Involvement Of Amygdala Research Articles

Finding the place without the whole: Timeline involvement of brain regions

Mastering the Morris water maze (MWM) requires the animal to consolidate, retain and retrieve spatial localizations of relevant visual cues. However, it is necessary to investigate whether a reorganization of the neural networks takes place when part of the spatial information is removed. We conducted four experiments using the MWM. A classical reference memory procedure was performed over five training days, RM5 (n=7), and eight days, RM8 (n=7), with the whole room and all the spatial cues presented. Another group of animals were trained in the same protocol, but they received an additional day of training with only partial cues, PC (n=8). Finally, a third group of animals performed the classical task, followed by an overtraining with partial cues for four more days, OPC (n=8). After completing these tasks, cytochrome c-oxidase activity (CO) in several brain limbic system structures was compared between groups. In addition, c-Fos positive cells were measured in the RM5, RM8, PC and OPC groups. No significant differences were found among the four groups in escape latencies or time spent in the target quadrant. CO revealed involvement of the prefrontal and parietal cortices, dorsal and ventral striatum, CA1 and CA3 subfields of the dorsal hippocampus, basolateral and lateral amygdala, and mammillary nuclei in the PC group, compared to the RM group. In the OPC group, involvement of the ventral striatum and anteroventral thalamus and the absence of amygdala involvement were revealed, compared to the PC group. C-Fos results highlighted the role of the prefrontal cortex, dorsal striatum, anterodorsal thalamus and CA3 in the PC group, compared to the OPC, RM5 and RM8 groups. The animals were able to find the escape platform even when only a portion of the space where the cues were placed was available. Although the groups did not differ behaviorally, energetic brain metabolism and immediate early gene expression revealed the engagement of different neural structures in the groups that received more training without the entire surrounding space.

Neural activity in monkey amygdala during performance of a multisensory operant task.

In this paper, we study the potential involvement of monkey amygdala in the evaluation of value encoding of visual and auditive stimuli associated with reward or no reward. We recorded the activity of 93 extracellular neurons from the monkey right amygdala, while performing a multisensory operant task. The activity of 78 task-related neurons was studied. Of these, 13 neurons (16%) responded to the value of visual stimuli, 22 neurons (28%) responded after the presentation of visual stimuli, 22 neurons (28%) showed an inhibition around the lever-pressing and were classified as action related neurons and 22 neurons (28%) responded after reward delivery. These findings suggest that neurons in the amygdala play a role in encoding value and processing visual information, participate in motor regulation and are sensitive to reward. The activity of these neurons did not change in the evaluation of auditive stimuli. These data support the hypothesis that amygdala neurons are specific to each sensory modality and that different groups of amygdala neurons process visual and auditive information.

The amygdala is critical for trace, delay, and contextual fear conditioning.

Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei within the amygdala. The present experiments further examine the contributions of amygdalar subnuclei to trace, delay, and contextual fear conditioning. Rats were trained using a 10-trial trace, delay, or unpaired fear conditioning procedure. Pretraining lesions targeting the entire basolateral amygdala (BLA) resulted in a deficit in trace, delay, and contextual fear conditioning. Immediate post-training infusions of the protein synthesis inhibitor, cycloheximide, targeting the basal nucleus of the amygdala (BA) attenuated trace and contextual fear memory expression, but had no effect on delay fear conditioning. However, infusions targeting the lateral nucleus of the amygdala (LA) immediately following conditioning attenuated contextual fear memory expression, but had no effect on delay or trace fear conditioning. In follow-up experiments, rats were trained using a three-trial delay conditioning procedure. Immediate post-training infusions targeting the LA produced deficits in both delay tone and context fear, while infusions targeting the BA produced deficits in context but not delay tone fear. These data fully support a role for the BLA in trace, delay, and contextual fear memories. Specifically, these data suggest that the BA may be more critical for trace fear conditioning, whereas the LA may be more critical for delay fear memories.

Differential involvement of amygdala and cortical NMDA receptors activation upon encoding in odor fear memory.

Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-d-aspartate (NMDA) receptors in the BLA and olfactory cortex at discrete moments of an odor fear conditioning session. We showed that NMDA receptors in BLA are critically involved in odor fear acquisition during the first association but not during the next ones. In the cortex, NMDA receptor activation at encoding is not necessary for recent odor fear memory while its role in remote memory storage needs further investigation.

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats.

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention.

Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia

The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3–7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1–2-μg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-μg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1–2-μg/rat) or (S)-WAY 100135 (0.25–1-μg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.

Role of glutamate receptors of central and basolateral amygdala nuclei on retrieval and reconsolidation of taste aversive memory

There are a number of experiments showing an important involvement of amygdala N-methyl-d-aspartate (NMDA) glutamate receptors on consolidation of conditioned taste aversion (CTA) memory. Interestingly, recent evidence has shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors are particularly involved in CTA retrieval. Memory reconsolidation has been proposed as a destabilization and re-stabilization process induced by memory reactivation. We have recently suggested that reconsolidation could be enabled in the absence of retrieval. Hence, we decided to analyze the participation of AMPA and NMDA receptors of the central (CeA) and basolateral amygdala (BLA) in CTA memory retrieval and reconsolidation. To do so, we tested whether administrations of an AMPA receptor blocker (NBQX) or an NMDA receptor blocker (APV) 15min before a second acquisition trial could have effects on taste aversion. We found that administration of NBQX in the BLA blocked retrieval, whereas APV blocked reconsolidation in the BLA, and consolidation in the CeA. When we administered both NBQX and APV into the BLA before the second acquisition trial, results showed impairment of both retrieval and reconsolidation. These results further support the idea that reconsolidation is independent of retrieval, since retrieval blockade in the BLA did not impair memory reconsolidation. These results suggest that glutamate receptors have different participation on retrieval and reconsolidation of CTA and further support the hypothesis that these two processes could be independent.

Forced swim stress but not exogenous corticosterone could induce the reinstatement of extinguished morphine conditioned place preference in rats: Involvement of glucocorticoid receptors in the basolateral amygdala

Addiction is a common psychiatric disease and stress has an important role in the drug seeking and relapse behaviors. The involvement of basolateral amygdala (BLA) in the effects of stress on reward pathway is discussed in several studies. In this study, we tried to find out the involvement of glucocorticoid receptors (GRs) in the BLA in stress-induced reinstatement of extinguished morphine-induced conditioned place preference (CPP) in rats. The CPP paradigm was done in adult male Wistar rats weighing 220–320g, and conditioning score and locomotor activity were recorded by Ethovision software. Animals received effective dose of morphine (5mg/kg) daily, during the 3-day conditioning phase. In extinction phase, rats were put in the CPP box for 30min a day for 8 days. After extinction, animals were injected by corticosterone (10m/kg) or exposed to forced swim stress (FSS) 10min before subcutaneous administration of ineffective dose of morphine (0.5mg/kg) in order to reinstate the extinguished morphine-CPP. To block the glucocorticoid receptors in the BLA, after stereotaxic surgery and placing two cannulae in this area bilaterally, animals received GR antagonist mifepristone (RU38486; 0.3, 3 and 30ng/0.3μl DMSO per side) prior to exposure to FSS then each animal received ineffective dose of morphine (0.5mg/kg) as drug-induced reinstatement. The results revealed that physical stress (FSS) but not exogenous corticosterone can significantly induce reinstatement of extinguished morphine-CPP, and intra-BLA mifepristone prevents the stress-induced reinstatement. It can be proposed that stress partially exerts its effect on the reward pathway via glucocorticoid receptors in the BLA.

Amygdala activation and symptom dimensions in obsessive–compulsive disorder

Despite knowledge of amygdala involvement in fear and anxiety, its contribution to the pathophysiology of obsessive-compulsive disorder (OCD) remains controversial. In the context of neuroimaging studies, it seems likely that the heterogeneity of the disorder might have contributed to a lack of consistent findings. To assess the influence of OCD symptom dimensions on amygdala responses to a well-validated emotional face-matching paradigm. Cross-sectional functional magnetic resonance imaging (fMRI) study of 67 patients with OCD and 67 age-, gender- and education-level matched healthy controls. The severity of aggression/checking and sexual/religious symptom dimensions were significantly associated with heightened amygdala activation in those with OCD when responding to fearful faces, whereas no such correlations were seen for other symptom dimensions. Amygdala functional alterations in OCD appear to be specifically modulated by symptom dimensions whose origins may be more closely linked to putative amygdala-centric processes, such as abnormal fear processing.

Amygdala hyperactivation during symptom provocation in obsessive-compulsive disorder and its modulation by distraction.

Anxiety disorders have been linked to a hyperactivated cortico-amygdalar circuitry. Recent findings highlight the amygdala's role in mediating elevated anxiety in obsessive–compulsive disorder (OCD). However, modulation of amygdala hyperactivation by attentional distraction – an effective emotion regulation strategy in healthy individuals – has not yet been examined. While undergoing functional magnetic resonance imaging twenty-one unmedicated OCD patients and 21 controls performed an evaluation and a distraction task during symptom provocation with individually tailored OCD-relevant pictures. To test the specificity of responses, additional aversive and neutral stimuli were included. Significant group-by-picture type interactions were observed within fronto–striato–limbic circuits including the amygdala. In these regions patients showed increased BOLD responses during processing of OCD triggers relative to healthy controls. Amygdala hyperactivation was present across OCD symptom dimensions indicating that it represents a common neural correlate. During distraction, we observed dampening of patients' amygdala hyperactivity to OCD-relevant stimuli. Augmented amygdala involvement in patients during symptom provocation, present across OCD symptom dimensions, might constitute a correlate of fear expression in OCD linking it to other anxiety disorders. Attentional distraction seemed to dampen emotional processing of disorder-relevant stimuli via amygdala downregulation. The clinical impact of this strategy to manage anxiety in OCD should be further elucidated.

Human amygdala response to dynamic facial expressions of positive and negative surprise.

Although brain imaging evidence accumulates to suggest that the amygdala plays a key role in the processing of novel stimuli, only little is known about its role in processing expressed novelty conveyed by surprised faces, and even less about possible interactive encoding of novelty and valence. Those investigations that have already probed human amygdala involvement in the processing of surprised facial expressions either used static pictures displaying negative surprise (as contained in fear) or "neutral" surprise, and manipulated valence by contextually priming or subjectively associating static surprise with either negative or positive information. Therefore, it still remains unresolved how the human amygdala differentially processes dynamic surprised facial expressions displaying either positive or negative surprise. Here, we created new artificial dynamic 3-dimensional facial expressions conveying surprise with an intrinsic positive (wonderment) or negative (fear) connotation, but also intrinsic positive (joy) or negative (anxiety) emotions not containing any surprise, in addition to neutral facial displays either containing ("typical surprise" expression) or not containing ("neutral") surprise. Results showed heightened amygdala activity to faces containing positive (vs. negative) surprise, which may either correspond to a specific wonderment effect as such, or to the computation of a negative expected value prediction error. Findings are discussed in the light of data obtained from a closely matched nonsocial lottery task, which revealed overlapping activity within the left amygdala to unexpected positive outcomes.

Staging TDP-43 pathology in Alzheimer’s disease

TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

The Functional and Structural Neural Basis of Individual Differences in Loss Aversion

Decision making under risk entails the anticipation of prospective outcomes, typically leading to the greater sensitivity to losses than gains known as loss aversion. Previous studies on the neural bases of choice-outcome anticipation and loss aversion provided inconsistent results, showing either bidirectional mesolimbic responses of activation for gains and deactivation for losses, or a specific amygdala involvement in processing losses. Here we focused on loss aversion with the aim to address interindividual differences in the neural bases of choice-outcome anticipation. Fifty-six healthy human participants accepted or rejected 104 mixed gambles offering equal (50%) chances of gaining or losing different amounts of money while their brain activity was measured with functional magnetic resonance imaging (fMRI). We report both bidirectional and gain/loss-specific responses while evaluating risky gambles, with amygdala and posterior insula specifically tracking the magnitude of potential losses. At the individual level, loss aversion was reflected both in limbic fMRI responses and in gray matter volume in a structural amygdala-thalamus-striatum network, in which the volume of the "output" centromedial amygdala nuclei mediating avoidance behavior was negatively correlated with monetary performance. We conclude that outcome anticipation and ensuing loss aversion involve multiple neural systems, showing functional and structural individual variability directly related to the actual financial outcomes of choices. By supporting the simultaneous involvement of both appetitive and aversive processing in economic decision making, these results contribute to the interpretation of existing inconsistencies on the neural bases of anticipating choice outcomes.

Positive facial affect - an fMRI study on the involvement of insula and amygdala.

Imitation of facial expressions engages the putative human mirror neuron system as well as the insula and the amygdala as part of the limbic system. The specific function of the latter two regions during emotional actions is still under debate. The current study investigated brain responses during imitation of positive in comparison to non-emotional facial expressions. Differences in brain activation of the amygdala and insula were additionally examined during observation and execution of facial expressions. Participants imitated, executed and observed happy and non-emotional facial expressions, as well as neutral faces. During imitation, higher right hemispheric activation emerged in the happy compared to the non-emotional condition in the right anterior insula and the right amygdala, in addition to the pre-supplementary motor area, middle temporal gyrus and the inferior frontal gyrus. Region-of-interest analyses revealed that the right insula was more strongly recruited by (i) imitation and execution than by observation of facial expressions, that (ii) the insula was significantly stronger activated by happy than by non-emotional facial expressions during observation and imitation and that (iii) the activation differences in the right amygdala between happy and non-emotional facial expressions were increased during imitation and execution, in comparison to sole observation. We suggest that the insula and the amygdala contribute specifically to the happy emotional connotation of the facial expressions depending on the task. The pattern of the insula activity might reflect increased bodily awareness during active execution compared to passive observation and during visual processing of the happy compared to non-emotional facial expressions. The activation specific for the happy facial expression of the amygdala during motor tasks, but not in the observation condition, might reflect increased autonomic activity or feedback from facial muscles to the amygdala.

Lipoid proteinosis with bilateral amygdalae calcifications, headache, and cognitive impairments

Lipoid proteinosis (LP) is a systemic autosomal recessive disorder caused by mutations in the ECM1 (extracellular matrix protein 1) gene1 and is occasionally associated with cognitive impairment, headache, and temporal lobe epilepsy.2 A 37-year-old woman with characteristic cutaneous lesions (figure 1), bilateral cataracts, and lens subluxation was evaluated for diffuse cognitive impairment and headache. Neuroimaging revealed bilateral amygdaloid calcifications typical for LP (figure 2). Sequencing the ECM1 gene identified homozygosity for a splice-site mutation, c.195 + 1G > C in intron 1. This case illustrates the various clinical manifestations of LP (none suggestive of amygdala involvement), which should be considered in the differential diagnosis of cerebral calcifications.

Non-beta-amyloid–related structural, metabolic and white matter fiber integrity changes in early-MCI

Background: According to the amyloid cascade hypothesis, b-amyloid (Ab) pathology is an early event in Alzheimer’s disease (AD), followed by structural, functional and finally cognitive changes. If Ab+ is essential for AD, Abcognitive decline is non-AD, whichmay involve changed structure and function compared to Abcognitively healthy persons (NL), but the changes should be different from those seen in Ab+ cognitive decline. In this study, we tested the specific hypothesis that there are differences in brain structure, metabolism, and white matter (WM) connectivity between AbNL and Abearly mild cognitive impairment (MCI). Furthermore, we assessed the relative importance of imaging modalities in classification of Abearly-MCI from AbNL in terms of effect size.Methods:Ab-negative status of NL and early-MCI subjects fromADNI-GO/2 studies was based on both their AV45-PETand CSF-Ab data, with cohort characteristics summarized in the table. Relative to NL, age-, sex-, and education-adjusted earlyMCI effect-size of regional cortical thickness, tissue volume,WM fractional anisotropy (FA), and regional metabolic PET uptake was estimate and corrected for multiple comparison at p1⁄40.05 significance level. Results: Compared to AbNL, Abearly-MCI had significant 1) cortical thinning in the left superior temporal (d1⁄4-0.49), right inferior temporal (d1⁄4-0.47), right posterior banks of the superior temporal sulcus (d1⁄4-0.46), and left caudal anterior cingulate (d1⁄4-0.46); 2) tissue volume loss in the left amygdala (d1⁄4-0.64), left hippocampus (d1⁄4-0.46), and increased third ventricle CSF (d1⁄40.55); 3) hypermetabolism in the bilateral paracentral (left: d1⁄41.05; right: d1⁄40.65); and 4) diffused WM integrity degradation including the left fornix (cres)/stria terminalis (d1⁄4-0.59), bilateral internal capsule (d1⁄40.36 -0.57), bilateral tapatum (d1⁄4-0.42 -0.54), right cerebral peduncle (d1⁄4-0.52), bilateral splenium and genu of corpus callosum (d1⁄4-0.38 -0.48), right external capsule (d1⁄4-0.42), and left posterior thalamic radiation (d1⁄4-0.37). Conclusions: Abcognitive decline at early-MCI stage involves both structural and functional brain changes. Althoughmetabolic and volumetric changes had greater effect size, impact on WM fiber integrity was more wide-spread. The involvement of hippocampal, amygdala, and temporal lobe atrophy, and WM degeneration at fornix/stria terminalis was surprising in these subjects without AD-related Ab pathology, suggesting a non-Ab-pathology-related cognitive decline mechanism.

The Effect of Retrieval Focus and Emotional Valence on the Medial Temporal Lobe Activity during Autobiographical Recollection

Laboratory-based episodic memory studies, using micro-events (pictures/words), point to a role of the amygdala (AMY), an emotion-based region, in the encoding and retrieval of emotionally valenced memories. However, autobiographical memory (AM) studies, using real-life personal events, do not conclusively support AMY’s involvement in AM recollection. This could be due to differences in instructions across the AM studies – i.e., whether emotional aspects were explicitly emphasized or not. The present study investigated the effect of retrieval focus on activity in emotion (AMY) and memory (hippocampus – HC) based regions of the medial temporal lobe in 17 subjects, who remembered emotional AMs while event-related fMRI data were recorded. The retrieval focus was manipulated by instructions to focus either on emotional (Emotion condition) or on other contextual (Context condition) details of the recollected AMs. The effect of retrieval focus according to the valence of AMs was also investigated by involving an equal proportion of positive and negative AMs. There were four main findings, showing both similarities and differences in retrieving positive and negative AMs. Regarding similarities, (1) focusing on Emotion was associated with increased scores of subjective re-experience of emotion and increased activity in the left AMY, for both positive and negative AMs, compared to focusing on Context; (2) the subjective emotional ratings were also positively correlated with bilateral AMY activity for both positive and negative AMs. Regarding differences, (3) focusing on Emotion was associated with increased activity for positive but not for negative AMs in the right AMY, and with (4) opposing patterns of activity linked to the valence of AMs in the left HC – i.e., increased activity for positive and decreased activity for negative AMs. These findings shed light on the role of AMY and HC in emotional AM recollection, linked to the retrieval focus and the valence of memories.

Amygdala Response to Preattentive Masked Fear in Children With Conduct Problems: The Role of Callous-Unemotional Traits

In children with conduct problems, high levels of callous-unemotional traits are associated with amygdala hypoactivity to consciously perceived fear, while low levels of callous-unemotional traits may be associated with amygdala hyperactivity. Behavioral data suggest that fear processing deficits in children with high callous-unemotional traits may extend to stimuli presented below conscious awareness (preattentively). The authors investigated the neural basis of this effect. Amygdala involvement was predicted on the basis of its role in preattentive affective processing in healthy adults and its dysfunction in previous studies of conduct problems. Functional MRI was used to measure neural responses to fearful and calm faces presented preattentively (for 17 ms followed by backward masking) in boys with conduct problems and high callous-unemotional traits (N=15), conduct problems and low callous-unemotional traits (N=15), and typically developing comparison boys (N=16). Amygdala response to fearful and calm faces was predicted to differentiate groups, with the greatest response in boys with conduct problems and low callous-unemotional traits and the lowest in boys with conduct problems and high callous-unemotional traits. In the right amygdala, a greater amygdala response was seen in boys with conduct problems and low callous-unemotional traits than in those with high callous-unemotional traits. The findings were not explained by symptom levels of conduct disorder, attention-deficit hyperactivity disorder, anxiety, or depression. These data demonstrate differential amygdala activity to preattentively presented fear in children with conduct problems grouped by callous-unemotional traits, with high levels associated with lower amygdala reactivity. The study's findings complement increasing evidence suggesting that callous-unemotional traits are an important specifier in the classification of children with conduct problems.

18-Methoxycoronaridine blocks context-induced reinstatement following cocaine self-administration in rats

Numerous studies utilizing drug self-administration have shown the importance of conditioned cues in maintaining and reinstating addictive behaviors. However, most used simple cues that fail to replicate the complexity of cues present in human craving and addiction. We have recently shown that music can induce behavioral and neurochemical changes in rats following classical conditioning with psychostimulants. However, such effects have yet to be characterized utilizing operant self-administration procedures, particularly with regard to craving and relapse. The goal of the present study was to validate the effectiveness of music as a contextual conditioned stimulus using cocaine in an operant reinstatement model of relapse. Rats were trained to lever press for cocaine with a musical cue, and were subsequently tested during reinstatement sessions to determine how musical conditioning affected drug seeking behavior. Additionally, in vivo microdialysis was used to determine basolateral amygdala involvement during reinstatement. Lastly, tests were conducted to determine whether the putative anti-addictive agent 18-methoxycoronaridine (18-MC) could attenuate cue-induced drug seeking behavior. Our results show that music-conditioned animals exhibited increased drug seeking behaviors when compared to controls during reinstatement test sessions. Furthermore, music-conditioned subjects exhibited increased extracellular dopamine in the basolateral amygdala during reinstatement sessions. Perhaps most importantly, 18-MC blocked musical cue-induced reinstatement. Thus, music can be a powerful contextual conditioned cue in rats, capable of inducing changes in both brain neurochemistry and drug seeking behavior during abstinence. The fact that 18-MC blocked cue-induced reinstatement suggests that α3β4 nicotinic receptors may be involved in the mechanism of craving, and that 18-MC may help prevent relapse to drug addiction in humans.

Oxytocin and Vasopressin Are Dysregulated in Williams Syndrome, a Genetic Disorder Affecting Social Behavior

The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ∼28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior.