Amygdala In Processing Research Articles

Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition.

The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABAA receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats.

Reverse engineering information processing in lateral amygdala during auditory tones.

Learning in the mammalian lateral amygdala (LA) during auditory fear conditioning (tone - foot shock pairing), one form of associative learning, requires N-methyl-D-aspartate (NMDA) receptor-dependent plasticity. Despite this fact being known for more than two decades, the biophysical details related to signal flow and the involvement of the coincidence detector, NMDAR, in this learning, remain unclear. Here we use a 4000-neuron computational model of the LA (containing two types of pyramidal cells, types A and C, and two types of interneurons, fast spiking FSI and low-threshold spiking LTS) to reverse engineer changes in information flow in the amygdala that underpin such learning; with a specific focus on the role of the coincidence detector NMDAR. The model also included a Ca2s based learning rule for synaptic plasticity. The physiologically constrained model provides insights into the underlying mechanisms that implement habituation to the tone, including the role of NMDARs in generating network activity which engenders synaptic plasticity in specific afferent synapses. Specifically, model runs revealed that NMDARs in tone-FSI synapses were more important during the spontaneous state, although LTS cells also played a role. Training trails with tone only also suggested long term depression in tone-PN as well as tone-FSI synapses, providing possible hypothesis related to underlying mechanisms that might implement the phenomenon of habituation.

Modulation of amygdala activity for emotional faces due to botulinum toxin type A injections that prevent frowning

According to the facial feedback hypothesis, when we see an angry or happy face, we contract or flex the relevant muscles to recreate the expression to assist in identifying and experiencing the emotion reflected. We investigated the facial feedback hypothesis by using botulinum toxin type A (onabotulinumtoxinA; onabotA) injections to induce temporary paralysis in the glabellar muscles (responsible for frowning) and measured functional brain activity during the processing of emotional faces. Ten females viewed pictures of happy and angry faces during two functional magnetic resonance imaging (fMRI) scan sessions: one prior (Pre) to onabotA and one following (Active) onabotA injections. We found Pre vs. Active onabotA modulation of activity in the amygdala for both happy and angry faces, as well as modulation of activity in the fusiform gyrus for happy faces. Consistent with our predictions, preventing frowning through inhibition of glabellar muscle contraction altered amygdala processing for emotional faces. The modulation of amygdala and fusiform gyrus activity following onabotA may reflect compensatory processes in a neuroanatomical circuit involved in emotional processing that is engaged when facial feedback is impaired. These data contribute to a growing literature suggesting that inhibition of glabellar muscle contraction alters neural activity for emotional processing.Clinical Trials.gov registration number: NCT03373162.

Frequency-specific gaze modulation of emotional face processing in the human amygdala.

Determining the social significance of emotional face expression is of major importance for adaptive behavior, and gaze direction provides critical information in this process. The amygdala is implicated in both emotion and gaze processing, but how and when it integrates expression and gaze cues remains unresolved. We tackled this question using intracranial electroencephalography in epileptic patients to assess both amygdala (n = 12) and orbitofrontal cortex (OFC; n = 11) time-frequency evoked responses to faces with different emotional expressions and different gaze directions. As predicted, self-relevant threat signals (averted fearful and directed angry faces) elicited stronger amygdala activity than self-irrelevant threat (directed fearful and averted angry faces). Fear effects started at early latencies in both amygdala and OFC (~110 and 160ms, respectively), while gaze direction effects and their interaction with emotion occurred at later latencies. Critically, the amygdala showed differential gamma band increases to fearful averted gaze (starting ~550ms) and to angry directed gaze (~470ms). Moreover, when comparing the 2 self-relevant threat conditions among them, we found higher gamma amygdala activity for averted fearful faces and higher beta OFC activity for angry directed faces. Together, these results reveal for the first time frequency-specific effects of emotion and gaze on amygdala and OFC neural activity.

Cortical-subcortical structural connections support transcranial magnetic stimulation engagement of the amygdala.

The amygdala processes valenced stimuli, influences emotion, and exhibits aberrant activity across anxiety disorders, depression, and PTSD. Interventions modulating amygdala activity hold promise as transdiagnostic psychiatric treatments. In 45 healthy participants, we investigated whether transcranial magnetic stimulation (TMS) elicits indirect changes in amygdala activity when applied to ventrolateral prefrontal cortex (vlPFC), a region important for emotion regulation. Harnessing in-scanner interleaved TMS/functional MRI (fMRI), we reveal that vlPFC neurostimulation evoked acute and focal modulations of amygdala fMRI BOLD signal. Larger TMS-evoked changes in the amygdala were associated with higher fiber density in a vlPFC–amygdala white matter pathway when stimulating vlPFC but not an anatomical control, suggesting this pathway facilitated stimulation-induced communication between cortex and subcortex. This work provides evidence of amygdala engagement by TMS, highlighting stimulation of vlPFC–amygdala circuits as a candidate treatment for transdiagnostic psychopathology. More broadly, it indicates that targeting cortical-subcortical structural connections may enhance the impact of TMS on subcortical neural activity and, by extension, subcortex-subserved behaviors.

Fast Detection of Snakes and Emotional Faces in the Macaque Amygdala.

Primate vision is reported to detect snakes and emotional faces faster than many other tested stimuli. Because the amygdala has been implicated in avoidance and emotional behaviors to biologically relevant stimuli and has neural connections with subcortical nuclei involved with vision, amygdalar neurons would be sensitive to snakes and emotional faces. In this study, neuronal activity in the amygdala was recorded from Japanese macaques (Macaca fuscata) during discrimination of eight categories of visual stimuli including snakes, monkey faces, human faces, carnivores, raptors, non-predators, monkey hands, and simple figures. Of 527 amygdalar neurons, 95 responded to one or more stimuli. Response characteristics of the amygdalar neurons indicated that they were more sensitive to the snakes and emotional faces than other stimuli. Response magnitudes and latencies of amygdalar neurons to snakes and monkey faces were stronger and faster than those to the other categories of stimuli, respectively. Furthermore, response magnitudes to the low pass-filtered snake images were larger than those to scrambled snake images. Finally, analyses of population activity of amygdalar neurons suggest that snakes and emotional faces were represented separately from the other stimuli during the 50–100 ms period from stimulus onset, and neutral faces during the 100–150 ms period. These response characteristics indicate that the amygdala processes fast and coarse visual information from emotional faces and snakes (but not other predators of primates) among the eight categories of the visual stimuli, and suggest that, like anthropoid primate visual systems, the amygdala has been shaped over evolutionary time to detect appearance of potentially threatening stimuli including both emotional faces and snakes, the first of the modern predators of primates.

Functional connectivity of intercalated nucleus with medial amygdala: A circuit relevant for chemosignal processing.

Medial amygdala processes social/reproductive chemosensory input, and its projections to preoptic and hypothalamic areas evoke appropriate behavioral and physiological responses. We and others have shown that different chemosensory signals elicit differential responses in medial amygdala subregions and in adjacent main intercalated nucleus (mICN). The largely GABAergic mICN receives no direct chemosensory input but, as we show, mICN has functional circuit connections with medial amygdala that could be responsible both for mICN chemosensitivity and for a feedforward inhibitory effect on posterior medial amygdala; which, in turn would affect chemosignal response. mICN is subject to inhibition by dopamine and is probably regulated by neuropeptides and input from frontal cortex. Thus, mICN is in position to modify chemosensory processing in medial amygdala and behavioral responses to social signals, according to internal brain state. Patch-clamp recordings from neurons in each relevant nucleus in horizontal brain-slices, with electrical stimulation in adjacent nuclei, reveal multiple functional connections between medial amygdala subregions and mICN. We highlight a triangular circuit which may underlie mICN chemosensitivity and its potential for modifying chemosensory information transmitted to basal forebrain. Anterior medial amygdala, which receives most of the chemosensory input, connects to posterior medial amygdala directly and both areas send information on to basal forebrain. Anterior medial amygdala can also modulate posterior medial amygdala indirectly via the mICN side-loop, which also provides a pathway for modulation by cortical input or, when inhibited by dopamine, could allow a more automatic response – as proposed for other amygdala circuits with similar ICN side loops.

Amygdaloid theta-band power increases during conflict processing in humans

The amygdala is a medial temporal lobe structure known to be involved in processing emotional conflict. However, its role in processing non-emotional conflict is not well understood. Previous studies have utilized the Stroop Task to examine brain modulation of humans under the color-word conflict scenario, which is non-emotional conflict processing, and found hippocampal theta-band (4–7 Hz) modulation. This study aims to survey amygdaloid theta power changes during non-emotional conflict processing using intracranial depth electrodes in nine epileptic patients (3 female; age 20–62). All patients were asked to perform a modified Stroop task. During task performance, local field potential (LFP) data was recorded from macro contacts sampled at 2 K Hz and used for analysis. Mean theta power change from baseline was compared between the incongruent and congruent task condition groups using a paired sample t-test. Seven patients were available for analysis after artifact exclusion. In five out of seven patients, statistically significant increases in theta-band power from baseline were noted during the incongruent task condition (paired sample t-test p < 0.001), including one patient exhibiting theta power increases in both task conditions. Average response time was 1.07 s (failure trials) and 1.04 s (success trials). No speed-accuracy tradeoff was noted in this analysis. These findings indicate that human amygdaloid theta-band modulation may play a role in processing non-emotional conflict. It builds directly upon work suggesting that the amygdala processes emotional conflict and provides a neurophysiological mechanism for non-emotional conflict processing as well.

Potent and Quick Responses to Conspecific Faces and Snakes in the Anterior Cingulate Cortex of Monkeys.

Appropriate processing of others’ facial emotions is a fundamental ability of primates in social situations. Several moods and anxiety disorders such as depression cause a negative bias in the perception of facial emotions. Depressive patients show abnormalities of activity and gray matter volume in the perigenual portion of the anterior cingulate cortex (ACC) and an increase of activation in the amygdala. However, it is not known whether neurons in the ACC have a function in the processing of facial emotions. Furthermore, detecting predators quickly and taking avoidance behavior are important functions in a matter of life and death for wild monkeys. the existence of predators in their vicinity is life-and-death information for monkeys. In the present study, we recorded the activity of single neurons from the monkey ACC and examined the responsiveness of the ACC neurons to various visual stimuli including monkey faces, snakes, foods, and artificial objects. About one-fourth of the recorded neurons showed a significant change in activity in response to the stimuli. The ACC neurons exhibited high selectivity to certain stimuli, and more neurons exhibited the maximal response to monkey faces and snakes than to foods and objects. The responses to monkey faces and snakes were faster and stronger compared to those to foods and objects. Almost all of the neurons that responded to video stimuli responded strongly to negative facial stimuli, threats, and scream. Most of the responsive neurons were located in the cingulate gyrus or the ventral bank of the cingulate sulcus just above or anterior to the genu of the corpus callosum, that is, the perigenual portion of the ACC, which has a strong mutual connection with the amygdala. These results suggest that the perigenual portion of the ACC in addition to the amygdala processes emotional information, especially negative life-and-death information such as conspecifics’ faces and snakes.

It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress.

Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons in vitro in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms.SIGNIFICANCE STATEMENT Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders.

Gradual wiring of olfactory input to amygdala feedback circuits

The amygdala facilitates odor driven behavioral responses by enhancing the saliency of olfactory signals. Before this processing, olfactory input is refined through the feedback provided by amygdala corticofugal projection (ACPs). Although the saliency of odor signals is subject to developmental changes, the stage at which this cortical feedback first occurs is not known. Using optogenetically-assisted intracellular recordings of the mouse cortical amygdala, we identified changes in the electrophysiological properties of ACPs at different developmental stages. These were consistent with a decrease in neuronal excitability and an increase in the amount of incoming accessory olfactory bulb (AOB) inputs, as confirmed by estimates of release probability, quantal size and contact number at the AOB-to-ACP synapse. Moreover, the proportion of ACPs activated in response to odors was dependent on the stage of development as revealed by c-Fos expression analysis. These results update standard accounts of how the amygdala processes social signals by emphasizing the occurrence of critical periods in the development of its sensory gating functions.

Neural Correlates of Empathy in Boys With Early Onset Conduct Disorder.

Background: A deficit in empathy has repeatedly been described in individuals with conduct disorder (CD), and in particular in those with callous unemotional traits. Until now, little is known about the neural basis of empathy in children and adolescents with early onset conduct disorder. The aim of this study was to examine neural responses during empathizing in children and adolescents with CD with a task that allowed to differentiate between the judgment of the emotional states of other people and the own emotional response to other people's emotional state. Moreover, we investigated associations of callous-unemotional traits and neural activations during empathizing.Methods: Using functional magnetic resonance imaging (fMRI) we investigated 14 boys with early onset CD and 15 typically developing (TDC) age matched controls between 8 and 16 years of age. Happy and sad faces were presented, and participants were asked to either infer the emotional state from the face (other-task) or to judge their own emotional response (self-task). A perceptual decision on faces was used as a control task. Individual empathic abilities and callous unemotional traits were assessed.Results: During the other task, TDC boys showed significantly larger right amygdala responses than CD boys. Higher empathic abilities (as assessed with the Bryant Index of Empathy) were associated with higher responses in the right amygdala within the CD boys and across the entire sample. Moreover, across the entire sample, callous-unemotional traits were negatively related to the BOLD-response in the right amygdala. CD boys showed larger responses in the dorsal and ventral medial prefrontal cortex across tasks and increased activation in dorsal medial prefrontal cortex specifically during the self-conditions, which were also related to empathic abilities within the CD boys.Conclusions: The data emphasize the important role of the amygdala in empathy related emotional processing. Diminished amygdala responses and their association with low empathy suggest a pivotal influence of impaired amygdala processing in early-onset CD, in particular for deficits in empathic behavior and related callous-unemotional-traits. Elevated response in the medial prefrontal cortex in boys with CD point toward increased involvement of brain areas related to self-referential processing and cognitive empathy during empathizing.

Developmental changes in plasticity, synaptic, glia, and connectivity protein levels in rat basolateral amygdala.

The basolateral complex of amygdala (BLA) processes emotionally arousing aversive and rewarding experiences. The BLA is critical for acquisition and storage of threat-based memories and the modulation of the consolidation of arousing explicit memories, that is, the memories that are encoded and stored by the medial temporal lobe. In addition, in conjunction with the medial prefrontal cortex (mPFC), the BLA plays an important role in fear memory extinction. The BLA develops relatively early in life, but little is known about the molecular changes that accompany its development. Here, we quantified relative basal expression levels of sets of plasticity, synaptic, glia, and connectivity proteins in the rat BLA at various developmental ages: postnatal day 17 (PN17, infants), PN24 (juveniles), and PN80 (young adults). We found that the levels of activation markers of brain plasticity, including phosphorylation of CREB at Ser133, CamKIIα at Thr286, pERK1/pERK2 at Thr202/Tyr204, and GluA1 at Ser831 and Ser845, were significantly higher in infant and juvenile compared with adult brain. In contrast, age increase was accompanied by a significant augmentation in the levels of proteins that mark synaptogenesis and synapse maturation, such as synaptophysin, PSD95, SynCAM, GAD65, GAD67, and GluN2A/GluN2B ratio. Finally, we observed significant age-associated changes in structural markers, including MAP2, MBP, and MAG, suggesting that the structural connectivity of the BLA increases over time. The biological differences in the BLA between developmental ages compared with adulthood suggest the need for caution in extrapolating conclusions based on BLA-related brain plasticity and behavioral studies conducted at different developmental stages.

Mu opioid receptor regulation of glutamate efflux in the central amygdala in response to predator odor

The amygdala plays an important role in the responses to predator threat. Glutamatergic processes in amygdala regulate the behavioral responses to predator stress, and we have found that exposure to ferret odor activates glutamatergic neurons of the basolateral amygdala [BLA] which are known to project to the central amygdala [CeA]. Therefore, we tested if predator stress would increase glutamate release in the rat CeA using in vivo microdialysis, while monitoring behavioral responses during a 1 h exposure to ferret odor. Since injections of mu opioid receptor [MOR] agonists and antagonists into the CeA modulate behavioral responses to predator odor, we locally infused the MOR agonist DAMGO or the MOR antagonist CTAP into the CeA during predator stress to examine effects on glutamate efflux and behavior. We found that ferret odor exposure increased glutamate, but not GABA, efflux in the CeA, and this effect was attenuated by tetrodotoxin. Interestingly, increases in glutamate efflux elicited by ferret odor exposure were blocked by infusion of CTAP, but CTAP did not alter the behavioral responses during predator stress. DAMGO alone enhanced glutamate efflux, but did not modulate glutamate efflux during predator stress. These studies demonstrate that ferret odor exposure, like other stressors, enhances glutamate efflux in the CeA. Further, they suggest that activation of MOR in the CeA may help shape the defensive response to predator odor and other threats.

Human amygdala response to unisensory and multisensory emotion input: No evidence for superadditivity from intracranial recordings

The amygdala is crucially implicated in processing emotional information from various sensory modalities. However, there is dearth of knowledge concerning the integration and relative time-course of its responses across different channels, i.e., for auditory, visual, and audiovisual input. Functional neuroimaging data in humans point to a possible role of this region in the multimodal integration of emotional signals, but direct evidence for anatomical and temporal overlap of unisensory and multisensory-evoked responses in amygdala is still lacking. We recorded event-related potentials (ERPs) and oscillatory activity from 9 amygdalae using intracranial electroencephalography (iEEG) in patients prior to epilepsy surgery, and compared electrophysiological responses to fearful, happy, or neutral stimuli presented either in voices alone, faces alone, or voices and faces simultaneously delivered. Results showed differential amygdala responses to fearful stimuli, in comparison to neutral, reaching significance 100–200 ms post-onset for auditory, visual and audiovisual stimuli. At later latencies, ∼400 ms post-onset, amygdala response to audiovisual information was also amplified in comparison to auditory or visual stimuli alone. Importantly, however, we found no evidence for either super- or subadditivity effects in any of the bimodal responses. These results suggest, first, that emotion processing in amygdala occurs at globally similar early stages of perceptual processing for auditory, visual, and audiovisual inputs; second, that overall larger responses to multisensory information occur at later stages only; and third, that the underlying mechanisms of this multisensory gain may reflect a purely additive response to concomitant visual and auditory inputs. Our findings provide novel insights on emotion processing across the sensory pathways, and their convergence within the limbic system.

Basal Forebrain and Brainstem Cholinergic Neurons Differentially Impact Amygdala Circuits and Learning-Related Behavior

The central cholinergic system and the amygdala are important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala, but it is unclear how these projections impact amygdala processes. Using optogenetic circuit-mapping strategies in choline acetyltransferase (ChAT)-cre mice, we demonstrate that amygdala-projecting basal forebrain and brainstem ChAT-containing neurons can differentially affect amygdala circuits and behavior. Photo-activating ChAT terminals invitro revealed the underlying synaptic impact of brainstem inputs to the central lateral division to be excitatory, mediated via the synergistic glutamatergic activation of AMPA and NMDA receptors. Incontrast, stimulating basal forebrain inputs to thebasal nucleus resulted in endogenous acetylcholine (ACh) release, resulting in biphasic inhibition-excitation responses onto principal neurons. Such response profiles are physiological hallmarks of neural oscillations and could thus form the basis of ACh-mediated rhythmicity in amygdala networks. Consistent with this, invivo basal forebrain ChAT+ activation strengthened amygdala basal nucleus theta and gamma frequency rhythmicity, both of which continued for seconds afterstimulation and were dependent on local muscarinic and nicotinic receptor activation, respectively. Activation of brainstem ChAT-containing neurons, however, resulted in a transient increase in central lateral amygdala activity that was independent of cholinergic receptors. In addition, driving these respective inputs inbehaving animals induced opposing appetitive and defensive learning-related behavioral changes. Because learning and memory are supported by both cellular and network-level processes in central cholinergic and amygdala networks, these results provide a route by which distinct cholinergic inputs can convey salient information to the amygdala and promote associative biophysical changes that underlie emotional memories.

Brain Circuits Mediating Opposing Effects on Emotion and Pain.

The amygdala is important for processing emotion, including negative emotion such as anxiety and depression induced by chronic pain. Although remarkable progress has been achieved in recent years on amygdala regulation of both negative (fear) and positive (reward) behavioral responses, our current understanding is still limited regarding how the amygdala processes and integrates these negative and positive emotion responses within the amygdala circuits. In this study with optogenetic stimulation of specific brain circuits, we investigated how amygdala circuits regulate negative and positive emotion behaviors, using pain as an emotional assay in male rats. We report here that activation of the excitatory pathway from the parabrachial nucleus (PBN) that relays peripheral pain signals to the central nucleus of amygdala (CeA) is sufficient to cause behaviors of negative emotion including anxiety, depression, and aversion in normal rats. In strong contrast, activation of the excitatory pathway from basolateral amygdala (BLA) that conveys processed corticolimbic signals to CeA dramatically opposes these behaviors of negative emotion, reducing anxiety and depression, and induces behavior of reward. Surprisingly, activating the PBN-CeA pathway to simulate pain signals does not change pain sensitivity itself, but activating the BLA-CeA pathway inhibits basal and sensitized pain. These findings demonstrate that the pain signal conveyed through the PBN-CeA pathway is sufficient to drive negative emotion and that the corticolimbic signal via the BLA-CeA pathway counteracts the negative emotion, suggesting a top-down brain mechanism for cognitive control of negative emotion under stressful environmental conditions such as pain.SIGNIFICANCE STATEMENT It remains unclear how the amygdala circuits integrate both negative and positive emotional responses and the brain circuits that link peripheral pain to negative emotion are largely unknown. Using optogenetic stimulation, this study shows that the excitatory projection from the parabrachial nucleus to the central nucleus of amygdala (CeA) is sufficient to drive behaviors of negative emotion including anxiety, depression, and aversion in rats. Conversely, activation of the excitatory projection from basolateral amygdala to CeA counteracts each of these behaviors of negative emotion. Thus, this study identifies a brain pathway that mediates pain-driven negative emotion and a brain pathway that counteracts these emotion behaviors in a top-down mechanism for brain control of negative emotion.

Neuropeptide signalling in the central nucleus of the amygdala.

The central amygdala has a rich repertoire of neuropeptides and neuropeptide receptors. The diverse ways in which they modulate neuronal activity and influence synaptic activity are discussed here mostly in the context of fear and anxiety-related behaviour but also with respect to nociception, hunger and satiety and chronic alcohol exposure that often come together with anxiety. It appears that neuropeptides exert rather specific effects on behaviour and physiology that can be quite different from the effects evoked by opto- or chemogenetical stimulation of the central amygdala neurons that synthesise them or express their receptors. Also, neuropeptides might work synergistically or antagonistically to fine-tune the final outcome of sensory processing in the central amygdala and bring about appropriate physiological and behavioural responses to threat. Taken together, we propose that neuropeptide signalling in the central amygdala mainly serves to establish or maintain emotional homeostasis in response to threatening and other sensory stimuli.

A Central Extended Amygdala Circuit That Modulates Anxiety.

Both the amygdala and the bed nucleus of the stria terminalis (BNST) have been implicated in maladaptive anxiety characteristics of anxiety disorders. However, the underlying circuit and cellular mechanisms have remained elusive. Here we show that mice with Erbb4 gene deficiency in somatostatin-expressing (SOM+) neurons exhibit heightened anxiety as measured in the elevated plus maze test and the open field test, two assays commonly used to assess anxiety-related behaviors in rodents. Using a combination of electrophysiological, molecular, genetic, and pharmacological techniques, we demonstrate that the abnormal anxiety in the mutant mice is caused by enhanced excitatory synaptic inputs onto SOM+ neurons in the central amygdala (CeA), and the resulting reduction in inhibition onto downstream SOM+ neurons in the BNST. Notably, our results indicate that an increase in dynorphin signaling in SOM+ CeA neurons mediates the paradoxical reduction in inhibition onto SOM+ BNST neurons, and that the consequent enhanced activity of SOM+ BNST neurons is both necessary for and sufficient to drive the elevated anxiety. Finally, we show that the elevated anxiety and the associated synaptic dysfunctions and increased dynorphin signaling in the CeA-BNST circuit of the Erbb4 mutant mice can be recapitulated by stress in wild-type mice. Together, our results unravel previously unknown circuit and cellular processes in the central extended amygdala that can cause maladaptive anxiety.SIGNIFICANCE STATEMENT The central extended amygdala has been implicated in anxiety-related behaviors, but the underlying mechanisms are unclear. Here we found that somatostatin-expressing neurons in the central amygdala (CeA) controls anxiety through modulation of the stria terminalis, a process that is mediated by an increase in dynorphin signaling in the CeA. Our results reveal circuit and cellular dysfunctions that may account for maladaptive anxiety.

Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABAA receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women. Saccadic eye velocity (SEV) is a measure of GABAA receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Post-mortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P<.005), as well as total DRSP scores (P<.01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABAA receptor.