Neuroscience seminars

Vision starts in the retina where images are transformed and coded into neuronal activity relevant for the brain. These coding steps function optimally over a wide range of conditions: from bright day on the beach to a moonless night. Under these very different conditions, specific retinal mechanisms continue to select relevant aspects of the visual world and send this information to the brain. We are studying the neuronal processing involved in these selection and adaptation processes. This knowledge is essential for understanding how the visual system works and forms the basis for research dedicated to restoring vision in blind people.

Desde la investigación en antropología evolutiva, las neurociencias del comportamiento parental y los estudios de cohortes de orfelinatos, los nuevos conocimientos confluyen en la mayor importancia critica del periodo postnatal inmediato para el desarrollo social humano. Surge la explicación biológica de la interdependencia de los cambios comportamentales en los adultos que crían y el recién nacido: Nature of Nurture. Del concepto unidireccional clásico de la necesidad de estimular un cerebro inmaduro, se comienza a comprender la naturaleza de la interacción en red entre el cerebro neonatal y el cerebro parental que también debe ser estimulado. Concebir, engendra y criar son etapas sucesivas de la reproducción pero no indispensablemente continuas. La función parental es primariamente dependiente de la disponibilidad para cuidar al recién nacido.

Behavioral states such as arousal and attention can have profound effects on sensory processing, determining how – sometimes whether – a stimulus is processed. This state-dependence is believed to arise, at least in part, as a result of inputs to cortex from subcortical structures that release neuromodulators such as acetylcholine, noradrenaline, and serotonin, often non-synaptically. The mechanisms that underlie the interaction between these “wireless” non-synaptic signals and the “wired” cortical circuit are not well understood. Furthermore, neuromodulatory signaling is traditionally considered broad in its impact across cortex (within a species) and consistent in its form and function across species (at least in mammals). The work I will present approaches the challenge of understanding neuromodulatory action in the cortex from a number of angles: anatomy, physiology, pharmacology, and chemistry. The overarching goal of our effort is to elucidate the mechanisms behind local neuromodulation in the cortex of non-human primates, and to reveal differences in structure and function across cortical model systems.

Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.

Over the last several decades, the tractable response properties of parahippocampal neurons have provided a new access key to understanding the cognitive process of self-localization: the ability to know where you are currently located in space. Defined by functionally discrete response properties, neurons in the medial entorhinal cortex and hippocampus are proposed to provide the basis for an internal neural map of space, which enables animals to perform path-integration based spatial navigation and supports the formation of spatial memories. My lab focuses on understanding the mechanisms that generate this neural map of space and how this map is used to support behavior. In this talk, I’ll discuss how learning and experience shapes our internal neural maps of space to guide behavior.

In this talk series, addiction neuroscientists from across the world share their personal stories/experiences on the beauty of addiction neuroscience and how/why they have decided to invest their scientific life in this field. We hope that this talk series would encourage and support a new generation of young and passionate addiction neuroscientists in different countries to revolutionize the field of addiction medicine.

Recent human gene discovery efforts show that gain-of-function (GOF) variants in the KCNT1gene, which encodes a Na+-activated K+ channel subunit, cause severe epilepsies and other neurodevelopmental disorders. Although the impact of these variants on the biophysical properties of the channels is well characterized, the mechanisms that link channel dysfunction to cellular and network hyperexcitability and human disease are unknown. Furthermore, precision therapies that correct channel biophysics in non-neuronal cells have had limited success in treating human disease, highlighting the need for a deeper understanding of how these variants affect neurons and networks. To address this gap, we developed a new mouse model with a pathogenic human variant knocked into the mouse Kcnt1gene. I will discuss our findings on the in vivo phenotypes of this mouse, focusing on our characterization of epileptiform neural activity using electrophysiology and widefield Ca++imaging. I will also talk about our investigations at the synaptic, cellular, and circuit levels, including the main finding that cortical inhibitory neurons in this model show a reduction in intrinsic excitability and action potential generation. Finally, I will discuss future directions to better understand the mechanisms underlying the cell-type specific effects, as well as the link between the cellular and network level effects of KCNT1 GOF.

Investigations of the neurophysiological processes underlying animal behaviors are almost exclusively done inside the laboratory, typically using few animal models born and reared under artificially stabilized conditions. Yet, animals living in the wild have to cope with much complex and variable environments. Thus, while the laboratory provides the technical possibilities for physiological research, the field offers a more realistic perspective about the animal´s behavioral abilities. We study neural circuits underlying the visually guided prey and predator behaviors in a semiterrestrial crab. By combining lab and field experiments we have, for example, found that the level of predation risk experienced by the animals in the wild affects the responsiveness of identified neurons involved in the animal escape response. Using this and other results from my lab I will illustrate and discuss the importance of complementing lab with field studies in wild animals for understanding the neural mechanisms subserving behavior.

Each day we experience myriad somatosensory stimuli: hugs from loved ones, warm showers, a mosquito bite, and sore muscles after a workout. These tactile, thermal, itch, and nociceptive signals are detected by peripheral sensory neuron terminals distributed throughout our body, propagated into the spinal cord, and then transmitted to the brain through ascending spinal pathways. Primary sensory neurons that detect a wide range of somatosensory stimuli have been identified and characterized. In contrast, very little is known about how peripheral signals are integrated and processed within the spinal cord and conveyed to the brain to generate somatosensory perception and behavioral responses. We tackled this question by developing new mouse genetic tools to define projection neuron (PN) subsets of the anterolateral pathway, a major ascending spinal cord pathway, and combining these new tools with advanced anatomical, physiological, and behavioral approaches. We found that Gpr83+ PNs, a newly identified subset of spinal cord output neurons, and Tacr1+ PNs are largely non-overlapping populations that innervate distinct sets of subnuclei within the lateral parabrachial nucleus (PBNL) of the pons in a zonally segregated manner. In addition, Gpr83+ PNs are highly sensitive to cutaneous mechanical stimuli, receive strong synaptic inputs from primary mechanosensory neurons, and convey tactile information bilaterally to the PBNL in a non-topographically organized manner. Remarkably, Gpr83+ mechanosensory limb of the anterolateral pathway controls behaviors associated with different hedonic values (appetitive or aversive) in a scalable manner. This is the first study to identify a dedicated spinal cord output pathway that conveys affective touch signals to the brain and to define parallel ascending circuit modules that cooperate to convey tactile, thermal and noxious cutaneous signals from the spinal cord to the brain. This study has also revealed exciting new therapeutic opportunities for developing treatments for neurological disorders associated with pain and affective touch.

Mammalian babies are “sensory traps” for parents. Various sensory cues from the newborn are tremendously efficient in triggering parental responses in caregivers. We recently showed that core aspects of maternal behavior such as pup retrieval in response to infant vocalizations rely on active learning of auditory cues from pups facilitated by the neurohormone oxytocin (OT). Release of OT from the hypothalamus might thus help induce recognition of different infant cues but it is unknown what sensory stimuli can activate OT neurons. I performed unprecedented in vivo whole-cell and cell-attached recordings from optically-identified OT neurons in awake dams. I found that OT neurons, but not other hypothalamic cells, increased their firing rate after playback of pup distress vocalizations. Using anatomical tracing approaches and channelrhodopsin-assisted circuit mapping, I identified the projections and brain areas (including inferior colliculus, auditory cortex, and posterior intralaminar thalamus) relaying auditory information about social sounds to OT neurons. In hypothalamic brain slices, when optogenetically stimulating thalamic afferences to mimic high-frequency thalamic discharge, observed in vivo during pup calls playback, I found that thalamic activity led to long-term depression of synaptic inhibition in OT neurons. This was mediated by postsynaptic NMDARs-induced internalization of GABAARs. Therefore, persistent activation of OT neurons following pup calls in vivo is likely mediated by disinhibition. This gain modulation of OT neurons by infant cries, may be important for sustaining motivation. Using a genetically-encoded OT sensor, I demonstrated that pup calls were efficient in triggering OT release in downstream motivational areas. When thalamus projections to hypothalamus were inhibited with chemogenetics, dams exhibited longer latencies to retrieve crying pups, suggesting that the thalamus-hypothalamus noncanonical auditory pathway may be a specific circuit for the detection of social sounds, important for disinhibiting OT neurons, gating OT release in downstream brain areas, and speeding up maternal behavior.

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s disease called “Logopenic Progressive Aphasia”, which presents with temporo-parietal atrophy yet relative sparing of hippocampal circuitry. Siddharth will discuss how, despite the unusual anatomical basis underlying this AD variant, degeneration of the angular gyrus in the left inferior parietal lobule contributes to memory deficits similar to those of typical amnesic Alzheimer’s disease. Christiana’s abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes severe deterioration of memory, cognition, behavior, and the ability to perform daily activities. The disease is characterized by the accumulation of two proteins in fibrillar form; Amyloid-β forms fibrils that accumulate as extracellular plaques while tau fibrils form intracellular tangles. Here we aim to translate findings from a commonly used AD mouse model to AD patients. Here we initiate and chronically inhibit neuropathology in lateral entorhinal cortex (LEC) layer two neurons in an AD mouse model. This is achieved by over-expressing P301L tau virally and chronically activating hM4Di DREADDs intracranially using the ligand dechloroclozapine. Biomarkers in cerebrospinal fluid (CSF) is measured longitudinally in the model using microdialysis, and we use this same system to intracranially administer drugs aimed at halting AD-related neuropathology. The models are additionally tested in a novel contextual memory task. Preliminary findings indicate that viral injections of P301L tau into LEC layer two reveal direct projections between this region and the outer molecular layer of dentate gyrus and the rest of hippocampus. Additionally, phosphorylated tau co-localize with ‘starter cells’ and appear to spread from the injection site. Preliminary microdialysis results suggest that the concentrations of CSF amyloid-β and tau proteins mirror changes observed along the disease cascade in patients. The disease-modifying drugs appear to halt neuropathological development in this preclincial model. These findings will lead to a novel platform for translational AD research, linking the extensive research done in rodents to clinical applications. Siddharth’s abstract: A distributed brain network supports our ability to remember past events. The parietal cortex is a critical member of this network, yet, its exact contributions to episodic remembering remain unclear. Neurodegenerative syndromes affecting the posterior neocortex offer a unique opportunity to understand the importance and role of parietal regions to episodic memory. In this talk, I introduce and explore the rare neurodegenerative syndrome of Logopenic Progressive Aphasia (LPA), an aphasic variant of Alzheimer’s disease presenting with early, left-lateralized temporo-parietal atrophy, amidst relatively spared hippocampal integrity. I then discuss two key studies from my recent Ph.D. work showcasing pervasive episodic and autobiographical memory dysfunction in LPA, to a level comparable to typical, amnesic Alzheimer’s disease. Using multimodal neuroimaging, I demonstrate how degeneration of the angular gyrus in the left inferior parietal lobule, and its structural connections to the hippocampus, contribute to amnesic profiles in this syndrome. I finally evaluate these findings in the context of memory profiles in other posterior cortical neurodegenerative syndromes as well as recent theoretical models underscoring the importance of the parietal cortex in the integration and representation of episodic contextual information.

The speakers will outline how neurologists in Bristol have been research-active during the COVID-19 pandemic including our contribution to national and international surveillance programmes as well as initiating research studies such as an evaluation of the impact of COVID anxiety on sleep and neurodegeneration and determining whether vascular changes in the eye predict COVID-19 severity.

Axons degenerate before the neuronal soma in many neurodegenerative diseases. Programmed axon death (Wallerian degeneration) is a widely-occurring mechanism of axon loss that is well understood and preventable in animals. Its aberrant activation by mutation of the pro-survival gene Nmnat2 directly causes axonopathy in mice with severity ranging from mild polyneuropathy to perinatal lethality. Rare biallelic mutations in the homologous human gene cause related phenotypes in patients. NMNAT2 is a negative regulator of the prodegenerative NADase SARM1. Constitutive activation of SARM1 is cytotoxic and the human SARM1 locus is significantly associated with sporadic ALS. Another negative regulator, STMN2, has also been implicated in ALS, where it is commonly depleted downstream of TDP-43. In mice, programmed axon death can be robustly blocked by deletion of Sarm1, or by overexpression, axonal targeting and/or stabilization of various NMNAT isoforms. This alleviates models of many human disorders including some forms of peripheral neuropathy, motor neuron diseases, glaucoma, Parkinson’s disease and traumatic brain injury, and it confers lifelong rescue on the lethal Nmnat2 null phenotype and other conditions. Drug discovery programs now aim to achieve similar outcomes in human disease. In order to optimize the use of such drugs, we have characterized a range of human NMNAT2 and SARM1 functional variants that underlie a spectrum of axon vulnerability in the human population. Individuals at the vulnerable end of this spectrum are those most likely to benefit from drugs blocking programmed axon death, and disorders associated with these genotypes are promising indications in which to apply them.