial behavior in these children. Results provide further support for differential trajectories by which experience and biology may influence the development of antisocial behavior in youth and highlight potential avenues for intervention.
... This will be examined both by a yawning paradigm designed by the current researchers (modeled after Platek et al., 2005) as well as an emotion-related startle paradigm (ERS) previously used in Anderson, Stanford, Wan, and Young (2011). Affective potentiation of the acoustic startle reflex (by Electromyograph [EMG] and Galvanic skin response [GSR]) is one of the most prominent psychophysiological measures of amygdalar responsiveness (Davis, 1989;Lang, Bradley, and Cuthbert, 1990;LeDoux, Iwata, Cicchetti, and Reis, 1988). Psychopaths reliably demonstrate an impairment of potentiation of the startle reflex (Patrick, Bradley, and Lang, 1993), while healthy controls reliably potentiate with negative affective valence and attenuate the fear response with positive affective valences (Lang et al., 1990). ...
Psychopathy is characterized by a general antisocial lifestyle with behaviors including being selfish, manipulative, impulsive, fearless, callous, possibly domineering, and particularly lacking in empathy. Contagious yawning in our species has been strongly linked to empathy. We exposed 135 students, male and female, who completed the Psychopathic Personality Inventory-Revised (PPI-R), to a yawning paradigm intended to induce a reactionary yawn. Further, we exposed males to an emotion-related startle paradigm meant to assess peripheral amygdalar reactivity. We found that scores on the PPI-R subscale Coldheartedness significantly predicted a reduced chance of yawning. Further, we found that emotion-related startle amplitudes were predictive of frequency of contagious yawning. These data suggest that psychopathic traits may be related to the empathic nature of contagious yawning in our species.
... There is a rich literature on startle potentiation as an index of defensive reactivity in animals and humans. Davis and colleagues (e.g., Davis, 1989 ;Davis, Falls, Campeau, & Kim, 1993 ) mapped the neural circuitry of fear -potentiated startle, defined as increased magnitude of the whole -body reaction to an abrupt noise probe in the presence of a fear cue, in animals. These investigators showed that the mecha- nism for this effect is a pathway from the central nucleus of the amygdala to the pontine reticular node of the basic startle circuit. ...
1Conceptualization and Assessment of Psychopathy2Empirical Evidence That Psychopathy Is Not Unitary3Two-Process Theory of Psychopathy4Refining the Measurement of Trait Fear and Externalizing Constructs5Physiological Response Indicators of Trait Fear and Externalizing6SummaryKeywords:psychopathy;antisocial personality;externalizing;emotion;fear;disinhibition;personality;startle;event-related potentials;error-related negativity;ERN;P300;time-frequency analysis
... It is quite clear that the operations of higher evaluative substrates can bias or modulate lower reflex mechanisms. One example is the priming of reflexive startle responses by aversive stimuli or contexts, as suggested by Brown, Kalish, and Farber,82 and more recently investigated by Davis, 83 Hoffman and I s~n ,~~ and Lang and colleagues." While the necessary pathways for the primary startle response lie entirely within the brainstem,83 higher limbic mechanisms appear to be essential for startle potentiation associated with conditioned Direct stimulation of the amygdala, for example, can enhance startle reflexes.x3 ...
The principle of evaluative bivalence asserts that behavioral processes often organize along the evaluative dimension, due to a fundamental pattern of bivalent neurobehavioral organization extending throughout the neuraxis. This principle offers a powerful approach to the explication of complex behavioral relationships and the integration of diverse literatures. It also offers a guiding conceptual framework for the study of neurobehavioral relationships which holds the promise of integrating rather than diversifying the study of neural mechanisms for disparate behavioral phenomena.
... Avoidance of light in a light/dark box is melanopsin-108,109 and ipRGC-dependent98 however anxiety from novel environments increases the level of light aversion,98,110 indicating that ipRGCs mediate both innate and anxiety-induced light aversion. The aversive capacity of light is also observed in mice in pavlovian, associative conditioning to a noxious stimulus.111,112 Normal and melanopsin-deficient mice showed enhanced learning in pavlovian fear conditioning, while mice lacking rod and cone photoreceptors did not. ...
Mammalian vision consists of the classic image-forming pathway involving rod and cone photoreceptors interacting through a neural network within the retina before sending signals to the brain, and a non image-forming pathway that uses a photosensitive cell employing an alternative and evolutionary ancient phototransduction system and a direct connection to various centers in the brain. Intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin, which is independently capable of photon detection while also receiving synaptic input from rod and cone photoreceptors via bipolar cells. These cells are the retinal sentry for subconscious visual processing that controls circadian photoentrainment and the pupillary light reflex. Classified as irradiance detectors, recent investigations have led to expanding roles for this specific cell type and its own neural pathways, some of which are blurring the boundaries between image-forming and non image-forming visual processes.
... Taken together, the underlying biological mechanisms of changes in overall startle magnitudes across the menstrual cycle are probably impacted by changing ovarian steroid concentrations in interaction with further neurotransmitter and hormonal pathways. Startle magnitude has been independently found to be impacted by neuromodulators such as dopamine and norepinephrine (e.g., [83][84][85]), serotonin (e.g., [86][87][88]) or CRF (overview: [89]) which also interact with each other (e.g., [90]). In turn, estrogen as well as progesterone impact the release of norepinephrine, dopamine and serotonin via a wide variety of mechanisms including effects on pre-and postsynaptic receptors and neurotransmitter release (for a review see: [91]). ...
Sex differences in fear and anxiety have been widely reported although results are not entirely consistent depending on measures used. Also, a possible influence of the menstrual cycle is often not taken into account, and effect sizes are not always discussed. In a sample of healthy young adults (n=111 women without hormonal contraceptives and n=107 men) the acoustic startle response (ASR) and emotional ASR modulation were analysed. We found no significant effect of sex on ASR (p=.269) but a significant effect of menstrual cycle (p=.027, η(2)=0.105). Compared to men, women showed increased ASR during the late luteal phase probably reflecting elevated negative emotionality, and during ovulation which, however, might be due to increased auditory sensitivity and changes in general CNS arousal. Neither sex nor menstrual cycle affected startle modulation. Thus, at least in young adults, menstrual cycle but not sex per se appears to contribute significantly to ASR variance.
... In humans, this work typically includes measuring the blink reflex [2] while in animal models, the whole body startle response is measured [14]. One of the major attractions for this work is that the neural circuitry for these primitive reflexes is well known [26,27]. It is clear that lower brain regions, including brainstem areas of the nucleus reticularis and periaqueductal grey, are critical for mediating the startle response [28,29]. ...
... The simplest and fastest pathway for reflexive eyeblinks that is modulated by emotional valence is the acoustic startle pathway. This pathway consists of cochlear root neurons which project to neurons in the nucleus reticularis pontis caudalis, and motoneurons in the facial motor nucleus (pinna reflex) and spinal cord121314. The nucleus reticularis pontis caudalis receives projections from the central nucleus of the amygdala [14,15]. ...
Eyeblinks, whether reflexive or voluntary, play an important role in protecting our vision. When viewing pictures, reflexive eyeblinks are known to be modulated by the emotional state induced thereby. More specifically, the hedonic valence (unpleasantness-pleasantness) induced by the picture has been shown to have a linear relationship with the amplitude of a startle blink elicited during picture viewing. This effect has been attributed to congruence between an ongoing state and task demands: an unpleasant emotional state is assumed to bias our attention towards potentially harmful stimuli, such as startle tones. However, recent research suggests that the valence-specific modulation may not be limited to the sensory parts of the reflexive pathway related to startle responses. Here, we examined the effect of emotional picture viewing on voluntary (in response to a written command) eyeblinks in adult humans. Emotional modulation of startle blinks was also evaluated. We found that when viewing unpleasant pictures, the amplitude of reflexive eyeblinks was augmented, but the amplitude of voluntary eyeblinks was unaffected. Nevertheless, the response latencies of voluntary eyeblinks were found to be delayed during the viewing of pleasant and unpleasant relative to neutral pictures. We conclude that these results support the theory that emotional experience augments sensory processing specific to potentially harmful stimuli. Further, the emotional state seems not to exert an effect on voluntarily elicited motor activity.
... The amygdala also plays a central role in emotional regulation and the physiology of arousal and is well known for its role in detecting threat to the organism in the environment. The amygdala receives sensory input from several adjacent brain structures and interfaces with several areas of the motor system that provide specific types of emotional response, including SNS and PNS regulation, somatic responses, and modulation of the startle response (e.g., Davis, 1989;Davis, Walker, & Lee, 1997;LeDoux, Farb, & Ruggiero, 1990). The potentiated startle reflex is a bio-behavioral probe of amygdala activity in response to intense stimuli. ...
Individuals with autism demonstrate atypical and variable responses to social and emotional stimuli, perhaps reflecting heterogeneity of the disorder. The goal of this study was to determine whether unique profiles of psychophysiological responses to such stimuli could be identified in individuals diagnosed with autism spectrum disorder (ASD), with fragile X syndrome (FXS), and with comorbid autism and fragile X syndrome (ASD + FXS), and in typically developing (TYP) individuals. This study included 52 boys (ages 10-17): idiopathic ASD (n = 12), FXS (n = 12), comorbid ASD + FXS (n = 17), and TYP (n = 11). Physiological responses, including potentiated startle, electrodermal response, heart rate variability, and vagal tone, were collected concurrently while participants viewed emotionally evocative pictures of human faces or nonsocial images. Although some of these measures have been utilized separately for investigations on these diagnostic groups, they have not been considered together. Results using Kruskal-Wallis one-way analysis of variance by ranks indicate statistically significant differences in distributions of autonomic regulation responses between groups. The most notable differences were between the ASD group and both the FXS groups on measures of sympathetic activity, with FXS groups evincing increased activity. Also, both the ASD and ASD + FXS groups showed significantly decreased parasympathetic activity compared with FXS and TYP groups. In addition, the ASD + FXS group demonstrated a unique distribution of startle potentiation and arousal modulation. This study provides evidence that autonomic arousal and regulation profiles could be useful for distinguishing subgroups of autism and shed light on the variability underlying emotional responsivity.
... edge of the neurobiology of the startle response and its potentiation (Davis, 1989(Davis, , 2006Grillon, Duncko, Covington, Kopperman, & Kling, 2007). Startle potentiation also can be measured with both minimal disruption of task-related processes and reduced influence by demand characteristics than measures under volitional control (e.g., self-report). ...
Research indicates that fear and anxiety are distinct processes with separable neurobiological substrates. Predictable versus unpredictable shock administration has been used to elicit fear versus anxiety, respectively. Recent research has demonstrated that alcohol may reduce anxiety but not fear. However, previous manipulations of predictability have varied both probability and temporal uncertainty of shock threat, leaving unresolved questions regarding which stimulus characteristics elicit anxiety and are sensitive to alcohol stress-response dampening (SRD). We developed a novel paradigm to closely parallel basic research in animals that systematically varied temporal uncertainty of threat while holding threat probability constant. Intoxicated (0.08% target blood alcohol concentration), placebo, and no-alcohol control participants viewed a series of visual threat cues. Certain cue duration (5 s) blocks were equivalent to predictable shock blocks eliciting fear in earlier research. Uncertain cue duration (5, 20, 50, or 80 s, intermixed) blocks introduced temporal uncertainty regarding impending shock to elicit anxiety. Startle potentiation relative to matched cue periods in no-shock blocks provided the primary measure of affective response. All threat cues produced robust startle potentiation. Alcohol reduced startle potentiation during the first 5 s of threat cue presentation in uncertain but not certain duration blocks. Alcohol also reduced startle potentiation at later times among longer uncertain duration cues, suggesting that alcohol SRD persisted. Trait negative emotionality and binge drinking status moderated alcohol SRD magnitude during uncertain threat. These translational findings corroborate previous reports regarding distinct substrates of fear versus anxiety and have implications for both alcoholism etiology and comorbidity with anxiety disorders. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
... Individuals with psychopathy may be impaired at one or both stages of the defense system process, causing them to be less responsive to threat than nonpsychopathic individuals. There is evidence to suggest that the normal pattern of physiological response to fear, which comprises both stages of the defense system process that is regulated by the amygdala (Davis, 1989), is deficient in individuals high on psychopathy. Specifically, Patrick (1994) found that the priming of defensive action (the defensive mobilization stage) in individuals with psychopathy is impaired. ...
There is evidence to suggest that an impaired ability to process distressing and threatening emotional stimuli may result in a callous-unemotional (CU) and thrill-andadventure- seeking (TAS) personality. In this study we examined emotional processing in fifty community children, each with one parent, using the emotional pictures dot-probe task, which is a computerized task measuring attention to emotional pictures in the form of a facilitation score. The relationship between emotional processing, CU traits, and TAS were examined to determine whether individuals high on CU traits would also be more TAS, and show a lack of facilitation to emotional pictures. The results generally did not support study hypotheses; however, post-hoc analyses comparing children based on ethnicity found that Caucasian and minority children with CU traits show different and often opposite affective responses to emotional pictures, as well as different behavioral correlates to these traits.
... One methodology that has been used to assess defensive reactivity to aversive stimuli is potentiation of the startle reflex to a sudden noise probe, measured via the whole-body " jump " reaction in animals or via the eyeblink response in humans. Davis and colleagues (e.g., Davis, 1989; Davis, Falls, Campeau, & Kim, 1993 ) established that the mechanism for fear-potentiated startle in animals is a projection from the central nucleus of the amygdala to the nucleus reticularis pontis caudalis, the brainstem junction of the startle circuit. In humans, the noise-elicited blink startle response is reliably enhanced during viewing of aversive pictures compared to neutral pictures (Lang, 1995; Lang, Bradley, & Cuthbert, 1990). ...
We propose that neuroscientific understanding of antisocial behavior can be advanced by focusing programmatic efforts on neurobehavioral trait constructs, that is, individual difference constructs with direct referents in neurobiology as well as behavior. As specific examples, we highlight inhibitory control and defensive reactivity as two such constructs with clear relevance for understanding antisocial behavior in the context of development. Variations in inhibitory control are theorized to reflect individual differences in the functioning of brain systems that operate to guide and inhibit behavior and regulate emotional response in the service of nonimmediate goals. Variations in defensive reactivity are posited to reflect individual differences in the sensitivity of the brain's aversive motivational (fear) system. We describe how these constructs have been conceptualized in the adult and child literatures and review work pertaining to traditional psychometric (rating and behaviorally based) assessment of these constructs and their known physiological correlates at differing ages as well as evidence linking these constructs to antisocial behavior problems in children and adults. We outline a psychoneurometric approach, which entails systematic development of neurobiological measures of target trait constructs through reference to psychological phenotypes, as a paradigm for linking clinical disorders to neurobiological systems. We provide a concrete illustration of this approach in the domain of externalizing proneness and discuss its broader implications for research on conduct disorder, antisocial personality, and psychopathy.
Shifting defensive mode from one to another by the imminence of threat is crucial for survival. The transition of defensive mode from freezing to flight is observed during the modified fear conditioning, however, the flight during fear conditioning is not well characterized. To characterize the flight behaviors during the fear conditioning, we conducted experiments in male mice focusing on the influence of the context, the intensity of the unconditioned stimulus and conditioned stimulus (CS), the schedule of conditioning, and the state of the subject. Flight behaviors triggered by salient CS showed characteristics of fear-potentiated defensive behaviors depending on the conditioned context, while repetitive conditioning enhanced the expression of the flight and developed an association between the CS and the flight. The salient auditory stimulus was the primary factor to trigger flight behaviors. Also, the spaced conditioning increased the expression of flight behaviors. Taken together, the flight behavior during fear conditioning is not a simple conditioned response nor simple fear-potentiated behavior, but a complicated mixture of multiple components of defensive behaviors. The transition of defensive mode could be induced by the integration of multiple innate and learned components of fear or anxiety.
Neuromedin B (NMB) and gastrin-releasing peptide (GRP) are the two mammalian analogs in the bombesin peptide family that exert a variety of actions including emotional processing, appetitive behaviors, cognition, and tumor growth. The bombesin-like peptides interact with three receptors: the NMB-preferring bombesin 1 (BB1) receptors, the GRP-preferring bombesin 2 (BB2) receptors and the orphan bombesin 3 (BB3) receptors. Whereas, injection of bombesin into the central amygdala reduces satiety and modulates blood pressure, the underlying cellular and molecular mechanisms have not been determined. As administration of bombesin induces the expression of Fos in the lateral nucleus of the central amygdala (CeL) which expresses BB1 receptors, we probed the effects of NMB on CeL neurons using in vitro and in vivo approaches. We showed that activation of the BB1 receptors increased action potential firing frequency recorded from CeL neurons via inhibition of the inwardly rectifying K+ (Kir) channels. Activities of phospholipase Cβ and protein kinase C were required, whereas intracellular Ca2+ release was unnecessary for BB1 receptor-elicited potentiation of neuronal excitability. Application of NMB directly into the CeA reduced blood pressure and heart rate and significantly reduced fear-potentiated startle. We may provide a cellular and molecular mechanism whereby bombesin-like peptides modulate anxiety and fear responses in the amygdala.
In this chapter, peripheral and central theories of emotions, including pathological aspects, such as alexithymia, autism, anxiety, and depression, are discussed in the light of interoception. The dissociation between actual and felt visceral events was not known to the authors of the classic theories; for them, body sensations indicated patterns of physiological activation. Empirical evidence shows that manipulated feedback on body changes impacts the emotional experience, which highlights the importance of perceived factors in the process. The vast majority of the empirical findings on the associations between interoceptive accuracy and various aspects of emotions were obtained using the Schandry paradigm, a method that is heavily impacted by top-down factors. Thus, the contribution of bottom-up interoceptive information and top-down factors cannot be separated in the available body of evidence. Felt body changes not only contribute to the affective experience but they are also subject to affective evaluation, thus the associations between emotions and perceived somatic changes are much more complex than assumed by the classic theories.
Through pharmacological manipulation of the serotonergic (5-Hydroxytryptamin, 5-HT) system, combined with behavioral analysis, we tested the hypothesis that fear responses to predictable and unpredictable threat are regulated through stimulation of 5-HT receptors (5-HT-R) in the anterodorsal section of the bed nucleus of the stria terminalis (adBNST). Local adBNST application of 5-HT1A-R antagonist WAY100635 and 5-HT1B-R antagonist NAS-181 before fear retrieval enhanced freezing, 24 h after predictable fear conditioning. In contrast, increased fear responses to unpredictable threat were blocked by 5-HT1A-R agonist Buspirone (given before conditioning or retrieval) and 5-HT1B-R agonist CP-94253 (applied before training). Prolonged fear responses were also blocked by local application of the 5-HT2A-R antagonist R-96544 before fear retrieval, and conversely, local application of the 5-HT2A-R agonist NBOH-2C-CN hydrochloride before fear retrieval enhanced freezing 24 h after predictable conditioning, indicating augmented fear responses. Activation of inhibitory 5-HT1A- or 5-HT1B-Rs and the blockade of the excitatory 5-HT2A-R before unpredictable fear conditioning significantly reduced freezing during retrieval. The results from this study suggest that modulation of inhibitory 5-HT1A/1B-R and/or excitatory 5-HT2A-R activity in the adBNST may represent potential targets for the development of new treatment strategies in anxiety disorders. In addition, this study supports the validity and reliability of the mouse model of modulated fear to predictable and unpredictable threats to study mechanisms of fear and anxiety in combination with pharmacological manipulations.
The role of peripheral physiology in the experience of emotion has been debated since the 19th century following the seminal proposal by William James that somatic responses to stimuli determine subjective emotion. Subsequent views have integrated forebrain’s ability to initiate, represent and simulate such physiological events. Modern affective neuroscience envisions an interacting network of “bottom-up” and “top-down” signaling in which the peripheral (PNS) and central nervous systems both receive and generate the experience of emotion. “Feelings” serves as a term for the perception of these physical changes whether emanating from actual somatic events or from the brain’s representation of such. ‘Interoception’ has come to represent the brain’s receipt and representation of these actual and “virtual” somatic changes that may or may not enter conscious awareness but, nonetheless, influence feelings. Such information can originate from diverse sources including endocrine, immune and gastrointestinal systems as well as the PNS. We here examine physiological feelings from diverse perspectives including current and historical theories, evolution, neuroanatomy and physiology, development, regulatory processes, pathology and linguistics.
As altricial infants gradually transition to adults, their proximate environment changes. In three short weeks, pups transition from a small world with the caregiver and siblings to a complex milieu rich in dangers as their environment expands. Such contrasting environments require different learning abilities and lead to distinct responses throughout development. Here, we will review some of the learned fear conditioned responses to threats in rats during their ontogeny, including behavioral and physiological measures that permit the assessment of learning and its supporting neurobiology from infancy through adulthood. In adulthood, odor-shock conditioning produces robust fear learning to the odor that depends upon the amygdala and related circuitry. Paradoxically, this conditioning in young pups fails to support fear learning and supports approach learning to the odor previously paired with shock. This approach learning is mediated by the infant attachment network that does not include the amygdala. During the age range when pups transition from the infant to the adult circuit (10-15 d old), pups have access to both networks: odor-shock conditioning in maternal presence uses the attachment circuit but the adult amygdala-dependent circuit when alone. However, throughout development (as young as 5 d old) the attachment associated learning can be overridden and amygdala-dependent fear learning supported, if the mother expresses fear in the presence of the pup. This social modulation of the fear permits the expression of defense reactions in life threatening situations informed by the caregiver but prevents the learning of the caregiver itself as a threat.
As altricial infants gradually transition to adults, their proximate environment changes. In three short weeks, pups transition from a small world with the caregiver and siblings to a complex milieu rich in dangers as their environment expands. Such contrasting environments require different learning abilities and lead to distinct responses throughout development. Here, we will review some of the learned fear conditioned responses to threats in rats during their ontogeny, including behavioral and physiological measures that permit the assessment of learning and its supporting neurobiology from infancy through adulthood. In adulthood, odor–shock conditioning produces robust fear learning to the odor that depends upon the amygdala and related circuitry. Paradoxically, this conditioning in young pups fails to support fear learning and supports approach learning to the odor previously paired with shock. This approach learning is mediated by the infant attachment network that does not include the amygdala. During the age range when pups transition from the infant to the adult circuit (10 –15 d old), pups have access to both networks: odor –shock conditioning in maternal presence uses the attachment circuit but the adult amygdala-dependent circuit when alone. However, throughout development (as young as 5 d old) the attachment associated learning can be overridden and amygdala-dependent fear learning supported, if the mother expresses fear in the presence of the pup. This social modulation of the fear permits the expression of defense reactions in life threatening situations informed by the caregiver but prevents the learning of the caregiver itself as a threat.
The National Institute of Mental Health's Research Domain Criteria (RDoC) initiative calls for the incorporation of neurobiological approaches and findings into conceptions of mental health problems through a focus on biobehavioral constructs investigated across multiple domains of measurement (units of analysis). Although the constructs in the RDoC system are characterized in "process terms" (i.e., as functional concepts with brain and behavioral referents), these constructs can also be framed as dispositions (i.e., as dimensions of variation in biobehavioral functioning across individuals). Focusing on one key RDoC construct, acute threat or "fear," the current article illustrates a construct-oriented psychoneurometric strategy for operationalizing this construct in individual difference terms-as threat sensitivity (THT+). Utilizing data from 454 adult participants, we demonstrate empirically that (a) a scale measure of THT+ designed to tap general fear/fearlessness predicts effectively to relevant clinical problems (i.e., fear disorder symptoms), (b) this scale measure shows reliable associations with physiological indices of acute reactivity to aversive visual stimuli, and (c) a cross-domain factor reflecting the intersection of scale and physiological indicators of THT+ predicts effectively to both clinical and neurophysiological criterion measures. Results illustrate how the psychoneurometric approach can be used to create a dimensional index of a biobehavioral trait construct, in this case THT+, which can serve as a bridge between phenomena in domains of psychopathology and neurobiology. Implications and future directions are discussed with reference to the RDoC initiative and existing report-based conceptions of psychological traits.
According to the classic clinical description of psychopathy offered by Hervey Cleckley, violence and persistent criminality are not essential aspects of the disorder. He theorized that the primary features of psychopathy derive from a constitutional deficit in affectivity that actually diminished the likelihood of intense emotional displays, vengeful grudges, and angry aggression.
Emotion is important to understanding aggression and violence because it is the force that drives behavior. Individuals who behave violently usually do so because they are moved to do so by strong emotions. However, empirical research indicates that psychopaths are highly aggressive, but also detached and unemotional. To resolve this apparent contradiction, it is necessary to consider that there may be different forms of aggression and different aspects of psychopathy. This paper outlines a theoretical model of emotion, and a methodology (the startle-probe technique), for investigating basic emotional processes in normal and abnormal individuals. Recent research of this kind in criminal offender populations suggests that the detached, predatory style of the “true” psychopath is related to a weakness in the defensive system of the brain that governs negative emotional response. In turn, this emotional weakness is related to a particular set of temperament traits, and specific forms of aggressive behavior.
The cerebral cortex and cerebellum are high level neural centers that must interact cooperatively to generate coordinated and efficient goal directed movements, including those necessary for a well-timed conditioned response. In this review we describe the progress made in utilizing the forebrain-dependent trace eyeblink conditioning paradigm to understand the neural substrates mediating cerebro-cerebellar interactions during learning and consolidation of conditioned responses. This review expands upon our previous hypothesis that the interaction occurs at sites that project to the pontine nuclei (Weiss & Disterhoft, 1996), by offering more details on the function of the hippocampus and prefrontal cortex during acquisition and the circuitry involved in facilitating pontine input to the cerebellum as a necessary requisite for trace eyeblink conditioning. Our discussion describes the role of the hippocampus, caudal anterior cingulate gyrus, basal ganglia, thalamus, and sensory cortex, including the benefit of utilizing the whisker barrel cortical system. We propose that permanent changes in the sensory cortex, along with input from the caudate and claustrum, and a homologue of the primate dorsolateral prefrontal cortex, serve to bridge the stimulus free trace interval and allow the cerebellum to generate a well-timed conditioned response.
Background
Most people who meet the diagnostic criteria for anti-social personality disorder (ASPD) do not meet the criteria for psychopathy. A differentiating feature is affective-interpersonal style. Eye blink startle reflex paradigms have been used to study affect.AimThe aim of this study is to explore an eye blink startle paradigm as a means of distinguishing between men with both ASPD and psychopathy, and men with ASPD alone.Methods
One hundred and thirty-six men were recruited as follows: 31 patients with ASPD and a Psychopathy Checklist-Revised (PCL-R) score of 26 or more, 22 patients with ASPD and a PCL-R score of 25 or less, 50 forensic hospital employees and 33 general population men, none in the latter two groups having abnormal personality traits. Each was presented with 16 pleasant, 16 unpleasant and 16 neutral pictures. Acoustic probes were presented during each category at 300, 800, 1300 and 3800 milliseconds (ms) after picture onset. Eye blink response was measured by electromyography.ResultsOverall, both patient groups showed significantly smaller eye blink responses to the startle stimuli compared with the community controls. Both the latter and the ASPD group showed the expected increase in eye blink response at longer startle latencies to unpleasant pictures than pleasant pictures, but this was not present either in the group with psychopathy or in the forensic hospital employees. With increasing startle latency onset, eye blink amplitude increased significantly in both the healthy comparison groups and the ASPD group, but not in the group with psychopathy.Conclusions
We replicated eye blink startle modulation deficiencies among men with psychopathy. We confirmed that the psychopathy and ASPD groups could be distinguished by startle stimulus onset asynchrony, but this pattern was also seen in one healthy group – the forensic hospital employees. This suggests a case for more research with more diverse comparison groups and more differentiation of personality traits before drawing definitive conclusions about distinctive startle response patterns among men with psychopathy. Copyright © 2014 John Wiley & Sons, Ltd.
This analysis postulates a motivational continuity from reflex reactions to complex, cognitively elaborated emotional expressions. Responses are motivated by either the positive-appetitive or the negative-aversive brain systems. Reflexes evoked during emotional processing are augmented if their affective valence (positive or negative) matches that of the active motivational system and inhibited when a mismatch is present. Research testing this biphasic model is described using the defensive startle probe reflex. It is shown that probe responses are reliably potentiated during perception and imagery of unpleasant events and reduced during pleasant events. The neurobehavioral foundations of this conception are presented, and the implications of probe analysis are elucidated for theories of emotion organization, the assessment of mood, and practical applications in psychopathology and neurological disorder.
The startle reflex can be modified by cognitive and affective variables. The present study investigated startle responses in 12 patients with panic disorder, 22 patients with social phobia and 15 healthy controls. The eye-blink component of the acoustic startle reflex was measured during baseline, pulse-alone, pre-pulse and fear-potentiated startle to disorder-specific threat words. Results indicated that patients with panic disorder exhibited significantly larger startle response amplitudes during baseline, pulsealone, pre-pulse and fear-potentiated trials than did healthy controls. Startle response amplitudes of patients with social phobia differed from healthy controls at effects of similar magnitude as the effects seen for patients with panic disorder, for all types of startle trials. During fear-potentiated trials, all groups exhibited largest startle amplitudes following the presentation of physical threat-related words, second largest magnitude to social threat-related words and the smallest to non-threatening words. It is recommended that future studies further examine startle response parameters in all forms of anxiety disorders.
This paper presents an integrative conceptual framework for understanding relationships between psychopathy and aggression, and reviews the extant relevant literature in relation to this framework. Issues pertaining to conceptualization and subtyping of aggression are reviewed with reference to contemporary emotion theory, and recent research on the emotional and temperamental underpinnings of criminal psychopathy is described. It is argued that different forms of aggression may be related to disparate facets of psychopathy, and that these relationships may be mediated by common dispositional factors. Methodological limitations of existing studies are identified, and suggestions for future research are offered.
Previous research has shown that the acoustic startle response, a simple reflex mediated by four synapses in the brainstem and spinal cord, can be increased when elicited in the presence of a light previously paired with a footshock. This fear-potentiated startle effect can be selectively blocked by drugs that decrease anxiety in humans as well as by lesions of the central nucleus of the amygdala, an area of the brain known to be critical for fear. This year we found that local infusion of N-methyl-D-aspartate (NMDA) selective antagonists such as AP5 or CPP completely block the acquisition of fear- potentiated startle. This effect could not be attributed to a decrease in shock sensitivity or vision and did not occur when these compounds were infused into the cerebellum. These data indicate that an NMDA-dependent mechanism in the amygdala is involved in fear conditioning and that fear-potentiated startle may provide an excellent behavioral model system to analyze cellular and biochemical mechanisms of learning and memory.
Postural displacements in response to emotional activation have recently been proposed as a direct and objective index of approach-avoidance behavior in humans. Here, we present the results of an experiment designed to assess spontaneous postural responses to discrete affective pictures, briefly presented in random order of valence. Our findings question the interpretation of phasic postural responses to emotional stimuli as approach-avoidance behavior. Further, we identify a robust dynamical pattern, characterized by specific features indicating that attentional processes may play a role in human postural responses to emotional stimuli.
The latency of the acoustic startle reflex in the rat is 8 msec, measured from tone onset to the beginning of the electromyographic response in the hindleg. This extremely short latency indicates that only a few synapses could be involved in some primary acoustic startle circuit. Acoustic startle is being used as a model system for studying habituation, sensitization, prepulse inhibition, classical conditioning, fear or anxiety, and drug effects on behavior. The present study attempted to delineate a short latency acoustic startle circuit, since this would provide critical information for further study in all of these areas. Bilateral lesions of the ventral cochlear nucleus, which receives the primary auditory input, abolish acoustic startle. Electrical, single pulse stimulation of the ventral cochlear nucleus elicits startle-like responses with a latency of about 7 msec. Bilateral lesions of the dorsal and ventral nuclei of the lateral lemniscus, which receive direct input from the ventral cochlear nuclei, abolish acoustic startle. Electrical stimulation of these nuclei elicits startle-like responses with a latency of about 6 msec. Bilateral lesions of ventral regions of the nucleus reticularis pontis caudalis, which contain cell bodies that give rise to the reticulospinal tract, abolish acoustic startle. Electrical stimulation of these points elicits startle-like responses with a latency of about 5 msec. Reaction product from horseradish peroxidase iontophoresed into this area is found in the nuclei of the lateral lemniscus. In contrast, lesions of the dorsal cochlear nuclei, vestibular nuclei, nucleus reticularis pontis oralis, nucleus reticularis gigantocellularis, and dorsal regions of the nucleus reticularis pontis caudalis fail to abolish acoustic startle. Also, "startle" cannot be elicited electrically from these areas. The data suggest that a primary acoustic startle circuit in the rat consists of auditory nerve, ventral cochlear nucleus, nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal interneuron, lower motor neuron, and muscles. Hence, five synapses, plus the neuromuscular junction, are probably involved.
A new neuroanatomical method for tracing connections in the central nervous system based on the anterograde axonal transport of the kidney bean lectin,Phaseolus vulgaris-leucoagglutinin (PHA-L) is described. The method, for which a detailed protocol is presented, offers several advantages over present techniques. First, when the lectin is delivered iontophoretically, PHA-L injection sites as small as 50–200 μm in diameter can be produced, and are clearly demarcated since the neurons within the labeled zone are completely filled. Second, many morphological features of such filled neurons are clearly demonstrated including their cell bodies, axons, dendritic arbors and even dendritic spines. Third, there is some evidence to suggest that only the neurons at the injection site that are filled transport demonstrable amounts of the tracer, raising the possibility that the effective injection site can be defined quite precisely. Fourth, even with the most restricted injections, the morphology of the labeled axons and axon terminals is clearly demonstrated; this includes boutons en passant, fine collateral branches, and various terminal specialization, all of which can be visualized as well as in the best rapid Golgi preparations. Fifth, when introduced iontophoretically, PHA-L appears to be transported preferentially in the anterograde direction; only rarely is it transported retrogradely. Sixth, PHA-L does not appear to be taken up and transported effectively by fibers of passage. Seventh, there is no discernible degradation of the transported PHA-L with survival times of up to 17 days. Finally, since the transported marker can be demonstrated with either peroxidase or fluorescent antibody techniques, it may be used in conjunction with other neuroanatomical methods. For example, double anterograde labeling experiments can be done using the autoradiographic method along with immunoperoxidase localization of PHA-L, and the retrogradely transported fluorescent dyes can be visualized in the same tissue sections as PHA-L localized with immunofluorescence techniques.
Drugs thought to increase intracellular levels of cAMP were infused intrathecally into the subarachnoid space of the lumbar spinal cord, and the effects on the acoustic startle response in rats were measured. Intrathecal infusions of the cAMP analogs dibutyryl cAMP or 8-bromo cAMP (12.5-100 micrograms) produced marked, dose-dependent increases in startle amplitude compared to the infusion of artificial cerebrospinal fluid (CSF). Local infusions of dibutyryl cAMP at more rostral levels of the spinal cord or brain failed to mimic the excitatory effect seen following lumbar intrathecal infusion. No excitation of startle was seen following intrathecal infusion of cAMP itself, ATP, 5'-AMP, or dibutyryl cGMP. A weak excitation of startle was seen following intrathecal, but not intraventricular, infusion of the water-soluble adenylate cyclase activator forskolin 7-deacetyl-7-O-hemisuccinic acid (forskolin-DHA; 5.0-100 micrograms, in artificial CSF), whereas forskolin itself [0.01-200 micrograms, in dimethyl sulfoxide (DMSO)] was without consistent effect. Finally, intrathecal infusion of the selective phosphodiesterase inhibitor Rolipram (12.5-200 micrograms) produced a marked excitation of startle similar in magnitude to the effects produced by cAMP analogs. The excitatory effects of intrathecally infused dibutyryl cAMP, 8-bromo cAMP, forskolin-DHA, or Rolipram support a functional link between spinal cord cAMP and the acoustic startle reflex. Possible sites of cAMP action on startle are discussed.
A series of experiments was performed to investigate the effects of corticotropin-releasing factor (CRF) on the amplitude of the acoustic startle response (ASR) in rats. Intracerebroventricular (ICV) administration of 1 microgram rat CRF significantly potentiated acoustic startle amplitude; these effects were reversed in a dose-dependent manner by pretreatment with the benzodiazepine chlordiazepoxide (CDP). Doses of CDP that antagonized CRF-potentiated ASR did not lower startle baseline or antagonize amphetamine- or strychnine-potentiated ASR. These results suggest that CRF has "anxiogenic" properties and may serve as a neuroendocrine modulator of stress-enhanced behaviors.
The present study demonstrated that electrical stimulation of the amygdala enhanced the acoustic startle response. A 25-ms train of 0.1-ms pulses initiated 5 ms before the onset of a 20-ms noise burst significantly increased startle at currents from 40 to 400 microA. Electrode placements just medial to the amygdala (in the pathway connecting the amygdala to the brain stem) increased startle with the lowest currents. Startle was also increased in all animals with stimulation in the central, medial, and intercalated nuclei of the amygdala. Stimulation in areas surrounding the amygdaloid complex was ineffective. In a second experiment, paired pulses with interpulse intervals between 0.1 and 20.0 ms delivered to the amygdala demonstrated that the stimulated axons had a distribution of refractory periods between 0.6 and 1.0 ms. This suggests that the population of neurons which subserves the enhancement of acoustic startle is fairly homogeneous and has small, myelinated axons.
The effect of a conditioned fear stimulus (CS) on responsiveness to pain was examined in three experiments. In Experiment 1, a CS that signaled shock attenuated freezing in response to shock, with the attenuation occurring several minutes after the shock. Naloxone blocked the effect of the CS. The effect of the CS, including its reversibility by naloxone, was retained over an interval of 90 days. Experiment 2 showed that this effect on freezing is due to associative fear conditioning, rather than blocking of conditioning to context by a novel cue. In Experiment 3, presenting a fear CS just prior to administering a tail-flick (radiant heat) test of nociception increased the tail-flick latencies; that is, the fear CS apparently induced hyperalgesia rather than analgesia. Because this result makes it difficult to interpret the change in freezing seen in the first experiment as reflecting antinociception, it raises questions about how pain might differentially affect different measures of pain responsiveness. A memory hypothesis is advanced to resolve the different effects obtained with the freezing and tail-flick tests.
Acoustic and electrical brain stimulation studies have revealed that the ventral nucleus of the lateral lemniscus is a specific site within the brain stem where a previously conditioned stimulus modulates a simple reflex, the acoustic startle response. Sixty rats were implanted with bilateral electrodes in the ventral cochlear nucleus (VCN), ventral acoustic stria (VAS), dorsal lateral lemniscus (DLL), ventral lateral lemniscus (VLL), or the nucleus reticularis pontis caudalis (RPC). Following recovery all rats were conditioned to be fearful of a light by pairing a light with a shock for 10 trials on each of 2 days. One day later, the rats were placed in cages equipped to measure startle responses. Startle was elicited either acoustically or electrically through the electrodes that had been implanted in various parts of the acoustic startle circuit. Startle was elicited in darkness or during a brief presentation of the ligh previously paired with the shock. In all groups, acoustic startle amplitude was significantly greater in the presence of the light than it was in darkness, which is consistent with previous data showing that fear increases startle. Startle elicited electrically from the VCN, VAS, and VLL was also significantly increased by the light. In contrast, startle elicited electrically in the DLL or the RPC was not affected by the light despite the fact that the same rats in the same test session had elevated acoustic startle amplitude in the presence of light. Thus, it seems that for the first time in a complex vertebrate, a locus has been found within the nervous system (the VLL) where a conditioned stimulus acts to alter neural transmission so as to affect behavior.
Two experiments investigated the effect of an auditory prestimulus (S1) on the amplitude and latency of the startle reflex to an intense tone burst (S2). In the first, with a fixed S1 intensity, with very short (<15 msec) ISIs reflex amplitudes were increased and latencies reduced by S1 presence and with longer intervals (⩾40 msec) amplitudes were reduced and latencies increased. Inhibition was apparent on the amplitude measure at lag times ineffective in altering the latency measure. In the second, with a fixed and long S1 duration reflex amplitudes increased with an increase in S1 intensity up to moderate (≈75 db) levels, but further increases in S1 produced a reduction in amplitudes. However any increase in S1 intensity over the minimum value tested (60 db) resulted in an increment in reflex latency. These experiments reveal the presence of three separable influences of auditory prestimuli on the acoustic startle reflex in the rat.
Conducted 6 experiments with a total of 69 male Holtzman albino rats. The temporal functions relating inhibition and facilitation of the startle reaction, elicited by an intense auditory stimulus, to momentary and to prolonged acoustic and visual stimuli were studied. The extent of inhibition was positively related to the intensity of the stimulus in both modalities. The extent of facilitation was positively related to the intensity of the visual stimulus but nonmonotonically related to the intensity of the auditory stimulus, a relationship confirmed in a study of the effects of background noise level on startle behavior. Data are correlated with physiological processes which provide similar effects at the electrophysiological level. Some implications drawn for experiments on classical conditioning and habituation are discussed. (46 ref.)
Although the amygdala complex has long been known to exert a profound influence on cardiovascular activity, the neuronal and connectional substrate mediating these influences remains unclear. This paper describes a direct amygdaloid projection to medullary sensory and motor structures involved in cardiovascular regulation, the nucleus of the solitary tract (NTS) and the dorsal motor nucleus (DVN), by the use of autoradiographic anterograde transport and retrograde horseradish peroxidase (HRP) techniques in rabbits. Since all of these structures are highly heterogeneous structurally and functionally, details of the specific areas of the neuronal origin and efferent distribution of the projection were examined in relation to these features and with reference to a cytoarchitecture description of the relevant forebrain regions in the rabbit. Amygdaloid projections to the NTS and DVN, as determined from HRP experiments, arise from an extensive population of neurons concentrated exclusively within the ipsilateral central nucleus and confined to and distributed throughout a large medial subdivision of this nucleus. Projection neurons, however, also distribute without apparent interruption beyond the amygdala dorsomedially into the sublenticular substantia innominata and the lateral part of the bed nucleus of the stria terminalis and thus delineate a single entity of possible anatomical unity across all three structures, extending rostrocaudally within the basal forebrain as a diagonal band. Descending central nucleus connections, based upon autoradiographic experiments, project heavily and extensively to both the NTS and the DVN. Within both nuclei, the projections have a highly specific distribution pattern, appearing to correspond largely to structural subdivisions, including the dorsomedial, medial, ventrolateral, ventral, and commissural NTS, and to cell group "a," a caudally located dorsomedial region, and peripheral regions of the DVN, some of which appear to be involved in cardiovascular regulation. The existence of such an extensive projection system connecting these specific regions is significant evidence in support to its potential for participation in the amygdaloid expression of cardiovascular influences and has important implications for the cellular analysis of the functional role of these influences.
A sensory event that occurs just prior to an intense startle-eliciting stimulus can modify either the latency or the amplitude of the response, depending on the lead time. Systematic analysis of these effects, using different measures across species (including humans), leads to the conclusion that they reflect differential activity within a neural system in which startle is instigated and that one of the inputs to this system is a separate (parallel) inhibitory pathway. Since a sensory event need only be near its absolute threshold to produce a reliable effect, it is also concluded that activity in a neural system in which startle is instigated may always represent one of the earliest steps in an organism's response to events in its sensory environment. It is suggested that analysis of reflex modification provides an avenue for research with intact organisms that can bridge the gap between the isolated preparations studied by the physiologist and the behavioral processes that concern psychologists. (59 ref)
One of the ultimate goals of neuroscience is to determine how the brain directs and changes behavior in man. Given the enormous complexity of this endeavor, an increasing number of neuroscientists have focused on invertebrates and lower vertebrates in an effort to simplify the problem. Eventually, however, it will be necessary to analyze the cellular basis of behavior in a complex mammalian brain. To approach the problem at this level, it would be useful to study a relatively simple behavior that can be elicited in mammals and that is sensitive to a variety of experimental treatments.
This chapter presents the current status of the concept of fear from a consistent viewpoint. Fear was considered to be a classically conditioned response, defined in terms of the prior appropriate pairing of neutral and noxious stimuli. As fear is unobservable, it may be measured only by its effect on other observable responses. Owing to this state of affairs, it is necessary, in studying fear, to maintain a clear conceptual separation between the fear response and the response used as its index. The chapter discusses four index responses that permit such a distinction. The chapter reviews the conditioning, measurement, and definition of fear. It focuses on aversive learning situations in which the conditioning of fear and its measurement are generally considered to be independent. Specifically, the interest will be in situations in which the noxious unconditioned stimulus is usually assumed to have its effect on the conditioning of fear but not directly on the measured response. The chapter describes four measures of fear and discusses some of the strengths and weaknesses of each measure and a theoretical rationale for the use of each as an index of fear.
Stimulation of supraspinal α2-adrenergic receptors by intraventricular infusion of the α2-adrenergic agonist ST-91 depresses a simple vertebrate behavior, the acoustic startle response. Intraventricular pretreatment with pertussis toxin, an agent known to inactivate the inhibitory guanine nucleotide binding protein (Gi) which can inhibit adenylate cyclase, completely prevented the depressant behavioral effect of ST-91. In contrast, pertussis toxin did not alter the depressant effect of intraventricular infusion of the 5-HT1B agonist 1-m-chlorophenylpiperazine (mCPP). Intraventricular infusion of the cyclic adenosine monophosphate (cAMP) analog 8-bromo-cAMP also reversed the depressant effect of ST-91 without altering the effect of mCPP. These data suggest that inhibition of adenylate cyclase may be involved in the effect of activation of central α2-adrenergic receptors.
As described by Brodal (5), the medial pontomedullary reticular formation is a complex brainstem region with a bewildering array of intrinsic intercon nections, long ascending projections to diencephalic levels and beyond, and long reticulospinal projections reaching all levels of the spinal cord. Accord ing to our present understanding, this region is involved in such functions as descending control of motor activity or of sensory relays, ascending control of cortical arousal, or control of autonomic activity. Each of these functions may be mediated either by fast, myelinated reticular efferent fibers or by the slowly conducting, unmyelinated aminergic systems that originate from nuclei classified (in the past, at least) as belonging to the reticular formation. Because of the complexity of reticular efferent systems, most investiga tions dealing with the reticular formation have focused upon a single reticu lar function and a restricted subset of reticular efferent pathways. This review, too, focuses on a single reticular efferent system-the fast, myeli nated reticulospinal projection to spinal motor nuclei-in an attempt to evaluate our current understanding of this system and to point out questions that need to be answered as we move toward a more integrative under standing of reticular function .
The efferent fiber connections of the nuclei of the amygdaloid complex with subcortical structures in the basal telencephalon, hypothalamus, midbrain, and pons have been studied in the rat and cat, using the autoradiographic method for tracing axonal connections. The cortical and thalamic projections of these nuclei have been described in previous papers (Krettek and Price, ′77b,c). Although the subcortical connections of the amygdaloid nuclei are widespread within the basal forebrain and brain stem, the projections of each nucleus have been found to be well defined, and distinct from those of the other amygdaloid nuclei.
The basolateral amygdaloid nucleus projects heavily to the lateral division of the bed nucleus of the stria terminalis (BNST), to the caudal part of the substantia innominata, and to the ventral part of the corpus striatum (nucleus accumbens and ventral putamen) and the olfactory tubercle; it projects more lightly to the lateral hypothalamus. The central nucleus also projects to the lateral division of the BNST and the lateral hypothalamus, but in addition it sends fibers to the lateral part of the substantia nigra and the marginal nucleus of the brachium conjunctivum. The basomedial nucleus has projections to the ventral striatum and olfactory tubercle which are similar to those of the basolateral nucleus, but it also projects to the core of the ventromedial hypothalamic nucleus and the premammillary nucleus, and to a central zone of the BNST which overlaps the medial and lateral divisions. The medial nucleus also projects to the core of the ventromedial nucleus and the premammillary nucleus, but sends fibers to the medial division of the BNST and does not project to the ventral striatum. The posterior cortical nucleus projects to the premammillary nucleus and to the medial division of the BNST, but a projection from this nucleus to the ventromedial nucleus has not been demonstrated. Projections to the “shell” of the ventromedial nucleus have been found only from the ventral part of the subiculum and from a structure at the junction of the amygdala and the hippocampal formation, which has been termed the amygdalo‐hippocampal area (AHA). The AHA also sends fibers to the medial part of the BNST and the premammillary nucleus.
Virtually no subcortical projections outside the amygdala itself have been demonstrated from the lateral nucleus, or from the olfactory cortical areas around the amygdala (the anterior cortical nucleus, the periamygdaloid cortex, and the posterior prepiriform cortex). However, portions of the endopiriform nucleus deep to the prepiriform cortex project to the ventral putamen, and to the lateral hypothalamus.
A startle-like response was evoked by electrical stimulation with one pulse in several brainstem sites of the primary acoustic startle circuit. If a second pulse was delivered 0.4-10 ms after the first pulse, a stronger response or a decreased current threshold resulted. The facilitatory effect of the second pulse increased as interpulse (C-T) interval increased from 0.4 to 2.0 ms in cochlear nucleus or ventral lateral lemniscus sites. In caudal pontine reticular formation sites, the effect of the second pulse increased sharply from 0.3 to 0.5 ms. These results suggest that very short refractory period axons mediate electrically elicited startle in reticular formation, and that longer refractory period axons mediate startle in cochlear nucleus or ventral lateral lemniscus. In reticular formation sites, the effect of the second pulse declined nearly exponentially from 2.0 to 50 ms with a time constant of about 4 ms. Stimulation of similar reticular formation sites in cats evokes monosynaptic EPSPs in spinal motoneurons with an almost identical time course, as reported by other investigators. This suggests that the startle response evoked from the reticular formation results from monosynaptic activation of spinal motoneurons. Temporal summation declined more slowly and irregularly in cochlear nucleus and ventral lateral lemniscus sites, suggesting that these sites are not monosynaptically connected with spinal motoneurons, a conclusion consistent with anatomical data. In reticular formation sites near the facial nerve, a second peak in the two-pulse curve was observed at a C-T interval of 10 ms. The second peak was blocked by local anesthesia of the face ipsilateral to the stimulating electrode, suggesting that a single twitch of facial muscles facilitates startle.
Separate groups of rats were given 30 pairings of a light (conditioned stimulus, CS) and 500-ms shock (unconditioned stimulus, US) at CS-US intervals of 0, 25, 50, 100, 200, 800, 3,200, 12,800, or 51,200 ms. Other groups had lights and shocks inconsistently paired. The startle reflex was elicited 2-4 days later with a noise burst alone or 25-51,200 ms after light onset. After CS-US pairings over a wide range of intervals (25-51,200 ms), startle was potentiated in testing, sometimes as rapidly as 50 ms after light onset. Magnitude of potentiation and resistance to extinction were generally greater with longer CS-US intervals. In several groups, potentiation was maximal at a test interval that matched the CS-US interval used in training. This temporal specificity sharpened with increasing numbers of training trials but even occurred with a single training trial in which a 51,200-ms CS-US interval was used. The data indicate that even during simple fear conditioning, animals rapidly learn a temporal CS-US relationship. This has important implications for understanding the neural mechanisms of fear conditioning.
Rats were implanted with bilateral cannulas in an area just medial to the ventral nucleus of the lateral lemniscus, an obligatory relay along the acoustic startle pathway. Bilateral infusions of excitatory amino acid transmitter antagonists into this region (10, 25 or 50 nmol per side) produced a rapid, dose-dependent depression of acoustic startle. gamma-D-Glutamylglycine, gamma-D-glutamylaminomethyl sulfonate and 2-amino-5-phosphonovalerate were equally effective in depressing the startle response over this dose range. These results indicate that excitatory amino acid transmitters play an important role in the expression of acoustic startle at this part of the startle pathway.
Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm are reviewed. This test measures conditioned fear by an increase in the amplitude of a simple reflex (the acoustic startle reflex) in the presence of a cue previously paired with a shock. This paradigm offers a number of advantages as an alternative to most animal tests of fear or anxiety because it involves no operant and is reflected by an enhancement rather than a suppression of ongoing behavior. Fear-potentiated startle is selectively decreased by drugs such as diazepam, morphine, and buspirone that reduce fear or anxiety clinically. Electrical stimulation techniques suggest that a visual conditioned stimulus ultimately alters acoustic startle at a specific point along the acoustic startle pathway. Relevant visual structures implicated in potentiated startle include the lateral geniculate nucleus, visual cortex, and deep and intermediate layers of the superior colliculus. The central nucleus of the amygdala and the caudal branch of the ventral amygdalofugal pathway projecting to or through the substantia nigra are also necessary for potentiated startle to occur. Electrical stimulation of the central nucleus of the amygdala markedly increases acoustic startle. By combining these behavioral, anatomical, physiological, and pharmacological approaches, it should soon be possible to determine each neural pathway that is required for a stimulus signaling fear to alter startle behavior. Once the exact structures are delineated, it should be possible to determine the neurotransmitters that are released during a state of fear and how this chemical information is relayed along these pathways so as to affect behavior.
This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to a spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.
The present study evaluated if startle measured electromyographically in the neck muscles (having a 5 msec latency) would exhibit behavioral and pharmacological plasticity known to alter startle measured in a stabilimeter device. A total of 15 rats were implanted with bilateral EMG electrodes in the dorsal neck muscles and subsequently exposed to a variety of manipulations known to affect the whole-body startle response. The peak-to-peak EMG response that occurred within 10 msec of startle stimulus onset displayed pre-pulse inhibition, enhancement by prior fear conditioning, inhibition by clonidine, and enhancement by strychnine. The data are discussed in terms of modulation of neural transmission along a primary startle-mediating pathway.
Rats were given 10 light-shock pairings on 2 successive days. At 24-48 hr following training, groups of rats received bilateral transection of the cerebellar peduncles, bilateral lesions of the red nucleus (which receives most of the cerebellar efferents), or bilateral lesions of the central nucleus of the amygdala. Control rats were sham operated. At 3-4 days after surgery, the rats were tested for potentiated startle (increased acoustic startle in the presence of the light previously paired with shock). Potentiated startle was blocked by lesions of the central nucleus of the amygdala. Transection of the cerebellar peduncles or lesions of the red nucleus did not block potentiated startle. A second experiment in which a visual prepulse test was used indicated that the blockade of potentiated startle observed in the animals with amygdala lesions could not be attributed to optic tract damage. A third experiment demonstrated that the absence of potentiation in the animals with amygdala lesions was not simply due to a lowered startle level ceiling, because these animals could show increased startle with increased stimulus intensity and with administration of strychnine, a drug that increases startle. Taken together, the results are consistent with the hypothesis that the amygdala is involved in fear conditioning, because potentiated startle is a measure of conditioned fear.
Twenty-four male albino Wistar rats were allocated to four groups and given either 23.2, 11.6 or 5.8 IU OXT/kg or vehicle (0.9% saline). A significant increase in startle response was observed in the 11.6 and 5.8 IU OXT/kg groups when compared to vehicle. Our results further support the suggestion that OXT is a "stress hormone" by implicating this peptide with increased emotionality/reactivity during a stressful experience.
The present review argues that the startle reflex is particularly well suited as a model system to analyze how drugs alter stimulus reactivity and reflex excitability. It then reviews all the literature to date on how drugs or lesions that are thought to alter neurochemical transmitter systems affect acoustic and/or tactile startle. Hypotheses are presented to account for how serotonin, dopamine, norepinephrine, acetylcholine, and opiates modulate startle. Effects on startle plasticity such as habituation, sensitization, and potentiation resulting from prior associative learning are also included.
Using the acoustic startle reflex as the behavioral measure, qualitatively different responses to the GABA antagonist picrotoxin were obtained in developing rats before and after 21 days postnatal (PN) age. Dose-dependent increases in acoustic startle were seen following picrotoxin in PN day 15-16 rat pups. In contrast, dose-dependent decreases in startle following picrotoxin were observed in adult rats. The switch from excitation to inhibition of startle was found to occur abruptly on PN day 21. Excitatory responses to picrotoxin were also found in adult rats following localized infusions of picrotoxin into lumbar spinal cord regions, but not into the forebrain. These results give evidence that picrotoxin-sensitive sites that modulate increases in startle reflex behavior mature first and are analogous to sites in the adult spinal cord, whereas picrotoxin-sensitive sites that modulate decreases in startle reflex behavior mature later (greater than or equal to PN day 21) and are localized in more rostral brain areas.
Startle-like responses were elicited electrically from the ventral cochlear nucleus (VCN) in darkness or in the presence of a light that had previously been paired with shocks. These startle-like responses were potentiated by the light and potentiation was selectively decreased by diazepam in a dose-related fashion (0.625 to 2.5 mg/kg). The benzodiazepine antagonist RO15-1788 attenuated the effect of diazepam. The data indicate that potentiation of electrically elicited startle behaves like acoustically elicited startle, providing further evidence that electrical elicitation of startle is a viable experimental technique.
Seizure threshold was measured in kindled rats by delivering trains of specified duration, consisting of bipolar pulses of specified width, at increasing current intensities, at specified intertrain intervals. The effect of decreasing pulse width was to elevate seizure threshold, but considerably less total energy was required to elicit a seizure. Seizure threshold was also found to be an inverse function of train duration, within asymptotic limits. Seizure "threshold" is not a single number but a function of stimulus-duration factors. In the case of train length, a putative threshold-altering agent may alter one or the other asymptotic value so that the curve is shifted upward or to the right.
Light microscopic autoradiography and quantitative photometric studies of autoradiographs were performed subsequent to injection of tritiated amino acids into various parts of the amygdala of the rat. The course of amygdalofugal fibers in the stria terminalis (bilaterally), longitudinal association bundle, medial amygdalo-hypothalamic pathway, and medial forebrain bundle is described. Evidence is provided for both additional transcapsular and paracapsular fibers and early descending stria terminalis fibers. Labeling of the ipsilateral main olfactory bulb and the bilateral acessory olfactory bulb was observed following injection into the cortical amygdaloid subnucleus. The termination of amygdalofugal fibers in the preoptic area and especially the subnucleu of the ventromedial and premamillary hypothalamic nuclei bilaterally were analysed by photometric measurement. A caudal amygdaloid projection system arises from the central amygdaloid nucleus. This system extends to the substantia nigra, lateral terminal nucleus of the accessory optic tract, central grey in the midbrain, and to the parabrachial nuclei, nucleus of the mesencephalic trigeminal tract, nucleus of the solitary tract in the hindbrain.
The latency of the acoustic startle reflex in the rat is 8 msec, measured from tone onset to the beginning of the electromyographic response in the hindleg. This extremely short latency indicates that only a few synapses could be involved in some primary acoustic startle circuit. Acoustic startle is being used as a model system for studying habituation, sensitization, prepulse inhibition, classical conditioning, fear or anxiety, and drug effects on behavior. The present study attempted to delineate a short latency acoustic startle circuit, since this would provide critical information for further study in all of these areas. Bilateral lesions of the ventral cochlear nucleus, which receives the primary auditory input, abolish acoustic startle. Electrical, single pulse stimulation of the ventral cochlear nucleus elicits startle-like responses with a latency of about 7 msec. Bilateral lesions of the dorsal and ventral nuclei of the lateral lemniscus, which receive direct input from the ventral cochlear nuclei, abolish acoustic startle. Electrical stimulation of these nuclei elicits startle-like responses with a latency of about 6 msec. Bilateral lesions of ventral regions of the nucleus reticularis pontis caudalis, which contain cell bodies that give rise to the reticulospinal tract, abolish acoustic startle. Electrical stimulation of these points elicits startle-like responses with a latency of about 5 msec. Reaction product from horseradish peroxidase iontophoresed into this area is found in the nuclei of the lateral lemniscus. In contrast, lesions of the dorsal cochlear nuclei, vestibular nuclei, nucleus reticularis pontis oralis, nucleus reticularis gigantocellularis, and dorsal regions of the nucleus reticularis pontis caudalis fail to abolish acoustic startle. Also, "startle" cannot be elicited electrically from these areas. The data suggest that a primary acoustic startle circuit in the rat consists of auditory nerve, ventral cochlear nucleus, nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal interneuron, lower motor neuron, and muscles. Hence, five synapses, plus the neuromuscular junction, are probably involved.
The present study investigated the effects of the glycine antagonist strychnine on the acoustic startle response in rats. Strychnine (0.25, 0.50, 1.0, 1.25, 1.5 and 2.0 mg/kg) administered intraperitoneally (i.p.) was found to produce a dose-dependent increase in startle amplitude that reached its greatest magnitude within 10-15 min after injection. These doses did not produce convulsions or behavioral activation. In order to localize the site of action of this excitatory strychnine effect, rats were implanted with catheters in the lumbar region of the spinal cord (intrathecal implantation), in the cisterna magna, or in the lateral ventricle and later tested for startle after microinjections of strychnine. Dose-dependent excitatory effects on acoustic startle were found when strychnine was injected onto the spinal cord (3.12-12.5 microgram) or into the cisterna magna (6.25-25.0 microgram), whereas infusion into the lateral ventricle produced inhibition (6.25-25.0 microgram). The peak increases in startle following intrathecal (164%) and intracisternal (144%) strychnine were similar to the increase seen following systemic strychnine (160%). Thus, the excitatory effect of systemic strychnine appears to be mediated in the spinal cord and/or brainstem, consistent with data showing that glycine receptors are primarily localized in the caudal regions of the central nervous system. Furthermore, these results suggest that glycine exerts a tonic inhibitory influence on acoustic startle. The possible relation of such a system to phenomena that involve reduction in startle amplitude (e.g., habituation, pre-pulse inhibition) is discussed.
To administer drugs into the spinal subarachnoid space of unanesthetized and intact rats and rabbits, a procedure is described whereby a polyethylene catheter (PE-10) may be inserted through a puncture of the atlanto-occipital membrane and secured to the skull. Calibration experiments carried out with bromophenol blue dye, 3H-naloxone and 14C-urea revealed first, that there was little rostro-caudal diffusion of the injectate along the spinal axis and secondly, that even for compounds such as naloxone which can rapidly permeate neural tissues, the levels which do appear in the brain are small following the spinal subarachnoid administration of the drug. Control injections, administered either acutely or repeatedly over a prolonged period of time, had no detectable effect on the animal's behavior. These observations, as well as the lack of pathology in the spinal cords of rats having such catheters for periods of up to 4 months suggests that the implant is well tolerated.
Male rats were trained on buzzer-shock presentations. In 15 animals, conditions produced a conditioned pain response; in the controls, conditions reduced or prevented formation of fear. The experimental group showed a significant progressive increase, extinction and spontaneous recovery in the average startle response whereas the controls changed but little.
Differential effects of selective dopamine agonists and antagonists on startle elicited electrically from the brainstem (abstr.). SOC. Neurosci. 1 4 849
- K R M Davis Melia
- W K M Berg
- Davis
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Double-pulse stimulation of startle-like responses in rats: Refractory periods and temporal summation Neural structures mediating acoustic and tactile startle reflexes and the acoustically-elicited pinna response in rats: Eikctrolytic and ibotenic acid studies (abstr.). SOC. Neurosci. 1 2 1273
- J S Yeomans
- J B Rosen
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Rolipram‐induced increase in sensorimotor reactivity measured with acoustic startle: Sites of action and possible monoaminergic mechanisms (abstr.)
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Lesions of the substantia innominata unmask an inhibitory effect of apomorphine on acoustic startle (abstr.)
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Spinal excitatory modulation of the startle reflex by substance P and serotonin (5‐HT1A) receptors (abstr.)
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Differential effects of selective dopamine agonists and antagonists on startle elicited electrically from the brainstem (abstr.)
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Neural structures mediating acoustic and tactile startle reflexes and the acoustically‐elicited pinna response in rats: Electrolytic and ibotenic acid studies (abstr.)
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