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Non-invasive assessment of human neurotransmitter function is a highly valuable tool in clinical research. Despite the current interest in task-based pharmacological MRI (phMRI) for the assessment of neural correlates of serotonin (5-HT) function, testaretest reliability of this technique has not yet been established. Using a placebo-controlled crossover design, we aimed to examine the repeatability of task-related phMRI with a single dose of oral citalopram in twelve healthy female subjects. Since we were interested in the drug's effect on neural correlates of 5-HT related cognitive processes, a sensorimotor and an emotional face processing paradigm were used. For both paradigms, we found no significant effects of the oral citalopram challenge on task-positive brain activity with whole-brain analysis. With ROI-based analysis, there was a small effect of the challenge related to emotional processing in the amygdala, but this effect could not be reproduced between sessions. We did however find reproducible effects of the challenge on task-negative BOLD-responses, particularly in the medial frontal cortex and paracingulate gyrus. In conclusion, our data shows that a single oral dose of citalopram does not reliably affect emotional processing and sensorimotor activity, but does influence task-negative processes in the frontal cortex. This latter finding validates previous studies indicating a role for 5-HT in suppression of the task-negative network during goal-directed behavior.

There are increasing reports about stress related cognitive and psychic declines in subjects who have no psychiatric premorbidity, depression, or major life trauma. Yet, little is known about the underlying neurobiology. Based on the typical symptomatology, fMRI data suggesting that stress activates the limbic circuits, and animal data showing a major involvement of the 5-HT sub(1A receptor in stress regulation, we hypothesized that enduring daily stress causes widespread limbic dysfunctions, and specific changes of the 5-HT) sub(1)A receptor. To test these hypotheses combined PET studies were carried out in 16 chronically stressed, and 16 non-stressed subjects. Limbic function was tested by measuring cerebral blood flow during rest, and when using an odor activation paradigm. 5-HT sub(1A receptor binding potential (BP) was assessed with [[super]11C]WAY100635. All subjects went through a battery of neuropsychological tests. Stressed subjects showed a functional disconnection between the amygdala and ACC/medial prefrontal cortex (mPFC), and an impaired odor activation of the ACC. They also displayed a reduced 5-HT) sub(1)A receptor BP in the anterior cingulate (ACC), the insular-cortex, and the hippocampus. Their performance in attention-, odor discrimination-, and semantic memory tasks was impaired, and correlated with the BP-values in the respective region. The degree of reported stress was inversely correlated with activation of ACC, and the 5-HT sub(1A receptor BP in the amygdala and hippocampus. Enduring every day psychosocial stress seems to be associated with a limbic reduction of 5-HT) sub(1)A receptor binding and functional disintegration of ACC/mPFC. These changes support the notion of an impaired top-down regulation of stress stimuli, and identify potential targets for early treatment.

The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ(+) neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ(-) neurons in CEl. Electrical silencing of PKC-δ(+) neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called CEl(off) units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.

The amygdala is composed of multiple nuclei with unique functions and connections in the limbic system and to the rest of the brain. However, standard in vivo neuroimaging tools to automatically delineate the amygdala into its multiple nuclei are still rare. By scanning postmortem specimens at high resolution (100–150µm) at 7T field strength (n = 10), we were able to visualize and label nine amygdala nuclei (anterior amygdaloid, cortico-amygdaloid transition area; basal, lateral, accessory basal, central, cortical medial, paralaminar nuclei). We created an atlas from these labels using a recently developed atlas building algorithm based on Bayesian inference. This atlas, which will be released as part of FreeSurfer, can be used to automatically segment nine amygdala nuclei from a standard resolution structural MR image. We applied this atlas to two publicly available datasets (ADNI and ABIDE) with standard resolution T1 data, used individual volumetric data of the amygdala nuclei as the measure and found that our atlas i) discriminates between Alzheimer's disease participants and age-matched control participants with 84% accuracy (AUC=0.915), and ii) discriminates between individuals with autism and age-, sex- and IQ-matched neurotypically developed control participants with 59.5% accuracy (AUC=0.59). For both datasets, the new ex vivo atlas significantly outperformed (all p < .05) estimations of the whole amygdala derived from the segmentation in FreeSurfer 5.1 (ADNI: 75%, ABIDE: 54% accuracy), as well as classification based on whole amygdala volume (using the sum of all amygdala nuclei volumes; ADNI: 81%, ABIDE: 55% accuracy). This new atlas and the segmentation tools that utilize it will provide neuroimaging researchers with the ability to explore the function and connectivity of the human amygdala nuclei with unprecedented detail in healthy adults as well as those with neurodevelopmental and neurodegenerative disorders. •We visualized 9 nuclei boundaries (anterior amygdaloid area, cortico-amygdaloid transition area; basal, lateral, accessory basal, central, cortical medial, paralaminar nuclei) using ultra-high-resolution ex vivo imaging.•Nuclei were consistent across cases and raters.•We built a segmentation atlas of the amygdala nuclei, which will be distributed with FreeSurfer.•Atlas was applied to 2 datasets and showed higher discriminability of Alzheimer's & autism than previously possible.•The atlas will provide neuroimaging researchers with the ability to test nucleus function with greater spatial specificity.

Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val[super]108/158Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders.

The amygdala is a major structure that orchestrates defensive reactions to environmental threats and is implicated in hypervigilance and symptoms of heightened arousal in posttraumatic stress disorder (PTSD). The basolateral and centromedial amygdala (CMA) complexes are functionally heterogeneous, with distinct roles in learning and expressing fear behaviors. PTSD differences in amygdala-complex function and functional connectivity with cortical and subcortical structures remain unclear. Recent military veterans with PTSD (n=20) and matched trauma-exposed controls (n=22) underwent a resting-state fMRI scan to measure task-free synchronous blood-oxygen level dependent activity. Whole-brain voxel-wise functional connectivity of basolateral and CMA seeds was compared between groups. The PTSD group had stronger functional connectivity of the basolateral amygdala (BLA) complex with the pregenual anterior cingulate cortex (ACC), dorsomedial prefrontal cortex, and dorsal ACC than the trauma-exposed control group (p<0.05; corrected). The trauma-exposed control group had stronger functional connectivity of the BLA complex with the left inferior frontal gyrus than the PTSD group (p<0.05; corrected). The CMA complex lacked connectivity differences between groups. We found PTSD modulates BLA complex connectivity with prefrontal cortical targets implicated in cognitive control of emotional information, which are central to explanations of core PTSD symptoms. PTSD differences in resting-state connectivity of BLA complex could be biasing processes in target regions that support behaviors central to prevailing laboratory models of PTSD such as associative fear learning. Further research is needed to investigate how differences in functional connectivity of amygdala complexes affect target regions that govern behavior, cognition, and affect in PTSD.

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.

Adaptive behaviour necessitates the formation of memories for fearful events, but also that these memories can be extinguished. Effective extinction prevents excessive and persistent reactions to perceived threat, as can occur in anxiety and 'trauma- and stressor-related' disorders . However, although there is evidence that fear learning and extinction are mediated by distinct neural circuits, the nature of the interaction between these circuits remains poorly understood . Here, through a combination of in vivo calcium imaging, functional manipulations, and slice physiology, we show that distinct inhibitory clusters of intercalated neurons (ITCs) in the mouse amygdala exert diametrically opposed roles during the acquisition and retrieval of fear extinction memory. Furthermore, we find that the ITC clusters antagonize one another through mutual synaptic inhibition and differentially access functionally distinct cortical- and midbrain-projecting amygdala output pathways. Our findings show that the balance of activity between ITC clusters represents a unique regulatory motif that orchestrates a distributed neural circuitry, which in turn regulates the switch between high- and low-fear states. These findings suggest that the ITCs have a broader role in a range of amygdala functions and associated brain states that underpins the capacity to adapt to salient environmental demands.

The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.