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Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield, Lindsay A., Najafi, Allison R., Ghorbanian, Yasamine, Soni, Neelakshi, Hingco, Edna E., Kim, Sung Jin, Jue, Ayer Darling, Swarup, Vivek, Inlay, Mathew A., Green, Kim N.·2020·Journal of Neuroinflammation
DOI 10.1186/s12974-020-01931-0PMC PMC7504855

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Abstract

Background: Microglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest. Methods: Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results: Here, we identify a monocyte signature that includes an upregulation in Ccr1 , Ms4a6b , Ms4a6c , Ms4a7 , Apobec1 , Lyz2 , Mrc1 , Tmem221 , Tlr8 , Lilrb4a , Msr1 , Nnt , and Wdfy1 and a downregulation of Siglech , Slc2a5 , and Ccl21a/b . We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions: These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

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Fig. 1 Combining irradiation, bone marrow transplant, and microglial depletion, achieves long-term and complete peripheral myeloid cell engraftment in the brain. a–c Experimental paradigm: Schematic depicting generation of chimeras with complete and long-term parenchymal engraftment of GFP+ bone marrow (BM)-derived peripheral myeloid cells in the brain, achieved by whole-body irradiation, BM transplant, and colony-stimulating factor 1 receptor (CSF1R)-dependent depletion. Four-month-old wild-type (WT) mice underwent whole-body irradiation (1000 cGy) and then BM transplant via retroorbital injection of 2 × 106 BM cells from age- and sex-matched CAG-GFP mice. 3.5 months following BM transplant, mice were treated with 600 ppm of PLX3397 for 14 days, achieving microglial depletion, and then were placed on control diet for 6 months. d Representative whole brain images of GFP+ (green) and IBA1+ (red) cell deposition in control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice. Inserts include higher-resolution images of GFP+ engrafting cells, which appear exclusively in blood vessels and meninges in GFP-BM CON mice. e Quantification of number of GFP+ and IBA1+ cells in the whole brain. f–h Quantification of percent GFP chimerism in the whole brain (f), blood via granulocytes (CD45+NK1.1−CD11b+GR1+ cells) measured at ~ 12 weeks post irradiation/BM transplant (g), and bone marrow via hematopoietic stem cells (HSC; Ter119−CD27+ckit+Sca+CD150+CD34− cells) measured at time of sacrifice (~ 10 months post irradiation/BM transplant; H). Data are represented as mean ± SEM (n = 8–9). ***p < 0.001. **p < 0.01. CTX cortex, HC hippocampus, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 50 μm (top panel); ~ 100 μm (lower panel)
Fig. 1 Combining irradiation, bone marrow transplant, and microglial depletion, achieves long-term and complete peripheral myeloid cell engraftment in the brain. a–c Experimental paradigm: Schematic depicting generation of chimeras with complete and long-term parenchymal engraftment of GFP+ bone marrow (BM)-derived peripheral myeloid cells in the brain, achieved by whole-body irradiation, BM transplant, and colony-stimulating factor 1 receptor (CSF1R)-dependent depletion. Four-month-old wild-type (WT) mice underwent whole-body irradiation (1000 cGy) and then BM transplant via retroorbital injection of 2 × 106 BM cells from age- and sex-matched CAG-GFP mice. 3.5 months following BM transplant, mice were treated with 600 ppm of PLX3397 for 14 days, achieving microglial depletion, and then were placed on control diet for 6 months. d Representative whole brain images of GFP+ (green) and IBA1+ (red) cell deposition in control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice. Inserts include higher-resolution images of GFP+ engrafting cells, which appear exclusively in blood vessels and meninges in GFP-BM CON mice. e Quantification of number of GFP+ and IBA1+ cells in the whole brain. f–h Quantification of percent GFP chimerism in the whole brain (f), blood via granulocytes (CD45+NK1.1−CD11b+GR1+ cells) measured at ~ 12 weeks post irradiation/BM transplant (g), and bone marrow via hematopoietic stem cells (HSC; Ter119−CD27+ckit+Sca+CD150+CD34− cells) measured at time of sacrifice (~ 10 months post irradiation/BM transplant; H). Data are represented as mean ± SEM (n = 8–9). ***p < 0.001. **p < 0.01. CTX cortex, HC hippocampus, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 50 μm (top panel); ~ 100 μm (lower panel)CC BY · PubMed Central
Fig. 2 Lasting effects of irradiation on BBB integrity, neurogenesis, and cell proliferation. a Representative whole brain images of blood-brain barrier (BBB) integrity via Prussian blue (blue) in control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice. Spleen provides as a positive control. Insert shows higher-resolution images of a Prussian blue+ spot. b Quantification of number of Prussian Blue+ spots in the whole brain. c Representative immunofluorescence images of immunoglobulin (IgG, blue), fibrinogen (red), and GFP (BM-derived cells, green) in the cortex. d Quantification of % area of IgG and fibrinogen colocalization in the cortex. e Representative immunofluorescence images of neurogenesis marker doublecortin+ (DCX, red), proliferation marker Ki67+ (light blue), DAPI+ (blue), and GFP+ (green) staining. f Quantification of Ki67+ cells per FOV in the dentate gyrus of the hippocampus. g Representative immunofluorescence images of neurogenesis marker doublecortin+ (DCX, red) and proliferation marker Ki67+ (light blue) staining. h Quantification of DCX staining intensity in the dentate gyrus of the hippocampus. i Representative immunofluorescence images of proliferating myeloid cells stained for IBA1 (blue), proliferation marker Ki67 (red), and GFP (green). j Quantification of Ki67+ IBA1+ (including GFP+ and GFP−) cells per FOV. Data are represented as mean ± SEM (n = 5–8). **p < 0.01, ***p < 0.001. CTX cortex, HC hippocampus, SVZ subventricular zone, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 50 μm
Fig. 2 Lasting effects of irradiation on BBB integrity, neurogenesis, and cell proliferation. a Representative whole brain images of blood-brain barrier (BBB) integrity via Prussian blue (blue) in control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice. Spleen provides as a positive control. Insert shows higher-resolution images of a Prussian blue+ spot. b Quantification of number of Prussian Blue+ spots in the whole brain. c Representative immunofluorescence images of immunoglobulin (IgG, blue), fibrinogen (red), and GFP (BM-derived cells, green) in the cortex. d Quantification of % area of IgG and fibrinogen colocalization in the cortex. e Representative immunofluorescence images of neurogenesis marker doublecortin+ (DCX, red), proliferation marker Ki67+ (light blue), DAPI+ (blue), and GFP+ (green) staining. f Quantification of Ki67+ cells per FOV in the dentate gyrus of the hippocampus. g Representative immunofluorescence images of neurogenesis marker doublecortin+ (DCX, red) and proliferation marker Ki67+ (light blue) staining. h Quantification of DCX staining intensity in the dentate gyrus of the hippocampus. i Representative immunofluorescence images of proliferating myeloid cells stained for IBA1 (blue), proliferation marker Ki67 (red), and GFP (green). j Quantification of Ki67+ IBA1+ (including GFP+ and GFP−) cells per FOV. Data are represented as mean ± SEM (n = 5–8). **p < 0.01, ***p < 0.001. CTX cortex, HC hippocampus, SVZ subventricular zone, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 50 μmCC BY · PubMed Central
Fig. 3 Myeloid cell characterization after long-term peripheral myeloid cell engraftment. a–d Representative immunofluorescence images of myeloid cells in the brains of control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice stained for common myeloid marker ionized calcium-binding adaptor molecule 1 (IBA1, blue), microglial specific marker P2RY12 (red), and GFP (BM-derived cells, green) in the cortex (a–c) and hippocampus (d). Higher-resolution image showing P2RY12 immunoreactivity of IBA1+ and GFP+ cells (c). White dotted areas indicate pockets of high P2RY12 immunoreactivity, which coincide with a lack GFP+ cells. e–m Quantification of P2RY12, IBA1, and GFP+ staining: % area of P2RY12+ pockets, defined also as areas lacking GFP+ cell infiltrates (e–g), IBA1+ cell number per field of view (FOV) (h), P2RY12+IBA1+ cell number per field of view (FOV) (i), GFP+IBA1+ cell number per field of view (FOV) (j). For these measurements, images were captured and quantified in the hippocampus. k–m Quantification of IBA1+ cell morphology: average cell body diameter size (k), average process area (l), and process branching complexity (m). For these measurements, images were captured and quantified in the hippocampus. GFP+ staining was also used to distinguish between remaining microglia (IBA1+GFP−) and infiltrating monocyte (IBA1+GFP+) morphologies in GFP-BM REPOP mice. n Representative immunofluorescence images of myeloid cells stained for IBA1 (blue), macrophage/monocyte marker CD68 (red), and GFP (green). o Quantification of CD68 staining area coverage per FOV. p Quantification of TMEM119 staining intensity in the hippocampus. q Representative immunofluorescence images of myeloid cells stained for IBA1 (blue), CNS myeloid cell-specific marker TMEM119 (red), and GFP (green) in the hippocampus. r Quantification of the average mean intensity of TMEM119 in IBA1+ cells per FOV, comparing remaining microglia (remain) and infiltrating BM-derived cells (infilt). s Representative immunofluorescence images of proliferating myeloid cells stained for IBA1 (blue), phagocytic marker AXL (red), and GFP (green). t Quantification of the average mean intensity of AXL in IBA1+ cells per FOV, comparing remaining microglia (remain) and infiltrating BM-derived cells (infilt). Data are represented as mean ± SEM (n = 4–9). *p < 0.05, **p < 0.01, ***p < 0.001. CTX cortex, HC hippocampus, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 150 μm (a); ~ 75 μm (b, d, n, q); ~ 60 μm (s); ~ 25 μm (c)
Fig. 3 Myeloid cell characterization after long-term peripheral myeloid cell engraftment. a–d Representative immunofluorescence images of myeloid cells in the brains of control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice stained for common myeloid marker ionized calcium-binding adaptor molecule 1 (IBA1, blue), microglial specific marker P2RY12 (red), and GFP (BM-derived cells, green) in the cortex (a–c) and hippocampus (d). Higher-resolution image showing P2RY12 immunoreactivity of IBA1+ and GFP+ cells (c). White dotted areas indicate pockets of high P2RY12 immunoreactivity, which coincide with a lack GFP+ cells. e–m Quantification of P2RY12, IBA1, and GFP+ staining: % area of P2RY12+ pockets, defined also as areas lacking GFP+ cell infiltrates (e–g), IBA1+ cell number per field of view (FOV) (h), P2RY12+IBA1+ cell number per field of view (FOV) (i), GFP+IBA1+ cell number per field of view (FOV) (j). For these measurements, images were captured and quantified in the hippocampus. k–m Quantification of IBA1+ cell morphology: average cell body diameter size (k), average process area (l), and process branching complexity (m). For these measurements, images were captured and quantified in the hippocampus. GFP+ staining was also used to distinguish between remaining microglia (IBA1+GFP−) and infiltrating monocyte (IBA1+GFP+) morphologies in GFP-BM REPOP mice. n Representative immunofluorescence images of myeloid cells stained for IBA1 (blue), macrophage/monocyte marker CD68 (red), and GFP (green). o Quantification of CD68 staining area coverage per FOV. p Quantification of TMEM119 staining intensity in the hippocampus. q Representative immunofluorescence images of myeloid cells stained for IBA1 (blue), CNS myeloid cell-specific marker TMEM119 (red), and GFP (green) in the hippocampus. r Quantification of the average mean intensity of TMEM119 in IBA1+ cells per FOV, comparing remaining microglia (remain) and infiltrating BM-derived cells (infilt). s Representative immunofluorescence images of proliferating myeloid cells stained for IBA1 (blue), phagocytic marker AXL (red), and GFP (green). t Quantification of the average mean intensity of AXL in IBA1+ cells per FOV, comparing remaining microglia (remain) and infiltrating BM-derived cells (infilt). Data are represented as mean ± SEM (n = 4–9). *p < 0.05, **p < 0.01, ***p < 0.001. CTX cortex, HC hippocampus, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 150 μm (a); ~ 75 μm (b, d, n, q); ~ 60 μm (s); ~ 25 μm (c)CC BY · PubMed Central
Fig. 4 Transcriptional changes following long-term peripheral myeloid cell engraftment. a Venn diagrams displaying the number of differentially expressed genes (DEGs, numbers provided) generated in transcriptional comparisons between mice (control, WT CON; irradiated, GFP-BM CON; monocyte-engrafted, GFP-BM REPOP) in the hippocampus (HC, gray), cortex (CTX, red), and thalamus + striatum (THAL, tan). b–d Volcano plots displaying the fold change of genes (log2 scale) and their p values (−log10 scale) between WT CON vs GFP-BM REPOP in the cortex (b), hippocampus (c), and thalamus + striatum (d). Plots are further separated by the effect of irradiation and presence of monocytes alone. e Heatmap of the monocyte signature (selected DEGs conserved in all three brain regions in monocyte-engrafted mice). f Signed bicor network shows the effects of brain region (BrainRegion), irradiation, and treatment, which are separated into distinct colored modules. g–i Monocyte signature: Module eigengene trajectory of darkgreen (g), heatmap of gene expression value in darkgreen (h), and a STRING interaction map of darkgreen (i). Red nodes indicate genes enriched in the gene ontology (GO) term defense response. (j–k) Irradiation: Module eigengene trajectory of salmon (j) and heatmap of gene expression value in salmon (K). l–n Effects of monocytes specific to the hippocampus: Module eigengene trajectory of red (l), heatmap of gene expression value in red (m), and a STRING interaction map of red (n). Red nodes indicate genes enriched in the GO term cilium organization. o Cell-type enrichment heatmap displays genes associated with specific cell types within a given color module. Values provided indicate the number of genes within the network associated with that a specific cell type. *** = 6+ genes. ** = 3+ genes.
Fig. 4 Transcriptional changes following long-term peripheral myeloid cell engraftment. a Venn diagrams displaying the number of differentially expressed genes (DEGs, numbers provided) generated in transcriptional comparisons between mice (control, WT CON; irradiated, GFP-BM CON; monocyte-engrafted, GFP-BM REPOP) in the hippocampus (HC, gray), cortex (CTX, red), and thalamus + striatum (THAL, tan). b–d Volcano plots displaying the fold change of genes (log2 scale) and their p values (−log10 scale) between WT CON vs GFP-BM REPOP in the cortex (b), hippocampus (c), and thalamus + striatum (d). Plots are further separated by the effect of irradiation and presence of monocytes alone. e Heatmap of the monocyte signature (selected DEGs conserved in all three brain regions in monocyte-engrafted mice). f Signed bicor network shows the effects of brain region (BrainRegion), irradiation, and treatment, which are separated into distinct colored modules. g–i Monocyte signature: Module eigengene trajectory of darkgreen (g), heatmap of gene expression value in darkgreen (h), and a STRING interaction map of darkgreen (i). Red nodes indicate genes enriched in the gene ontology (GO) term defense response. (j–k) Irradiation: Module eigengene trajectory of salmon (j) and heatmap of gene expression value in salmon (K). l–n Effects of monocytes specific to the hippocampus: Module eigengene trajectory of red (l), heatmap of gene expression value in red (m), and a STRING interaction map of red (n). Red nodes indicate genes enriched in the GO term cilium organization. o Cell-type enrichment heatmap displays genes associated with specific cell types within a given color module. Values provided indicate the number of genes within the network associated with that a specific cell type. *** = 6+ genes. ** = 3+ genes.CC BY · PubMed Central
Fig. 5 The differential and brain region-dependent effects of long-term peripheral myeloid cell engraftment on astrocytic and neuronal properties. a Representative whole brain images of GFP (green) and common astrocyte marker glial fibrillary acidic protein (GFAP, red) cell deposition in monocyte-engrafted mice. b–c Representative immunofluorescence images of different astrocyte subtypes stained for GFAP (red) and S100β (blue) in the in the cortex (B) and hippocampus (C) of control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice. GFP (green) stains BM-derived cells. d–g Quantification of S100β+ and GFAP+ cell number in the cortex (D, F) and cell number in the hippocampus (e, g). h Quantification of GFAP staining intensity in the hippocampus. (i) Quantification of NeuN+ cell number in the whole cortex. (j) Representative immunofluorescence images stained for neuronal marker NeuN (red) and GFP (green, BM-derived cells) in the cortex and hippocampus. (k) Representative immunofluorescence images of microtubule associated protein 2 (MAP2, red) and GFP (green, BM-derived cells) in the cortex and hippocampus. (l) Representative immunofluorescence brain images of synaptic marker PSD95 (postsynaptic density protein 95, red) and GFP (green, BM-derived cells) in the cortex and hippocampus. L’ provides representative images of spots modeling using Imaris spots module software overlaid on PSD95+ staining. (m) Representative immunofluorescence brain images of synaptic marker SV2A (synaptic vesicle glycoprotein 2A, red) and GFP (green, BM-derived cells) in the cortex. (n–s) Quantification of the integrated density of MAP2 staining in the cortex (n) and hippocampus (o), total number of PSD95+ spots per field of view in the cortex (p) and hippocampus (q), and total number of SV2A+ spots per field of view in the cortex (r) and hippocampus (s). Data are represented as mean ± SEM (n = 4–9). *p < 0.05, **p < 0.01. ***p < 0.001. CTX cortex, HC hippocampus, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 150 μm (B–C, j–left panel); ~ 200 μm (j–right panel); ~40 μm (k); ~ 30 μm (l, m) ~ 15 μm (L’)
Fig. 5 The differential and brain region-dependent effects of long-term peripheral myeloid cell engraftment on astrocytic and neuronal properties. a Representative whole brain images of GFP (green) and common astrocyte marker glial fibrillary acidic protein (GFAP, red) cell deposition in monocyte-engrafted mice. b–c Representative immunofluorescence images of different astrocyte subtypes stained for GFAP (red) and S100β (blue) in the in the cortex (B) and hippocampus (C) of control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice. GFP (green) stains BM-derived cells. d–g Quantification of S100β+ and GFAP+ cell number in the cortex (D, F) and cell number in the hippocampus (e, g). h Quantification of GFAP staining intensity in the hippocampus. (i) Quantification of NeuN+ cell number in the whole cortex. (j) Representative immunofluorescence images stained for neuronal marker NeuN (red) and GFP (green, BM-derived cells) in the cortex and hippocampus. (k) Representative immunofluorescence images of microtubule associated protein 2 (MAP2, red) and GFP (green, BM-derived cells) in the cortex and hippocampus. (l) Representative immunofluorescence brain images of synaptic marker PSD95 (postsynaptic density protein 95, red) and GFP (green, BM-derived cells) in the cortex and hippocampus. L’ provides representative images of spots modeling using Imaris spots module software overlaid on PSD95+ staining. (m) Representative immunofluorescence brain images of synaptic marker SV2A (synaptic vesicle glycoprotein 2A, red) and GFP (green, BM-derived cells) in the cortex. (n–s) Quantification of the integrated density of MAP2 staining in the cortex (n) and hippocampus (o), total number of PSD95+ spots per field of view in the cortex (p) and hippocampus (q), and total number of SV2A+ spots per field of view in the cortex (r) and hippocampus (s). Data are represented as mean ± SEM (n = 4–9). *p < 0.05, **p < 0.01. ***p < 0.001. CTX cortex, HC hippocampus, GFP green fluorescent protein, IBA1 ionized calcium adapter molecule 1. Scale bar ~ 150 μm (B–C, j–left panel); ~ 200 μm (j–right panel); ~40 μm (k); ~ 30 μm (l, m) ~ 15 μm (L’)CC BY · PubMed Central
Fig. 6 Effects of long-term peripheral myeloid cell engraftment on behavior and cognition. (a–d) Quantification of elevated plus maze performance at 1 month (a–b) and 6 months (c–d) post CSF1Ri treatment in control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice as assessed by time spent in open and closed arms (b, d). Total distance moved was also measured to control for locomotive changes (a, c). (e–j) Quantification of open field (e, h) and novel place recognition (g, j) performance at 1 month (e–g) and 6 months (h–j) as assessed by total distance moved (e, h) and percent preference index (f–g, i–j), respectively. Preference index is the ratio of the amount of time spent exploring any one of two objects (A or B) in the training phase or the novel-placed object (C) in the test phase over the total time spent exploring both objects, i.e. C/(B + C) × 100 in the test phase. Quantification of training also provided (f, i). (k–n) Quantification of rotarod performance at 1 months (k–l) and 6 months (m–n). (o–r) Quantification of contextual fear conditioning at 1 months (o–p) and 6 months (q–r) post CSF1Ri-induced monocyte engraftment as assessed by percentage of inactivity at testing (p, r). Quantification of training also provided (o, q). s–t Quantification of social interaction test performance at 6 months post CSF1Ri treatment as assessed by time spent in an empty zone or zone containing a stranger mouse (t). Total distance moved was also measured to control for locomotive changes (s). u–w Quantification of spontaneous alternation (Y-maze) performance at 6 months post CSF1Ri treatment as assessed by zone alternation frequency (w). Total distance moved and total number of arm entries was also measured to control for locomotive changes (u) and motivation/movement (v), respectively. *p < 0.05. ***p < 0.001
Fig. 6 Effects of long-term peripheral myeloid cell engraftment on behavior and cognition. (a–d) Quantification of elevated plus maze performance at 1 month (a–b) and 6 months (c–d) post CSF1Ri treatment in control (WT CON), irradiated (GFP-BM CON), and monocyte-engrafted (GFP-BM REPOP) mice as assessed by time spent in open and closed arms (b, d). Total distance moved was also measured to control for locomotive changes (a, c). (e–j) Quantification of open field (e, h) and novel place recognition (g, j) performance at 1 month (e–g) and 6 months (h–j) as assessed by total distance moved (e, h) and percent preference index (f–g, i–j), respectively. Preference index is the ratio of the amount of time spent exploring any one of two objects (A or B) in the training phase or the novel-placed object (C) in the test phase over the total time spent exploring both objects, i.e. C/(B + C) × 100 in the test phase. Quantification of training also provided (f, i). (k–n) Quantification of rotarod performance at 1 months (k–l) and 6 months (m–n). (o–r) Quantification of contextual fear conditioning at 1 months (o–p) and 6 months (q–r) post CSF1Ri-induced monocyte engraftment as assessed by percentage of inactivity at testing (p, r). Quantification of training also provided (o, q). s–t Quantification of social interaction test performance at 6 months post CSF1Ri treatment as assessed by time spent in an empty zone or zone containing a stranger mouse (t). Total distance moved was also measured to control for locomotive changes (s). u–w Quantification of spontaneous alternation (Y-maze) performance at 6 months post CSF1Ri treatment as assessed by zone alternation frequency (w). Total distance moved and total number of arm entries was also measured to control for locomotive changes (u) and motivation/movement (v), respectively. *p < 0.05. ***p < 0.001CC BY · PubMed Central

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Cited by

Metadata

Authors
Hohsfield, L. A., Najafi, A. R., Ghorbanian, Y., Soni, N., Hingco, E. E., Kim, S. J., Jue, A. D., Swarup, V., Inlay, M. A., & Green, K. N.
ORCID
Green, Kim N.
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2020-09-20
Volume
17
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-020-01931-0
PMC
PMC7504855
Cited by
66
References
38
Language
en
Licence
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS083801)
  • National Institute on Aging (R01AG056768, P50AG016573)
  • Alzheimer's Association (AARF-16-442762)
  • National Institutes of Health (NS082174)

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