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Aversive Pavlovian conditioning is an important tool used to investigate neurobiological mechanisms underlying the acquisition and expression of fear. Most studies have used nonprimate species employing electrical shock as the unconditioned stimulus (US). Although important advances have been made in understanding the neural substrates of conditioned fear, the extent to which these findings apply to primates is unclear. Research in primates has not progressed because of the lack of a conditioning paradigm that does not use shock. Therefore, we developed a method that uses a US consisting of a loud noise coupled with a stream of compressed air aimed at the face to aversively condition heart rate response in rhesus monkeys. With this US, rhesus monkeys rapidly acquire a conditioned bradycardia. The availability of an easy, reliable, and efficient method of aversive conditioning that does not require electrical shock, will facilitate studies investigating neurobiological mechanisms underlying the acquisition and expression of fear in primates.
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In children, behavioral inhibition (BI) in response to potential threat predicts the development of anxiety and affective disorders, and primate lesion studies suggest involvement of the orbitofrontal cortex (OFC) in mediating BI. Lesion studies are essential for establishing causality in brain-behavior relationships, but should be interpreted cautiously because the impact of a discrete lesion on a complex neural circuit extends beyond the lesion location. Complementary functional imaging methods assessing how lesions influence other parts of the circuit can aid in precisely understanding how lesions affect behavior. Using this combination of approaches in monkeys, we found that OFC lesions concomitantly alter BI and metabolism in the bed nucleus of stria terminalis (BNST) region and that individual differences in BNST activity predict BI. Thus it appears that an important function of the OFC in response to threat is to modulate the BNST, which may more directly influence the expression of BI.
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Temperamentally anxious individuals can be identified in childhood and are at risk to develop anxiety and depressive disorders. In addition, these individuals tend to have extreme asymmetric right prefrontal brain activity. Although common and clinically important, little is known about the pathophysiology of anxious temperament. Regardless, indirect evidence from rodent studies and difficult to interpret primate studies is used to support the hypothesis that the amygdala plays a central role. In previous studies using rhesus monkeys, we characterized an anxious temperament endophenotype that is associated with excessive anxiety and fear-related responses and increased electrical activity in right frontal brain regions. To examine the role of the amygdala in mediating this endophenotype and other fearful responses, we prepared monkeys with selective fiber sparing ibotenic acid lesions of the amygdala. Unconditioned trait-like anxiety-fear responses remained intact in monkeys with >95% bilateral amygdala destruction. In addition, the lesions did not affect EEG frontal asymmetry. However, acute unconditioned fear responses, such as those elicited by exposure to a snake and to an unfamiliar threatening conspecific were blunted in monkeys with >70% lesions. These findings demonstrate that the primate amygdala is involved in mediating some acute unconditioned fear responses but challenge the notion that the amygdala is the key structure underlying the dispositional behavioral and physiological characteristics of anxious temperament.
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Numerous studies demonstrate that the rhesus monkey is an excellent species with which to investigate mechanisms underlying human emotion and psychopathology. To examine the role of the central nucleus of the amygdala (CeA) in mediating the behavioral and physiological responses associated with fear and anxiety, we used rhesus monkeys to assess the effects of excitotoxic lesions of the CeA. Behavioral and physiological responses of nine monkeys with bilateral CeA destruction (ranging from 46 to 98%) were compared with five animals with asymmetric lesions (42-86.5% destruction on the most affected side) and with 16 unoperated controls. Results suggest that similar to rodent species, the primate CeA plays a role in mediating fear- and anxiety-related behavioral and endocrine responses. Compared with controls and the asymmetric-lesion group, bilaterally lesioned monkeys displayed significantly less fear-related behavior when exposed to a snake and less freezing behavior when confronted by a human intruder. In addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin-releasing factor (CRF), and both lesioned groups had decreased plasma ACTH concentrations. In contrast to these findings, patterns of asymmetric frontal brain electrical activity, as assessed by regional scalp EEG, did not significantly differ between control and lesioned monkeys. These findings suggest that in primates, the CeA is involved in mediating fear- and anxiety-related behavioral and pituitary-adrenal responses as well as in modulating brain CRF activity.
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Subregional analyses of the hippocampus have suggested a selective role for the CA1 subregion in intermediate/long-term spatial memory and consolidation, but not short-term acquisition or encoding processes. It remains unclear how the direct cortical projection to CA1 via the perforant path (pp) contributes to these CA1-dependent processes. It has been suggested that dopamine selectively modulates the pp projection to CA1 while having little to no effect on the Schaffer collateral (SC) projection to CA1. This series of behavioral and electrophysiological experiments takes advantage of this pharmacological dissociation to demonstrate that the direct pp inputs to CA1 are critical in CA1-dependent intermediate-term retention and retrieval function. Here we demonstrate that local infusion of the nonselective dopamine agonist, apomorphine (10, 15 microg), into the CA1 subregion of awake animals produces impairments in between-day retention and retrieval, sparing within-day encoding of a modified Hebb-Williams maze and contextual conditioning of fear. In contrast, apomorphine produces no deficits when infused into the CA3 subregion. To complement the behavioral analyses, electrophysiological data was collected. In anesthetized animals, local infusion of the same doses of apomorphine significantly modifies evoked responses in the distal dendrites of CA1 following angular bundle stimulation, but produces no significant effects in the more proximal dendritic layer following stimulation of the SC. These results support a modulatory role for dopamine in the EC-CA1, but not CA3-CA1 circuitry, and suggest the possibility of a more fundamental role for EC-CA1 synaptic transmission in terms of intermediate-term, but not short-term spatial memory.
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BACKGROUND: Excessive behavioral inhibition during childhood marks anxious temperament and is a risk factor for the development of anxiety and affective disorders. Studies in nonhuman primates can provide important information related to the expression of this risk factor, since threat-induced freezing in rhesus monkeys is a trait-like characteristic analogous to human behavioral inhibition. The orbitofrontal cortex (OFC) and amygdala are part of a circuit involved in the processing of emotions and associated physiological responses. Earlier work demonstrated involvement of the primate central nucleus of the amygdala (CeA) in mediating anxious temperament. This study assessed the role of the primate OFC in mediating anxious temperament and its involvement in fear responses. METHODS: Twelve adolescent rhesus monkeys were studied (six lesion and six control monkeys). Lesions were targeted at regions of the OFC that are most interconnected with the amygdala. Behavior and physiological parameters were assessed before and after the lesions. RESULTS: The OFC lesions significantly decreased threat-induced freezing and marginally decreased fearful responses to a snake. The lesions also resulted in a leftward shift in frontal brain electrical activity consistent with a reduction in anxiety. The lesions did not significantly decrease hypothalamic-pituitary-adrenal (HPA) activity or cerebrospinal fluid (CSF) concentrations of corticotrophin-releasing factor (CRF). CONCLUSIONS: These findings demonstrate a role for the OFC in mediating anxious temperament and fear-related responses in adolescent primates. Because of the similarities between rhesus monkey threat-induced freezing and childhood behavioral inhibition, these findings are relevant to understanding mechanisms underlying anxious temperament in humans.
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The serotonin transporter (5-HTT) plays a critical role in regulating serotonergic neurotransmission and is implicated in the pathophysiology of anxiety and affective disorders. Positron emission tomography scans using [(11)C]DASB [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] to measure 5-HTT availability (an index of receptor density and binding) were performed in 34 rhesus monkeys in which the relationship between regional brain glucose metabolism and anxious temperament was previously established. 5-HTT availability in the amygdalohippocampal area and bed nucleus of the stria terminalis correlated positively with individual differences in a behavioral and neuroendocrine composite of anxious temperament. 5-HTT availability also correlated positively with stress-induced metabolic activity within these regions. Collectively, these findings suggest that serotonergic modulation of neuronal excitability in the neural circuitry associated with anxiety mediates the developmental risk for affect-related psychopathology.
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The length polymorphism of the serotonin (5-HT) transporter gene promoter region has been implicated in altered 5-HT function and, in turn, neuropsychiatric illnesses, such as anxiety and depression. The nonhuman primate has been used as a model to study anxiety-related mechanisms in humans based upon similarities in behavior and the presence of a similar 5-HT transporter gene polymorphism. Stressful and threatening contexts in the nonhuman primate model have revealed 5-HT transporter genotype dependent differences in regional glucose metabolism. Using the rhesus monkey, we examined the extent to which serotonin transporter genotype is associated with 5-HT transporter binding in brain regions implicated in emotion-related pathology. METHODS: Genotype data and high resolution PET scans were acquired in 29 rhesus (Macaca mulatta) monkeys. [C-11]DASB dynamic PET scans were acquired for 90 min in the anesthetized animals and images of distribution volume ratio (DVR) were created to serve as a metric of 5-HT transporter binding for group comparison based on a reference region method of analysis. Regional and voxelwise statistical analysis were performed with corrections for anatomical differences in gray matter probability, sex, age and radioligand mass. RESULTS: There were no significant differences when comparing l/l homozygotes with s-carriers in the regions of the brain implicated in anxiety and mood related illnesses (amygdala, striatum, thalamus, raphe nuclei, temporal and prefrontal cortex). There was a significant sex difference in 5-HT transporter binding in all regions with females having 18%-28% higher DVR than males. CONCLUSIONS: Because these findings are consistent with similar genotype findings in humans, this further strengthens the use of the rhesus model for studying anxiety-related neuropathologies.
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A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [18F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.
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This brief commentary highlights seven sins in the study of emotion that are explicitly treated in contemporary affective neuroscience. These sins are (1) Affect and cognition are subserved by separate and independent neural circuits; (2) Affect is subcortical; (3) Emotions are in the head; (4) Emotions can be studied from a purely psychological perspective; (5) Emotions are similar in structure across age and species; (6) Specific emotions are instantiated in discrete locations in the brain; and (7) Emotions are conscious feeling states. Each of these is briefly discussed and evidence from affective neuroscience that bears on these sins is noted. The articles in this Special Issue underscore the vitality of research in affective neuroscience and illustrate how some of these sins can be addressed and rectified using concepts and methods from affective neuroscience.
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BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) system activation is adaptive in response to stress, and HPA dysregulation occurs in stress-related psychopathology. It is important to understand the mechanisms that modulate HPA output, yet few studies have addressed the neural circuitry associated with HPA regulation in primates and humans. Using high-resolution F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we assessed the relation between individual differences in brain activity and HPA function across multiple contexts that varied in stressfulness. METHODS: Using a logical AND conjunctions analysis, we assessed cortisol and brain metabolic activity with FDG-PET in 35 adolescent rhesus monkeys exposed to two threat and two home-cage conditions. To test the robustness of our findings, we used similar methods in an archival data set. In this data set, brain metabolic activity and cortisol were assessed in 17 adolescent male rhesus monkeys that were exposed to three stress-related contexts. RESULTS: Results from the two studies revealed that subgenual prefrontal cortex (PFC) metabolism (Brodmann's area 25/24) consistently predicted individual differences in plasma cortisol concentrations regardless of the context in which brain activity and cortisol were assessed. CONCLUSIONS: These findings suggest that activation in subgenual PFC may be related to HPA output across a variety of contexts (including familiar settings and novel or threatening situations). Individuals prone to elevated subgenual PFC activity across multiple contexts may be individuals who consistently show heightened cortisol and may be at risk for stress-related HPA dysregulation.
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Recent evidence suggests that frontal brain electrical activity reveals asymmetries in activation in response to positive vs negative affective stimuli. This study was designed to evaluate whether this asymmetry is present at birth. Newborn infants were presented with water followed by a sucrose solution and then by a citric acid solution. Facial expression was videotaped during the presentation of the liquids and EEG was recorded from the frontal and parietal scalp regions on the left and right side. Usable EEG data were obtained from 16 newborn infants in response to these taste conditions. Videotaping of facial expression in response to these stimuli indicated the presence of disgust during both water (the first taste introduced) and citric acid. EEG was Fourier Transformed and power in the 1-3, 3-6 and 6-12 Hz bands was computed. The findings revealed that the water condition produced reductions in right-hemisphere power in the two higher frequency bands in both the scalp regions compared with the other two conditions. The sucrose condition produced greater relative left-sided activation in both regions compared with the water condition. These data, in conjunction with our previous findings of asymmetries in 10-month-old infants, indicate that stimulus-elicited affective asymmetries in brain electrical activity are present at birth.
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Rats were implanted bilaterally with cannulae into the dorsal hippocampus and trained in a Pavlovian fear-conditioning paradigm. Four groups of rats were infused intra-cranially with 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7-dihydrochloride), a potent inhibitor of both protein kinase C (PKC) and cAMP-dependent protein kinase (PKA), at different time intervals in order to examine their involvement in the acquisition and consolidation of contextual fear memory. We demonstrate a significant consolidation deficit of long-term contextual fear-conditioning memory that is maximal when PKA and PKC are inhibited at 90 min post-training. These results suggest the existence of a critical time window, during which these enzymes must be activated for the consolidation of long-term memories.
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[F-18]Mefway was developed to provide an F-18 labeled positron emission tomography (PET) neuroligand with high affinity for the serotonin 5-HT(1A) receptor to improve the in vivo assessment of the 5-HT(1A) system. The goal of this work was to compare the in vivo kinetics of [F-18]mefway, [F-18]MPPF, and [C-11]WAY100635 in the rhesus monkey. METHODS: Each of four monkeys were given bolus injections of [F-18]mefway, [C-11]WAY100635, and [F-18]MPPF and scans were acquired with a microPET P4 scanner. Arterial blood was sampled to assay parent compound throughout the time course of the PET experiment. Time activity curves were extracted in the high 5-HT(1A) binding areas of the anterior cingulate cortex (ACG), mesial temporal cortex, raphe nuclei, and insula cortex. Time activity curves were also extracted in the cerebellum, which was used as a reference region. The in vivo kinetics of the radiotracers were compared based on the nondisplaceable distribution volume (V(ND) ) and binding potential (BP(ND) ). RESULTS: At 30 min, the fraction of radioactivity in the plasma due to parent compound was 19%, 28%, and 29% and cleared from the arterial plasma at rates of 0.0031, 0.0078, and 0.0069 (min⁻¹) ([F-18]mefway, [F-18]MPPF, [C-11]WAY100635). The BP(ND) in the brain regions were mesial temporal cortex: 7.4 ± 0.6, 3.1 ± 0.4, 7.0 ± 1.2, ACG: 7.2 ± 1.2, 2.1 ± 0.2, 7.9 ± 1.2; raphe nuclei: 3.7 ± 0.6, 1.3 ± 0.3, 3.3 ± 0.7; and insula cortex: 4.2 ± 0.6, 1.2 ± 0.1, 4.7 ± 1.0 for [F-18]mefway, [F-18]MPPF, and [C-11]WAY100635 respectively. CONCLUSIONS: In the rhesus monkey, [F-18]mefway has similar in vivo kinetics to [C-11]WAY100635 and yields greater than 2-fold higher BP(ND) than [F-18]MPPF. These properties make [F-18]mefway a promising radiotracer for 5-HT(1A) assay, providing higher counting statistics and a greater dynamic range in BP(ND).
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