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Joseph E. Ledoux - One of the best experts on this subject based on the ideXlab platform.
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Chemogenetic Inhibition Reveals That Processing Relative But Not Absolute Threat Requires Basal Amygdala.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019Co-Authors: Vincent D. Campese, Ian T. Kim, Mian Hou, Saurav Gupta, Cassandra Draus, Botagoz Kurpas, Kelsey Burke, Joseph E. LedouxAbstract:While our understanding of appetitive motivation has benefited immensely from the use of selective outcome devaluation tools, the same cannot be said about aversive motivation. Findings from appetitive conditioning studies have shown that Basal Amygdala is required for behaviors that are sensitive to updates in outcome value, but similar results in aversive motivation are difficult to interpret due to a lack of outcome specificity. The studies reported here sought to develop procedures to isolate sensory-specific processes in aversive learning and behavior and to assess the possible contribution of the Basal Amygdala. Post-training changes to outcome value produced commensurate changes to subsequently tested conditioned responding in male rodents. Specifically, increases in shock intensity (i.e., inflation) augmented, while repeated exposure to (i.e., habituation of) an aversive sound (klaxon-horn) reduced freezing to conditioned stimuli previously paired with these outcomes. This was extended to a discriminative procedure, in which following revaluation of one event, but not the other, responding was found to be dependent on outcome value signaled by each cue. Chemogenetic inactivation of Basal Amygdala impaired this discrimination between stimuli signaling differently valued outcomes, but did not affect the revaluation process itself. These findings demonstrate a contribution of the Basal Amygdala to aversive outcome-dependent motivational processes.SIGNIFICANCE STATEMENT The specific content of pavlovian associative learning has been well studied in appetitive motivation, where the value of different foods can be easily manipulated. This has facilitated our understanding of the neural circuits that generate different forms of motivation (i.e., sensory specific vs general). Studies of aversive learning have not produced the same degree of understanding with regard to sensory specificity due to a lack of tools for evaluating sensory-specific processes. Here we use a variant of outcome devaluation procedures with aversive stimuli to study the role of Basal Amygdala in discriminating between aversive stimuli conveying different degrees of threat. These findings have implications for how we study generalized threat to identify dysregulation that can contribute to generalized anxiety.
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Active avoidance requires a serial Basal Amygdala to nucleus accumbens shell circuit.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015Co-Authors: Franchesca Ramirez, Joseph E. Ledoux, Justin M. Moscarello, Robert M. SearsAbstract:Freezing is a species-typical defensive reaction to conditioned threats. While the neural circuitry of aversive Pavlovian behavior has been extensively studied, less is known about the circuitry underlying more active responses to danger. Here we show that the flow of information between the Basal Amygdala (BA) and the nucleus accumbens (NAcc) is necessary for signaled active avoidance behavior. Rats trained to avoid shock by shuttling during an auditory conditioned stimulus showed increased expression of the activity-dependent protein c-Fos in the NAcc, specifically the shell subregion (NAccSh). Silencing neural activity in the NAccSh, but not in the adjacent NAcc core, disrupted avoidance behavior. Disconnection of the BA and the NAccSh was just as effective at disrupting avoidance behavior as bilateral NAccSh inactivations, suggesting learned avoidance behavior requires an intact BA-NAccSh circuit. Together, these data highlight an essential role for the Amygdalar projection to the ventral striatum in aversively motivated actions.
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diverse effects of conditioned threat stimuli on behavior
Cold Spring Harbor Symposia on Quantitative Biology, 2014Co-Authors: Justin M. Moscarello, Joseph E. LedouxAbstract:: Aversive Pavlovian memory coordinates the defensive behavioral response to learned threats. The Amygdala is a key locus for the acquisition and storage of aversive associations. Information about conditioned and unconditioned stimuli converge in the lateral Amygdala, which is a hot spot for the plasticity induced by associative learning. Central Amygdala uses Pavlovian memory to coordinate the conditioned reaction to an aversive conditioned stimulus. Aversive associations can also access the brain networks of instrumental action. The offset of an aversive conditioned stimulus can reinforce behavior, recruiting a pathway that includes the lateral and Basal Amygdala, as opposed to the lateral and central Amygdala circuit for Pavlovian reactions. Aversive conditioned stimuli can also modulate ongoing behavior, suppressing appetitive actions and facilitating aversive actions. Facilitation depends on an Amygdalar network involving the lateral and central, as well as medial, nuclei. Thus, aversive Pavlovian memory has wide-reaching effects on defensive behavior, coordinating reactive to active responses to environmental threats.
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sidman instrumental avoidance initially depends on lateral and Basal Amygdala and is constrained by central Amygdala mediated pavlovian processes
Biological Psychiatry, 2010Co-Authors: Gabriel Lazaromunoz, Joseph E. Ledoux, Christopher K CainAbstract:Background The lateral (LA) and central (CE), but not Basal (B), Amygdala nuclei are necessary for reactive Pavlovian fear responses such as freezing. The Amygdala also plays a key role in the acquisition and expression of active instrumental defensive behaviors, but little is known about the specific roles of Amygdala nuclei. Using a Sidman active avoidance (AA) task, we examined the necessity of LA, B, and CE for learning and performance. Pavlovian freezing was simultaneously assessed to examine the contributions of Amygdala nuclei to the transition from reactive to active defensive responding. Methods Rats received electrolytic lesions of LA, CE, or B before AA training, or following overtraining. Rats that expressed low levels of AA performance during training received bilateral electrolytic lesions to CE to eliminate competing freezing reactions and rescue AA. AA performance and freezing were assessed. Results Damage to LA and B, but not CE, impaired the acquisition of AA. Performance of AA became Amygdala-independent following overtraining. CE lesions abolished Pavlovian freezing and rescued instrumental AA performance in rats that expressed low levels of avoidance responses and high levels of freezing during training. Conclusions Although the acquisition of Pavlovian fear depends on LA and CE, but not B, acquisition of instrumental AA is dependent on LA and B, but not CE. CE-dependent Pavlovian processes that control freezing can constrain avoidance behavior. Performance of well-trained AA becomes independent of all three Amygdala nuclei. Thus, it appears that different output pathways of LA mediate reactive and active conditioned defensive responding.
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Emotional perseveration: an update on prefrontal-Amygdala interactions in fear extinction.
Learning & memory (Cold Spring Harbor N.Y.), 2004Co-Authors: Francisco Sotres-bayon, David E. A. Bush, Joseph E. LedouxAbstract:Fear extinction refers to the ability to adapt as situations change by learning to suppress a previously learned fear. This process involves a gradual reduction in the capacity of a fear-conditioned stimulus to elicit fear by presenting the conditioned stimulus repeatedly on its own. Fear extinction is context-dependent and is generally considered to involve the establishment of inhibitory control of the prefrontal cortex over Amygdala-based fear processes. In this paper, we review research progress on the neural basis of fear extinction with a focus on the role of the Amygdala and the prefrontal cortex. We evaluate two competing hypotheses for how the medial prefrontal cortex inhibits Amygdala output. In addition, we present new findings showing that lesions of the Basal Amygdala do not affect fear extinction. Based on this result, we propose an updated model for integrating hippocampal-based contextual information with prefrontal-Amygdala circuitry.
Susan Sangha - One of the best experts on this subject based on the ideXlab platform.
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plasticity of fear and safety neurons of the Amygdala in response to fear extinction
Frontiers in Behavioral Neuroscience, 2015Co-Authors: Susan SanghaAbstract:Fear inhibition learning induces plasticity and remodeling of circuits within the Amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety and reward conditioning task, Sangha et al (2013) have previously reported several neural microcircuits within the Basal Amygdala which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these ‘safety’ neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of ‘safety’ neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the ‘safety’ neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated Basal Amygdala circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes.
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Safety Encoding in the Basal Amygdala
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Susan Sangha, James Z. Chadick, Patricia H. JanakAbstract:Learning to fear and avoid life-threatening stimuli are critical survival skills but are maladaptive when they persist in the absence of a direct threat. Thus, it is important to detect when a situation is safe and to increase behaviors leading to naturally rewarding actions, such as feeding and mating. It is unclear how the brain distinguishes between dangerous and safe situations. Here, we present a novel protocol designed to investigate the processing of cues that predict danger, safety, or reward (sucrose). In vivo single unit recordings were obtained in the Basal Amygdala of freely behaving rats undergoing simultaneous reward, fear, and safety conditioning. We observed a population of neurons that did not respond to a Fear Cue but did change their firing rate during the combined presentation of a fear cue simultaneous with a second, safety, cue; this combination of Fear + Safety Cues signified “no shock.” This neural population consisted of two subpopulations: neurons that responded to the Fear + Safety Cue but not the Fear or Reward Cue (“safety” neurons), and neurons that responded to the Fear + Safety and Reward Cue but not the Fear Cue (“safety + reward” neurons). These data demonstrate the presence of neurons in the Basal Amygdala that are selectively responsive to Safety Cues. Furthermore, these data suggest that safety and reward learning use overlapping mechanisms in the Basal Amygdala.
Allan Siegel - One of the best experts on this subject based on the ideXlab platform.
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Amygdaloid kindled seizures can induce functional and pathological changes in thymus of rat: role of the sympathetic nervous system.
Neurobiology of disease, 2005Co-Authors: Rekha Bhatt, Pranela Rameshwar, Suresh Bhatt, Meera Hameed, Allan SiegelAbstract:The present study sought to determine the effects of long-term kindled seizures of the Basal Amygdala upon immune function in rat, utilizing the thymus, as a principal target for study. Histopathology from kindled Sprague-Dawley rats revealed the presence of epithelial cell thymoma in 70% of these rats. The results revealed an increased rate of apoptosis and proliferation in thymic epithelial cells. Analysis of thymocytes indicated a decrease in the ratio of CD4 to CD8 positive T cells and reduced proliferative response to T-cell mitogens. To determine whether these effects were mediated through the sympathetic nervous system, animals were treated with guanethidine, which blocked the development of epithelial cell thymomas, while mifepristone treatment, employed to determine the possible role of the hypothalamic-pituitary axis, was ineffective in attenuating thymoma development. Thus, the present study demonstrated that functional and pathological changes in the thymus during kindled seizures are mediated through the sympathetic nervous system.
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Effects of kindled seizures upon hematopoiesis in rats.
Epilepsy Research, 2003Co-Authors: Rekha Bhatt, Pranela Rameshwar, Kenneth R Goldstein, Allan SiegelAbstract:Abstract Objective : Studies conducted in epilepsy patients and experimental animals have suggested a linkage between seizure activity and alterations in immune functions. However, little is known about the underlying mechanisms. The present study sought to determine whether chronic seizures result in changes in hematopoietic functions that contribute to alterations in immune function. Materials and methods : Sprague–Dawley rats were implanted with electrodes in the Basal Amygdala or frontal cortex for induction of focal seizures by kindling. After inducing stage 5 seizures for 30 days, rats were sacrificed and assays for colony-forming units granulocyte/macrophage (CFU-GM) were performed to study progenitor cell functions. Long-term culture-initiating culture (LTC-IC) assays were employed to determine the effects of kindling upon bone marrow stroma. A Western blot for caspase-3 and CFU-GM assays from peripheral blood were used to determine the cause of reduced cellularity of bone marrow. Results : Kindled seizures of the Basal Amygdala resulted in decreases in bone marrow cellularity and hyperproliferation of colony-forming cells in peripheral blood and bone marrow. Modified LTC-IC assays, where co-cultures of bone marrow cells and stroma from experimental animals were employed, revealed that hyperproliferation of progenitor cells was not associated with alterations in stromal functions. The changes observed in this study were associated with seizure foci in the Basal amygdaloid complex but not the frontal cortex. Conclusion : Kindled seizures of the Basal Amygdala induce hyperproliferation of bone marrow progenitor cells, suggesting that alterations in immunological functions observed following seizure activity may be due to changes in hematopoietic functions. Such changes appear to be site specific within the brain.
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Effects of kindled seizures upon hematopoiesis in rats.
Epilepsy research, 2003Co-Authors: Rekha Bhatt, Pranela Rameshwar, Kenneth Goldstein, Allan SiegelAbstract:Studies conducted in epilepsy patients and experimental animals have suggested a linkage between seizure activity and alterations in immune functions. However, little is known about the underlying mechanisms. The present study sought to determine whether chronic seizures result in changes in hematopoietic functions that contribute to alterations in immune function. Sprague-Dawley rats were implanted with electrodes in the Basal Amygdala or frontal cortex for induction of focal seizures by kindling. After inducing stage 5 seizures for 30 days, rats were sacrificed and assays for colony-forming units granulocyte/macrophage (CFU-GM) were performed to study progenitor cell functions. Long-term culture-initiating culture (LTC-IC) assays were employed to determine the effects of kindling upon bone marrow stroma. A Western blot for caspase-3 and CFU-GM assays from peripheral blood were used to determine the cause of reduced cellularity of bone marrow. Kindled seizures of the Basal Amygdala resulted in decreases in bone marrow cellularity and hyperproliferation of colony-forming cells in peripheral blood and bone marrow. Modified LTC-IC assays, where co-cultures of bone marrow cells and stroma from experimental animals were employed, revealed that hyperproliferation of progenitor cells was not associated with alterations in stromal functions. The changes observed in this study were associated with seizure foci in the Basal amygdaloid complex but not the frontal cortex. Kindled seizures of the Basal Amygdala induce hyperproliferation of bone marrow progenitor cells, suggesting that alterations in immunological functions observed following seizure activity may be due to changes in hematopoietic functions. Such changes appear to be site specific within the brain.
Joseph L. Price - One of the best experts on this subject based on the ideXlab platform.
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Paraventricular thalamic nucleus: subcortical connections and innervation by serotonin, orexin, and corticotropin-releasing hormone in macaque monkeys.
The Journal of comparative neurology, 2009Co-Authors: David T. Hsu, Joseph L. PriceAbstract:The present study examines subcortical connections of paraventricular thalamic nucleus (Pa) following small anterograde and retrograde tracer injections in cynomolgus monkeys (Macaca fascicularis). An anterograde tracer injection into the dorsal midline thalamus revealed strong projections to the accumbens nucleus, Basal Amygdala, lateral septum, and hypothalamus. Retrograde tracer injections into these areas labeled neurons specifically in Pa. Following a retrograde tracer injection into Pa, labeled neurons were found in the hypothalamus, dorsal raphe, and periaqueductal gray. Pa contained a remarkably high density of axons and axonal varicosities immunoreactive for serotonin (5-HT) and orexin/hypocretin (ORX), as well as a moderate density of fibers immunoreactive for corticotropin-releasing hormone (CRH). A retrograde tracer injection into Pa combined with immunohistochemistry demonstrated that ORX and 5-HT axons originate from neurons in the hypothalamus and midbrain. Pa-projecting neurons were localized in the same nuclei of the hypothalamus, Amygdala, and midbrain as CRH neurons, although no double labeling was found. The connections of Pa and its innervation by 5-HT, ORX, and CRH suggest that it may relay stress signals between the midbrain and hypothalamus with the accumbens nucleus, Basal Amygdala, and subgenual cortex as part of a circuit that manages stress and possibly stress-related psychopathologies.
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paraventricular thalamic nucleus subcortical connections and innervation by serotonin orexin and corticotropin releasing hormone in macaque monkeys
The Journal of Comparative Neurology, 2009Co-Authors: Joseph L. PriceAbstract:The present study examines subcortical connections of paraventricular thalamic nucleus (Pa) following small anterograde and retrograde tracer injections in cynomolgus monkeys (Macaca fascicularis). An anterograde tracer injection into the dorsal midline thalamus revealed strong projections to the accumbens nucleus, Basal Amygdala, lateral septum, and hypothalamus. Retrograde tracer injections into these areas labeled neurons specifically in Pa. Following a retrograde tracer injection into Pa, labeled neurons were found in the hypothalamus, dorsal raphe, and periaqueductal gray. Pa contained a remarkably high density of axons and axonal varicosities immunoreactive for serotonin (5-HT) and orexin/hypocretin (ORX), as well as a moderate density of fibers immunoreactive for corticotropin-releasing hormone (CRH). A retrograde tracer injection into Pa combined with immunohistochemistry demonstrated that ORX and 5-HT axons originate from neurons in the hypothalamus and midbrain. Pa-projecting neurons were localized in the same nuclei of the hypothalamus, Amygdala, and midbrain as CRH neurons, although no double labeling was found. The connections of Pa and its innervation by 5-HT, ORX, and CRH suggest that it may relay stress signals between the midbrain and hypothalamus with the accumbens nucleus, Basal Amygdala, and subgenual cortex as part of a circuit that manages stress and possibly stress-related psychopathologies. J. Comp. Neurol. 512:825–848, 2009. © 2008 Wiley-Liss, Inc.
Mark L. Andermann - One of the best experts on this subject based on the ideXlab platform.
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State-specific gating of salient cues by midbrain dopaminergic input to Basal Amygdala
Nature neuroscience, 2019Co-Authors: Andrew Lutas, Hakan Kucukdereli, Osama Alturkistani, Crista Carty, Arthur U. Sugden, Kayla Fernando, Veronica Diaz, Vanessa Flores-maldonado, Mark L. AndermannAbstract:Basal Amygdala (BA) neurons guide associative learning via acquisition of responses to stimuli that predict salient appetitive or aversive outcomes. We examined the learning- and state-dependent dynamics of BA neurons and ventral tegmental area (VTA) dopamine (DA) axons that innervate BA (VTADA→BA) using two-photon imaging and photometry in behaving mice. BA neurons did not respond to arbitrary visual stimuli, but acquired responses to stimuli that predicted either rewards or punishments. Most VTADA→BA axons were activated by both rewards and punishments, and they acquired responses to cues predicting these outcomes during learning. Responses to cues predicting food rewards in VTADA→BA axons and BA neurons in hungry mice were strongly attenuated following satiation, while responses to cues predicting unavoidable punishments persisted or increased. Therefore, VTADA→BA axons may provide a reinforcement signal of motivational salience that invigorates adaptive behaviors by promoting learned responses to appetitive or aversive cues in distinct, intermingled sets of BA excitatory neurons.
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State-specific gating of salient cues by midbrain dopaminergic input to Basal Amygdala
2019Co-Authors: Andrew Lutas, Hakan Kucukdereli, Osama Alturkistani, Crista Carty, Arthur U. Sugden, Kayla Fernando, Veronica Diaz, Vanessa Flores-maldonado, Mark L. AndermannAbstract:Basal Amygdala (BA) neurons guide associative learning via acquisition of responses to stimuli that predict salient appetitive or aversive outcomes. We examined the learning- and state-dependent dynamics of BA neurons and ventral tegmental area dopamine axons that innervate BA (VTADA>BA) using two-photon imaging and photometry in behaving mice. BA neurons did not respond to arbitrary visual stimuli, but acquired responses to stimuli that predicted either rewards or punishments. Most VTADA>BA axons were activated by both rewards and punishments, and acquired responses to cues predicting these outcomes during learning. Responses to cues predicting food rewards in VTADA>BA axons and BA neurons in hungry mice were strongly attenuated following satiation, while responses to cues predicting unavoidable punishments persisted or increased. Therefore, VTADA>BA axons may provide a reinforcement signal of motivational salience that invigorates adaptive behaviors by promoting learned responses to appetitive or aversive cues in distinct, intermingled sets of BA excitatory neurons.
