Neural Mechanisms of Early-Life Social Stress as a Developmental Risk Factor for Severe Psychiatric Disorders

Reinwald, Jonathan; Becker, Robert E.; Mallien, Anne Stephanie; Falfán-Melgoza, Claudia; Sack, Markus; Hohenberg, Christian Clemm von; Braun, Urs; Linan, Alejandro Cosa; Gass, Natalia; Vasilescu, Andrei-Nicolae; Tollens, Fabian; Lebhardt, Philipp; Pfeiffer, Natascha; Inta, Dragoš; Meyer‐Lindenberg, Andreas; Gass, Peter; Sartorius, Alexander; Weber‐Fahr, Wolfgang

doi:10.1016/j.biopsych.2017.12.010

Cited by 25 publications

(16 citation statements)

References 140 publications

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“…A common animal model used to study different facets of mental disorders is early-life social isolation in rodents [ 1 ]. In rats, this isolation can induce long-lasting alterations in functional connectivity, behavior, and molecular expression [ 1 , 12 – 14 ]. The exposure to social deprivation is considered one of the most reliable preclinical models of schizophrenia, as it simulates the core features of mental disorders, e.g.…”

Section: Introductionmentioning

confidence: 99%

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

et al. 2020

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Early life stress compromises brain development and can contribute to the development of mental illnesses. A common animal model used to study different facets of psychiatric disorders is social isolation from early life on. In rats, this isolation can induce long-lasting alterations in molecular expression and in behavior. Since social isolation models severe psychiatric symptoms, it is to be expected that it affects the overall wellbeing of the animals. As also promoted by the 3Rs principle, though, it is pivotal to decrease the burden of laboratory animals by limiting the number of subjects (reduce, replace) and by improving the animals’ wellbeing (refine). The aim of this study was therefore to test possible refinement strategies such as resocialization and mere adult social isolation. We examined whether the alternatives still triggered the necessary phenotype while minimizing the stress load on the animals. Interestingly, we did not find reduced wellbeing-associated burrowing performance in isolated rats. The hyperactive phenotype seen in socially isolated animals was observed for rats undergoing the adult-only isolation, but resocializing ameliorated the locomotor abnormality. Isolation strongly affected markers of neuroplasticity in the prefrontal cortex independent of timing: mRNA levels of Arc , Bdnf and the pool of Bdnf transcripts with the 3’ long UTR were reduced in all groups. Bdnf splice variant IV expression was reduced in lifelong-isolated animals. Some of these deficits normalized after resocialization; likewise, exon VI Bdnf mRNA levels were reduced only in animals persistently isolated. Conversely, social deprivation did not affect the expression of Gad67 and Pvb , two GABAergic markers, whereas changes occurred in the expression of dopamine d1 and d2 receptors. As adult isolation was sufficient to trigger the hyperactive phenotype and impaired neuroplasticity in the prefrontal cortex, it could be a candidate for a refinement strategy for certain research questions. To fully grade the severity of post-weaning social isolation and the alternatives, adult isolation and resocialization, a more profound and multimodal assessment approach is necessary.

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Section: Introductionmentioning

confidence: 99%

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

et al. 2020

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“…This model is of particular interest since the manipulations are conducted early in life and caused long-term neurodevelopmental, behavioral, structural, and neurochemical alterations with a translational relevance for a spectrum of symptoms seen in schizophrenia. 82 Interestingly, a single dose of cariprazine (0.1-0.3 mg/kg) or aripiprazole (3 mg/kg) reduced the hyperactivity and reversed the cognitive deficits in the novel object recognition (NOR) test that were observed in rats exposed to a combination of PCP and social isolation. 83 Moreover, only cariprazine was able to correct pro-social behavioral and body-sniffing, which may reflect a potential effectiveness of cariprazine, but not aripiprazole, in treating negative symptoms.…”

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confidence: 98%

The role of dopamine D₃receptors in the mechanism of action of cariprazine

et al. 2019

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Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

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“…Image pre-processing was performed as in our previous studies 27,28 and comprised the following steps: (1) correction of each EPI time-series for magnetic field (B0) inhomogeneities and movement using "realign & unwarp" SPM function (SPM8: http://www.fil.ion.ucl.ac.uk/spm/ software/spm8); (2) regressing out the estimated movement parameter vectors from each voxel (FSL, version 4.1. http://www.fmrib.ox.ac.uk/fsl); (3) filtering out respiratory and cardiac signals using Aztec software; 29 (4) slicetiming correction (SPM8); (5) spatial normalization to a rat brain template in Paxinos space (SPM8); 30 (6) filtering out the cerebrospinal fluid signal from the normalized images (FSL); (7) scrubbing data frames with a frame-wise displacement >0.03 mm (linear interpolation) in order to capture the remaining motion-related artifacts; 31 (8) global signal regression; (9) band-pass filtering (0.01-0.1 Hz) (Analysis of Functional NeuroImages version 2) 32 .…”

Section: Mri Acquisition and Pre-processingmentioning

confidence: 99%

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

et al. 2020

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As ketamine is increasingly used as an effective antidepressant with rapid action, sustaining its short-lived efficacy over a longer period of time using a schedule of repeated injections appears as an option. An open question is whether repeated and single administrations would affect convergent neurocircuits. We used a combination of one of the most robust animal models of depression with high-field neuroimaging to perform a whole-brain delineation of functional mechanisms underlying ketamine's effects. Rats from two genetic strains, depressive-like and resilient, received seven treatments of 10 mg/kg S-ketamine (N = 14 depressive-like, N = 11 resilient) or placebo (N = 12 depressive-like, N = 10 resilient) and underwent resting-state functional magnetic resonance imaging. Using graph theoretical models of brain networks, we compared effects of repeated ketamine with those of single administration from a separate dataset of our previous study. Compared to single treatment, repeated ketamine evoked strain-specific brain network randomization, resembling characteristics of the depressive-like strain and patients. Several affected regions belonged to the auditory, visual, and motor circuitry, hinting at possible cumulative side effects. Finally, when compared to saline, repeated ketamine affected only a few local topological properties and had no effects on global properties. In combination with the lack of clear differences compared to placebo, our findings point toward an inefficacy of ketamine's long-term administration on brain topology, making questionable the postulated effect of repeated administration and being consistent with the recently reported absence of repeated ketamine's antidepressant efficacy in several placebo-controlled studies.

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Neural Mechanisms of Early-Life Social Stress as a Developmental Risk Factor for Severe Psychiatric Disorders

Cited by 25 publications

References 140 publications

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

The role of dopamine D₃receptors in the mechanism of action of cariprazine

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

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Neural Mechanisms of Early-Life Social Stress as a Developmental Risk Factor for Severe Psychiatric Disorders

Cited by 25 publications

References 140 publications

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

The role of dopamine D3receptors in the mechanism of action of cariprazine

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

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The role of dopamine D₃receptors in the mechanism of action of cariprazine