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Michael Davis

Publications and source records attributed to Michael Davis.

At least 55 records · Page 3Linked to original sources

AX+, BX- discrimination learning in the fear-potentiated startle paradigm: possible relevance to inhibitory fear learning in extinction.

The neural mechanisms of fear suppression most commonly are studied through the use of extinction, a behavioral procedure in which a feared stimulus (i.e., one previously paired with shock) is nonreinforced repeatedly, leading to a reduction or elimination of the fear response. Although extinction is perhaps the most convenient index of fear inhibition, a great deal of behavioral work suggests that postextinction training conditioned stimuli are both excitatory and inhibitory, making it difficult to determine whether a neural manipulation affects inhibition, excitation, or some combination thereof. For this reason we sought to develop a behavioral procedure that would render a stimulus primarily inhibitory while at the same time avoiding some of the issues raised by the traditional conditioned inhibition paradigm, namely second-order conditioning, external inhibition, and configural learning. Using the fear-potentiated startle paradigm, we adapted an AX+, BX- training procedure in which stimuli A and X were presented simultaneously and paired with shock, and stimuli B and X were presented simultaneously in the absence of shock. In testing, high levels of fear-potentiated startle were seen in the presence of A and AX and much lower levels were seen in the presence of B and AB, as would be predicted if stimulus B were a conditioned inhibitor. We believe this method is a viable alternative to the traditional conditioned inhibition training procedure and will be useful for studying the neural mechanisms of fear inhibition.

Acoustic Stimulation↗

Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning.

Brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), play a critical role in activity-dependent synaptic plasticity and have been implicated as mediators of hippocampal-dependent learning and memory. The present study is the first to demonstrate a role for BDNF and TrkB in amygdala-dependent learning. Here, the use of Pavlovian fear conditioning as a learning model allows us to examine the concise role of BDNF in the amygdala after a single learning session and within a well understood neural circuit. Using in situ hybridization, mRNA levels of six different trophic factors [BDNF, neurotrophin (NT) 4/5, NGF, NT3, aFGF, and bFGF) were measured at varying time points during the consolidation period after fear conditioning. We found temporally specific changes only in BDNF gene expression in the basolateral amygdala after paired stimuli that supported learning but not after exposure to neutral or aversive stimuli alone. Using Western blotting, we found that the Trk receptor undergoes increased phosphorylation during this consolidation period, suggesting an activation of the receptor subsequent to BDNF release. Furthermore, disruption of neurotrophin signaling with intra-amygdala infusion of the Trk receptor antagonist K252a disrupted acquisition of fear conditioning. To address the specific role of the TrkB receptor, we created a novel lentiviral vector expressing a dominant-negative TrkB isoform (TrkB.T1), which specifically blocked TrkB activation in vitro. In vivo, TrkB.T1 lentivirus blocked fear acquisition without disrupting baseline startle or expression of fear. These data suggest that BDNF signaling through TrkB receptors in the amygdala is required for the acquisition of conditioned fear.

Amygdala↗

Are fear memories made and maintained by the same NMDA receptor-dependent mechanisms?

A recent finding indicates that inducible knockout of the NR1 NMDA receptor subunit promotes the loss of fear memories formed months earlier. One view is that posttraining NMDA receptor activation protects modified synapses from "synaptic drift." An alternative view is that NMDA receptors help maintain appropriate connectivity in memory-encoding networks.

Animals↗

Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear.

BACKGROUND: Traditional pharmacological approaches to treating psychiatric disorders focus on correcting presumed biochemical abnormalities. However, some disorders, particularly the anxiety-related disorders exemplified by specific phobia, have an emotional learning component to them that can be facilitated with psychotherapy. OBJECTIVE: To determine whether D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor that has previously been shown to improve extinction of fear in rodents, will also improve extinction of fear in human phobic patients undergoing behavioral exposure therapy. DESIGN: Randomized, double-blind, placebo-controlled trial examining DCS vs placebo treatment in combination with a precisely controlled exposure paradigm. SETTING: Participants were recruited from the general community to a research clinic. PARTICIPANTS: Twenty-eight subjects with acrophobia diagnosed by the Structured Clinical Interview for DSM-IV were enrolled. INTERVENTIONS: After we obtained pretreatment measures of fear, subjects were treated with 2 sessions of behavioral exposure therapy using virtual reality exposure to heights within a virtual glass elevator. Single doses of placebo or DCS were taken prior to each of the 2 sessions of virtual reality exposure therapy. Subjects, therapists, and assessors were blind to the treatment condition. Subjects returned at 1 week and 3 months posttreatment for measures to determine the presence and severity of acrophobia symptoms. MAIN OUTCOME MEASURES: Included were measures of acrophobia within the virtual environment, measures of acrophobia in the real world, and general measures of overall improvement. An objective measure of fear, electrodermal skin fluctuation, was also included during the virtual exposure to heights. Symptoms were assessed by self-report and by independent assessors at approximately 1 week and 3 months posttreatment. RESULTS: Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome measures. Subjects receiving DCS had significantly more improvement compared with subjects receiving placebo within the virtual environment (1 week after treatment, P</=.001; 3 months later, P</=.05). Subjects receiving DCS also showed significantly greater decreases in posttreatment skin conductance fluctuations during the virtual exposure (P</=.05). Additionally, subjects receiving DCS had significantly greater improvement compared with subjects receiving placebo on general measures of real-world acrophobia symptoms (acrophobia avoidance [P</=.02], acrophobia anxiety [P</=.01], attitudes toward heights [P</=.04], clinical global improvement [P</=.01], and number of self-exposures to real-world heights [P</=.01]); the improvement was evident early in treatment and was maintained at 3 months. CONCLUSION: These pilot data provide initial support for the use of acute dosing of DCS as an adjunct to exposure-based psychotherapy to accelerate the associative learning processes that contribute to correcting psychopathology.

Adult↗

The substantia nigra pars reticulata mediates the enhancement of startle by the dopamine D1 receptor agonist SKF 82958 in rats.

RATIONAL AND OBJECTIVES: Several studies have shown that the substantia nigra pars reticulata (SNr) is a critical site of action mediating dopamine agonist effects on motor behaviors. Because dopaminergic and GABA ergic mechanisms may interact in the SNr, we tested the contribution of both dopamine and GABA receptors in the SNr on the enhancement of startle by the dopamine D1 agonist SKF 82958. METHODS: Male Sprague-Dawley rats were implanted with cannulae into the SNr and 1 week later infused with either the D1 antagonist SCH 23390 (0.1, 1 microg) or the GABA(A) antagonist bicuculline (0.1 microg), followed by a systemic challenge with the D1 agonist SKF 82958 (1 mg/kg). Other rats were infused with the GABA(A) agonist muscimol (0.1 microg) or SKF 82958 (0.1, 1, 5 microg). RESULTS: Both SCH 23390 and bicuculline infused into the SNr completely blocked the enhancement of startle by systemic SKF 82958. Muscimol infused into the SNr produced a significant increase in startle by itself, whereas SKF 82958 had no effect. CONCLUSIONS: These results suggest that activation of D1 receptors in the SNr is necessary for the enhancement of startle by SKF 82958, but that activation of these receptors alone is not sufficient to increase startle. These results also suggest that GABA transmission in the SNr may be involved in the enhancement of startle by SKF 82958. Based on these data, we propose that activation of striatonigral neurons by D1 receptor agonists facilitates GABA release in the SNr to produce the observed enhancement of startle.

Animals↗

Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans.

RATIONALE: Beta-adrenergic receptors are involved in the consolidation of emotional memories. Yet, a number of studies using Pavlovian cued fear conditioning have been unable to demonstrate an effect of beta-adrenergic blockade on acquisition or retention of fear conditioning. Evidence for the involvement of beta-adrenergic receptors in emotional memories comes mostly from studies using fear inhibitory avoidance in rodents. It is possible that fear inhibitory avoidance is more akin to contextual conditioning than to cued fear conditioning, suggesting that context conditioning may be disrupted by beta-adrenergic blockade. OBJECTIVE: This study investigated the effects of the beta-adrenergic blocker propranolol on cued and contextual fear conditioning in humans. METHODS: Subjects were given either placebo (n=15) or 40 mg propranolol (n=15) prior to differential cued conditioning. A week later, they were tested for retention of context and cued fear conditioning using physiological (startle reflex and electrodermal activity) and subjective measures of emotional arousal. RESULTS: The results were consistent with the hypothesis. The skin conductance level (SCL) and the subjective measure of arousal suggested reduced emotional arousal upon returning to the conditioning context in the propranolol group, compared to the placebo group. The acquisition and retention of cued fear conditioning were not affected by propranolol. CONCLUSIONS: These results suggest that beta-adrenergic receptors are involved in contextual fear conditioning.

Adrenergic beta-Antagonists↗

Involvement of central amygdalar and bed nucleus of the stria terminalis corticotropin-releasing factor in behavioral responses to social defeat.

The authors investigated whether corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) is a critical component of the neural circuitry mediating conditioned defeat. In this model, hamsters that have experienced social defeat subsequently display only submissive-defensive agonistic behavior instead of territorial aggression. Conditioned defeat was significantly reduced following infusion of the CRF receptor antagonist D-Phe CRF((12-41)) into the BNST but not into the CeA. In another experiment, hamsters given unilateral lesions of the CeA and infusions of D-Phe CRF((12-41)) into the contralateral BNST displayed significantly less submissive behavior than did controls. These data suggest that CRF acts within a neural circuit that includes the amygdala and the BNST to modulate agonistic behavior following social defeat.

Amygdala↗

Inhibition of fear potentiated startle in rats following peripheral administration of secretin.

RATIONALE: Previous results indicate that peripheral administration of secretin leads to robust Fos protein expression in the central nucleus of the rat amygdala. The implications of this observation on rat brain function, if any, remain unclear. OBJECTIVES: We examined the effect of systemic secretin administration on the expression of fear-potentiated startle in rats, a behavioral response known to require an intact, functional central nucleus of the amygdala. METHODS: Rats were trained to associate a neutral light conditioned stimulus (CS) with footshock, a fear-inducing unconditioned stimulus (US). Twenty-four hours later, rats were administered secretin or vehicle and were tested immediately for their startle response to a loud noise in the presence or absence of the light. RESULTS: Within a dose range relevant to its clinical use in autistic children, secretin dose-dependently decreased the magnitude of fear-potentiated startle in rats. CONCLUSIONS: This investigation provides additional evidence that systemically administered secretin can influence a neural network implicated in the acquisition and expression of emotional behaviors, including fear and anxiety.

Amygdala↗

The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT).

OBJECTIVES: The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial was a multicenter trial of atrioventricular junction ablation and pacing (AVJAP) compared with pharmacologic ventricular rate control (medication [MED]) in patients with mild to moderately symptomatic permanent atrial fibrillation (AF). BACKGROUND: There have been very few prospective randomized trials, undertaken in highly symptomatic patients, comparing AVJAP with pharmacologic methods of ventricular rate control for patients with permanent AF. METHODS: There were 99 patients (70 men, mean age 68 +/- 8.6 years) at five centers. Forty-nine patients were randomized to AVJAP while 50 patients were randomized to pharmacologic control. The primary end point was cardiac function measured by echocardiography and exercise tolerance. The secondary end points were ventricular rate control, evaluated by 24-h ambulatory electrocardiographic monitoring, and quality of life. Data were collected at randomization and then at one month, six months, and 12 months post-randomization. RESULTS: At 12 months follow-up there was no significant difference in left ventricular ejection fraction (AVJAP: 54 +/- 17%; MED: 61 +/- 13% [p = ns]) or exercise duration on treadmill testing (AVJAP: 4.1 +/- 2 min; MED: 4.6 +/- 2 min [p = ns]); however, the peak ventricular rate was lower in the AVJAP group during exercise (112 +/- 17 beats/min vs. 153 +/- 36 beats/min, p < 0.05) and activities of daily life (117 +/- 16 beats/min vs. 152 +/- 37 beats/min, p < 0.05). The CAST quality-of-life questionnaire revealed that patients in the AVJAP group had fewer symptoms at six months (p = 0.003) and at 12 months (p = 0.004). The observed relative risk reduction in symptoms at 12 months was 18%. Global subjective semiquantitative measurement of quality of life using the "ladder of life" revealed that the AVJAP group reported a 6% better quality of life at six months (p = 0.011). CONCLUSIONS: In this trial, AVJAP for patients with mild to moderately symptomatic permanent AF did not worsen cardiac function during long-term follow-up, and quality of life was improved.

Activities of Daily Living↗

Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety.

The bed nucleus of the stria terminalis is a limbic forebrain structure that receives heavy projections from, among other areas, the basolateral amygdala, and projects in turn to hypothalamic and brainstem target areas that mediate many of the autonomic and behavioral responses to aversive or threatening stimuli. Despite its strategic anatomical position, initial attempts to implicate the bed nucleus of the stria terminalis in conditioned fear were largely unsuccessful. Recent studies have shown, however, that the bed nucleus of the stria terminalis does participate in certain types of anxiety and stress responses. In this work, we review these findings and suggest from the emerging pattern of evidence that, although the bed nucleus of the stria terminalis may not be necessary for rapid-onset, short-duration behaviors which occur in response to specific threats, the bed nucleus of the stria terminalis may mediate slower-onset, longer-lasting responses that frequently accompany sustained threats, and that may persist even after threat termination.

Amygdala↗

What's philosophically interesting about engineering ethics?

What makes a subject philosophically interesting is hard-to-resolve confusion about fundamental concepts. Engineering ethics suffers from at least three such fundamental confusions. First, there is confusion about what the "ethics" in engineering ethics is (ordinary morality, philosophical ethics, special standards, or something else?) Second, there is confusion about what the profession of engineering is (a function, discipline, occupation, kind of organization, or something else?) Third, there is confusion about what the discipline of engineering is. These fundamental confusions in engineering ethics connect with philosophically interesting work in moral theory, political philosophy, and philosophy of science. Work in these areas may help with the philosophical problems of engineering ethics. But, equally important, work in engineering ethics may help with the philosophical problems in these others fields.

Engineering↗

What can we learn by looking for the first code of professional ethics?

The first code of professional ethics must: (1) be a code of ethics; (2) apply to members of a profession; (3) apply to all members of that profession; and (4) apply only to members of that profession. The value of these criteria depends on how we define "code", "ethics", and "profession", terms the literature on professions has defined in many ways. This paper applies one set of definitions of "code", "ethics", and "profession" to a part of what we now know of the history of professions, thereby illustrating how the choice of definition can alter substantially both our answer to the question of which came first and (more importantly) our understanding of professional codes (and the professions that adopt them). Because most who write on codes of professional ethics seem to take for granted that physicians produced the first professional code, whether the Hippocratic Oath, Percival's Medical Ethics, the 1847 Code of Ethics of the American Medical Association (AMA), or some other document, I focus my discussion on these codes.

American Medical Association↗

Role of the amygdala in fear extinction measured with potentiated startle.

Although much is now known about the neural basis of excitatory fear conditioning, much less is known about the neural basis of inhibitory conditioning. One type of inhibitory conditioning is extinction, a process in which stimuli that elicit fear by virtue of previous associations with aversive stimuli such as shock (excitatory fear conditioning) are now presented in the absence of the aversive stimuli (extinction training). As a result, the ability of the conditioned stimulus to elicit fear gradually diminishes. Extinction is different from forgetting and does not reflect an erasure of the original fear memory. Instead, extinction is an active form of inhibitory learning that competes with excitatory fear conditioning. Infusions into the amygdala (a brain area essential for excitatory fear conditioning) of either NMDA receptor antagonists or inhibitors of the NMDA-receptor-linked mitogen-activated protein kinase cascade block extinction learning. Conversely, the NMDA receptor agonist D-cycloserine facilitates extinction after either systemic administration or intra-amygdala infusion. Because therapeutic interventions based on extinction procedures are commonly used to treat fear disorders, and because D-cycloserine is a widely available and safe compound, D-cycloserine or similar agents might be usefully combined with traditional extinction-based approaches in the treatment of clinical fear.

Amygdala↗

Applying learning principles to the treatment of post-trauma reactions.

Posttraumatic stress disorder (PTSD) can be characterized as a failure of recovery caused, in part, by a failure of fear extinction after trauma. By studying the process of extinction, we can be informed regarding the etiology and maintenance of PTSD. The normal response to trauma in humans includes a set of predictable reactions including reexperiencing, avoidance, and hyperarousal that typically extinguish in the days and weeks after the trauma. In the majority of people exposed to trauma, these responses extinguish over time. However, in a substantial minority, extinction fails and these persisting responses become the symptoms of PTSD. Therefore, one of our fundamental hypotheses is that PTSD is a disorder caused in part by the failure of extinction of predictable posttraumatic physiological and psychological reactions. The most empirically validated treatments for PTSD involve exposure of the patient to trauma-related cues in the absence of danger that then lead to the extinction of these reexperiencing, avoidance, and arousal symptoms. There is also mounting evidence that individuals with PTSD are more resistant to extinction. Regarding early interventions with traumatized individuals, there is mounting evidence that some early one-time interventions actually may impede extinction, whereas interventions delivered in more than one session, at least several weeks after the trauma, to individuals continuing to experience above average reactions, generally are effective in preventing the development of PTSD. Thus, there appears to be an interaction between timing of the intervention, number of intervention sessions, and either arousal level and/or risk status in determining whether the intervention will be helpful, harmful, or neutral.

Arousal↗