Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression

Muir, Jessie; Lopez, Joëlle; Bagot, Rosemary C.

doi:10.1038/s41386-018-0291-6

Cited by 71 publications

(46 citation statements)

References 97 publications

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“…We focus on studies that have taken advantage of circuit-based interrogation techniques to understand how emotionally salient information is encoded ( Figure 1). This is not an exhaustive analysis, as many other regions have been implicated in emotional regulation [18][19][20][21], and this topic have been covered in a number of excellent recent reviews [22][23][24][25][26][27][28]. In addition, it is likely that brain-wide recording methods may reveal other regions and circuits that play important roles in emotional informational processing.…”

Section: Box 2 Classification Of Biomarkersmentioning

confidence: 99%

Circuit-Based Biomarkers for Mood and Anxiety Disorders

Xia

Kheirbek

2020

Trends in Neurosciences

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Mood and anxiety disorders are complex heterogeneous syndromes that manifest in dysfunctions across multiple brain regions, cell types, and circuits. Biomarkers using brain-wide activity patterns in humans have proven useful in distinguishing between disorder subtypes and identifying effective treatments. In order to improve biomarker identification, it is crucial to understand the basic circuitry underpinning brain-wide activity patterns. Leveraging a large repertoire of techniques, animal studies have examined roles of specific cell types and circuits in driving maladaptive behavior. Recent advances in multiregion recording techniques, data-driven analysis approaches, and machine-learning-based behavioral analysis tools can further push the boundary of animal studies and bridge the gap with human studies, to assess how brain-wide activity patterns encode and drive emotional behavior. Together, these efforts will allow identifying more precise biomarkers to enhance diagnosis and treatment. Distributed Neural Circuits Underly Mood and Anxiety Disorders Mood and anxiety disorders disrupt basic functions of individuals' lives, and are among the leading causes of disability [1]. In the USA, it is estimated that at a given timepoint, 10-20% of adults are impacted, and 20-30% of adults will experience a mood or anxiety disorder at some point in their lives (https://www.hcp.med.harvard.edu/ncs). However, most existing treatments are not effective [2,3]; largely due to a lack of clear understanding of disease etiology. The search for effective treatment is further complicated by the fact that mood and anxiety disorders are heterogeneous syndromes with various subtypes, where patients present diverse symptoms even for the same disorder, and often respond differently to the same treatment [4-7]. Highlights Mood and anxiety disorders are complex neural-circuit-based conditions that arise from dysfunctions across multiple cell types, brain regions, and circuits. Recent efforts in identifying circuit-based biomarkers using brain-wide activity patterns have shown promising results in stratifying disorder subtypes and identifying effective treatments for patients with mood and anxiety disorders.

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Section: Box 2 Classification Of Biomarkersmentioning

confidence: 99%

Circuit-Based Biomarkers for Mood and Anxiety Disorders

Xia

Kheirbek

2020

Trends in Neurosciences

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“…Brain regions, such as the prefrontal cortex (PFC) and the nucleus accumbens (NAc) that are implicated in depression pathogenesis 11 , 13 – 16 show high susceptibility to display structural and functional alterations under exposure to chronic stress 12 , 17 – 19 . In the search for potential mechanisms underlying those changes, several studies have reported gene expression changes in the PFC and NAc in both, depressive patients 16 , 20 – 22 and rodent models of chronic stress 23 – 25 .…”

Section: Introductionmentioning

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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“…Studies have shown that mTOR is involved in the regulation and control of the size of neurons in the dentate gyrus and hippocampus ( Hay and Sonenberg, 2004 ). As an important meeting point for multiple signaling pathways, mTOR has been shown to control the neuronal development ( Kwon et al, 2006 ; Swiech et al, 2008 ), differentiation ( Jaworski and Sheng, 2006 ; Muir et al, 2019 ), and regeneration by regulating global or local protein synthesis. Several studies ( Dash et al, 2006 ; Bekinschtein et al, 2007 ; Parsons et al, 2010 ) have also reported that mTOR activation is related to memory formation and spatial memory.…”

Section: Discussionmentioning

confidence: 99%

Effects of Akt/mTOR/p70S6K Signaling Pathway Regulation on Neuron Remodeling Caused by Translocation Repair

Yuan

et al. 2020

Front. Neurosci.

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Peripheral nerve injury repair has been considered a difficult problem in the field of trauma for a long time. Conventional surgical methods are not applicable in some special types of nerve injury, prompting scholars to seek to develop more effective nerve translocation repair technologies. The purpose of this study was to explore the functional state of neurons in injured lower limbs after translocation repair, with a view to preliminarily clarify the molecular mechanisms underlying this process. Eighteen Sprague–Dawley rats were divided into the normal, tibial nerve in situ repair, and common peroneal nerve transposition repair tibial nerve groups. Nerve function assessment and immunohistochemical staining of neurofilament 200 (NF-200), protein kinase B (Akt), mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (p70S6K) in the dorsal root ganglia were performed at 12 weeks after surgery. Tibial nerve function and neuroelectrophysiological analysis, osmic acid staining, muscle strength testing, and muscle fiber staining showed that the nerve translocation repair could restore the function of the recipient nerve to a certain extent; however, the repair was not as efficient as the in situ repair. Immunohistochemical staining showed that the translocation repair resulted in changes in the microstructure of neuronal cell bodies, and the expressions of Akt, mTOR, and p70S6K in the three dorsal root ganglia groups were significantly different ( p < 0.05). This study demonstrates that the nerve translocation repair technology sets up a new reflex loop, with the corresponding neuroskeletal adjustments, in which, donor neurons dominate the recipient nerves. This indicates that nerve translocation repair technology can lead to neuronal remodeling and is important as a supplementary treatment for a peripheral nerve injury. Furthermore, the Akt/mTOR/p70S6K signaling pathway may be involved in the formation of the new neural reflex loop created as a result of the translocation repair.

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Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression

Cited by 71 publications

References 97 publications

Circuit-Based Biomarkers for Mood and Anxiety Disorders

Circuit-Based Biomarkers for Mood and Anxiety Disorders

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

Effects of Akt/mTOR/p70S6K Signaling Pathway Regulation on Neuron Remodeling Caused by Translocation Repair

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