Early-life stress induces persistent astrocyte dysfunction resulting in fear generalisation
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eLife assessment
Early-life adversity or stress can enhance stress susceptibility by causing changes in emotion, cognition, and reward-seeking behaviors. This important manuscript highlights the involvement of lateral amygdala astrocytes in fear generalization and the associated synaptic plasticity, which are parallel to the effects of early life stress. With an elegant combination of behavioral models, morphological and functional assessments using immunostaining, electrophysiology, and viral-mediated loss-of-function approaches, the authors provide solid correlational and causal evidence that is consistent with the hypothesis that early life stress produces neural and behavioral dysfunction via perturbing lateral amygdala astrocytic function.
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Abstract
Early-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioral and cognitive deficits. While the effects of early-life stress on neuronal function have been well-described, we still know very little about the contribution of non-neuronal brain cells. Investigating the complex interactions between distinct brain cell types is critical to fully understand how cellular changes manifest as behavioral deficits following early-life stress. Here, using male and female mice we report that early-life stress induces anxiety-like behavior and fear generalisation in an amygdala-dependent learning and memory task. These behavioral changes were associated with impaired synaptic plasticity, increased neural excitability, and astrocyte dysfunction. Genetic perturbation of amygdala astrocyte function by either silencing these cells or reducing astrocyte network function was sufficient to replicate cellular, synaptic, and fear memory changes associated with early-life stress. These data provide mechanistic links between early-life stress and astrocyte dysfunction. Our data reveal a role of astrocytes in tuning emotionally salient memory with astrocyte dysfunction resulting in fear generalisation. Further understanding of how astrocytes are affected by stress might offer new insights into the long-term impact of early-life stress on affective states.
Article activity feed
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eLife assessment
Early-life adversity or stress can enhance stress susceptibility by causing changes in emotion, cognition, and reward-seeking behaviors. This important manuscript highlights the involvement of lateral amygdala astrocytes in fear generalization and the associated synaptic plasticity, which are parallel to the effects of early life stress. With an elegant combination of behavioral models, morphological and functional assessments using immunostaining, electrophysiology, and viral-mediated loss-of-function approaches, the authors provide solid correlational and causal evidence that is consistent with the hypothesis that early life stress produces neural and behavioral dysfunction via perturbing lateral amygdala astrocytic function.
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Reviewer #1 (Public Review):
Summary:
The manuscript asks the question of whether astrocytes contribute to behavioral deficits triggered by early life stress. This question is tested by experiments that monitor the effects of early life stress on anxiety-like behaviors, long-term potentiation in the lateral amygdala, and immunohistochemistry of astrocyte-specific (GFAP, Cx43, GLT-1) and general activity (c-Fos ) markers. Secondarily, astrocyte activity in the lateral amygdala is impaired by viruses that suppress gap-junction coupling or reduce astrocyte Ca2+ followed by behavioral, synaptic plasticity, and c-Fos staining. Early life stress is found to reduce the expression of GFAP and Cx43 and to induce translocation of the glucocorticoid receptor to astrocytic nuclei. Both early life stress and astrocyte manipulations are found to …
Reviewer #1 (Public Review):
Summary:
The manuscript asks the question of whether astrocytes contribute to behavioral deficits triggered by early life stress. This question is tested by experiments that monitor the effects of early life stress on anxiety-like behaviors, long-term potentiation in the lateral amygdala, and immunohistochemistry of astrocyte-specific (GFAP, Cx43, GLT-1) and general activity (c-Fos ) markers. Secondarily, astrocyte activity in the lateral amygdala is impaired by viruses that suppress gap-junction coupling or reduce astrocyte Ca2+ followed by behavioral, synaptic plasticity, and c-Fos staining. Early life stress is found to reduce the expression of GFAP and Cx43 and to induce translocation of the glucocorticoid receptor to astrocytic nuclei. Both early life stress and astrocyte manipulations are found to result in the generalization of fear to neutral auditory cues. All of the experiments are done well with appropriate statistics and control groups. The manuscript is very well-written and the data are presented clearly. The authors' conclusion that lateral amygdala astrocytes regulate amygdala-dependent behaviors is strongly supported by the data. However, the extent to which astrocytes contribute to behavioral and neuronal consequences of early life stress remains open to debate.
Strengths:
A strong combination of behavioral, electrophysiology, and immunostaining approaches is utilized and possible sex differences in behavioral data are considered. The experiments clearly demonstrate that disruption of astrocyte networks or reduction of astrocyte Ca2+ provokes generalization of fear and impairs long-term potentiation in the lateral amygdala. The provocative finding that astrocyte dysfunction accounts for a subset of behavioral effects of early life stress (e.g. not elevated plus or distance traveled observations) is also perceived as a strength.
Weaknesses:
The main weakness is the absence of more direct evidence that behavioral and neuronal plasticity after early life stress can be attributed to astrocytes. It remains unknown what would happen if astrocyte activity were disrupted concurrently with early life stress or if the facilitation of astrocyte Ca2+ would attenuate early life stress outcomes. As is, the only evidence that early life stress involves astrocytes is nuclear translocation of GR and downregulation of GFAP and Cx43 in Figure 3 which may or may not provoke astrocyte Ca2+ or astrocyte network activity changes.
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Reviewer #2 (Public Review):
Summary:
In this manuscript, Guayasamin et al. show that early-life stress (ELS) can induce a shift in fear generalisation in mice. They took advantage of a fear conditioning paradigm followed by a discrimination test and complemented learning and memory findings with measurements for anxiety-like behaviors. Next, astrocytic dysfunction in the lateral amygdala was investigated at the cellular level by combining staining for c-Fos with astrocyte-related proteins. Changes in excitatory neurotransmission were observed in acute brains slices after ELS suggesting impaired communication between neurons and astrocytes. To confirm the causality of astrocytic-neuronal dysfunction in behavioral changes, viral manipulations were performed in unstressed mice. Occlusion of functional coupling with a dominant negative …
Reviewer #2 (Public Review):
Summary:
In this manuscript, Guayasamin et al. show that early-life stress (ELS) can induce a shift in fear generalisation in mice. They took advantage of a fear conditioning paradigm followed by a discrimination test and complemented learning and memory findings with measurements for anxiety-like behaviors. Next, astrocytic dysfunction in the lateral amygdala was investigated at the cellular level by combining staining for c-Fos with astrocyte-related proteins. Changes in excitatory neurotransmission were observed in acute brains slices after ELS suggesting impaired communication between neurons and astrocytes. To confirm the causality of astrocytic-neuronal dysfunction in behavioral changes, viral manipulations were performed in unstressed mice. Occlusion of functional coupling with a dominant negative construct for gap junction connexin 43 or reduction in astrocytic calcium with CalEx mimicked the behavioral changes observed after ELS suggesting that dysfunction of the astrocytic network underlies ELS-induced memory impairments.
Strengths:
Overall, this well-written manuscript highlights a key role for astrocytes in regulating stress-induced behavioral and synaptic deficits in the lateral amygdala in the context of ELS. Results are innovative, and methodological approaches relevant to decipher the role of astrocytes in behaviors. As mentioned by the authors, non-neuronal cells are receiving increasing attention in the neuroscience, stress, and psychiatry fields.
Weaknesses:
I do have several suggestions and comments to address that I believe will improve the clarity and impact of the work. For example, there is currently a lack of information on the timeline for behavioral experiments, tissue collection, etc.
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Reviewer #3 (Public Review):
Summary
The authors show that ELS induces a number of brain and behavioral changes in the adult lateral amygdala. These changes include enduring astrocytic dysfunction, and inducing astrocytic dysfunction via genetic interventions is sufficient to phenocopy the behavioral and neural phenotypes. This suggests that astrocyte dysfunction may play a causal role in ELS-associated pathologies.
Strengths:
A strength is the shift in focus to astrocytes to understand how ELS alters adult behavior.
Weaknesses:
The mechanistic links between some of the correlates - altered astrocytic function, changes in neural excitability, and synaptic plasticity in the lateral amygdala and behaviour - are underdeveloped.
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