Brain-Body Interactions

Gestational exposure to environmental toxins, infections, and stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism spectrum disorder. We modeled some of these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly dysregulated the maternal immune system. Male but not female offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions, along with disruptions of gut structure and microbiome composition. Cellularly, prenatal stressors impaired microglial synaptic pruning in males during early postnatal development. Precise inhibition of microglial phagocytosis during the same critical period mimicked the impact of prenatal stressors on the male-specific social deficits. Conversely, modifying the gut microbiome rescued the social and cellular deficits, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development, perhaps via a gut-brain disruption.

The increasing prevalence of obesity and type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating energy homeostasis to accelerate the identification of new medications. Recent reports indicate that obesity medication, 5-hydroxytryptamine (5-HT, serotonin)2C receptor (5-HT2CR) agonist lorcaserin improves glycemic control in association with weight loss in obese patients with T2D. We examined whether lorcaserin has a direct effect on insulin sensitivity and how this effect is achieved. We clarify that lorcaserin dose-dependently improves glycemic control in a mouse model of T2D without altering body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin’s glucoregulatory effects, via activation of brain pro-opiomelanocortin (POMC) peptides. We observed that lorcaserin reduces hepatic glucose production and improves insulin sensitivity. These data suggest that lorcaserin’s action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

We seek to determine how circadian rhythms and sleep are integrated with physiological processes to provide optimal fitness and health. Using initially a Drosophila model, and more recently also mammalian models, we have found that aspects of the blood brain barrier (BBB) are controlled by the circadian clock. BBB properties are also influenced by sleep:wake state in Drosophila, and, in fact, appear to be contribute to functions of sleep. This and other work, which implicates sleep in the regulation of metabolic processes, is providing insights into sleep function

This talk will focus on two areas. I will firstly discuss some new data, starting with insights from rare human genetic variants, which helps to clarify the role of the central melanocortin system in the acquisition of nutrients and their disposition into growth, the acquisition of lean mass and sexual maturation . I will then discuss some aspects of the emerging biology of GDF15; a sentinel hormone conveying information regarding a range of somatic stresses to the brain.

In this lecture, Dr Stevens will discuss recent work that implicates brain immune cells, called microglia, in sculpting of synaptic connections during development and their relevance to autism, schizophrenia and other brain disorders. Her recent work revealed a key role for microglia and a group of immune related molecules called complement in normal developmental synaptic pruning, a normal process required to establish precise brain wiring. Emerging evidence suggests aberrant regulation of this pruning pathway may contribute to synaptic and cognitive dysfunction in a host of brain disorders, including schizophrenia. Recent research has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in complement C4, gene plays a well-known role in the immune system but also helps sculpt developing synapses in the mouse visual system (Sekar et al., 2016). Together these findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. Stevens will discuss this and ongoing work to understand the mechanisms by which complement and microglia prune specific synapses in the brain. A deeper understanding of how these immune mechanisms mediate synaptic pruning may provide novel insight into how to protect synapses in autism and other brain disorders, including Alzheimer’s and Huntington’s Disease.

Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence support the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioural and neuroendocrine mechanisms underlying these adaptations are unclear and form the focus of our research.

Coordinated activity across networks of neurons is a hallmark of both resting and active behavioral states in many species, including worms, flies, fish, mice and humans. These global patterns alter energy metabolism in the brain over seconds to hours, making oxygen consumption and glucose uptake widely used proxies of neural activity. However, whether changes in neural activity are causally related to changes in metabolic flux in intact circuits on the sub-second timescales associated with behavior, is unclear. Moreover, it is unclear whether differences between rest and action are associated with spatiotemporally structured changes in neuronal energy metabolism at the subcellular level. My work combines two-photon microscopy across the fruit fly brain with sensors that allow simultaneous measurements of neural activity and metabolic flux, across both resting and active behavioral states. It demonstrates that neural activity drives changes in metabolic flux, creating a tight coupling between these signals that can be measured across large-scale brain networks. Further, using local optogenetic perturbation, I show that even transient increases in neural activity result in rapid and persistent increases in cytosolic ATP, suggesting that neuronal metabolism predictively allocates resources to meet the energy demands of future neural activity. Finally, these studies reveal that the initiation of even minimal behavioral movements causes large-scale changes in the pattern of neural activity and energy metabolism, revealing unexpectedly widespread engagement of the central brain.

Puberty is a brain-driven phenomenon, which is under the control of sophisticated regulatory networks that integrate a large number of endogenous and environmental signals, including metabolic and nutritional cues. Puberty onset is tightly bound to the state of body energy reserves, and deregulation of energy/metabolic homeostasis is often associated with alterations in the timing of puberty. However, despite recent progress in the field, our knowledge of the specific molecular mechanisms and pathways whereby our brain decode metabolic information to modulate puberty onset remains fragmentary and incomplete. Compelling evidence, gathered over the last fifteen years, supports an essential role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine control of puberty. Kiss1 neurons are major components of the hypothalamic GnRH pulse generator, whose full activation is mandatory pubertal onset. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. However, the modulatory influence of metabolic signals (e.g., leptin) on Kiss1 neurons might be predominantly indirect and likely involves also the interaction with other transmitters and neuronal populations. In my presentation, I will review herein recent work of our group, using preclinical models, addressing the molecular mechanisms whereby Kiss1 neurons are modulated by metabolic signals, and thereby contribute to the nutritional control of puberty. In this context, the putative roles of the energy/metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1, in the metabolic control of Kiss1 neurons and puberty will be discussed. In addition, I will summarize recent findings from our team pointing out a role of central de novo ceramide signaling in mediating the impact of obesity of (earlier) puberty onset, via non-canonical, kisspeptin-related pathways. These findings are posed of translational interest, as perturbations of these molecular pathways could contribute to the alterations of pubertal timing linked to conditions of metabolic stress in humans, ranging from malnutrition to obesity, and might become druggable targets for better management of pubertal disorders.

Peripheral nerve injury can cause debilitating disease and immune-cell mediated destruction of the affected nerve. While the focus of most studies has been on the nerve-degenerative response, the effect of loss of innervation on lymph node function is largely unclear. Here, I will discuss the cellular and molecular events caused by local denervation and loss of direct neural input to the popliteal lymph node that induce an inflammatory response and lymph node expansion.

In this presentation, we will discuss the cellular and molecular properties of the retrotrapezoid nucleus (RTN), an integrative and interoceptive control node for the respiratory motor system. We will present the molecular profiling that has allowed definitive identification of a cluster of tonically active neurons that provide a requisite drive to the respiratory central pattern generator (CPG) and other pre-motor neurons. We will discuss the ionic basis for steady pacemaker-like firing, including by a large subthreshold oscillation; and for neuromodulatory influences on RTN activity, including by arousal state-dependent neurotransmitters and CO2/H+. The CO2/H+-dependent modulation of RTN excitability represents the sensory component of a homeostatic system by which the brain regulates breathing to maintain blood gases and tissue pH; it relies on two intrinsic molecular proton detectors, both a proton-activated G protein-coupled receptor (GPR4) and a proton-inhibited background K+ channel (TASK-2). We will also discuss downstream neurotransmitter signaling to the respiratory CPG, focusing especially on a newly-identified peptidergic modulation of the preBötzinger complex that becomes activated following birth and the initiation of air breathing. Finally, we will suggest how the cellular and molecular properties of RTN neurons identified in rodent models may contribute to understanding human respiratory disorders, such as congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS).

Sleep is generally associated with the brain but poor sleep impacts the entire body - many diseases are caused or exacerbated by sleep loss. Our work is uncovering ways in which sleep and the body interact. We found a special, two-way relationship between sleep and the gut: the gut is uniquely impacted by sleep loss, and it actively controls sleep quality. These findings could help us understand the origins of sleep as well as develop strategies to offset the negative consequences of inadequate sleep.

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these two evolutionarily highly conserved systems is long recognized, the pathophysiological mechanisms regulating their reciprocal crosstalk in cardiovascular diseases became object of investigation only more recently. In the last years, our group elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. In my talk, I will focus on the molecular mechanisms that regulate the neuro-immune crosstalk in hypertension. I will elaborate on the mechanistic insights into this brain-spleen axis led us uncover a new molecular pathway mediating the neuroimmune interaction established by noradrenergic-mediated release in the spleen of placental growth factor (PlGF), an angiogenic growth factor potentially targetable with pharmacological approaches.

The microbiota-gut-brain axis is emerging as a research area of increasing interest for those investigating the biological and physiological basis of brain development and behaviour during early life, adolescence & ageing. The routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, via the enteric nervous system or by way of microbial metabolites such as short chain fatty acids. Studies in animal models have shown that the development of an appropriate stress response is dependent on the microbiota. Developmentally, a variety of factors can impact the microbiota in early life including mode of birth delivery, antibiotic exposure, mode of nutritional provision, infection, stress as well as host genetics. Recently, the gut microbiota has been implicated in regulating the stress response, and social behaviour. Moreover, fundamental brain processes from adult hippocampal neurogenesis to myelination to microglia activation have been shown to be regulated by the microbiome. Further studies will focus on understanding the mechanisms underlying such brain effects and how they can be exploited by microbiota-targeted interventions including ‘psychobiotics’ and diet

PIEZO ion channels detect force in cellular membranes. They are expressed in a wide variety of mammalian tissues, including the vasculature, lymphatic system, and the nervous system. We have found that PIEZO2 in sensory neurons is required for the mechanical senses of touch and proprioception, but our understanding of internal organ sensing, interoception, is far behind. I will describe our findings on the role of PIEZO ion channels in the lesser-known interoceptive senses in multiple organ systems.

Microglia are the immune cells of the brain, and play increasingly appreciated roles in synapse formation, brain plasticity, and cognition. A growing appreciation that the immune system involved in diseases like schizophrenia, epilepsy, and neurodegenerative diseases has led to renewed interest in how microglia regulate synaptic connectivity. Our group previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel regulator of microglial activation and function. I will discuss a mechanism by which microglia regulate synaptic plasticity and long-term memories by engulfing brain extracellular matrix (ECM) proteins. These studies raise the question of how these pathways may be altered or could be modified in the context of disease.

Empirical evidence and theoretical models both increasingly emphasize the importance of interoceptive processing in mental health. Indeed, many mood and psychiatric disorders involve disturbed feelings and/or beliefs about the visceral body. However, current methods to measure interoceptive ability are limited in a number of ways, restricting the utility and interpretation of interoceptive biomarkers in psychiatry. I will present some newly developed measures and models which aim to improve our understanding of disordered brain-body interaction in psychiatric illnesses.

Mindsets are core assumptions about the nature and workings of things in the world that orient us to a particular set of attributions, expectations, and goals. Our study of mindsets is, in part, inspired by research on the placebo effect, a robust demonstration of the ability of mindsets, conscious or subconscious, to elicit physiological changes in the body. This talk will explore the role of mindsets in three stages of chronic disease progression: genetic predisposition, behavioral prevention, and clinical treatment. I will discuss the mechanisms through which mindsets influence health as well as the myriad ways that mindsets can be more effectively leveraged to motivate healthy behaviors and improve 21st century healthcare.

The development and maintenance of many tissues are fueled by stem cells. Many studies have addressed how intrinsic factors and local signals from neighboring niche cells maintain stem cell identity and proliferative potential. In contrast, it is poorly understood how stem cell activity is controlled by systemic, tissue-extrinsic signals in response to environmental cues and changes in physiological status. Our laboratory has been focusing on female germline stem cells (fGSCs) in the fruit fly Drosophila melanogaster as a model system and studying neuroendocrine control of fGSC increase. The increase of fGSCs is induced by mating stimuli. We have previously reported that mating-induced fGSC increase is regulated by the ovarian steroid hormone and the enteroendocrine peptide hormone [Ameku & Niwa, PLOS Genetics 2016; Ameku et al. PLOS Biology 2018]. In this presentation, we report our recent finding showing a neuronal mechanism of mating-induced fGSC increase. We first found that the ovarian somatic cell-specific RNAi for Oamb, a G protein-coupled receptor for the neurotransmitter octopamine, failed to induce fGSC proliferation after mating. Both ex vivo and in vivo experiments revealed that octopamine and Oamb positively regulated mating-induced fGSC increase via intracellular Ca 2+ signaling. We also found that a small subset of octopaminergic neurons directly projected to the ovary, and neuronal activity of these neurons was required for mating-induced fGSC increase. This study provides a mechanism describing how the neuronal system controls stem cell behavior through stem cell niche signaling [Yoshinari et al. eLife 2020]. Here I will also present our recent data showing how the neuroendocrine system couples fGSC behavior to multiple environmental cues, such as mating and nutrition.