Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction
- Department of Neuroscience, United States
- Neuroscience Graduate Group, Perelman School of Medicine, United States
- Department of Psychology, University of Pennsylvania, United States
Figures
Figure 1 with 1 supplement
Neurexin1α disruption leads to deficits in value-based selection of actions.
(A) Schematic of trial structure wherein mice perform repeated self-initiated trials with contrasting reward volumes associated with each port. Animals were tested at four relative reward ratios …
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Figure 1—source data 1
Source Data for Figure 1.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig1-data1-v2.xlsx
Figure 1—figure supplement 1
Additional Behavioral Analyses in Nrxn1a KO mice.
(A) Schematic of visual discrimination task. Mice acquired a simple goal-direction contingency over repeated sessions. (B) Task engagement was measured as the total number of registered trial …
Figure 2 with 1 supplement
Neurexin1α mutants display altered outcome-dependent task engagement.
(A) A proxy of task engagement was measured as the average latency from trial onset (center-light ON) to initiation. Nrxn1α KOs (blue, n = 10) do not exhibit global deficits in task engagement in …
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Figure 2—source data 1
Source data for Figure 2.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig2-data1-v2.xlsx
Figure 2—figure supplement 1
Additional Task Latency and Reward Volume Data.
(A) Nrxn1α KO mice exhibit extended choice latencies across reward environments. (B) There are no genotypic differences in the total session reward consumption, regardless of reward contrast (left) …
Figure 3
Neurexin1α mutants display a deficit in the selection of actions based on costs.
(A) Effort paradigm schematic. Mice distribute choices in a session with fixed contingency lasting 150 trials. Animals were given choices with equal reward outcomes, but different effort …
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Figure 3—source data 1
Source Data for Figure 3.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig3-data1-v2.xlsx
Figure 4 with 1 supplement
A deficit in value updating underlies abnormal allocation of choices in Neurexin1α mutants.
(A) Q-learning reinforcement model. Mouse choice was modeled as a probabilistic choice between two options of different value (QL,QR) using a softmax decision function. Data from each reinforcement …
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Figure 4—source data 1
Source Data for Figure 4.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig4-data1-v2.xlsx
Figure 4—figure supplement 1
Additional Reinforcement Learning Model Parameters.
(A–D) Model biases. A bias term was generated for each relative reward ratio to capture potential difference in how animals develop biases in different reward environments. There is no statistically …
Figure 5 with 1 supplement
Restricted telencephalic excitatory neuron deletion of Neurexin1α recapitulates choice abnormalities of constitutive KO.
(A) Nrxn1α was conditionally inactivated in telencephalic excitatory neurons by crossing a Nrxn1α-conditional knockout allele onto NexCre line. Controls for both the Nex (light gray) and …
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Figure 5—source data 1
Source Data for Figure 5.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig5-data1-v2.xlsx
Figure 5—figure supplement 1
Additional Behavioral Analysis of Telencephalic Excitatory Neuron Nrx1a Deletion.
(A) In-task adaptability. There is a main effect for genotype on the adaptability measures between Nrxn1αfl/fl; NexCre controls and mutant mice. Otherwise there are no differences in adaptability …
Figure 6 with 1 supplement
Specific deletion of Neurexin1α in thalamic nuclei does not reproduce choice abnormalities observed in constitutive KO.
(A) Neurexin1α was conditionally inactivated in thalamic progenitor cells by crossing the Neurexin1α-conditional knockout line onto the Olig3-Cre line. (B) Coronal section of Olig3Cre; Ai14 reporter …
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Figure 6—source data 1
Source Data for Figure 6.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig6-data1-v2.xlsx
Figure 6—figure supplement 1
Additional behavioral analysis of thalamic neuron Nrx1a deletion.
(A) In-task adaptability. There is no effect for genotype on the adaptability measures of OligCre control and OligCre; Nrxn1αfl/fl mutant mice. (B) Relative initiation latency. We noted no …
Figure 7 with 1 supplement
Quantifying value correlates in putative direct pathway SPNs of the dorsomedial striatum.
(A) Schematic of experimental scheme. Control (Nrxn1α+/+; NexCre/+, n = 7) mice were injected with a retro-AAV2-EF1α−3xFLAG-Cre virus in the substantia nigra, pars reticulata (SNr). Ipsilateral …
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Figure 7—source data 1
Source Data for Figure 7.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig7-data1-v2.xlsx
Figure 7—figure supplement 1
Additional Photometry Analyses in Wildtype and Mutant Mice.
(A) Mean photometry signals for animals in engaged and disengaged epochs of the task revealed statistically smaller signals during periods of task engagement, without phenotypic differences. Engaged …
Figure 8 with 1 supplement
Restricted telencephalic excitatory neuron deletion of Neurexin1α produces a deficit in fast peak activity in p-dSPNs of the DMS.
(A and B) PSTH of ΔF/F for Nex-control (Nrxn1α+/+; NexCre/+, n = 7, gray) and Nex-Nrxn1αcKO (Nrxn1αfl/fl; NexCre/+, n = 6, purple) mice, respectively, aligned to initiation event (segregated by …
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Figure 8—source data 1
Source Data for Figure 8.
- https://cdn.elifesciences.org/articles/54838/elife-54838-fig8-data1-v2.xlsx
Figure 8—figure supplement 1
Retrograde labeling strategy does not alter excitatory or inhibitory basal synaptic transmission.
(A, Left) Experimental schematic where putative dSPNs are labeled with either retroAAV2.
EF1α−3xFLAG-Cre (together with AAV5.EF1α.DIO::tdTOM in striatum for visualization of retrogradely labeled neurons) or retroAAV2.hSyn-GFP-ΔCre (an enzymatically inactive truncated version of Cre) in the SNr. (A, right) Visualization of infected p-dSPNs for acute slice whole cell recordings. (B) No difference in mIPSC amplitude or frequency was noted between Cre and ΔCre viral constructs. (C) Schematic to test the effect of adult retrograde Cre expression on excitatory synaptic connectivity to p-dSPNs. (D) No difference in mEPSC amplitude or frequency was noted between Cre and ΔCre viral constructs. B and D analyzed by t-test. Data represented as mean ± SEM.
Author response image 1
Author response image 2
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Author response image 4
Photometry traces by trial.
10 individual traces selected from trials following large reward (blue) and trials following small reward (red). Panel A and C show z-scored data while B and C show raw ΔF/F(%).
Author response image 5
Comparison of raw averaged signals (A) and z-scored signals (B).
Additional files
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Source data 1
Table of Summary Statistics.
- https://cdn.elifesciences.org/articles/54838/elife-54838-data1-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/54838/elife-54838-transrepform-v2.docx
