Journal: bioRxiv

Article Title: Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer’s disease

doi: 10.1101/2025.03.26.645537

Figure Lengend Snippet: a. Schematic coronal brain section indicating the mPFC prelimbic region in dark grey, where tdTomato + parvalbumin (PV) cells and pyramidal (PYR) cells were recorded in APP/PS1 PV-Cre tdTomato (APP/PS1) and PV-Cre tdTomato (control) mice. Representative differential interference contrast images (left) and a corresponding fluorescent image (right). fmi= forceps minor of the corpus callosum. ML= midline. Recordings were performed in 16 ( b-i ) and 20 ( j-q ) week-old mice. b . Resting membrane potential was unaltered in PV cells at 16 weeks of age. Mann-Whitney test: U = 433, p = 0.98, n = 29/30 cells, N = 4 mice/genotype. Ctr= control. c . Action potential (AP) firing of PV cells upon a depolarizing current step (250 pA). d. AP frequency in PV cells in response to 0-425 pA depolarizing current steps did not differ between genotypes. Two-way repeated measures ANOVA genotype x current F (10,390) = 0.44, p = 0.93, n = 29/30 cells, N = 4 mice/genotype. e. Rheobase was unchanged in PV cells. Unpaired t-test: t 57 = 0.08, p = 0.93, n = 29/30 cells, N = 4 mice/genotype. Ctr= control. f . Resting membrane potential of PYR cells did not differ between genotypes. Unpaired t-test: t 36 = 0.51, p = 0.61, n = 17/21 cells from N = 4/6 control vs. APP/PS1 mice, respectively. Ctr= control. g. AP firing of PYR cells upon a depolarizing current step (250 pA). h. AP frequency in PYR cells in response to 0-250 pA depolarizing current steps did not differ between genotypes. Two-way repeated measures ANOVA genotype x current F (10,370) = 0.25, p = 0.99, n = 17/21 from N = 4/6 control vs. APP/PS1 mice, respectively. i. APP/PS1 mice show a lower rheobase in PYR cells. Mann-Whitney test: U = 111, * p = 0.048, n = 17/21 cells from N = 4/6 control vs. APP/PS1 mice, respectively. Ctr= control. j . Resting membrane potential was unaltered in PV cells at 20 weeks of age. Unpaired t-test: t 35 = 0.93, p = 0.36, n = 22/15 cells from N = 6/7 control and APP/PS1 mice, respectively. Ctr= control. k. AP firing of PV cells upon a depolarizing current step (250 pA). l. APP/PS1 mice show an increased AP frequency in PV cells in response to 0-425 pA depolarizing current steps. Two-way repeated measures ANOVA genotype x current F (17,595) = 4.05, * p < 0.0001, n = 22/15 cells, N = 6/7 control and APP/PS1 mice, respectively. m . Rheobase was unchanged in PV cells. Unpaired t-test: t 35 = 1.67, p = 0.10, 22/15 cells, N = 6/7 control and APP/PS1 mice, respectively. Ctr= control. n. Resting membrane potential of PYR cells did not differ between genotypes. Unpaired t-test: t 74 = 0.92, p = 0.36, n = 37/39 cells, N = 9 mice/genotype. Ctr= control. o . AP firing of PYR cells upon a depolarizing current step (250 pA). p . AP frequency in PYR cells in response to 0-250 pA depolarizing current steps did not differ between genotypes. Two-way repeated measures ANOVA genotype x current F (10,740) = 1.80, p = 0.08, n = 37/39 cells, N = 9 mice/genotype. q. APP/PS1 mice show a decrease in PYR cell rheobase. Unpaired t-test: t 74 = 2.34, * p = 0.022, n = 37/39 cells, N = 9 mice/genotype. Ctr= control. Graphs show mean ± s.e.m.

Article Snippet: Pyramidal, PV and SST cells were recorded in the mPFC using a Multiclamp 700B amplifier (Molecular devices, Sunnyvale, CA) and sampled at 10 kHz low pass filter at 4 kHz and digitized with Axon Digidata 1440 A (Molecular Devices).

Techniques: Control, Membrane, MANN-WHITNEY

Journal: bioRxiv

Article Title: Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer’s disease

doi: 10.1101/2025.03.26.645537

Figure Lengend Snippet: SST cell excitability is unaltered in the mPFC of 20-week-old APP/PS1 mice. a. Schematic coronal brain section indicating the mPFC prelimbic region in dark grey, where AAV-hSyn::DIO-mCherry was microinjected and mCherry + SST cells were recorded in APP/PS1 SST-Cre (APP/PS1) and SST-Cre (control) mice. Representative fluorescent image is depicted b. Resting membrane potential was unaltered in SST cells. Unpaired t-test: t 31 = 0.73, p = 0.47, n = 17/16 cells, N = 5/7 control vs. APP/PS1 mice, respectively. c. Action potential (AP) firing of SST cells upon a depolarizing current step (250 pA) d. AP frequency in SST cells in response to 0-250 pA depolarizing current steps did not differ between genotypes. Genotype x current two-way repeated measures ANOVA F (10,310) = 0.23, p = 0.99, n = 17/16 cells, N = 5/7 control vs. APP/PS1 mice. e. Rheobase was unchanged in SST cells Mann-Whitney test: U = 119, p = 0.75, n = 17/16 cells, N = 5/7 control vs. APP/PS1 mice, respectively. Graphs show mean ± s.e.m.

Article Snippet: Pyramidal, PV and SST cells were recorded in the mPFC using a Multiclamp 700B amplifier (Molecular devices, Sunnyvale, CA) and sampled at 10 kHz low pass filter at 4 kHz and digitized with Axon Digidata 1440 A (Molecular Devices).

Techniques: Control, Membrane, MANN-WHITNEY

Journal: bioRxiv

Article Title: Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer’s disease

doi: 10.1101/2025.03.26.645537

Figure Lengend Snippet:

Article Snippet: Pyramidal, PV and SST cells were recorded in the mPFC using a Multiclamp 700B amplifier (Molecular devices, Sunnyvale, CA) and sampled at 10 kHz low pass filter at 4 kHz and digitized with Axon Digidata 1440 A (Molecular Devices).

Techniques: Membrane

Journal: bioRxiv

Article Title: Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer’s disease

doi: 10.1101/2025.03.26.645537

Figure Lengend Snippet: a . Coronal brain section indicating the mPFC region (dark grey) where AAV-Fos::CreER T2 and Cre-dependent AAV-hSyn::DIO-mCherry were injected. Mice underwent CFC at 16 weeks old and engram cells were tagged. Thirty days after CFC, mice were re-exposed to the training context and then immediately sacrificed for whole-cell patch-clamp electrophysiology. b . Left: Representative image showing labeled mCherry + engram cells in the mPFC. Right: recordings were made from mCherry + and mCherry - pyramidal cells. c . Example sIPSC traces of mCherry + and mCherry - for WT control and APP/PS1 mice d . Example sEPSC traces of mCherry + and mCherry - cells for WT and APP/PS1 mice e. Frequency of sIPSCs differed between mCherry + and mCherry - cells in APP/PS1, but not WT, mice. Two-way repeated measure ANOVA genotype x cell-type F (1,43) = 5.44, * p = 0.024. Post-hoc Bonferroni APP/PS1 mCherry + vs. mCherry - * p = 0.011. n = 22 per cell-type from N = 6 WT mice, n = 23 per cell-type from N = 7 APP/PS1 mice. f. sIPSC amplitude did not differ between cell-type and genotype. g. Frequency of sEPSCs was enhanced in mCherry + cells compared to mCherry - cells in both genotypes. Two-way repeated measure ANOVA cell-type F (1,36) = 7.26, * p = 0.011 n = 20 per cell type from N = 6 WT mice, n = 23 per cell-type from N = 7 APP/PS1 mice h. sEPSC amplitude did not differ between cell-type and genotype. Graphs show mean ± s.e.m.

Article Snippet: Pyramidal, PV and SST cells were recorded in the mPFC using a Multiclamp 700B amplifier (Molecular devices, Sunnyvale, CA) and sampled at 10 kHz low pass filter at 4 kHz and digitized with Axon Digidata 1440 A (Molecular Devices).

Techniques: Injection, Patch Clamp, Labeling, Control

Journal: bioRxiv

Article Title: Co-release of opposing signaling molecules from cortical neurons controls the escalation and release of aggression

doi: 10.1101/2025.03.13.643119

Figure Lengend Snippet: A . UMAP plot showing clustering of Tac2 neurons with other defined cortical cell types. B . Bar graph showing the proportion of excitatory and inhibitory neurons that express Tac2 . C . Bar graph showing the proportion of Tac2 counts in cortical cell types. D-G . Representative images of RNAscope™ fluorescent in situ hybridization. scale bar represents 100μm. Tac2: Tachykinin-2, CRF: corticotropin releasing factor, SOM: somatostatin, PV: parvalbumin, VIP: Vasoactive intestinal peptide. H . Diagram showing prelimbic and infralimbic regions of medial prefrontal cortex with cortical layers. L1-3: layers 1-3, L5: layer 5, L6: layer 6. I . Pie chart showing percent of Tac2 cells expressing CRF (N=6 animals, 3 GH, 3 SI; 2 Male, ∼ 3 sections/animal), SOM (N=4 animals, 2 GH, 2 SI; 1 Male, ∼3 sections/animal), PV (N=6 animals, 3 GH, 3 SI; 4 Male, ∼3 sections/animal), and VIP (N=8 animals (4 GH, 4 SI; 4M). J . Pie chart showing the percent of Tac2 cells in cortical layers. K . Pie chart showing the percent of Tac2 cells that percent VIP in early (L1-3) and deep (L5-6) cortical layers. L . Diagram showing prelimbic and infralimbic regions of medial prefrontal cortex with cortical layers. L1-3: layers 1-3, L5: layer 5, L6: layer 6. M . Representative image showing Tac2 cFos in situ hybridization across the cortical layers. Bar represents 100µm. N . Bar graph showing the percent of Tac2 cells expressing cFos in layers 1-3 (N = 4, 2 SI, 2 GH, 2 Males, ∼ 3 sections/animal); nested t-test p < 0.01. O . Bar graph showing the percent of Tac2 cells expressing cFos in layer 5 (N = 4, 2 SI, 2 GH, 2 Males, ∼3 sections/animal); nested t-test p > 0.05. P . Bar graph showing the percent of Tac2 cells expressing cFos in layer 6 (N = 4, 2 SI, 2 GH, 2 Males, ∼3 sections/animal); nested t-test p > 0.05. Q . Diagram showing viral infusion into infralimbic mPFC. R . Representative image showing Tac2 neuron axons labeled with GFP and the cortical layers. S . Representative image showing Tac2 neuronal terminals (synaptophysin) in red (mRuby). T . Merged image showing axonal arbor (green) and terminals (red) of Tac2 neurons. R-T scale bar represents 100μm. Bars are mean ± SEM ns p > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001

Article Snippet: Male and female Tac2-IRES-Cre mice 8-10 weeks were single housed and had surgeries performed to infuse a Cre-dependent adeno-associated virus (AAV) expressing membrane-GFP and synaptophysin fused to mRuby (AAV2-hSynb-FLEx-mGFP-2A-Synaptophysin-mRuby) infused into the mPFC (Addgene #: 71760-AAV2, titer: 2.7 x 10 GC/mL, lot: v138755).

Techniques: RNAscope, In Situ Hybridization, Expressing, Labeling