Ferguson Lab
The Ferguson lab aims to understand the molecular and circuit-specific mechanisms that underlie neuropsychiatric disorders. Major depressive disorder (MDD) is a leading cause of disability, with ~20% of individuals suffering from clinical depression during their lifetime.
Depression is a heterogeneous syndrome consisting of several subtypes and abnormalities in multiple brain regions. Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is limited.
The Ferguson lab has developed several leading-edge technical approaches to elegantly dissect the cell and circuit-specific mechanisms of depression including cell- type specific RNA-Seq, cell and circuit-specific optogenetic approaches, epigenetic remodeling using CRISPR/Cas9, operant measures of reward, single- cell RNA-seq and the establishment of 19 unique transgenic lines. Using these cutting-edge molecular and circuit approaches, the Ferguson lab aims to develop better diagnostic tests, treatments, and preventive measures for depression.
Depression is a heterogeneous syndrome consisting of several subtypes and abnormalities in multiple brain regions. Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is limited.
The Ferguson lab has developed several leading-edge technical approaches to elegantly dissect the cell and circuit-specific mechanisms of depression including cell- type specific RNA-Seq, cell and circuit-specific optogenetic approaches, epigenetic remodeling using CRISPR/Cas9, operant measures of reward, single- cell RNA-seq and the establishment of 19 unique transgenic lines. Using these cutting-edge molecular and circuit approaches, the Ferguson lab aims to develop better diagnostic tests, treatments, and preventive measures for depression.
Test mice were exposed to an unfamiliar and aggressive male CD1 retired breeder mouse for 10 min/d for up to 10 d. After direct interaction with the CD1 aggressor, animals were placed in an adjacent compartment of the same cage for the next 24 h with sensory, but not physical, contact. Control animals were housed in equivalent cages but with members of the same strain. Twenty-four hours after the last social defeat, animals were assayed on the social interaction test and sorted into either susceptible or unsusceptible (resilient) phenotypes based on interaction scores (Krishnan et al., 2007)
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Project 2. Dissect Mouse Reward Circuit
Current therapeutic interventions for major depressive disorder (MDD) are not widely effective, likely due to the nonselective nature of antidepressants. This limited efficacy leaves more than 50% of MDD patients symptomatic and in need of adequate treatment. To advance the development of new pharmaceutical interventions, novel molecular targets must be identified. The nucleus accumbens (NAc), a brain region that is key in the pathology of depression, contains a heterogenous neuron population that is predominantly D1- and D2-medium spiny neurons (MSNs). Previously, we have shown that the transcriptomic profiles of D1- and D2-MSNs are distinct, and that the D1 transcriptome correlates with susceptibility to depression. |
Project 3. Cell-Type Specific RNA-Sequencing
MSN subtype specific transcriptomics in the Nucleus Accubens. a Schematic diagram of RT; D1-Cre and RT; D2-Cre mice generation and purification of MSN-subtype specific transcripts. The exogenous exon 4-HA cassette is expressed when the floxed exon 4 is excised in Cre-expressing cells. The HA-tagged polyribosome allows cell-type specific mRNA preparation from D1-MSNs (RT; D1-Cre) or D2-MSNs (RT; D2-Cre). b, c Validation of RiboTag mice with immunohistochemistry across brain regions (sagittal; scale bar, 2 mm) (b) and in the NAc (coronal; scale bar, 50 μm) sections (c). d Schematic diagram of experimental design. e Read mapping composition of each RNA-seq sample on the mouse genome, mm10 (% average for coding regions: IPs, 59.2% vs inputs, 58.8%; for intronic regions: IPs, 5.5% vs inputs, 13.4%). f Clustering of RNA-seq samples of RT; D1- and D2-Cre in a MDS plot. g Sample correlation heatmap were plotted with clustering (The dendrogram annotations on the right side axis: D1, light gray; D2, dark gray).