Functional ultrasound reveals functional connectome adaptations in an NMDAR hypofunction model
Poster No:
2380
Submission Type:
Abstract Submission
Authors:
Tudor Ionescu1, Marion Ponserre2, Alessa Franz3, Serena Deiana2, Niklas Schülert2, Thorsten Lamla2, Rhiannan Williams2, Carsten Wotjak2, Scott Hobson2, Bastian Hengerer2, Julien Dine2, Azar Omrani2
Institutions:
1Boehringer Ingelheim, Biberach an der Riss, Baden Wuerttemberg, 2Boehringer Ingelheim, Biberach an der Riss, Germany, 3Boehringer Ingelheim, Biberach an Riss, Germany
First Author:
Co-Author(s):
Introduction:
The development of animal models accurately capturing the complex features of schizophrenia has proven unfeasible due to the heterogeneity of the spectrum. However, certain clinical endphenotypes can be reproduced by animal models. In this context, NMDA receptor hypofunction achieved by acute or subchronic NMDA receptor antagonist administration to rodents has been extensively reported to recapitulate a wide range of relevant symptoms and biomarkers seen in patients.
Functional ultrasound (fUS) is a newly-emerging technique which has shown significant promise in recent years as a viable alternative of retrieving neuronal information via neurovascular coupling to fMRI. Studies have shown that it can match fMRI in terms of spatiotemporal resolution and outperform it with regards to sensitivity, while being less expensive and generally easier to handle due to the lack of a strong magnetic field.
Here, we revisited the NMDA hypofunction model using fUS, along with a number of additional state-of-the art technologies, such as optogenetic-assisted circuit mapping, accompanied by behavioral assessments of the model. We generated a unique set of biomarkers to characterize the model from molecules to cells and from local to macroscale circuitry, revealing aberrations centered around the PFC. The translational hallmarks described may offer a deeper understanding and enable a more precise use of the model in future studies.
Functional ultrasound (fUS) is a newly-emerging technique which has shown significant promise in recent years as a viable alternative of retrieving neuronal information via neurovascular coupling to fMRI. Studies have shown that it can match fMRI in terms of spatiotemporal resolution and outperform it with regards to sensitivity, while being less expensive and generally easier to handle due to the lack of a strong magnetic field.
Here, we revisited the NMDA hypofunction model using fUS, along with a number of additional state-of-the art technologies, such as optogenetic-assisted circuit mapping, accompanied by behavioral assessments of the model. We generated a unique set of biomarkers to characterize the model from molecules to cells and from local to macroscale circuitry, revealing aberrations centered around the PFC. The translational hallmarks described may offer a deeper understanding and enable a more precise use of the model in future studies.
Methods:
For fUS experiments (60 minutes using the Iconeus One scanner, Iconeus) we used healthy C57BL/6JRj mice (10 mice per cohort, sedation induced using isoflurane and maintained using dexmedetomidine). The subchronic PCP model involved seven consecutive daily administrations of 10mg/kg PCP. We performed measurements at day 0, concomittently with the first dose, to capture the acute PCP effects, as well as at days 8 and 14, to identify subchronic alterations. We acquired a left-hemispheric oblique slice, covering the areas listed in Fig. 1. To temporally characterize the effects of PCP, we calculated FC dynamically using a sliding-window approach (10-minute windows, 30-second steps). We performed between-cohort edge-wise comparisons at all timepoints (two-sample t-tests, also yielding Z-score matrices for the differences between cohorts, FDR control was applied).
In separate cohorts, we performed behavioral experiments to evaluate cognitive deficits (T-maze alternation and auditory steady-state responses), ex-vivo electrophysiology combined with optogenetics to evaluate the connectivity between ventral hippocampus and the prelimbic area, as well as immunonhistochemistry with high-throughput confocal microscopy to evaluate several prefrontal markers (among whic parvalbumin).
In separate cohorts, we performed behavioral experiments to evaluate cognitive deficits (T-maze alternation and auditory steady-state responses), ex-vivo electrophysiology combined with optogenetics to evaluate the connectivity between ventral hippocampus and the prelimbic area, as well as immunonhistochemistry with high-throughput confocal microscopy to evaluate several prefrontal markers (among whic parvalbumin).
Results:
At baseline, we observed highly similar connectomes between cohorts (Fig. 1A, D). Acute PCP increased FC globally (Fig. 1B, F and I. In contrast, we saw robust subchronic reductions in frontal (PL and ACg) and frontostriatal FC (between PL and CPu) at both days 8 (Fig. 1C, G) and 15 (Fig. 1D, H). The robustness of the dysconnectivity patterns is demonstrated by the strong correlation of the differences at days 8 and 15 (Fig. 1J-K). Overall, shifting from acute to subchronic NMDAR blockade led to a transition from a hyperconnected to a hypoconnected state with most pronounced aberrances across frontal and frontostriatal circuits.
Using the same regime, we found, among others, impaired working memory (T-maze) and ASSR, impaired frontohippocampal connectivity (electrophysiology) and reduced prelimbic PV expression (Fig 2).
Using the same regime, we found, among others, impaired working memory (T-maze) and ASSR, impaired frontohippocampal connectivity (electrophysiology) and reduced prelimbic PV expression (Fig 2).
Conclusions:
Our data reveal which aspects of local and long-range circuitry are disturbed by the subchronic PCP model, which also recapitulate strongly translational hallmarks of the schizophrenia spectrum. Future studies may therefore more precisely target frontostriatal resting-state or frontohippocampal task-evoked dysconnectivity to assess whether pharmacological interventions can restore the observed deficits.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 2
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
Novel Imaging Acquisition Methods:
Imaging Methods Other 1
Keywords:
ANIMAL STUDIES
DISORDERS
ELECTROPHYSIOLOGY
Schizophrenia
ULTRASOUND
1|2Indicates the priority used for review
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