Layer 2/3 pyramidal cells in the medial prefrontal cortex moderate stress induced depressive behaviors

Shrestha, Prerana; Mousa, Awni; Heintz, Nathaniel

doi:10.7554/elife.08752

Cited by 73 publications

(77 citation statements)

References 65 publications

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“…1C and 4B), suggesting that any further alterations induced by genetic or environmental factors could lead to the development of age-dependent brain disorders. Our interpretation is further supported by a recent animal model study demonstrating the importance of medial prefrontal cortex layer 2/3 in stress-induced depressive behaviors (Shrestha et al, 2015). …”

Section: Discussionsupporting

confidence: 86%

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging

Pabba

Scifo

Kapadia

et al. 2017

Neurobiology of Aging

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The orbitofrontal cortex (OFC) is vulnerable to normal and pathological aging. Currently, layer resolution large-scale proteomic studies describing “normal” age-related alterations at OFC are not available. Here, we performed a large-scale exploratory high-throughput mass spectrometry-based protein analysis on OFC layer 2/3 from 15 “young” (15–43 years) and 18 “old” (62–88 years) human male subjects. We detected 4,193 proteins and identified 127 differently expressed proteins (DE) (p-value ≤0.05; effect size >20%), including 65 up- and 62 down-regulated proteins (e.g., GFAP, CALB1). Using a previously-described categorization of biological aging based on somatic tissues, i.e., peripheral “hallmarks of aging”, and considering overlap in protein function, we show highest representation of altered cell-cell communication (54%), deregulated nutrient sensing (39%) and loss of proteostasis (35%) in the set of OFC layer 2/3 DE proteins. DE proteins also showed a significant association with several neurological disorders, e.g., Alzheimer’s disease and schizophrenia. Notably, despite age-related changes in individual protein levels, protein co-expression modules were remarkably conserved across age groups, suggesting robust functional homeostasis. Collectively, these results provide biological insight into aging and associated homeostatic mechanisms that maintain normal brain function with advancing age.

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Section: Discussionsupporting

confidence: 86%

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging

Pabba

Scifo

Kapadia

et al. 2017

Neurobiology of Aging

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“…The limited sensitivity this approach did not allow accurate determination of the co-expression of Oxtr and Crhbp, although we reproducibly detected CRHBP in >50% of OxtrINs. The significance of this result is enhanced both by the finding that the CRH receptor ( Crhr1 ), which was present in the input cortical samples but not enriched in the IP (Figure 3A), is expressed specifically in layer 2/3 pyramidal cells (Figure S3D) and by our recent demonstration that layer 2/3 pyramidal cells in the mPFC can mediate stress-induced depressive behaviors (Shrestha et al, 2015). …”

Section: Resultsmentioning

confidence: 83%

“…These cells are particularly vulnerable to stress, which typically induces alterations in their morphology and synaptic function (Shansky and Morrison, 2009; Moench and Wellman, 2014). Layer 2/3 pyramidal cells in the mPFC also express the Wolfram syndrome gene, and it has been demonstrated recently that they are required to modulate stress-induced depressive behaviors (Shrestha et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

A Cortical Circuit for Sexually Dimorphic Oxytocin-Dependent Anxiety Behaviors

Nakajima

Ibañez–Tallon

et al. 2016

Cell

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195

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SUMMARY The frequency of human social and emotional disorders varies significantly between males and females. We have recently reported that oxytocin receptor interneurons (OxtrINs) modulate female sociosexual behavior. Here we show that in male mice OxtrINs regulate anxiety-related behaviors. We demonstrate that corticotropin releasing hormone binding protein (CRHBP), an antagonist of the stress hormone CRH, is specifically expressed in OxtrINs. Production of CRHBP blocks the CRH-induced potentiation of postsynaptic layer 2/3 pyramidal cell activity of male but not female mice, thus producing an anxiolytic effect. Our data identify OxtrINs as critical for modulation of social and emotional behaviors in both females and males, and reveal a molecular mechanism that acts on local mPFC circuits to coordinate responses to OXT and CRH. They suggest that additional studies of the impact of the OXT/OXTR and CRHBP/CRH pathways in males and females will be important in development of gender specific therapies.

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“…The TRAP approach has been employed to profile translation in dozens of cell types in the mouse CNS (Doyle et al, 2008; Mellen et al, 2012; Nakajima et al, 2014; Schmidt et al, 2012; Shrestha et al, 2015) and visceral organs (Grgic et al, 2014; Zhou et al, 2013) and has been valuable in teasing apart neural circuits underlying complex CNS disease. TRAP has been used to identify a single cortical cell type that mediates antidepressant responses (Schmidt et al, 2012), a population of oxytocin receptor expressing interneurons in the prefrontal cortex that modulate sociosexual behavior in females (Nakajima et al, 2014), and cortical cells that integrate stress responses in the context of depressive-like behaviors (Shrestha et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Rapid Molecular Profiling of Defined Cell Types Using Viral TRAP

et al. 2017

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SUMMARY Translational profiling methodologies enable the systematic characterization of cell types in complex tissues such as the mammalian brain, where neuronal isolation is exceptionally difficult. Here, we report a versatile strategy to profile CNS cell types in a spatiotemporally-restricted fashion by engineering a Cre-dependent adeno-associated virus expressing an EGFP-tagged ribosomal protein (AAV-FLEX-EGFPL10a) to access translating mRNAs by TRAP. We demonstrate the utility of this AAV to target a variety of genetically and anatomically defined neural populations expressing Cre recombinase and illustrate the ability of this viral TRAP (vTRAP) approach to recapitulate the molecular profiles obtained by bacTRAP in corticothalamic neurons across multiple serotypes. Furthermore, spatially restricting AAV injections enabled the elucidation of regional differences in gene expression within this cell type. Taken together, these results establish the broad applicability of the vTRAP strategy for the molecular dissection of any CNS or peripheral cell type that can be engineered to express Cre.

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Layer 2/3 pyramidal cells in the medial prefrontal cortex moderate stress induced depressive behaviors

Cited by 73 publications

References 65 publications

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging

A Cortical Circuit for Sexually Dimorphic Oxytocin-Dependent Anxiety Behaviors

Rapid Molecular Profiling of Defined Cell Types Using Viral TRAP

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