Parkinson’s is a debilitating neurodegenerative disease affecting nearly 10 million people worldwide. The pathology appears to depend on the diffusion of abnormal aggregates of the endogenous α-synuclein protein across the nervous system. How the diffusion occurs remains controversial. Clinical evidence suggests that the gastrointestinal tract is a site of origin for α-synuclein, which then may spread to the brain. I will present studies in mice in which we tried to map the body-brain pathways via which the pathology may spread from the gut. I will also mention the potential role of gut immune cells in this process. [more]

A variety of environmental stressors, such as temperature (hot and cold), infection, natural enemies, and starvation, can threaten life. To survive environmental stresses, mammals exert autonomic and behavioral responses as fundamental functions mediated by the CNS. Remarkable progress has recently been made in understanding the central circuit mechanisms of physiological responses to such stressors. A “trunk” neural pathway from the dorsomedial hypothalamus (DMH) to the rostral medullary raphe region (rMR) regulates sympathetic outflows to effector organs for homeostasis. Thermal and infection stress inputs to the preoptic area of the hypothalamus dynamically alter the DMH→rMR transmission to elicit thermoregulatory, febrile, and cardiovascular responses. Psychological stress signaling from the prefrontal cortex to the DMH drives sympathetic and behavioral responses for stress coping, representing a psychosomatic connection from the corticolimbic emotion circuit to the autonomic and somatic motor systems. Under starvation stress, medullary reticular neurons activated by hunger signaling from the hypothalamus suppress thermogenic drive from the rMR for energy saving and prime mastication to promote food intake. I will present a unified neural network for environmental stress responses, which provides novel insights into the integrative central regulation of organ functions that enables mammals to inhabit diverse environments on earth. [more]

Serotonin has wide-ranging effects on many physiological activities, from feeding and gut motility to mood and motor learning. However, the identity of central serotonergic neurons and the neuronal circuits within which they are embedded are largely unknown at single cell and synaptic level. We have used a scanning transmission electron microscopy dataset of a whole Drosophila larva to elucidate the central sensory-motor circuit that controls swallowing and its coordination with the enteric nervous system. The circuit is composed of Piezo-expressing mechanosensory neurons arrayed along the esophagus which are able to sense the passage of food. Their afferent signal is conveyed onto a set of central serotonergic neurons that project back out via the larval vagus nerve and facilitates swallowing motor pattern. Serotonin release by these neurons modulates serotonin receptor-expressing motor neurons that innervate the muscles underlying esophageal peristalsis. These motor neurons also share an efferent copy of their motor activity with the Piezo neurons sensing food passage. Our analysis reveals an elemental circuit architecture through which successful completion of a rewarding motor task provides a reinforcing and stabilizing signal to the CNS for facilitation of motor learning. [more]

The brain and body are in a continuous dialog that is essential for our physical and mental health. Little is known about how this dialog is achieved at the neurobiological level. A large corpus of work implicates the insular cortex as a central node for bi-directional brain-body communication. However, direct evidence for its functional role is scarce. We developed a microprism-based cellular imaging approach to monitor insular cortex activity in behaving mice across different physiological need states. We combine this imaging approach with manipulations of peripheral physiology and related hypothalamic circuits to investigate the underlying mechanisms. I will first present our recent data suggesting that insular cortex population activity represents both current bodily states, as well as future predicted ones. I will then describe our current efforts to understand these predictions under conditions of conflicting physiological needs, and the potential role of these predictions in regulating bodily physiology. [more]

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Psychedelics, including psilocybin and LSD, are undergoing a “renaissance” as possible treatments for a range of psychiatric and neurological disorders, especially because of their fast onset of therapeutic activity. There has been a rapid push to clinical trials since the 2018 designation of psilocybin as a “breakthrough therapy” by the US FDA, based on its efficacy in treatment-resistant depression, including 4 clinical trials currently underway in patients with anorexia nervosa (AN). While the outcomes of these trials will show efficacy one way or the other, it is imperative to understand the biological mechanisms through which psilocybin may act to produce therapeutic outcomes, in order to best direct treatment to individuals likely to respond. This is especially important given the climate of intense media hype that may bias the outcomes of clinical trials based on an expectation of efficacy. We have tested the effects of a single dose of psilocybin on the development of pathological weight loss in the most well-established animal model of AN, known as activity-based anorexia, and suggest a role for reinforcement learning and behavioural flexibility in the positive effects of psilocybin on energy balance. We are now focused on uncovering the neurobiological substrates that underpin these effects, by examining changes in serotonin receptor expression and the brain-derived neurotropic factor (BDNF) signalling pathway. [more]

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The Melanin-concentrating hormone (MCH) is a neuropeptide implicated in a wide range of functions. Its role is best described as an orexigenic peptide since acute MCH applications induce an increase in food intake. MCH-immunoreactive fibers (MCH-ir) are found diffused throughout virtually the entire CNS. In contrast, the production of MCH and messenger RNA (mRNA) from its precursor (ppMCH) is concentrated, in mammals, in neurons of two hypothalamic regions: the lateral hypothalamic area [LHA] and the incerto-hypothalamic area (IHy). Only during lactation, MCH-ir neurons and ppMCH mRNA expression appear in new hypothalamic territories, such as the ventromedial part of the medial preoptic area (vmMPOA). The amount of MCH synthesis in this region increases with the progress of lactation, being maximum in the final phase [around 19th- 21st days] when it disappears. The origin of these cells is still unknown. A possible explanation for this phenomenon is the de novo appearance or neuroplasticity of those cells in the vmMPOA region, which would characterize the necessity of MCH signaling to decline the maternal behavior/lactation period of lactating females. [more]

In aging populations, questions around the processes of aging become more and more pressing as aging-associated and neurodegenerative diseases such as Alzheimer’s, Parkinson’s and diabetes mellitus increasingly strain our health systems. Understanding the molecular mechanisms involved in degenerative aging processes can help develop new therapeutic approaches that lead to a healthier way of living for older and ill individuals, and eventually for us all. [more]

Interoception incorporates the afferent signalling, central processing and neural and mental representation of internal bodily signals. Historically, within the fields of physiology, psychology and neuroscience, there has been inconsistency in the way that individual differences in interoception are defined and measured. This talk will detail empirical results which demonstrate dimensions of interoception with and without conscious access, with a particular focus on the heart. In normative samples, these interoceptive dimensions are distinct and dissociable. The integration of afferent signals with brain can augment or attenuate perceptive, cognitive and emotion processing. Selective alterations in interoceptive processing are evident in clinical conditions such as schizophrenia and autism, while specific interoceptive disturbances are associated with transdiagnostic symptom expression such as anxiety and dissociation. Understanding the multifaceted nature of interoception and body-brain interactions can open up new avenues for targeted treatment. [more]

Prompt behavioural reactions to external aversive stimuli are essential for individual's survival. He will discuss the contribution of lateral habenula in encoding such aversive stimuli in the brain and the importance of synaptic plasticity in this structure for behaviourally-relevant events. [more]

The underlying basis for understanding of how brain control energy homeostasis, resides in a functional and coordinate communicating pathways between peripheral endocrine organs and the brain, in which the hypothalamus plays a pivotal role in the integration and processing of peripheral metabolic cues into satiety and feeding signals. Based on human GWAS and targeted mouse mutagenesis models, it has recently been revealed that obesity might due to a brain disease which might be a consequence of a brain misunderstanding the peripheral metabolic status in defense of body weightgain. As matter of fact, a growing body of evidences demonstrate a link between obesity and a defective brain´s nutrient/hormone sensing. Likewise, our studies have shown that hypothalamic astrocytes regulate glucose get access into the brain by sensing peripheral changes in insulin levels and ultimately controlling feeding (García-Cáceres et al., Cell 2016). Using specific transgenic mouse models for targeting metabolic receptors in these glial cells we have demonstrated that not only astrocytes respond to hormones derived from pancreas but also from adipose tissue (leptin), as well as circulating nutrients (lipids, glucose) (Kim et al., Nature Neurosci. 2014; Gao et al., Diabetes 2018; García-Cáceres et al., Cell 2016). Overall our previous work supports that hormone/nutrient signaling in astrocytes is determinant of the manner in which brain sense whole-body metabolic demands. We are now continuing on investigating whether hypothalamic astrocyte-neuron circuits require a precise finely-tuned and coordinated communication with metabolic cues derived from peripheral endocrine organ for maintaining a balanced control of food intake, body weight and metabolism. Furthermore, we hypothesize that impairment of such crosstalk during exposure to hypercaloric environments may contribute to the pathogenesis of obesity and type-2 diabetes. To test this overarching hypothesis, we are developing a functional mouse model for understanding of body-brain connection with particular focus on the role of astrocytes for the control of body weight and energy metabolism in health and disease. [more]

Protein kinases are the key components of almost every signalling pathway involved in normal development and disease. MAPKs play a key role in the regulation of diverse cellular programs and participate extensively in the control of cell fate decisions such as proliferation, differentiation, and death, as well as in the regulation of stress responses. The main stress-activated MAPKs are the p38 and c-Jun N-terminal kinase (JNK) families. The p38MAPK family has four isoforms encoded by distinct genes located tandemly in 2 chromosomes: p38, , and . Although the role of all p38s have been thought to be similar, we think the less-studied members p38 and  have different and specific regulation and function. We will discuss about our recent findings that suggest that these kinases have specific function and regulation. We will focus our attention in their implication in obesity related diseases. [more]

Obesity is intertwined with behaviour. Many eating-related behaviours have been proposed to explain obesity, such as food addiction, disinhibition and emotional eating. However, these behaviours tend to similarities based on both statistics and definitions. I propose that these behaviours can be aggregated into a single broad trait – Uncontrolled Eating. Such an approach enables reviewing and meta‐analysing evidence done on each individual behaviour. I review evidence how the aggregated Uncontrolled Eating has robust associations with body mass index, food intake, personality traits, and brain systems. I also map out Uncontrolled Eating’s behavioural similarity with other addictions and psychiatric conditions. In summary, Uncontrolled Eating summarises important behavioural aspects of obesity. [more]

The brain relies on glucose for fuel but has limited storage capacity. To facilitate adequate glucose availability, the brain senses glucose, initiates feeding behaviour, and controls system glucose metabolism. To date, the majority of studies investigating the sensing and central control of glucose have focused on the hypothalamus and the brainstem. However, recent findings have revealed an unexpected and fascinating role for the striatum, a brain nucleus mainly known for its role in reward behaviour, in glucose homeostasis. I will present a series of experiments, in both humans and rodents, supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. With rodent studies we also unraveled the neural route via which the striatum, and especially the nucleus accumbens shell, communicates with the liver to regulate glucose production. [more]

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When interacting with their environment animals constantly make decisions. These decisions frequently aim at maximizing reward while avoiding negative consequences such as energy costs, pain, or long-term disadvantages. Faced with a choice, animals consider and integrate several parameters such as their internal and behavioral state as well as external stimuli. Often decisions are shaped by prior experiences such as exposure to a given stimulus in a certain condition. But preferences and aversions can be innate, and an instinctive reaction can be essential to secure survival. Nevertheless, even these innate preferences need to be evaluated in a context-dependent manner and hence, context strongly impinges on behavior. While it is generally accepted that context influences behavior, our knowledge of the neural mechanisms of how internal state and external conditions alter ongoing behavior is scarce. The goal of my research is to provide a comprehensive understanding of the neural and molecular basis of context-specific behavior. To this end, my group studies how internal states shape chemosensory processing and behavior. In this talk, I will present two examples of our recent work in the fly on reproductive state-dependent decision making and on the role of need and motivation in foraging behavior. [more]

Mammals, including rodents show a broad range of defensive behaviors as a mean of coping with threatful stimuli including freezing and avoidance behaviors. Several studies emphasized the role of the dorsal medial prefrontal cortex (dmPFC) in encoding the acquisition as well as the expression of freezing behavior. However the role of this structure in processing avoidance behavior and the contribution of distinct prefrontal circuits to both freezing and avoidance responses are largely unknown. To further investigate the role of dmPFC circuits in encoding passive and active fear-coping strategies, we developed in the laboratory a novel behavioral paradigm in which a mouse has the possibility to choose either to passively freeze to an aversive stimulus or to actively avoid it as a function of contextual contingencies. Using this behavioral paradigm we investigated whether the same circuits mediate freezing and avoidance behaviors or if distinct neuronal circuits are involved. To address this question, we used a combination of behavioral, neuronal tracing, immunochemistry, single unit and patch clamp recordings and optogenetic approaches. Our results indicate that (i) dmPFC and dorsolateral and lateral periaqueductal grey (dl/lPAG) sub-regions are activated during avoidance behavior, (ii) a subpopulation of dmPFC neurons encode avoidance but not freezing behavior, (iii) this neuronal population project to the dl/lPAG, (iv) the optogenetic activation or inhibition of this pathway promoted and blocked the acquisition of conditioned avoidance and (v) avoidance learning was associated with the development of plasticity at dmPFC to dl/lPAG synapses. Together, these data demonstrate for the first time that activity-dependent plasticity in a subpopulation of dmPFC cells projecting to the dl/lPAG pathway controls avoidance learning. [more]

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Sleep architecture carries important information about brain health. Here we show that active compared to quiet sleep in infants heralds a marked change from long- to short-range functional connectivity across broad-frequency neural activity. This change in cortical connectivity is attenuated following preterm birth and pre-empts visual performance at two years. Biophysical modeling shows that active sleep is defined by reduced energy in a large-scale, uniform mode of spatiotemporal neural activity and increased energy in two non-uniform anteroposterior modes. This distinct energy redistribution leads to the emergence of more complex connectivity patterns in active sleep compared to quiet sleep. Preterm-born infants show an attenuation in this sleep-related reorganization of connectivity that carries novel prognostic information. [more]

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Late onset diseases such as cancer and neurodegenerative diseases represent an enormous burden in our ageing population. An in depth understanding of molecular pathomechanisms is a prerequisite for the development of novel treatment strategies. Our major research interest is in regulatory RNA-protein interactions, an important and often overlooked cellular phenomenon that plays an essential role in disease-development. RNA-function depends on the 3-dimensional structure of the RNA as well as on interaction with RNA-binding proteins. The main goal of our research is to identify and characterize regulatory RNA-protein interactions in healthy and disease tissue, especially in late onset diseases such as cancer and neurodegenerative diseases.In my group, we have identified an RNA-protein complex containing the ubiquitin ligase MID1 that plays an important role in regulating protein synthesis and that is significantly upregulated in late onset diseases including Huntington’s disease, Alzheimer’s disease or certain types of cancer. This aberrant MID1-activity leads to an increased protein production of proteins that are causal for disease-development.Thus, our data suggest that MID1 is a key regulator in disease development. Furthermore, our preliminary results indicate that MID1 localizes to cytosolic RNA granules and interacts with proteins involved in RNA granule assembly, RNA transport and local protein synthesis. In our ongoing experiments we further investigate the exact molecular function of MID1 and its interactome, especially focusing on the molecular pathways that are triggered by MID1 over-expression in disease tissue. Interestingly, these pathways include mTOR-signaling and insulin / insulin-like growth factor-1 (IGF-1) signaling pathways. [more]

Visceral organs have long been believed to act as major regulators of emotional state. However, the specific role of gut-borne signals in motivated behavior remains elusive to this day. The talk will describe the connectivity and behavioral functions of a neural circuit that links gut sensory neurons to brain reward systems. Implications for our current ideas on the role of the gut-brain axis will be discussed. [more]