The Seagulls Experience is an institutional video presented in VHS format running for approximate... more The Seagulls Experience is an institutional video presented in VHS format running for approximately 14 minutes. It shows the strength, credibility, and competency of Seagulls Flight Foundation, Inc., a residential treatment and rehabilitation center for chemical dependents. The video concretely presents the organization\u27s concept, programs, and philosophy by means of varied footages and interviews
Basal forebrain cholinergic neurons are thought to modulate how organisms process and respond to ... more Basal forebrain cholinergic neurons are thought to modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, memory, and motivated behavior. We questioned whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of ancillary roles in stimulus processing. We found that cholinergic neurons are active during behavioral responding for a reward - even in the absence of reward or discrete stimuli. Photostimulation of cholinergic neurons in the basal forebrain or their terminals in the basolateral amygdala (BLA) selectively drove conditioned responding (licking), but not unconditioned licking nor innate motor outputs. In vivo electrophysiological recordings revealed reward-contingency-dependent-gating of cholinergic suppression of BLA neural activity during cholinergic photostimulation, but not dorsomedial prefrontal cortex (dmPFC). Finally, cholinergic terminals suppressed BLA projection neuron ...
a Médico Cirujanos; b Médico Neumólogo; c Interno de Medicina. Resumen Introducción: En el Perú, ... more a Médico Cirujanos; b Médico Neumólogo; c Interno de Medicina. Resumen Introducción: En el Perú, Lima y Callao constituyen regiones con riesgo alto de transmisión activa de tuberculosis. La tuberculosis multidrogorresistente se presenta en el 5,54% de los casos nuevos de tuberculosis pulmonar (TB MDR primaria) en Lima y Callao. Sus factores de riesgo no han sido estudiados en pacientes del Callao. Objetivos: Determinar los factores de riesgo para TB MDR primaria en pacientes atendidos en centros de salud de Callao, durante los años 2009-2010. Diseño: Estudio caso control. Lugar: Centros de Salud de Callao. Participantes: Participaron 29 pacientes con TB MDR primaria y 37 con tuberculosis sensible, según los registros del Programa de Control de Tuberculosis y las historias clínicas ubicadas en los centros de salud. Intervenciones: Toda la información fue obtenida de fuentes secundarias. En el análisis bivariado se calculó el OR de cada covariable. Para el cálculo de los OR multivaria...
Routledge International Handbook of Migration Studies, 2019
Historically in the United States, periods of large-scale immigration have been accompanied by pe... more Historically in the United States, periods of large-scale immigration have been accompanied by perceptions of threat and stereotypes of the feared criminality of immigrants. A century ago major commissions investigated the connection of immigration to crime; each found lower levels of criminal involvement among the foreign-born. The present period echoes that past. Over the past quarter century, alarms have been raised about large-scale immigration, and especially about undocumented immigrants from Latin America. But over the same period, violent crime and property crime rates have been cut in half; the decline in crime has been more pronounced in cities with larger shares of immigrants; and foreign-born young men are much less likely to be incarcerated than natives. The evidence demonstrating lower levels of criminal involvement among immigrants is supported by a growing number of contemporary studies. At the same time the period has been marked by the criminalization of immigration itself, and by the confluence of immigration and criminal law and enforcement apparatuses. A series of critical events succeeded by moral panics influenced the passage of hyper-restrictive laws and a massive injection of institutional resources that has built the "crimmigration" enforcement apparatus into the "formidable machinery" underpinning mass deportation today.
The ability to observe, interpret, and learn behaviors and emotions from conspecifics is crucial ... more The ability to observe, interpret, and learn behaviors and emotions from conspecifics is crucial for survival, as it bypasses direct experience to avoid potential dangers and maximize rewards and benefits. The anterior cingulate cortex (ACC) and its extended neural connections are emerging as important networks for the detection, encoding, and interpretation of social signals during observational learning. Evidence from rodents and primates (including humans) suggests that the social interactions that occur while individuals are exposed to important information in their environment lead to transfer of information across individuals that promotes adaptive behaviors in the form of either social affiliation, alertness, or avoidance. In this review, we first showcase anatomical and functional connections of the ACC in primates and rodents that contribute to the perception of social signals. We then discuss species-specific cognitive and social functions of the ACC and differentiate between neural activity related to 'self' and 'other', extending into the difference between social signals received and processed by the self, versus observing social interactions among others. We next describe behavioral and neural events that contribute to social learning via observation. Finally, we discuss some of the neural mechanisms underlying observational learning within the ACC and its extended network.
Nature Research wishes to improve the reproducibility of the work that we publish. This form prov... more Nature Research wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency in reporting. For further information on Nature Research policies, see Authors & Referees and the Editorial Policy Checklist. Statistical parameters When statistical analyses are reported, confirm that the following items are present in the relevant location (e.g. figure legend, table legend, main text, or Methods section). n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement An indication of whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s) used AND whether they are one-or two-sided Only common tests should be described solely by name; describe more complex techniques in the Methods section.
Much is known about the neural circuits of conditioned fear and its relevance to understanding an... more Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studie...
Observational learning is a powerful survival tool allowing individuals to learn about threat-pre... more Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this...
Orchestrating appropriate behavioral responses in the face of competing signals that predict eith... more Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral amygdala (BLA) and prelimbic (PL) medial prefrontal cortex (mPFC) have been implicated in reward-seeking and fearrelated responses, but how information flows between these reciprocally-connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task where in shock-and sucrose-predictive cues were simultaneously presented to induce competition. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, the majority of optogenetically-identified PL-projecting BLA neurons recorded encoded the shock-associated cue, and more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally, BLA→PL photostimulation increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. The BLA→PL circuit plays a critical role in governing the selection of behavioral responses in the face of competing signals. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Prolonged stress exposure is a risk factor for developing posttraumatic stress disorder, a disord... more Prolonged stress exposure is a risk factor for developing posttraumatic stress disorder, a disorder characterized by the ‘over-encoding’ of a traumatic experience. A potential mechanism by which this occurs is through upregulation of growth hormone (GH) in the amygdala. Here we test the hypotheses that GH promotes the over-encoding of fearful memories by increasing the number of neurons activated during memory encoding and biasing the allocation of neuronal activation, one aspect of the process by which neurons compete to encode memories, to favor neurons that have stronger inputs. Viral overexpression of GH in the amygdala increased the number of amygdala cells activated by fear memory formation. GH-overexpressing cells were especially biased to express the immediate early gene c-Fos after fear conditioning, revealing strong autocrine actions of GH in the amygdala. In addition, we observed dramatically enhanced dendritic spine density in GH-overexpressing neurons. These data elucid...
The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and socia... more The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and social behaviors. It remains to be elucidated, however, whether direct projections from the BLA to the mPFC play a functional role in these behaviors. We used optogenetic approaches in behaving mice to either activate or inhibit BLA inputs to the mPFC during behavioral assays that assess anxiety-like behavior and social interaction. Channelrhodopsin-2 (ChR2)mediated activation of BLA inputs to the mPFC produced anxiogenic effects in the elevated plus maze and open field test, whereas halorhodopsin (NpHR)-mediated inhibition produced anxiolytic effects. Furthermore, activation of the BLA-mPFC pathway reduced social interaction in the resident-intruder test, whereas inhibition facilitated social interaction. These results establish a causal relationship between activity in the BLA-mPFC pathway and the bidirectional modulation of anxiety-related and social behaviors.
It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different ... more It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different aspects of appetitive behavior, however, physiological support for this hypothesis has been lacking. In the present study, we used multichannel single-unit recording to compare the response of neurons in the prelimbic (PL) and infralimbic (IL) subregions of the mPFC, in rats pressing a lever to obtain sucrose pellets on a variable interval schedule of reinforcement (VI-60). Approximately 25% of neurons in both structures exhibited prominent excitatory responses during rewarded, but not unrewarded, lever presses. The time courses of reward responses in PL and IL, however, were markedly different. Most PL neurons exhibited fast and transient responses at the delivery of sucrose pellets, whereas most IL neurons exhibited delayed and prolonged responses associated with the collection of earned sucrose pellets. We further examined the functional significance of reward responses in IL and PL with local pharmacological inactivation. IL inactivation significantly delayed the collection of earned sucrose pellets, whereas PL inactivation produced no discernible effects. These findings support the hypothesis that PL and IL signal distinct aspects of appetitive behavior, and suggest that IL signaling facilitates reward collection.
During auditory fear conditioning, it is well established that lateral amygdala (LA) neurons pote... more During auditory fear conditioning, it is well established that lateral amygdala (LA) neurons potentiate their response to the tone conditioned stimulus, and that this potentiation is required for conditioned fear behavior. Conditioned tone responses in LA, however, last only a few hundred milliseconds and cannot be responsible for sustained fear responses to a tone lasting tens of seconds. Recent evidence from inactivation and stimulation studies suggests that the prelimbic (PL) prefrontal cortex is necessary for expression of learned fears, but the timing of PL tone responses and correlations with fear behavior have not been studied. Using multichannel unit recording techniques in behaving rats, we observed sustained conditioned tone responses in PL that were correlated with freezing behavior on a second-to-second basis during the presentation of a 30 s tone. PL tone responses were also correlated with conditioned freezing across different experimental phases (habituation, conditioning, extinction). Moreover, the persistence of PL responses after extinction training was associated with failure to express extinction memory. Together with previous inactivation findings, the present results suggest that PL transforms transient amygdala inputs to a sustained output that drives conditioned fear responses and gates the expression of extinction. Given the relatively long latency of conditioned responses we observed in PL (ϳ100 ms after tone onset), we propose that PL integrates inputs from the amygdala, hippocampus, and other cortical sources to regulate the expression of fear memories.
Extinction of conditioned fear is an active learning process requiring N-methyl-D-aspartate recep... more Extinction of conditioned fear is an active learning process requiring N-methyl-D-aspartate receptors (NMDARs), but the timing, location, and neural mechanisms of NMDAR-mediated processing in extinction are a matter of debate. Here we show that infusion of the NMDAR antagonist CPP into the ventromedial prefrontal cortex (vmPFC) prior to, or immediately after, extinction training impaired 24 hr recall of extinction. These findings indicate that consolidation of extinction requires posttraining activation of NMDARs within the vmPFC. Using multichannel unit recording, we observed that CPP selectively reduced burst firing in vmPFC neurons, suggesting that bursting in vmPFC is necessary for consolidation of extinction. In support of this, we found that the degree of bursting in infralimbic vmPFC neurons shortly after extinction predicted subsequent recall of extinction. We suggest that NMDAR-dependent bursting in the infralimbic vmPFC initiates calcium-dependent molecular cascades that stabilize extinction memory, thereby allowing for successful recall of extinction.
Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to... more Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is no clear relationship between the levels of these hormones and stress-associated mental illnesses such as posttraumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin-releasing factor (CRF) or corticosterone. Repeated intraamygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was enhanced by ghrelin receptor stimulation. Virusmediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear-enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and growth hormone in maladaptive changes following prolonged stress.
The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Audit... more The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Auditory fear conditioning increases the tone responses of lateral amygdala neurons, but the increase is transient, lasting only a few hundred milliseconds after tone onset. It was recently reported that that the prelimbic (PL) prefrontal cortex transforms transient lateral amygdala input into a sustained PL output, which could drive fear responses via projections to the lateral division of basal amygdala (BL). To explore the possible mechanisms involved in this transformation, we developed a large-scale biophysical model of the BL-PL network, consisting of 850 conductance-based Hodgkin-Huxley-type cells, calcium-based learning, and neuromodulator effects. The model predicts that sustained firing in PL can be derived from BL-induced release of dopamine and norepinephrine that is maintained by PL-BL interconnections. These predictions were confirmed with physiological recordings from PL neuron...
Background: Transcutaneous electric acupoint stimulation (TEAS) avoids the use of needles, and in... more Background: Transcutaneous electric acupoint stimulation (TEAS) avoids the use of needles, and instead delivers a mild electric current at traditional acupoints. This technique has been used for treating heroin addiction, but has not been systematically tested for other drugs of abuse. This study aims to investigate the effects of TEAS on drug addiction.
The Seagulls Experience is an institutional video presented in VHS format running for approximate... more The Seagulls Experience is an institutional video presented in VHS format running for approximately 14 minutes. It shows the strength, credibility, and competency of Seagulls Flight Foundation, Inc., a residential treatment and rehabilitation center for chemical dependents. The video concretely presents the organization\u27s concept, programs, and philosophy by means of varied footages and interviews
Basal forebrain cholinergic neurons are thought to modulate how organisms process and respond to ... more Basal forebrain cholinergic neurons are thought to modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, memory, and motivated behavior. We questioned whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of ancillary roles in stimulus processing. We found that cholinergic neurons are active during behavioral responding for a reward - even in the absence of reward or discrete stimuli. Photostimulation of cholinergic neurons in the basal forebrain or their terminals in the basolateral amygdala (BLA) selectively drove conditioned responding (licking), but not unconditioned licking nor innate motor outputs. In vivo electrophysiological recordings revealed reward-contingency-dependent-gating of cholinergic suppression of BLA neural activity during cholinergic photostimulation, but not dorsomedial prefrontal cortex (dmPFC). Finally, cholinergic terminals suppressed BLA projection neuron ...
a Médico Cirujanos; b Médico Neumólogo; c Interno de Medicina. Resumen Introducción: En el Perú, ... more a Médico Cirujanos; b Médico Neumólogo; c Interno de Medicina. Resumen Introducción: En el Perú, Lima y Callao constituyen regiones con riesgo alto de transmisión activa de tuberculosis. La tuberculosis multidrogorresistente se presenta en el 5,54% de los casos nuevos de tuberculosis pulmonar (TB MDR primaria) en Lima y Callao. Sus factores de riesgo no han sido estudiados en pacientes del Callao. Objetivos: Determinar los factores de riesgo para TB MDR primaria en pacientes atendidos en centros de salud de Callao, durante los años 2009-2010. Diseño: Estudio caso control. Lugar: Centros de Salud de Callao. Participantes: Participaron 29 pacientes con TB MDR primaria y 37 con tuberculosis sensible, según los registros del Programa de Control de Tuberculosis y las historias clínicas ubicadas en los centros de salud. Intervenciones: Toda la información fue obtenida de fuentes secundarias. En el análisis bivariado se calculó el OR de cada covariable. Para el cálculo de los OR multivaria...
Routledge International Handbook of Migration Studies, 2019
Historically in the United States, periods of large-scale immigration have been accompanied by pe... more Historically in the United States, periods of large-scale immigration have been accompanied by perceptions of threat and stereotypes of the feared criminality of immigrants. A century ago major commissions investigated the connection of immigration to crime; each found lower levels of criminal involvement among the foreign-born. The present period echoes that past. Over the past quarter century, alarms have been raised about large-scale immigration, and especially about undocumented immigrants from Latin America. But over the same period, violent crime and property crime rates have been cut in half; the decline in crime has been more pronounced in cities with larger shares of immigrants; and foreign-born young men are much less likely to be incarcerated than natives. The evidence demonstrating lower levels of criminal involvement among immigrants is supported by a growing number of contemporary studies. At the same time the period has been marked by the criminalization of immigration itself, and by the confluence of immigration and criminal law and enforcement apparatuses. A series of critical events succeeded by moral panics influenced the passage of hyper-restrictive laws and a massive injection of institutional resources that has built the "crimmigration" enforcement apparatus into the "formidable machinery" underpinning mass deportation today.
The ability to observe, interpret, and learn behaviors and emotions from conspecifics is crucial ... more The ability to observe, interpret, and learn behaviors and emotions from conspecifics is crucial for survival, as it bypasses direct experience to avoid potential dangers and maximize rewards and benefits. The anterior cingulate cortex (ACC) and its extended neural connections are emerging as important networks for the detection, encoding, and interpretation of social signals during observational learning. Evidence from rodents and primates (including humans) suggests that the social interactions that occur while individuals are exposed to important information in their environment lead to transfer of information across individuals that promotes adaptive behaviors in the form of either social affiliation, alertness, or avoidance. In this review, we first showcase anatomical and functional connections of the ACC in primates and rodents that contribute to the perception of social signals. We then discuss species-specific cognitive and social functions of the ACC and differentiate between neural activity related to 'self' and 'other', extending into the difference between social signals received and processed by the self, versus observing social interactions among others. We next describe behavioral and neural events that contribute to social learning via observation. Finally, we discuss some of the neural mechanisms underlying observational learning within the ACC and its extended network.
Nature Research wishes to improve the reproducibility of the work that we publish. This form prov... more Nature Research wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency in reporting. For further information on Nature Research policies, see Authors & Referees and the Editorial Policy Checklist. Statistical parameters When statistical analyses are reported, confirm that the following items are present in the relevant location (e.g. figure legend, table legend, main text, or Methods section). n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement An indication of whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s) used AND whether they are one-or two-sided Only common tests should be described solely by name; describe more complex techniques in the Methods section.
Much is known about the neural circuits of conditioned fear and its relevance to understanding an... more Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studie...
Observational learning is a powerful survival tool allowing individuals to learn about threat-pre... more Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this...
Orchestrating appropriate behavioral responses in the face of competing signals that predict eith... more Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral amygdala (BLA) and prelimbic (PL) medial prefrontal cortex (mPFC) have been implicated in reward-seeking and fearrelated responses, but how information flows between these reciprocally-connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task where in shock-and sucrose-predictive cues were simultaneously presented to induce competition. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, the majority of optogenetically-identified PL-projecting BLA neurons recorded encoded the shock-associated cue, and more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally, BLA→PL photostimulation increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. The BLA→PL circuit plays a critical role in governing the selection of behavioral responses in the face of competing signals. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Prolonged stress exposure is a risk factor for developing posttraumatic stress disorder, a disord... more Prolonged stress exposure is a risk factor for developing posttraumatic stress disorder, a disorder characterized by the ‘over-encoding’ of a traumatic experience. A potential mechanism by which this occurs is through upregulation of growth hormone (GH) in the amygdala. Here we test the hypotheses that GH promotes the over-encoding of fearful memories by increasing the number of neurons activated during memory encoding and biasing the allocation of neuronal activation, one aspect of the process by which neurons compete to encode memories, to favor neurons that have stronger inputs. Viral overexpression of GH in the amygdala increased the number of amygdala cells activated by fear memory formation. GH-overexpressing cells were especially biased to express the immediate early gene c-Fos after fear conditioning, revealing strong autocrine actions of GH in the amygdala. In addition, we observed dramatically enhanced dendritic spine density in GH-overexpressing neurons. These data elucid...
The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and socia... more The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and social behaviors. It remains to be elucidated, however, whether direct projections from the BLA to the mPFC play a functional role in these behaviors. We used optogenetic approaches in behaving mice to either activate or inhibit BLA inputs to the mPFC during behavioral assays that assess anxiety-like behavior and social interaction. Channelrhodopsin-2 (ChR2)mediated activation of BLA inputs to the mPFC produced anxiogenic effects in the elevated plus maze and open field test, whereas halorhodopsin (NpHR)-mediated inhibition produced anxiolytic effects. Furthermore, activation of the BLA-mPFC pathway reduced social interaction in the resident-intruder test, whereas inhibition facilitated social interaction. These results establish a causal relationship between activity in the BLA-mPFC pathway and the bidirectional modulation of anxiety-related and social behaviors.
It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different ... more It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different aspects of appetitive behavior, however, physiological support for this hypothesis has been lacking. In the present study, we used multichannel single-unit recording to compare the response of neurons in the prelimbic (PL) and infralimbic (IL) subregions of the mPFC, in rats pressing a lever to obtain sucrose pellets on a variable interval schedule of reinforcement (VI-60). Approximately 25% of neurons in both structures exhibited prominent excitatory responses during rewarded, but not unrewarded, lever presses. The time courses of reward responses in PL and IL, however, were markedly different. Most PL neurons exhibited fast and transient responses at the delivery of sucrose pellets, whereas most IL neurons exhibited delayed and prolonged responses associated with the collection of earned sucrose pellets. We further examined the functional significance of reward responses in IL and PL with local pharmacological inactivation. IL inactivation significantly delayed the collection of earned sucrose pellets, whereas PL inactivation produced no discernible effects. These findings support the hypothesis that PL and IL signal distinct aspects of appetitive behavior, and suggest that IL signaling facilitates reward collection.
During auditory fear conditioning, it is well established that lateral amygdala (LA) neurons pote... more During auditory fear conditioning, it is well established that lateral amygdala (LA) neurons potentiate their response to the tone conditioned stimulus, and that this potentiation is required for conditioned fear behavior. Conditioned tone responses in LA, however, last only a few hundred milliseconds and cannot be responsible for sustained fear responses to a tone lasting tens of seconds. Recent evidence from inactivation and stimulation studies suggests that the prelimbic (PL) prefrontal cortex is necessary for expression of learned fears, but the timing of PL tone responses and correlations with fear behavior have not been studied. Using multichannel unit recording techniques in behaving rats, we observed sustained conditioned tone responses in PL that were correlated with freezing behavior on a second-to-second basis during the presentation of a 30 s tone. PL tone responses were also correlated with conditioned freezing across different experimental phases (habituation, conditioning, extinction). Moreover, the persistence of PL responses after extinction training was associated with failure to express extinction memory. Together with previous inactivation findings, the present results suggest that PL transforms transient amygdala inputs to a sustained output that drives conditioned fear responses and gates the expression of extinction. Given the relatively long latency of conditioned responses we observed in PL (ϳ100 ms after tone onset), we propose that PL integrates inputs from the amygdala, hippocampus, and other cortical sources to regulate the expression of fear memories.
Extinction of conditioned fear is an active learning process requiring N-methyl-D-aspartate recep... more Extinction of conditioned fear is an active learning process requiring N-methyl-D-aspartate receptors (NMDARs), but the timing, location, and neural mechanisms of NMDAR-mediated processing in extinction are a matter of debate. Here we show that infusion of the NMDAR antagonist CPP into the ventromedial prefrontal cortex (vmPFC) prior to, or immediately after, extinction training impaired 24 hr recall of extinction. These findings indicate that consolidation of extinction requires posttraining activation of NMDARs within the vmPFC. Using multichannel unit recording, we observed that CPP selectively reduced burst firing in vmPFC neurons, suggesting that bursting in vmPFC is necessary for consolidation of extinction. In support of this, we found that the degree of bursting in infralimbic vmPFC neurons shortly after extinction predicted subsequent recall of extinction. We suggest that NMDAR-dependent bursting in the infralimbic vmPFC initiates calcium-dependent molecular cascades that stabilize extinction memory, thereby allowing for successful recall of extinction.
Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to... more Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is no clear relationship between the levels of these hormones and stress-associated mental illnesses such as posttraumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin-releasing factor (CRF) or corticosterone. Repeated intraamygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was enhanced by ghrelin receptor stimulation. Virusmediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear-enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and growth hormone in maladaptive changes following prolonged stress.
The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Audit... more The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Auditory fear conditioning increases the tone responses of lateral amygdala neurons, but the increase is transient, lasting only a few hundred milliseconds after tone onset. It was recently reported that that the prelimbic (PL) prefrontal cortex transforms transient lateral amygdala input into a sustained PL output, which could drive fear responses via projections to the lateral division of basal amygdala (BL). To explore the possible mechanisms involved in this transformation, we developed a large-scale biophysical model of the BL-PL network, consisting of 850 conductance-based Hodgkin-Huxley-type cells, calcium-based learning, and neuromodulator effects. The model predicts that sustained firing in PL can be derived from BL-induced release of dopamine and norepinephrine that is maintained by PL-BL interconnections. These predictions were confirmed with physiological recordings from PL neuron...
Background: Transcutaneous electric acupoint stimulation (TEAS) avoids the use of needles, and in... more Background: Transcutaneous electric acupoint stimulation (TEAS) avoids the use of needles, and instead delivers a mild electric current at traditional acupoints. This technique has been used for treating heroin addiction, but has not been systematically tested for other drugs of abuse. This study aims to investigate the effects of TEAS on drug addiction.
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Papers by Anthony Robles