Physiology seminars

My laboratory has made an intriguing discovery that mitochondrial stress in one tissue can be communicated to distal tissues. We find that mitochondrial stress in the nervous system triggers the production of entities known as mitokines. These mitokines are discharged from the nervous system, orchestrating a response in peripheral tissues that extends the lifespan of C. elegans. The revelation came as a surprise, given the prevalent belief that cell autonomous mechanisms would underlie the relationship between mitochondrial function and aging. It was also surprising given the prevailing dogma that mitochondrial function must be increased, not decreased, to improve health and longevity. Our work also underscores the fact that mitochondria, which originated as a microbial entity and later evolved into an intracellular symbiont, have retained their capacity for intercommunication, now facilitated by signals from the nervous system. We hypothesize that this communication has evolved as a mechanism to reduce infection from pathogens.

Various clinical cases have provided evidence linking cardiovascular, neurological, and psychiatric disorders to changes in the brain-heart interaction. Our recent experimental evidence on patients with disorders of consciousness revealed that observing brain-heart interactions helps to detect residual consciousness, even in patients with absence of behavioral signs of consciousness. Those findings support hypotheses suggesting that visceral activity is involved in the neurobiology of consciousness and sum to the existing evidence in healthy participants in which the neural responses to heartbeats reveal perceptual and self-consciousness. Furthermore, the presence of non-linear, complex, and bidirectional communication between brain and heartbeat dynamics can provide further insights into the physiological state of the patient following severe brain injury. These developments on methodologies to analyze brain-heart interactions open new avenues for understanding neural functioning at a large-scale level, uncovering that peripheral bodily activity can influence brain homeostatic processes, cognition, and behavior.

The neurobiological mechanisms of arousal and anesthesia remain poorly understood. Recent evidence highlights the key role of interactions between the cerebral cortex and the diffusely projecting matrix thalamic nuclei. Here, we interrogate these processes in a whole-brain corticothalamic neural mass model endowed with targeted and diffusely projecting thalamocortical nuclei inferred from empirical data. This model captures key features seen in propofol anesthesia, including diminished network integration, lowered state diversity, impaired susceptibility to perturbation, and decreased corticocortical coherence. Collectively, these signatures reflect a suppression of information transfer across the cerebral cortex. We recover these signatures of conscious arousal by selectively stimulating the matrix thalamus, recapitulating empirical results in macaque, as well as wake-like information processing states that reflect the thalamic modulation of largescale cortical attractor dynamics. Our results highlight the role of matrix thalamocortical projections in shaping many features of complex cortical dynamics to facilitate the unique communication states supporting conscious awareness.

Humans and other animals evolved in habitats fraught with a range of environmental challenges to their bodies and brains. Accordingly, cells and organ systems possess adaptive stress-responsive signaling pathways that enable them to not only withstand environmental challenges, but also to prepare for future challenges and function more efficiently. These phylogenetically conserved processes are the foundation of the hormesis principle in which repeated exposures to low to moderate amounts of an environmental challenge improve cellular and organismal fitness. Here I describe cellular and molecular mechanisms by which cells in the brain and body respond to intermittent fasting and exercise in ways that enhance performance and counteract aging and disease processes. Switching back and forth between adaptive stress response (during fasting and exercise) and growth and plasticity (eating, resting, sleeping) modes enhances the performance and resilience of various organ systems. While pharmacological interventions that engage a particular hormetic mechanism are being developed, it seems unlikely that any will prove superior to fasting and exercise.

On a fast timescale, neurons mostly interact by short, stereotypical electrical impulses or spikes. Why? A common answer is that spikes are useful for long-distance communication, to avoid alterations while traveling along axons. But as it turns out, spikes are seen in many places outside neurons: in the heart, in muscles, in plants and even in protists. From these examples, it appears that action potentials mediate some form of coordinated action, a timed event. From this perspective, spikes should not be seen simply as noisy implementations of underlying continuous signals (a sort of analog-to-digital conversion), but rather as events or actions. I will give a number of examples of functional spike-based interactions in living systems.

The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.

In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses, and electrically through potassium-evoked currents that are amplified through gap-junctional coupling between tumor cells This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.

Like all neural tissue, the retina has a high metabolic demand, and requires a constant supply of oxygen. Second and third order neurons are supplied by the retinal circulation, whose characteristics are similar to brain circulation. However, the photoreceptor region, which occupies half of the retinal thickness, is avascular, and relies on diffusion of oxygen from the choroidal circulation, whose properties are very different, as well as the retinal circulation. By fitting diffusion models to oxygen measurements made with oxygen microelectrodes, it is possible to understand the relative roles of the two circulations under normal conditions of light and darkness, and what happens if the retina is detached or the retinal circulation is occluded. Most of this work has been done in vivo in rat, cat, and monkey, but recent work in the isolated mouse retina will also be discussed.

Gut-derived signals regulate metabolism, appetite, and behaviors important for mental health. We have performed a large-scale multidimensional screen to identify gut hormones and nutrient-sensing mechanisms in the intestine that regulate metabolism and behavior in the fruit fly Drosophila. We identified several gut hormones that affect fecundity, stress responses, metabolism, feeding, and sleep behaviors, many of which seem to act sex-specifically. We show that in response to nutrient intake, the enteroendocrine cells (EECs) of the adult Drosophila midgut release hormones that act via inter-organ relays to coordinate metabolism and feeding decisions. These findings suggest that crosstalk between the gut and other tissues regulates food choice according to metabolic needs, providing insight into how that intestine processes nutritional inputs and into the gut-derived signals that relay information regulating nutrient-specific hungers to maintain metabolic homeostasis.

The peripheral airways are technically challenging to assess and have been overlooked in the assessment of chronic respiratory diseases such as Asthma, in both the clinical and research space. Evidence of the importance of the small airways in Asthma is building, and small airways dysfunction is implicated in poor Asthma control, airway hyperresponsiveness, and exacerbation risk. The aim of this research was to complete comprehensive global, regional, and spatial assessments of airway function and ventilation in Asthma using physiological and MRI techniques. Specific ventilation imaging (SVI) and Phase resolved functional lung imaging (PREFUL) formed the spatial assessments. SVI uses oxygen as a contrast agent and looks at rate of change in signal to assess ventilation heterogeneity, PREFUL is a completely contrast free technique that uses Fourier decomposition to determine fractional ventilation.

Neurodegenerative diseases are chronic and inexorable conditions characterised by the presence of insoluble aggregates of abnormally ubiquinated and phosphorylated proteins. Recent evidence also suggests that protein misfolding can propagate throughout the body in a prion-like fashion via the interstitial or cerebrospinal fluids (CSF). As protein aggregation occurs well before the onset of brain damage and symptoms, new biomarkers sensitive to early pathology, together with therapeutic strategies that include eliminating seed proteins and blocking cell-to-cell spread, are of vital importance. The glymphatic system, which facilitates the continuous exchange of CSF and interstitial fluid to clear the brain of waste, presents as a potential biomarker of disease severity, therapeutic target, and drug delivery system. In this webinar, Associate Professor David Wright from the Department of Neuroscience, Monash University, will outline recent advances in using MRI to investigate the glymphatic system. He will also present some of his lab’s recent work investigating glymphatic clearance in preclinical models of motor neurone disease. Associate Professor David Wright is an NHMRC Emerging Leadership Fellow and the Director of Preclinical Imaging in the Department of Neuroscience, Monash University and the Alfred Research Alliance, Alfred Health. His research encompasses the development, application and analysis of advanced magnetic resonance imaging techniques for the study of disease, with a particular emphasis on neurodegenerative disorders. Although less than three years post PhD, he has published over 60 peer-reviewed journal articles in leading neuroscience journals such as Nature Medicine, Brain, and Cerebral Cortex.

Beyond vision, light triggers a variety of non-image forming responses. Amongst these is the pupillary light reflex, commonly used by ophthalmologists to gauge the function of the optic nerve head. In my talk, I will share some of our latest work on optimizing the use of the pupillary light reflex to detect functional loss in ocular diseases in clinics.

A critical function of sensory systems is to reliably extract ethologically relevant features from the complex natural environment. A classic model to study feature detection is the direction-selective circuit of the mammalian retina. In this talk, I will discuss our recent work on how visual contexts dynamically influence the neural processing of motion signals in the direction-selective circuit in the mouse retina.

Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer’s disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. We found evidence that the cerebrovasculature is an important target of circulatory factors and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. Furthermore, plasma proteins are taken up broadly into the young brain through receptor mediated transport which declines with aging. At the same time, brain derived proteins are detectable in plasma allowing us to measure physiological changes linked to brain aging in plasma. We are exploring the relevance of these findings for neurodegeneration and potential applications towards therapies.

Liset M de la Prida is a Physicist (1994) and PhD in Neuroscience (1998), who leads the Laboratorio de Circuitos Neuronales at the Instituto Cajal, Madrid, Spain (http://www.hippo-circuitlab.es). The main focus of her lab is to understand the function of the hippocampal circuits in the normal and the diseased brain, in particular oscillations and neuronal representations. She is a leading international expert in the study of the basic mechanisms of physiological ripples and epileptic fast ripples, with strong visibility as developer of novel groundbreaking electrophysiological tools. Dr. de la Prida serves as an Editor for prestigious journals including eLife, Journal of Neuroscience Methods and eNeuro, and has commissioning duties in the American Epilepsy Society, FENS and the Spanish Society for Neurosciences.

The research in my lab focuses on sensory signal processing, particularly in cases where sensory systems perform at or near the limits imposed by physics. Photon counting in the visual system is a beautiful example. At its peak sensitivity, the performance of the visual system is limited largely by the division of light into discrete photons. This observation has several implications for phototransduction and signal processing in the retina: rod photoreceptors must transduce single photon absorptions with high fidelity, single photon signals in photoreceptors, which are only 0.03 – 0.1 mV, must be reliably transmitted to second-order cells in the retina, and absorption of a single photon by a single rod must produce a noticeable change in the pattern of action potentials sent from the eye to the brain. My approach is to combine quantitative physiological experiments and theory to understand photon counting in terms of basic biophysical mechanisms. Fortunately there is more to visual perception than counting photons. The visual system is very adept at operating over a wide range of light intensities (about 12 orders of magnitude). Over most of this range, vision is mediated by cone photoreceptors. Thus adaptation is paramount to cone vision. Again one would like to understand quantitatively how the biophysical mechanisms involved in phototransduction, synaptic transmission, and neural coding contribute to adaptation.