Review

Authors: P Sah, E S L Faber, M Lopez De Armentia...

A converging body of literature over the last 50 years has implicated the amygdala in assigning emotional significance or value to sensory information. In particular, the amygdala has been shown to be an essential component of the circuitry underlying fear-related responses. Disorders in the processing of fear-related information are likely to be the underlying cause of some anxiety disorders in humans such as posttraumatic stress. The amygdaloid complex is a group of more than 10 nuclei that are located in the midtemporal lobe. These nuclei can be distinguished both on cytoarchitectonic and connectional grounds. Anatomical tract tracing studies have shown that these nuclei have extensive intranuclear and internuclear connections. The afferent and efferent connections of the amygdala have also been mapped in detail, showing that the amygdaloid complex has extensive connections with cortical and subcortical regions. Analysis of fear conditioning in rats has suggested that long-term synaptic plasticity of inputs to the amygdala underlies the acquisition and perhaps storage of the fear memory. In agreement with this proposal, synaptic plasticity has been demonstrated at synapses in the amygdala in both in vitro and in vivo studies. In this review, we examine the anatomical and physiological substrates proposed to underlie amygdala function.

Topics: Amygdala; Animals; Conditioning, Psychological; Fear; Humans; Neural Pathways; Neuronal Plasticity

PubMed: 12843409
DOI: 10.1152/physrev.00002.2003

Authors: Tao Yang, Kai Yu, Xian Zhang...

The central amygdala (CeA) is implicated in a range of mental processes including attention, motivation, memory formation and extinction and in behaviours driven by either aversive or appetitive stimuli. How it participates in these divergent functions remains elusive. Here we show that somatostatin-expressing (Sst) CeA neurons, which mediate much of CeA functions, generate experience-dependent and stimulus-specific evaluative signals essential for learning. The population responses of these neurons in mice encode the identities of a wide range of salient stimuli, with the responses of separate subpopulations selectively representing the stimuli that have contrasting valences, sensory modalities or physical properties (for example, shock and water reward). These signals scale with stimulus intensity, undergo pronounced amplification and transformation during learning, and are required for both reward and aversive learning. Notably, these signals contribute to the responses of dopamine neurons to reward and reward prediction error, but not to their responses to aversive stimuli. In line with this, Sst CeA neuron outputs to dopamine areas are required for reward learning, but are dispensable for aversive learning. Our results suggest that Sst CeA neurons selectively process information about differing salient events for evaluation during learning, supporting the diverse roles of the CeA. In particular, the information for dopamine neurons facilitates reward evaluation.

Topics: Animals; Mice; Avoidance Learning; Central Amygdaloid Nucleus; Dopaminergic Neurons; Motivation; Reward; Neuronal Plasticity; Somatostatin; Electroshock

PubMed: 37020025
DOI: 10.1038/s41586-023-05910-2

Authors: Fabrice Chaudun, Laurena Python, Yu Liu...

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs. Among the opioid receptors, µ-opioid receptors have a key role, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.

Topics: Animals; Female; Male; Mice; Analgesics, Opioid; Central Amygdaloid Nucleus; Dopamine; Dopaminergic Neurons; Fentanyl; Mice, Inbred C57BL; Nucleus Accumbens; Opioid-Related Disorders; Optogenetics; Receptors, Opioid, mu; Reinforcement, Psychology; Substance Withdrawal Syndrome; Ventral Tegmental Area

PubMed: 38778097
DOI: 10.1038/s41586-024-07440-x

Authors: Chandrashekhar D Borkar, Claire E Stelly, Xin Fu...

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA); however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.

Topics: Avoidance Learning; Central Amygdaloid Nucleus; Neurons; Prefrontal Cortex; Excitatory Amino Acid Agents; Glutamic Acid; Neural Pathways; Calcium; Electrophysiology; Pons

PubMed: 38233522
DOI: 10.1038/s41586-023-06912-w

Authors: Michael C Chiang, Eileen K Nguyen, Martha Canto-Bustos...

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.

Topics: Animals; Avoidance Learning; Central Amygdaloid Nucleus; Escape Reaction; Mice; Neural Pathways; Neurons, Efferent; Nociception; Optogenetics; Pain; Parabrachial Nucleus; Periaqueductal Gray; Septal Nuclei; Ventromedial Hypothalamic Nucleus

PubMed: 32289251
DOI: 10.1016/j.neuron.2020.03.014

Authors: Sandra Villar-Conde, Veronica Astillero-Lopez, Melania Gonzalez-Rodriguez...

α-Synuclein, a protein mostly present in presynaptic terminals, accumulates neuropathologically in Parkinson's disease in a 6-stage sequence and propagates in the nervous system in a prion-like manner through neurons and glia. In stage 3, the substantia nigra are affected, provoking motor symptoms and the amygdaloid complex, leading to different nonmotor symptoms; from here, synucleinopathy spreads to the temporal cortex and beyond. The expected increase in Parkinson's disease incidence accelerates the need for detection biomarkers; however, the heterogeneity of this disease, including pathological aggregates and pathophysiological pathways, poses a challenge in the search for new therapeutic targets and biomarkers. Proteomic analyses are lacking, and the literature regarding synucleinopathy, neural and glial involvement, and volume of the human amygdaloid complex is controversial. Therefore, the present study combines both proteomic and stereological probes. Data-independent acquisition-parallel accumulation of serial fragmentation proteomic analysis revealed a remarkable proteomic impact, especially at the synaptic level in the human amygdaloid complex in Parkinson's disease. Among the 199 differentially expressed proteins, guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1), elongation factor 1-alpha 1 (EEF1A1), myelin proteolipid protein (PLP1), neuroplastin (NPTN), 14-3-3 protein eta (YWHAH), gene associated with retinoic and interferon-induced mortality 19 protein (GRIM19), and orosomucoid-2 (ORM2) stand out as potential biomarkers in Parkinson's disease. Stereological analysis, however, did not reveal alterations regarding synucleinopathy, neural or glial populations, or volume changes. To our knowledge, this is the first proteomic study of the human amygdaloid complex in Parkinson's disease, and it identified possible biomarkers of the disease. Lewy pathology could not be sufficient to cause neurodegeneration or alteration of microglial and astroglial populations in the human amygdaloid complex in Parkinson's disease. Nevertheless, damage at the proteomic level is manifest, showing up significant synaptic involvement.

Topics: Humans; Parkinson Disease; Synucleinopathies; Proteomics; alpha-Synuclein; Amygdala; Biomarkers

PubMed: 37947401
DOI: 10.1016/j.mcpro.2023.100673

Authors: Yan-Hui Sun, Bo-Wu Hu, Li-Heng Tan...

The amygdaloid complex consists of multiple nuclei and is a key node in controlling temporal lobe epilepsy (TLE) in both human and animal model studies. However, the specific nucleus in the amygdaloid complex and the neural circuitry governing seizures remain unknown. Here, it is discovered that activation of glutamatergic neurons in the posterior basolateral amygdala (pBLA) induces severe seizures and even mortality. The pBLA glutamatergic neurons project collateral connections to multiple brain regions, including the insular cortex (IC), bed nucleus of the stria terminalis (BNST), and central amygdala (CeA). Stimulation of pBLA-targeted IC neurons triggers seizures, whereas ablation of IC neurons suppresses seizures induced by activating pBLA glutamatergic neurons. GABAergic neurons in the BNST and CeA establish feedback inhibition on pBLA glutamatergic neurons. Deleting GABAergic neurons in the BNST or CeA leads to sporadic seizures, highlighting their role in balancing pBLA activity. Furthermore, pBLA neurons receive glutamatergic inputs from the ventral hippocampal CA1 (vCA1). Ablation of pBLA glutamatergic neurons mitigates both acute and chronic seizures in the intrahippocampal kainic acid-induced mouse model of TLE. Together, these findings identify the pBLA as a pivotal nucleus in the amygdaloid complex for regulating epileptic seizures in TLE.

Topics: Epilepsy, Temporal Lobe; Animals; Mice; Basolateral Nuclear Complex; Disease Models, Animal; Male; Amygdala; Neurons

PubMed: 39476381
DOI: 10.1002/advs.202407525

Authors: Yan-Li Ren, Wei-Wei Chu, Xing-Wen Yang...

ETHNOPHARMACOLOGICAL RELEVANCE

The use of lavender as sleep aid or hypnotic agent can be traced back as early as ancient Romans and Greeks. Yet, objective experimental data on whether and how lavender enhances sleep duration or/and sleep quality remain lacking.

AIM OF THE STUDY

We aimed to characterize the sleep-wake regulating effects of lavender in the mouse and to demonstrate the brain targets and neural circuits involved.

MATERIALS AND METHODS

A self-made precise odor delivery system combined with chronic polysomnographic recordings was employed to assess the sleep-wake effects of inhalation with lavender essential oil (LEO, extracted from lavender) and its different constituents during the light and dark phases in free-moving C57BL/6J mice. Neuroviral labeling, in situ hybridization and pharmacogenetics were combined to identify the neural circuits and targets involved. Finally, an insomniac model of DL-4-Chlorophenylalanine (PCPA)-treated mice was established to examine the sleep-inducing potential of LEO.

RESULTS

We found that inhalation of LEO with a concentration at 25.0% during the light (inactive) phase significantly shortened the latency to non-rapid eye movement (NREM) sleep, increased the total amount of NREM sleep at the expense of wakefulness (W), and enhanced cortical EEG slow wave activities, notably delta power spectra density. We further identified linalool, d-limonene, 1,8-cineole, linalyl acetate and terpinene-4-ol as the major effective sleep-promoting monomer components. Importantly, we found that LEO no longer produced any of the above sleep-promoting effect following either nasal injection of zinc sulfate which interrupts the olfactory pathway, or pharmacogenetics silencing of central amygdala GABAergic neurons. Finally, LEO reestablished NREM sleep with short latency in PCPA-treated insomniac mice, effects comparable with those induced by a potent sedative diazepam.

CONCLUSIONS

We have characterized the quantitative and qualitative sleep-promoting effects of LEO and its effective components via the olfactory pathway and central amygdala GABA neuronal targets. The hypnotic property of LEO is reinforced by its ability to restore sleep in insomnia. Our study thus establishes a neurobiological basis for aromatherapy of sleep disorders using lavender.

Topics: Animals; Lavandula; GABAergic Neurons; Oils, Volatile; Mice, Inbred C57BL; Male; Olfactory Perception; Sleep; Mice; Plant Oils; Central Amygdaloid Nucleus; Wakefulness; Hypnotics and Sedatives; Administration, Inhalation

PubMed: 39426576
DOI: 10.1016/j.jep.2024.118942

Authors: Wen-Hsien Hou, Meet Jariwala, Kai-Yi Wang...

Engrams, which are cellular substrates of memory traces, have been identified in various brain areas, including the amygdala. While most identified engrams are composed of excitatory, glutamatergic neurons, GABAergic inhibitory engrams have been relatively overlooked. Here, we report the identification of an inhibitory engram in the central lateral amygdala (CeL), a key area for auditory fear conditioning. This engram is primarily composed of GABAergic somatostatin-expressing (SST(+)) and, to a lesser extent, protein kinase C-δ-expressing (PKC-δ(+)) neurons. Fear memory is accompanied by a preferential enhancement of synaptic inhibition onto PKC-δ(+) neurons. Silencing this CeL GABAergic engram disinhibits the activity of targeted extra-amygdaloid areas, selectively increasing the expression of fear. Our findings define the behavioral function of an engram formed exclusively by GABAergic inhibitory neurons in the mammalian brain.

Topics: Animals; Fear; Memory; Mice; GABAergic Neurons; Somatostatin; Protein Kinase C-delta; Male; Central Amygdaloid Nucleus; Mice, Inbred C57BL; Amygdala

PubMed: 39106862
DOI: 10.1016/j.celrep.2024.114468

Authors: Fang-Ling Xuan, Ling Yan, Yanli Li...

Stress is a trigger for the development of psychiatric disorders. However, how stress trait differs in schizophrenia patients is still unclear. Stress also induces and exacerbates immune activation in psychiatric disorders. Plexins (Plxn) and its ligands semaphorins (Sema) are important cellular receptors with plural functions in both the brain and the immune system. Recently, the role of Plxn/Sema in regulation of neuroinflammation was also noticed. Here, when investigating immune mechanisms underlying stress susceptibility in schizophrenia, we discovered the role of Plxnb2 in stress response. Patients of first-episode schizophrenia (FES) with high stress (FES-hs, =51) and low stress (FES-ls, =50) perception and healthy controls (HCs) (=49) were first recruited for neuroimaging and blood bulk RNA sequencing (RNA-seq). A mouse model of chronic unpredictable stress (CUS) and intra-amygdaloid functional blocking of Plxnb2 were further explored to depict target gene functions. Compared to HCs, FES-hs patients had bigger caudate and thalamus (FDR=0.02&0.001, respectively) whereas FES-ls patients had smaller amygdala (FDR=0.002). Blood RNA-seq showed differentially expressed and its ligands among patient groups and HCs (FDR<0.05~0.01). Amygdaloid size and level were both negatively correlated with stress perception (<0.01&0.05, respectively), which fully mediated the amygdaloid positive association with expression (β=0.9318, 95% CI: 0.058~1.886) in FES-hs patients. In mice, Plxnb2 was enriched in astrocytes and microglia and CUS reduced its expression in astrocytes (<0.05). Inhibition of amygdaloid Plxnb2 by its functional blocking monoclonal antibody (mAb)-102 induced mice anxiety (<0.05), amygdaloid enlargement (<0.05), and microglial ramification (<0.001) compared to saline. These data suggest that regulates amygdala-dependent stress responses.

Topics: Animals; Mice; Amygdala; Ligands; Perception; Schizophrenia; Semaphorins

PubMed: 36325348
DOI: 10.3389/fimmu.2022.1005067