Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors

Yu, Kai; Silva, Pedro Garcia da; Albeanu, Dinu F.; Li, Bo

doi:10.1523/jneurosci.4419-15.2016

Cited by 148 publications

(209 citation statements)

References 30 publications

(4 reference statements)

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“…7 In depression/anxiety patients, the density of somatostatin-positive inhibitory interneurons in the amygdala was reported to be reduced. 12 This is consistent with the previous study finding that the centrolateral amygdala (CeL; in particular the somatostatin-expressing neurons in the CeL) is critical for both learning and the expression of defensive responses 13,14 and validates the importance of the central amygdala in emotion processing.…”

Section: Introductionsupporting

confidence: 92%

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Molecular basis for and chemogenetic modulation of comorbidities in GABRG2‐deficient epilepsies

et al. 2019

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Summary Objective: GABAA receptor subunit gene mutations are significant causes of epilepsy, which are often accompanied with various neuropsychiatric comorbidities, but the underlying mechanisms are unclear. It has been suggested that the comorbidities are caused by seizures as they often present in severe epilepsies. However, findings from both humans and animal models argue against this conclusion. Mutations in the GABAA receptor γ2 subunit gene GABRG2 have been associated with anxiety alone or with severe epilepsy syndromes and comorbid anxiety, suggesting a core molecular defect gives rise to the phenotypical spectrum. Here we determined the pathophysiology of comorbid anxiety in epilepsy and identified the central nucleus of the amygdala (CeA) as a primary neurosubstrate and a potential rescue via neuromodulation of CeA neurons. Methods: We used brain slice recordings, subcellular fractionation and western blot, immunohistochemistry, confocal microscopy and a battery of behavior tests in combination with a chemogenetic approach to characterize anxiety and its underlying mechanisms in a Gabrg2+/Q390X knockin mouse and a Gabrg2+/− knockout mouse, each associated with a different epilepsy syndrome. Results: We found that impaired GABAergic neurotransmission in CeA underlies anxiety in epilepsy, which is due to reduced GABAA receptor subunit expression resulting from the mutations. Impaired GABAA receptor expression reduced GABAergic neurotransmission in CeA, but not in BLA. Activation or inactivation of inhibitory neurons using a chemogenetic approach in CeA alone modulated anxiety-like behaviors. Similarly, pharmacological enhancement of GABAergic signaling via γ2 subunit-containing receptors rescued the anxiety. Significance: Together, these data demonstrate the molecular basis for a comorbidity of epilepsy and suggest that impaired GABAA receptor function in CeA due to mutation per se could at least contribute to anxiety. Modulation of CeA neurons could cause or suppress anxiety, suggesting a potential use of CeA neurons as therapeutic targets for treatment of anxiety in addition to traditional pharmacological approaches.

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Section: Introductionsupporting

confidence: 92%

“…Recordings of GABAergic mIPSCs were obtained from CeA neurons in brain slices as previously described 13 . Whole-cell patch clamp recordings from neurons were made at room temperature from CeA visualized with an upright Nikon eclipse FN-1 IR-DIC microscope.…”

Section: Methodsmentioning

confidence: 99%

Molecular basis for and chemogenetic modulation of comorbidities in GABRG2‐deficient epilepsies

et al. 2019

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“…We also found that the CEAl is characterized as a whole by PKC-δ-expressing neurons, with the exception of the CEAi in the rat, but not in the mouse. The CEAl is also divided into a central zone containing dynorphin (Marchant et al, 2007), CRH, and TH (Marchant et al (2007), and probably other peptides such as somatostatin (Chieng & Christie, 2010;Yu, Garcia da Silva, Albeanu, & Li, 2016). It is also divided into a lateral zone that is intensely innervated by CGRP axons that make very clear pericellular nets around cell bodies that correspond to PKC-δ cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization of McDonald's intermediate part of the Central nucleus of the amygdala in the rat

Barbier

Fellmann

Risold

2018

J of Comparative Neurology

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The actual organization of the central nucleus of the amygdala (CEA) in the rat is mostly based on cytoarchitecture and the distribution of several cell types, as described by McDonald in 1982. Four divisions were identified by this author. However, since this original work, one of these divisions, the intermediate part, has not been consistently recognized based on Nissl-stained material. In the present study, we observed that a compact condensation of retrogradely labeled cells is found in the CEA after fluorogold injection in the anterior region of the tuberal lateral hypothalamic area (LHA) in the rat. We then searched for neurochemical markers of this cell condensation and found that it is quite specifically labeled for calbindin (Cb), but also contains calretinin (Cr), tyrosine hydroxylase (TH) and methionine-enkephalin (Met-Enk) immunohistochemical signals. These neurochemical features are specific to this cell group which, therefore, is distinct from the other parts of the CEA. We then performed cholera toxin injections in the mouse LHA to identify this cell group in this species. We found that neurons exist in the medial and rostral CEAl that project into the LHA but they have a less tight organization than in the rat.

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“…While these projections have been known for some time now, studies have begun to identify circuits within the central nucleus that govern whether active or passive fear responses are expressed (e.g., Gozzi et al 2010). Other recent work has identified specific cell types in the central nucleus which favor the expression of passive fear behavior (i.e., freezing), while other cell types drive the expression of active fear responses (Yu et al 2016;Fadok et al 2017). It is tempting to speculate that the balance of these mechanisms might be shifted in females such that they are more likely to engage in active fear responses.…”

Section: Discussionmentioning

confidence: 99%

Response-specific sex difference in the retention of fear extinction

Voulo

Parsons

2017

Learn. Mem.

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Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction in male and female rats using both fear-potentiated startle and freezing behavior as measures. Rats were trained to fear cues that predicted the occurrence of shock and then subsequently exposed to an extinction training procedure where the cue was presented repeatedly in the absence of shock. Retention of the extinction memory was assessed the next day. Our results showed that females exhibited less retention of fear extinction, but only when measured by fear-potentiated startle. Our results highlight the importance of using multiple indices of fear behavior, particularly when comparing sexes on measures of extinction learning.Not all individuals who experience trauma during their lifetime will develop post-traumatic stress disorder (PTSD). One of the greatest risk factors for developing this disorder is being female, with the lifetime prevalence rate twice as high for women as it is for men (Kessler et al. 1995;Kilpatrick et al. 2013). Fear conditioning studies in rodents allow us to study the behavioral and neural mechanisms that may underlie PTSD (Parsons and Ressler 2013), yet very few fear conditioning studies in rodents have used females as subjects (Lebron-Milad and Milad 2012). Despite the increased prevalence of PTSD and other fear and anxiety-based disorders in females, nonhuman animal studies testing for sex differences in fear conditioning have largely failed to capture this difference.Fear conditioning studies typically use a procedure in which a discrete cue (e.g., auditory stimulus) signals the occurrence of an aversive stimulus, usually a brief shock. Under normal circumstances, animals learn to fear the discrete cue associated with shock and will also learn to fear the context (i.e., place) in which shock occurs. A handful of studies have directly compared animals of both sexes on tests of cued and contextual fear conditioning. Some of these reports have shown that while males and females exhibit equivalent levels of fear conditioning to discrete cues (Maren et al. 1994;Baran et al. 2009;Milad et al. 2009a;Barker and Galea 2010;Gruene et al. 2015a;Fenton et al. 2016), males often show evidence of better contextual conditioning (Maren et al. 1994;Chang et al. 2009;Barker and Galea 2010). Other studies have tested for sex differences in fear extinction learning, a form of learning through which animals learn to inhibit responding to cues that once signaled an aversive event. Over the last several years, the study of fear extinction has received considerable attention (Milad and Quirk 2012) due in part to the fact that humans with PTSD display impaired extinction (Milad et al. 2009b;Norrholm et al. 2011). Recent findings in rodents are mixed with regard t...

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Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors

Cited by 148 publications

References 30 publications

Molecular basis for and chemogenetic modulation of comorbidities in GABRG2‐deficient epilepsies

Molecular basis for and chemogenetic modulation of comorbidities in GABRG2‐deficient epilepsies

Characterization of McDonald's intermediate part of the Central nucleus of the amygdala in the rat

Response-specific sex difference in the retention of fear extinction

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