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 super11CWAY100635. 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.
Basolateral amygdala (BLA) principal cells are capable of driving and antagonizing behaviors of opposing valence. BLA neurons project to the central amygdala (CeA), which also participates in ...negative and positive behaviors. However, the CeA has primarily been studied as the site for negative behaviors, and the causal role for CeA circuits underlying appetitive behaviors is poorly understood. Here, we identify several genetically distinct populations of CeA neurons that mediate appetitive behaviors and dissect the BLA-to-CeA circuit for appetitive behaviors. Protein phosphatase 1 regulatory subunit 1B+ BLA pyramidal neurons to dopamine receptor 1+ CeA neurons define a pathway for promoting appetitive behaviors, while R-spondin 2+ BLA pyramidal neurons to dopamine receptor 2+ CeA neurons define a pathway for suppressing appetitive behaviors. These data reveal genetically defined neural circuits in the amygdala that promote and suppress appetitive behaviors analogous to the direct and indirect pathways of the basal ganglia.
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•Several genetically distinct CeA neurons mediate appetitive behaviors•BLA Ppp1r1b+ neurons project to CeA neurons that mediate appetitive behaviors•BLA Rspo2+ neurons project to CeA neurons that suppress appetitive behaviors•BLA-to-CeA pathways are analogous to corticostriatal direct and indirect pathways
Kim and Zhang et al. dissect genetically defined circuits for appetitive behaviors from the basolateral amygdala to the central amygdala that are genetically analogous to the direct and indirect pathways of the cortex and striatum.
Abstract Background Current neuroimaging perspectives on a variety of mental disorders emphasize dysfunction of the amygdala. The neuropeptide oxytocin (OXT), a key mediator in the regulation of ...social cognition and behavior, accumulates in cerebrospinal fluid after intranasal administration in macaques and humans and modulates amygdala reactivity in both species. However, the translation of neuromodulatory OXT effects to novel treatment approaches is hampered by the absence of studies defining the most effective dose and dose-response latency for targeting the amygdala. Methods To address this highly relevant issue, a total of 116 healthy men underwent functional magnetic resonance imaging (fMRI) using a randomized, double-blind, placebo-controlled crossover study design. The experimental rationale was to systematically vary dose-test latencies (15-40, 45-70, 75-100min) and doses of OXT (12IU, 24IU, 48IU) in order to identify the most robust effects on amygdala reactivity. During fMRI, subjects completed an emotional face recognition task including stimuli with varying intensities ranging from low (highly ambiguous) to high (less ambiguous). Results Our results indicate that the OXT-induced inhibition of amygdala responses to fear was most effective in a time window between 45 and 70min after administration of a 24IU dose. Furthermore, the observed effect was most evident in subjects scoring high on measures of autistic-like traits. Behavioral response patterns suggest that OXT specifically reduced an emotional bias in the perception of ambiguous faces. Conclusion These findings provide initial evidence of the most effective dose and dose-test interval for future experimental or therapeutic regimens aimed at targeting amygdala functioning using intranasal OXT administration.ClinicalTrials.gov ID: NCT03011970. Trial Name: ‘Temporal Dynamics and Pharmacokinetics of Intranasally Administered Oxytocin’ URL: https://clinicaltrials.gov/ct2/show/NCT03011970?term=Pharmacokinetics+Oxytocin&rank=4
It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in ...mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase
probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.
This article introduces a novel hypothesis regarding amygdala function in psychopathy. The first part of this article introduces the concept of psychopathy and describes the main cognitive and ...affective impairments demonstrated by this population; that is, a deficit in fear-recognition, lower conditioned fear responses and poor performance in passive avoidance, and response-reversal learning tasks. Evidence for amygdala dysfunction in psychopathy is considered with regard to these deficits; however, the idea of unified amygdala function is untenable. A model of differential amygdala activation in which the basolateral amygdala (BLA) is underactive while the activity of the central amygdala (CeA) is of average to above average levels is proposed to provide a more accurate and up-to-date account for the specific cognitive and emotional deficits found in psychopathy. In addition, the model provides a mechanism by which attentional-based models and emotion-based models of psychopathy can coexist. Data to support the differential amygdala activation model are provided from studies from both human and animal research. Supporting evidence concerning some of the neurochemicals implicated in psychopathy is then reviewed. Implications of the model and areas of future research are discussed.
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) Valsuper108/158Met 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 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.
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.
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