Research into learning and memory over the past decades has revealed key neurotransmitters that regulate these processes, many of which are evolutionarily conserved across diverse species. The monoamine neurotransmitter dopamine is one example of this, with countless studies demonstrating its importance in regulating behavioural plasticity. However, dopaminergic neural networks in the mammalian brain consist of hundreds or thousands of neurons, and thus cannot be studied at the level of single neurons acting within defined neural circuits. The nematode Caenorhabditis elegans (C. elegans) has an experimentally tractable nervous system with a completely characterized synaptic connectome. This makes it an advantageous system to undertake mechanistic studies into how dopamine encodes lasting yet flexible behavioural plasticity in the nervous system. In this review, we synthesize the research to date exploring the importance of dopaminergic signalling in learning, memory formation, and forgetting, focusing on research in C. elegans. We also explore the potential for dopamine-specific fluorescent biosensors in C. elegans to visualize dopaminergic neural circuits during learning and memory formation in real-time. We propose that the use of these sensors in C. elegans, in combination with optogenetic and other light-based approaches, will further illuminate the detailed spatiotemporal requirements for encoding behavioural plasticity in an accessible experimental system. Understanding the key molecules and circuit mechanisms that regulate learning and forgetting in more compact invertebrate nervous systems may reveal new druggable targets for enhancing memory storage and delaying memory loss in bigger brains.
This scientific commentary refers to 'Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-β deposition' by Rowland et al. (https://doi.org/10.1042/NS20230016). Insulin-degrading enzyme (IDE) and neprilysin (NEP) have been proposed as two Aβ-degrading enzymes supported by human genetics and in vivo data. Rowland et al. provide complementary evidence of a key role for IDE in Aβ metabolism in human-induced pluripotent stem cell (iPSC)-derived cortical neurons.
Abstract Axonal transport is the essential process by which neurons actively traffic a variety of cargoes between the cell soma and axon terminals. Accordingly, dysfunctional axonal transport is linked to many nervous system conditions. Therefore, being able to image and quantify this dynamic process in live neurons of animal disease models is beneficial for understanding neuropathology and testing new therapies at the preclinical level. As such, intravital approaches have been developed to assess cargo movement in the hindlimb sciatic nerves of live, anaesthetised mice. Here, we describe an adapted method for in vivo imaging of axonal transport in intact median and ulnar nerves of the rodent forelimb. Injection of a fluorescently labelled and non-toxic fragment of tetanus neurotoxin (HCT) into the mouse forepaw permits the identification of signalling endosomes in intact axons of median and ulnar nerves. Through immunofluorescent analysis of forelimb lumbrical muscles and median/ulnar nerves, we confirmed that HCT is taken up at motor nerve terminals and predominantly locates to motor axons. We then showed that the baseline trafficking of signalling endosomes is similar between the median/ulnar nerves and the sciatic nerve in adult wild-type mice. Importantly, this adapted method can be readily tailored for assessment of additional cargoes, such as mitochondria. By measuring transport in forelimb and hindlimb nerves, comparative anatomical and functional analyses can be performed in rodent disease models to aid our understanding of peripheral nerve disease pathogenesis and response to injury.
Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence to support these mechanistic links, with placental inflammatory responses and dysregulation of placental function implicated. This leads to changes in fetal brain cytokine balance and altered epigenetic regulation of key neurodevelopmental pathways. The prenatal timing of such mIA-evoked changes, and the accompanying fetal developmental responses to an altered in utero environment, will determine the scope of the impacts on neurodevelopmental processes. Such dysregulation can impart enduring neuropathological changes, which manifest subsequently in the postnatal period as altered neurodevelopmental behaviours in the offspring. Hence, elucidation of the functional changes that occur at the molecular level in the placenta is vital in improving our understanding of the mechanisms that underlie the pathogenesis of NDDs. This has notable relevance to the recent COVID-19 pandemic, where inflammatory responses in the placenta to SARS-CoV-2 infection during pregnancy and NDDs in early childhood have been reported. This review presents an integrated overview of these collective topics and describes the possible contribution of prenatal programming through placental effects as an underlying mechanism that links to NDD risk, underpinned by altered epigenetic regulation of neurodevelopmental pathways.
The contribution of the immune system to the pathophysiology of neurodegenerative Parkinson's disease (PD) is increasingly being recognised, with alterations in the innate and adaptive arms of the immune system underlying central and peripheral inflammation in PD. As chief modulators of the immune response, cytokines have been intensely studied in the field of PD both in terms of trying to understand their contribution to disease pathogenesis, and if they may comprise much needed therapeutic targets for a disease with no current modifying therapy. This review summarises current knowledge on key cytokines implicated in PD (TNFα, IL-6, IL-1β, IL-10, IL-4 and IL-1RA) that can modulate both pro-inflammatory and anti-inflammatory effects. Cytokine activity in PD is clearly a complicated process mediated by substantial cross-talk of signalling pathways and the need to balance pro- and anti-inflammatory effects. However, understanding cytokine activity may hold promise for unlocking new insight into PD and how it may be halted.
