Gliomas are brain tumors formed by networks of connected tumor cells, nested in and interacting with neuronal networks. Neuronal activities interfere with tumor growth and occurrence of seizures affects glioma prognosis, while the developing tumor triggers seizures in the infiltrated cortex. Oncometabolites produced by tumor cells and neurotransmitters affect both the generation of epileptic activities by neurons and the growth of glioma cells through synaptic-related mechanisms, involving both GABAergic / Chloride pathways and glutamatergic signaling. From a clinical sight, epilepsy occurrence is beneficial to glioma prognosis but growing tumors are epileptogenic, which constitutes a paradox. This lecture will review how inhibitory and excitatory signaling drives glioma growth and how epileptic and oncological processes are interfering, with a special focus on the human brain.

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.

Within the vertebrate neocortex and other telencephalic structures, molecularly-defined neurons tend to segregate at first order into GABAergic types and glutamatergic types. Two fundamental questions arise: (1) do non-telencephalic neurons similarly segregate by neurotransmitter status, and (2) do GABAergic (or glutamatergic) types sampled in different structures share many molecular features in common, beyond the few genes directly responsible for neurotransmitter synthesis and release? To address these questions, we used single-nucleus RNA sequencing, analyzing over 2.4 million brain cells sampled from 16 locations in a primate (the common marmoset). Unexpectedly, we find the answer to both is “no”. I will discuss implications for generalizing associations between neurotransmitter utilization and other phenotypes, and share ongoing efforts to map the biodistributions of cell types in the primate brain.

Evolutionarily, the expansion of the human neocortex accounts for many of the unique cognitive abilities of humans. This expansion appears to reflect the increased proliferative potential of basal progenitors (BPs) in mammalian evolution. Further cortical progenitors generate both glutamatergic excitatory neurons (ENs) and GABAergic inhibitory interneurons (INs) in human cortex, whereas they produce exclusively ENs in rodents. The increased proliferative capacity and neuronal subtype generation of cortical progenitors in mammalian evolution may have evolved through epigenetic alterations. However, whether or how the epigenome in cortical progenitors differs between humans and other species is unknown. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in amplification, neuronal subtype generation and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Furthermore, we found that the elevated H3 acetylation activates expression of IN genes in in developing mouse cortex and promote proliferation of IN progenitor-like cells in cortex of Pax6 mutant mouse models. Mechanistically, H3K9ac drives the BP amplification and proliferation of these IN progenitor-like cells by increasing expression of the evolutionarily regulated gene, TRNP1. Our findings demonstrate a previously unknown mechanism that controls neocortex expansion and generation of neuronal subtypes. Keywords: Cortical development, neurogenesis, basal progenitors, cortical size, gyrification, excitatory neuron, inhibitory interneuron, epigenetic profiling, epigenetic regulation, H3 acetylation, H3K9ac, TRNP1, PAX6

Normative development in adolescence indicates that the prefrontal cortex is still under development thereby unable to exert efficient top-down inhibitory control on subcortical regions such as the basolateral amygdala and the nucleus accumbens. This imbalance in the developmental trajectory between cortical and subcortical regions is implicated in expression of the prototypical impulsive, compulsive, reward seeking and risk-taking adolescent behavior. Here we demonstrate that a chronic mild unpredictable stress procedure during adolescence in male Wistar rats arrests the normal behavioral maturation such that they continue to express adolescent-like impulsive, hyperactive, and compulsive behaviors into late adulthood. This arrest in behavioral maturation is associated with the hypoexcitability of prelimbic cortex (PLC) pyramidal neurons and reduced PLC-mediated synaptic glutamatergic control of BLA and nucleus accumbens core (NAcC) neurons that lasts late into adulthood. At the same time stress exposure in adolescence results in the hyperexcitability of the BLA pyramidal neurons sending stronger glutamatergic projections to the NAcC. Chemogenetic reversal of the PLC hypoexcitability decreased compulsivity and improved the expression of goal-directed behavior in rats exposed to stress during adolescence, suggesting a causal role for PLC hypoexcitability in this stress-induced arrested behavioral development. (https://www.biorxiv.org/content/10.1101/2021.11.21.469381v1.abstract)

Neurons in the suprachiasmatic nucleus (SCN, the brain’s master circadian clock) display a 24 hour cycle in the their rate of action potential discharge whereby firing rates are high during the light phase and lower during the dark phase. Although it is generally agreed that this cycle of activity is a key mediator of the clock’s neural and humoral output, surprisingly little is known about how changes in clock electrical activity can mediate scheduled physiological changes at different times of day. Using opto- and chemogenetic approaches in mice we have shown that the onset of electrical activity in vasopressin releasing SCN neurons near Zeitgeber time 22 (ZT22) activates glutamatergic thirst-promoting neurons in the OVLT (organum vasculosum lamina terminalis) to promote water intake prior to sleep. This effect is mediated by activity-dependent release of vasopressin from the axon terminals of SCN neurons which acts as a neurotransmitter on OVLT neurons. More recently we found that the clock receives excitatory input from a different subset of sodium sensing neurons in the OVLT. Activation of these neurons by a systemic salt load delivered at ZT19 stimulated the electrical activity of SCN neurons which are normally silent at this time. Remarkably, this effect induced an acute reduction in non-shivering thermogenesis and body temperature, which is an adaptive response to the salt load. These findings provide information regarding the mechanisms by which the SCN promotes scheduled physiological rhythms and indicates that the clock’s output circuitry can also be recruited to mediate an unscheduled homeostatic response.

Many studies have investigated the major glutamatergic inputs to the cerebellum, mossy fibres and climbing fibres, however far less is known about its neuromodulatory inputs. In particular, anatomical studies have described cholinergic input to the cerebellum, yet little is known about its role(s). In this talk, I will present our recent findings which demonstrate that manipulating acetylcholine receptors in the cerebellum causes effects at both a cellular and behavioural level. Activating acetylcholine receptors alters the intrinsic properties and synaptic inputs of cerebellar output neurons, and blocking these receptors results in deficits in a range of behavioural tasks.

The ability to encode the direction of image motion is fundamental to our sense of vision. Direction selectivity along the four cardinal directions is thought to originate in direction-selective ganglion cells (DSGCs), due to directionally-tuned GABAergic suppression by starburst cells. Here, by utilizing two-photon glutamate imaging to measure synaptic release, we reveal that direction selectivity along all four directions arises earlier than expected, at bipolar cell outputs. Thus, DSGCs receive directionally-aligned glutamatergic inputs from bipolar cell boutons. We further show that this bouton-specific tuning relies on cholinergic excitation and GABAergic inhibition from starburst cells. In this way, starburst cells are able to refine directional tuning in the excitatory visual pathway by modulating the activity of DSGC dendrites and their axonal inputs using two different neurotransmitters.

Neural and behavioral responses to sensory stimuli are notoriously variable from trial to trial. Does this mean the brain is inherently noisy or that we don’t completely understand the nature of the brain and behavior? Here we monitor the state of activity of the animal through videography of the face, including pupil and whisker movements, as well as walking, while also monitoring the ability of the animal to perform a difficult auditory or visual task. We find that the state of the animal is continuously changing and is never stable. The animal is constantly becoming more or less activated (aroused) on a second and subsecond scale. These changes in state are reflected in all of the neural systems we have measured, including cortical, thalamic, and neuromodulatory activity. Rapid changes in cortical activity are highly correlated with changes in neural responses to sensory stimuli and the ability of the animal to perform auditory or visual detection tasks. On the intracellular level, these changes in forebrain activity are associated with large changes in neuronal membrane potential and the nature of network activity (e.g. from slow rhythm generation to sustained activation and depolarization). Monitoring cholinergic and noradrenergic axonal activity reveals widespread correlations across the cortex. However, we suggest that a significant component of these rapid state changes arise from glutamatergic pathways (e.g. corticocortical or thalamocortical), owing to their rapidity. Understanding the neural mechanisms of state-dependent variations in brain and behavior promises to significantly “denoise” our understanding of the brain.

How are actions linked with subsequent outcomes to guide choices? The nucleus accumbens (NAc), which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex (PL) and midline regions of the thalamus (mTH). However, little is known about what is represented in PL or mTH neurons that project to NAc (PL-NAc and mTH-NAc). By comparing these inputs during a reinforcement learning task in mice, we discovered that i) PL-NAc preferentially represents actions and choices, ii) mTH-NAc preferentially represents cues, iii) choice-selective activity in PL-NAc is organized in sequences that persist beyond the outcome. Through computational modelling, we demonstrate that these sequences can support the neural implementation of temporal difference learning, a powerful algorithm to connect actions and outcomes across time. Finally, we test and confirm predictions of our circuit model by direct manipulation of PL-NAc neurons. Thus, we integrate experiment and modelling to suggest a neural solution for credit assignment.