Chronic Stress Remodels Synapses in an Amygdala Circuit–Specific Manner

Zhang, Junyu; Liu, Taohui; He, Ye; Pan, Han‐Qing; Zhang, Wenhua; Yin, Xiaoping; Tian, Xiao-Li; Li, Baoming; Wang, Xiaodong; Holmes, Andrew; Yuan, Ti‐Fei; Pan, Bing‐Xing

doi:10.1016/j.biopsych.2018.06.019

Cited by 131 publications

(99 citation statements)

References 64 publications

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“…Dendritic spines are important locations for the formation of neuronal circuits and network structures. A reduction in dendritic spine density is bound to reduce synapse formation and thus impair cognitive function [43]. Our previous study showed that CCH can lead to a reduction in dendritic spines.…”

Section: Resultsmentioning

confidence: 99%

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Yao

Zhang

et al. 2019

Neural Plasticity

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Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

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Section: Resultsmentioning

confidence: 99%

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Yao

Zhang

et al. 2019

Neural Plasticity

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“…In the future, it will be important to perform similar mitochondrial analyses as the ones included in the current study to investigate chronic stress effects in other brain regions critically involved in the brain response to chronic stress and MDD, such as the orbitofrontal cortex (OFC), hippocampus and amygdala 74 , 75 . These studies will be particularly relevant to understand the link between mitochondria and stress-induced changes in neuronal structure as, in contrast to the hypotrophy induced by stress in the medial PFC 47 – 50 or in the hippocampus 76 , 77 , the basolateral amygdala 78 (but see 79 ) and the OFC show dendritic hypotrophy 80 following similar stress protocols. In addition, future functional studies will be needed to elucidate the underlying molecular mechanisms of how the herein defined mitochondrial gene expression changes can act as a vulnerability factor for the development and/or pathology of stress-induced depression.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Weger

Alpern

Cherix

et al. 2020

Sci Rep

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Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

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“…Some, but not all, chronic stress paradigms increase activity in the BLA (Shepard et al, 2016;Lowery-Gionta et al, 2018;Zhang et al, 2019), enhancing excitatory output at BLA-to-PFC synapses and inducing an anxiety phenotype. Whether a stress-induced increase in excitatory BLA projections to the PFC is driving the activity of prefrontal PV cells remains to be determined.…”

Section: Macrocircuit Inputs Possibly Driving Gabaergic Changes In Thmentioning

confidence: 99%

“…Whether a stress-induced increase in excitatory BLA projections to the PFC is driving the activity of prefrontal PV cells remains to be determined. Chronic stress also increases spine density and glutamatergic signaling in BLA projections to the ventral hippocampus, increasing activity of this region (Zhang et al, 2019). The ventral hippocampus directly innervates the PFC and excites PV interneurons (Gabbott et al, 2002;Caballero et al, 2014b).…”

Section: Macrocircuit Inputs Possibly Driving Gabaergic Changes In Thmentioning

confidence: 99%

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

Page

Coutellier

2019

Neuroscience & Biobehavioral Reviews

146

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Chronic stress-related emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory γaminobutyric acid (GABA) system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. In this dissertation, I propose and discuss the hypothesis that chronic stress-induced anxiety involves hypoactivity of the PFC due to increased inhibition, mediated in part through increased activity of prefrontal parvalbumin (PV)-expressing inhibitory interneurons. Differing sensitivity of the prefrontal GABAergic system and PV neurons to chronic stress may also underlie sex differences in the prevalence of anxiety disorders, with women presenting with anxiety at higher rates than men. I first present evidence that chronic stress increases the activity of prefrontal PV neurons, and that increased activity of this cell population induces hypoactivity of the PFC. Furthermore, increasing prefrontal PV cell activity using DREADDs (designer receptors exclusively activated by designer drugs) induces anxietylike behaviors specifically in females (Chapter 2). However, acute inhibition of prefrontal PV cells using DREADDs is insufficient to rescue stress-induced anxiety-like behavior, though it does modulate activity and synaptic plasticity in the PFC in a sex

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Chronic Stress Remodels Synapses in an Amygdala Circuit–Specific Manner

Abstract: Chronic stress caused BLA PN neuronal remodeling with a previously unrecognized degree of circuit specificity, offering new insight into the pathophysiological basis of depression, anxiety disorders, and other stress-related conditions.

Cited by 131 publications

References 64 publications

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

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