Hesse, S. | bioRxiv Science

bioRxiv2020

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Results showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. We also found that MPH-induced variations in DAT-and NET-enriched FC were significantly correlated with inter-individual differences in effects of MPH on key behavioural responses associated with the reinforcement-learning task. Our findings show that MPH-related FC changes are specifically associated with DAT and provide evidence that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to distinct molecular targets.

neuroscience↗

bioRxiv2020

Sleep Deprivation alters the influence of biological sex on active-phase sleep behavior

Poor sleep is a hazard of daily life that oftentimes cannot be avoided. Gender differences in daily sleep and wake patterns are widely reported; however, it remains unclear how biological sex, which is comprised of genetic and endocrine components, directly influences sleep regulatory processes. In the majority of model systems studied thus far, sex differences in daily sleep amount are predominant during the active (wake) phase of the sleep-wake cycle. The pervasiveness of sex differences in sleep amount throughout phylogeny suggests a strong underlying genetic component. The goal of the current study is to determine if sex differences in active-phase sleep amount are dependent on sex chromosomes in mice. Sleep was examined in the four-core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of sex phenotype (male or female). In this line, sex phenotype is determined by the presence or absence of the Sry gene, which is dissociated from the Y chromosome. Polysomnographic sleep recordings were obtained from gonadectomized (GDX) FCG mice to examine spontaneous sleep states and the ability to recover from sleep loss. We report that during the active-phase, the presence of the Sry gene accounts for most sex differences during spontaneous sleep; however, during recovery from sleep loss, sex differences in sleep amount are partially driven by sex chromosome complement. These results suggest that genetic factors on the sex chromosomes encode the homeostatic response to sleep loss.

neuroscience↗