Biology subjects

Schwarting, R. K.

Publications and source records attributed to Schwarting, R. K..

4 recordsLinked to original sources

bioRxiv2024

Early life stress-induced miR-708-5p affects bipolar disorder-associated phenotypes through neuronatin downregulation

Mood-disorders (MDs) are caused by a complex interplay of genetic and environmental (GxE) risk factors. However, the molecular pathways engaged by GxE risk factors to trigger specific MD-associated endophenotypes are still poorly understood. Here, by using unbiased small RNA sequencing in peripheral blood mononuclear cells (PBMCs), we identified the BD-associated miR-708-5p as one of the most strongly upregulated microRNAs in peripheral blood of both healthy human subjects with a high genetic or environmental (early life stress) predisposition to develop MDs. miR-708 is also upregulated in the hippocampus of rats which underwent juvenile social isolation, a rodent model of early life stress. Furthermore, ectopic overexpression of miR-708-5p in the hippocampus of adult male mice is sufficient to elicit MD-associated behavioural endophenotypes, demonstrating a causal role for elevated miR-708-5p levels in MD development. We further show that miR-708-5p directly targets Neuronatin (Nnat), an endoplasmic reticulum (ER) resident protein involved in calcium homeostasis. Consequently, restoring Nnat expression in the hippocampus of miR-708-5p overexpressing mice rescues miR-708-5p dependent behavioural phenotypes. Finally, miR-708-5p is strongly upregulated in PBMCs derived from patients diagnosed with MD, in particular BD males. Peripheral expression of miR-708-5p, in conjunction with the previously identified miR-499-5p, allows to differentiate male BD patients from patients suffering from major depressive disorder (MDD) and healthy controls. In summary, we describe a functional role for the miR-708-5p/Nnat pathway in MD etiology and identify miR-708-5p as a potential biomarker for the differential diagnosis of MDs.

neuroscience↗

bioRxiv2022

Correlations across timing cues in natural vocalizations predict judging synthetic sound burst durations.

It is well known that animals rely on multiple sources of information in order to successfully identify sounds in natural environments, to make decisions that are optimal for their survival. For example, rats use duration and pitch cues to respond appropriately to prosocial and distress vocalizations (Saito et al., 2019). Vocalization duration cues are known to co-vary with other temporal cues (Khatami et al., 2018), yet little is known about whether animals rely upon such co-variations to successfully discriminate sounds. In the current study, we find natural alarm vocalizations in rats have onset and offset slopes that are correlated with their duration. Accordingly, vocalizations with faster onset slopes are more likely to have shorter durations. Given that vocalization slopes begin and end within milliseconds, they could provide rapid perceptual cues for predicting and discriminating vocalization duration. To examine this possibility, we train rodents to discriminate duration differences in sequences of synthetic vocalizations and examine how artificially changing the slope impacts duration judgments. We find animals are biased to misjudge a range of synthetic vocalizations as being shorter in duration when the onset and offset slopes are artificially fast. Moreover, this bias is reduced when rats are exposed to multiple synthetic vocalization bursts. The observed perceptual bias is accurately captured by a Bayesian decision-theoretic model that utilizes the empirical joint distribution of duration and onset slopes in natural vocalizations as a prior during duration judgements of synthetic vocalizations. This model also explains why the bias is reduced when more evidence is accumulated across multiple bursts, reducing the priors influence. These results support the theory that animals are sensitive to fine-grained statistical co-variations in auditory timing cues and integrate this information optimally with incoming sensory evidence to guide their decisions.

animal behavior and cognition↗

bioRxiv2021

Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 L-type voltage gated calcium channel subunit CACNB2

Bipolar disorder (BD) is a chronic mood disorder characterized by alternating manic and depressive episodes, often in conjunction with cognitive deficits. Dysregulation of neuroplasticity and calcium homeostasis as a result of complex genetic environment interactions are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that a BD-associated microRNA, miR-499-5p, regulates neuronal dendrite development and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients and healthy subjects at risk of developing the disorder due to a history of childhood maltreatment. This up-regulation is paralleled in the hippocampus of rats which underwent juvenile social isolation. Elevating miR-499-5p levels in rat hippocampal pyramidal neurons impairs dendritogenesis and reduces surface expression and activity of the voltage-gated L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory {beta}-subunit of Cav1.2, as a direct target of miR-499-5p in neurons. CACNB2 downregulation is required for the miR-499-5p dependent impairment of dendritogenesis, suggesting that CACNB2 is an important downstream target of miR-499-5p in the regulation of neuroplasticity. Finally, elevating miR-499-5p in the hippocampus in vivo is sufficient to induce short-term memory impairments in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. Taken together, we propose that stress-induced upregulation of miR-499-5p contributes to dendritic impairments and deregulated calcium homeostasis in BD, with specific implications for the neurocognitive dysfunction frequently observed in BD patients.

neuroscience↗

bioRxiv2020

Diazepam attenuates the effects of cocaine on locomotion, 50-kHz ultrasonic vocalizations and phasic dopamine release in the nucleus accumbens of rats

Background and PurposeCurrently, no effective drug exists to treat cocaine use disorders, which affect millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine release in the nucleus accumbens of rodents. In addition, we have recently shown that diazepam blocks the increase in dopamine release and the affective marker 50-kHz ultrasonic vocalizations (USV) induced by DL-amphetamine in rats. Experimental ApproachHere we tested whether administration of 2.5 mg{middle dot}kg-1 diazepam (i.p.) in adult male Wistar rats could block the effects of 20 mg{middle dot}kg-1 cocaine (i.p.) on electrically evoked phasic dopamine release in the nucleus accumbens measured by fast-scan cyclic voltammetry, as well as 50-kHz USV and locomotor activity. Key ResultsCocaine injection increased evoked dopamine release up to 3-fold within 5 min and the increase was significantly higher than baseline for at least 90 min. The injection of diazepam 15 min later attenuated the cocaine effect by nearly 50% and this attenuation was maintained for at least 30 min. Stimulant drugs, natural rewards and reward predictive cues are known to evoke 50-kHz USV in adult rats. In the present study, cocaine increased the number of 50-kHz USV of the flat, step, trill, and mixed kinds by 12-fold. This effect was at maximum 5 min after cocaine injection, decreased with time and lasted at least 40 min. Diazepam significantly blocked this effect for the entire duration of the session. The distance travelled by control rats during a 40-min session of exploration in an open field was at maximum in the first 5 min and decayed progressively until the end of the session. Cocaine-treated rats travelled significantly longer distances when compared to the control group, while diazepam significantly attenuated cocaine-induced locomotion by up to 50%. Conclusions and implicationThese results suggest that the neurochemical, affective, and stimulant effects of cocaine can be mitigated by diazepam. What is already knownO_LIDiazepam decreases dopamine release in the rodent nucleus accumbens (NAc) and reduces some effects produced by DL-amphetamine. C_LI What this study addsO_LIDiazepam attenuated the increase in phasic dopamine release caused by cocaine. C_LIO_LIDiazepam blocked the effect of cocaine on 50-kHz USV and locomotor activity. C_LI Clinical significanceO_LIThis study demonstrates that diazepam can block specific effects of cocaine that likely contribute to addiction. C_LI

pharmacology and toxicology↗