Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of neurodevelopmental disorders: Prenatal immune activation and peripubertal stress

Capellán, Roberto; Moreno-Fernández, Mario; Orihuel, Javier; Roura-Martínez, David; Ucha, Marcos; Ambrosio, Emilio; Higuera-Matas, Alejandro

doi:10.1016/j.schres.2019.11.007

Cited by 7 publications

(3 citation statements)

References 59 publications

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“…An additional explanation may rely on the observed increased dorsal striatal volume due to PUS evident only in rats with a history of MIA (especially in the left hemisphere), an effect that was concomitant to a decrease in NAA+NAAG levels in MIA+PUS rats. NAAG is an agonist of the mGluR3 receptor and negatively modulates glutamate levels (30) therefore, the reduced levels of this peptide may result in increased glutamate levels, which is what we observed in a previous study in MIA+PUS rats where we used ex vivo 11T MRS (which allowed us to have a separate measure of glutamate from glutamine peak) (31). Considering all these pieces of evidence, it could be suggested that there might be an acceleration of habit formation in MIA+PUS rats after the initial contact with cocaine that may render their responding for cocaine divorced from the (decreased) rewarding actions of the drug (as observed in PUS rats).…”

Section: -Neuroimaging Studiessupporting

confidence: 57%

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Capellán

Orihuel

Marcos

et al. 2021

Preprint

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Substance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to 5 episodes of unpredictable stress every other day during adolescence (from postnatal day 28 to 38). When rats reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, conditioning processes and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration while PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and reversed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted Pavlovian or instrumental conditioning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. MIA+PUS altered the structure and function of the dorsal striatum increasing its volume and interfering with glutamatergic dynamics. MIA did not affect the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the restored cocaine intake. PUS had a profound effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction.

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Section: -Neuroimaging Studiessupporting

confidence: 57%

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Capellán

Orihuel

Marcos

et al. 2021

Preprint

Self Cite

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show abstract

“…This effect was concomitant to a decrease in NAA + NAAG levels in MIA + PUS rats. NAAG is an agonist of the mGluR3 receptor and negatively modulates glutamate levels [28] therefore, the reduced levels of this peptide may result in increased glutamate levels, which is what we observed in a previous study in MIA + PUS rats where we used ex vivo 11 T MRS (which allowed us to have a separate measure of glutamate from glutamine peak) [29]. all these pieces of evidence, it could be suggested that MIA + PUS rats show an acceleration of habit formation after the initial contact with cocaine that may render their responding for cocaine divorced from the (decreased) rewarding actions of the drug (as observed in PUS rats).…”

Section: Neuroimaging Studiessupporting

confidence: 53%

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

et al. 2023

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Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

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“…Prepulse inhibition of the acoustic startle response (PPI) was measured at approximately PD103 in a non-restrictive methacrylate cage (28x15x17cm) containing a vibration-sensitive platform (Cibertec), which was calibrated daily calibrated using a 200g weight. The test had a duration of 26 min and was carried out following a sequence previously described by our laboratory (Capellán et al, 2019). Prepulses of 4 or 12 dB above the background noise (65 dB) were used with intervals of 30 or 120 ms between prepulse and pulse (120 dB).…”

Section: Sensorimotor Gatingmentioning

confidence: 99%

LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND Δ⁹-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS

Moreno-Fernández

Ucha

Paiva

et al. 2023

Preprint

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The causality in the association between cannabis use and the risk of developing schizophrenia has been the subject of intense debate in the last years. The development of animal models recapitulating several aspects of the disease is crucial for shedding light on this issue. Maternal infections are a known risk for schizophrenia. Here, we used the maternal immune activation (MIA) model combined with THC exposure during adolescence to examine several behaviours in rats (working memory in the Y maze, sociability in the three-chamber test, sucrose preference as a measure, prepulse inhibition and formation of incidental associations) that are similar to the different symptom clusters of the disease. To this end, we administered LPS to pregnant dams and when the offspring reached adolescence, we exposed them to a mild dose of THC to examine their behaviour in adulthood. We also studied several parameters in the dams, including locomotor activity in the open field, elevated plus maze performance and their response to LPS, that could predict symptom severity of the offspring, but found no evidence of any predictive value of these variables. In the adult offspring, MIA was associated with impaired working memory and sensorimotor gating, but surprisingly, it increased sociability, social novelty and sucrose preference. THC, on its own, impaired sociability and social memory, but there were no interactions between MIA and THC exposure. These results suggest that, in this model, THC during adolescence does not trigger or aggravate symptoms related to schizophrenia in rats.

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Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of neurodevelopmental disorders: Prenatal immune activation and peripubertal stress

Cited by 7 publications

References 59 publications

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND Δ⁹-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS

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Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of neurodevelopmental disorders: Prenatal immune activation and peripubertal stress

Cited by 7 publications

References 59 publications

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND Δ9-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS

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LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND Δ⁹-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS