Workshop: Mechanisms of CNS Transient Dynamics

Title: (Nested) transients in the visual system: we observe them... do we need them?

Abstract: Brain rhythms have frequently been described as sustained phenomena. Yet, upon detailed examination, it becomes apparent that these rhythms typically manifest as transient events, with various frequencies nested within one another. In my presentation, I will present data collected over the years that illustrate this complex structure for gamma, beta, and alpha frequencies.

The discussion will finish with theoretical perspectives on why these brain activities might be transient, rather than sustained, to enable the brain to process intricate visual information, such as visual scenes.

Title: Circuit mechanisms of transient population responses in the auditory cortex

Abstract: Across sensory systems, transient patterns of neural activity arise following the onset (ON) and offset (OFF) of stimuli. While ON responses have been widely studied, the mechanisms generating OFF responses in cortical areas have not been fully elucidated. We examine the hypothesis that transient OFF responses are generated through recurrent network interactions. To test this hypothesis, we performed population analyses of two-photon calcium recordings in the auditory cortex of awake mice listening to auditory stimuli. We find that network models can generate strongly transient population activity at stimulus offset, and account for the low-dimensional organization of population responses and their global structure across stimuli.

Title: Beta bursts: does diversity in waveform = diversity in function?

Abstract: Neural activity in several frequency bands, most notably beta, has recently been more widely acknowledged to occur as transient burst events. Beta band power has been implicated in a wide range of cognitive processes, which makes it difficult to determine its precise computational functional role. Many studies that do take into account the transient nature of beta activity tend to detect only high amplitude bursts, and treat them as homogeneous events. I will present a new method for burst detection that does not rely on fixed power thresholds, and an analysis that separates bursts based on their waveform shape. I will then present the results from several studies showing that bursts with different waveform shapes exhibit a range of rate dynamics prior to and during movement, suggesting that they may play different functional roles in sensorimotor processes. Finally, I will show how these waveform-specific rate dynamics can be leveraged to achieve accuracy levels equivalent to, or exceeding, the state of the art in noninvasive decoding of imagined movement. Taken together, these results suggest that burst waveforms might provide a window onto cortical circuit activity, and that the wide range of functional roles ascribed to beta power may be due to a consequence of the overzealous application of the Fourier transform and the natural time scale of cortical dynamics.

Title: Basal ganglia neuromodulators: Transient signals for long lasting effects?

Abstract: Humans and animals are confronted with complex inputs from their environment, which demand a single response. Typically, chosen responses are those that yield favorable outcomes or reinforcement. This form of control involves action-selection through cortico-basal ganglia-cortical circuit. The basal ganglia are the also the main brain target for neuromodulation, predominantly by dopamine and acetylcholine. These neuromodulatory inputs origins are very different: while dopamine is released from projections of the midbrain structures of the VTA and SNc, acetylcholine is produced locally by striatal cholinergic interneurons. Both inputs have a tonically active mode, interrupted by transient signals in response to behaviorally relevant events. Curiously, although the cell bodies of dopamine neurons and of cholinergic interneurons are very distant, these transient signals coincide temporally and their outputs are spatially co-localized. Physiologically, these dopaminergic and cholinergic inputs have complex reciprocal interactions but the immediate and long-term cognitive effect of this interaction is unclear. In this talk I will present results from non-human primate and rodent recordings of dopamine and acetylcholine neurons and the effects of their activity on neural representation in the striatum and the hippocampus. With this, I will propose a framework for the distinct roles of the dopamine and acetylcholine transient signals for the learning of value and of attention.

Title: A potential angiogenic role for early spontaneous activity in the immature central nervous system

Abstract: Intense spontaneous neural bursting activity is omnipresent in the developing central nervous system. It is well established that it occurs during short “critical” periods of synaptogenesis, enabling Hebbian wiring of network connectivity. At the same time, by continuously producing strong bursting episodes, developing neurones are extremely energy-demanding. Resting ionic levels are restored via metabolic pumps that receive the necessary energy from oxygen supplied by blood vessels. Not surprisingly, angiogenesis occurs precisely while immature neurons are spontaneously active, suggesting that early neural activity per se may guide blood vessels development. However, remarkably little is known about this potentially important role for early neural activity. We investigate these questions in the neonatal mouse retina, where blood vessels initially grow in a superficial plane, while waves of spontaneous activity sweep across the retinal ganglion cell layer (GCL), just underneath the growing vasculature. We discovered transient clusters of auto-fluorescent cellular complexes in the GCL, forming an annulus around the optic disc, gradually expanding to the periphery. Remarkably, they appear locked to the frontline of the growing vasculature, reaching the periphery by P7-8, after which they completely disappear. Large-scale pan-retinal multielectrode array recordings and calcium imaging of the waves reveal that their initiation points are localized just outside the outer edge of the growing superficial vascular plexus and follow a developmental center-to-periphery pattern similar to the clusters and blood vessels. Blocking Pannexin1 (PANX1) hemichannels activity with probenecid significantly decreases wave frequency. Single-cell RNA sequencing derived from auto-fluorescent clusters reveals that they express genes related to microglia, neurones, endothelial cells and apoptosis. Moreover, they specifically co-localise with Heme oxygenase (HO)-1 expressing microglia that form a large annulus around the growing superficial vascular plexus. The autofluorescent clusters are preferentially found at the outer edge of the HO-1 microglia population. Closer inspection reveals that the autofluorescence signal resides in vacuoles within HO-1 microglia, indicating metabolic stress and ensuing phagocytosis.

These observations suggest that during early stages of spontaneous activity in the neonatal retina, transient hyperactive cells in the GCL are responsible for generating retinal waves in activity hotspots that reside outside the growing vasculature. These hotspots of intense neural activity attract new blood vessels to increase local oxygen supply. These hyperactive cells express PANX-1 hemichannels that release ATP (or other purinergic agonists) upon depolarization, attracting HO-1 microglia that establish contact with these cells, eventually eliminating them once blood vessels have reached their vicinity. We propose that this mechanism may be universal in the developing CNS, where blood vessels are known to invade neural territories once neurones become electrically active.

Title: Unraveling the Complexity of Brainstem-Spinal Locomotor Control

Abstract: All animals must adapt their locomotion for various tasks such as changing speeds, gaits, and directions. This adaptation relies on the dynamic activity of neural circuits in the spinal cord and brainstem.

Experimental studies, aided by targeted genetic approaches, have revealed specific neuronal populations within the spinal cord and brainstem that play key roles in generating and controlling locomotor dynamics such as gait and speed transitions or changing the direction of movement.

However, the complexity of these circuits poses a challenge for experimental methods alone. To gain deeper insights, we use computational modeling to explore how these neuronal populations interact and coordinate locomotor behaviors. By integrating data from multiple sources, our models provide valuable insights into the organization and function of these circuits, shedding light on the mechanisms underlying brainstem-spinal locomotor control.