Homeostasis and self-regulation of developing circuits: from single neurons to networks

3 March, 2014
at CoSyNe


This workshop will address common mechanisms governing the activity-dependent organization and tuning of neural circuits during development. It will focus on two main themes:

Multiple forms of plasticity, including Hebbian and homeostatic rules, not only sculpt out and refine the connectivity of neural circuits, but also influence single neuron physiology and thus determine neural computations. This interplay of different activity-dependent mechanisms, together with genetic and molecular specification of neural properties, complicates the interpretation of experimental manipulations. Theoretical approaches, ranging from mechanistic models to conceptual frameworks, have played an important role in disentangling the contributions and roles of different mechanisms. Here we aim to bring together scientists from experimental and theoretical communities to expose recent progress and to discuss current open questions.


Morning Session
08:00 - Introduction
08:10 - Timothy O'Leary - Brandeis University: Neuronal variability, cell types, network homeostasis and pathological compensation from a simple, biologically plausible ion channel expression model
08:45 - Alex Ward - Stanford University: Establishing wiring specificity in the fly olfactory system.
09:20 - Break
09:40 - Joel Tabak - Florida State University: A universal pattern of activity in developing neural networks?
10:15 - Christian Lohmann - Netherlands Institute for Neuroscience: Spontaneous activity wires developing circuits with subcellular precision

Afternoon Session
16:30 - J. Nathan Kutz - University of Washington, Seattle: A reaction-diffusion model of cholinergic retinal waves
17:05 - Jianhua Cang - Northwestern University: Critical Period Plasticity and Binocular Matching in the Mouse Visual cortex
17:40 - Break
18:00 - Adrienne Fairhall - University of Washington, Seattle: Structure of spontaneous activity in developing cortex.
18:35 - Mark Hübener - Max Planck Institute of Neurobiology, Munich: How sensory deprivation and learning change neuronal responses in mouse visual cortex
19:10 - General Discussion


This workshop is part of the CoSyNe2014 conference. Please register for the workshops to take part.


Julijana Gjorgjieva - Harvard
Matthias H Hennig - Edinburgh


Critical Period Plasticity and Binocular Matching in the Mouse Visual cortex
Jianhua Cang
Department of Neurobiology
Northwestern University

Neural circuits are shaped by experience during critical periods in early life. My lab has demonstrated that critical period plasticity drives binocular matching of orientation preference in the mouse visual cortex (Wang, Sarnaik, and Cang, 2010). Although studies have started to reveal the genetic and epigenetic mechanisms that control the opening and closure of the critical periods, the functional significance of a properly-timed critical period in visual system development is not yet clear. In this seminar, I will present our recently-published data that address this question.

Structure of spontaneous activity in developing cortex
Adrienne Fairhall
Department of Physiology and Biophysics
University of Washington, Seattle

During early development, mouse cortex exhibits spontaneous large-scale waves of activity that occur during the first week after birth. During the same period, the intrinsic properties of cortical neurons move toward a state in which individual neurons adapt to the variance of their inputs. We study the impact that this intrinsic change may have on network activity. The wave-like activity has been shown to originate from a restricted region of cortex located ventrally; what distinguishes this region as a “pace-maker” is still unclear. Our recent studies in collaboration with the laboratory of Dr Bill Moody examine spatial variations in the distribution of spontaneous activity and in the presence of clusters of local activity, possibly signaling the presence of local gap junctionally coupled subnetworks.

How sensory deprivation and learning change neuronal responses in mouse visual cortex
Mark Hübener
Max Planck Institute of Neurobiology, Martinsried, Germany

Neuronal response properties in the brain are not static. They can change during development, after deprivation, and following learning. We study such functional plasticity, using orientation selectivity in the mouse visual cortex as a model. In stripe rearing experiments, we found a clear effect of passive exposure of mice to contours of only one orientation. While diverse mechanisms are likely contributing to the observed changes, they are at least partially mediated by an instructive process, by which individual neurons change their orientation preference. We next asked whether orientation tuning also shows plasticity under behaviorally relevant conditions. We trained mice on an operant orientation discrimination learning task and used a genetically encoded calcium indicator to repeatedly measure orientation tuning of individual V1 neurons before and after learning. We found changes in orientation selectivity, tuning width and response amplitude, which correlated with behavioral task performance, suggesting that specific functional changes reflecting visual learning are present as early as V1.

A reaction-diffusion model of cholinergic retinal waves
J. Nathan Kutz
Department of Applied Mathematics
University of Washington, Seattle

Prior to receiving visual stimuli, spontaneous, correlated activity called retinal waves drives activity-dependent developmental programs. Early-stage waves mediated by acetylcholine (ACh) manifest as slow, spreading bursts of action potentials. They are believed to be initiated by the spontaneous firing of Starburst Amacrine Cells (SACs), whose dense, recurrent connectivity then propagates this activity laterally. Their extended inter-wave intervals and shifting wave boundaries are the result of the slow after-hyperpolarization of the SACs creating an evolving mosaic of recruitable and refractory cells, which can and cannot participate in waves. Recent evidence suggests that cholinergic waves may be modulated by the extracellular concentration of ACh. Here, we construct a simplified, biophysically consistent, reaction-diffusion model of cholinergic retinal waves capable of recapitulating wave dynamics observed in mice retina recordings. The dense, recurrent connectivity of SACs is modeled through local, excitatory coupling occurring via the volume release and diffusion of ACh. In contrast with previous, simulation-based models, we are able to use non-linear wave theory to connect wave features to underlying physiological parameters, making the model useful in determining appropriate pharmacological manipulations to experimentally produce waves of a prescribed spatiotemporal character. The model is used to determine how ACh may modulate wave activity, and how the noise rate and sAHP refractory period contributes to critical wave size variability.

Spontaneous activity wires developing circuits with subcellular precision
Christian Lohmann
Department of Synapse and Network Development
Netherlands Institute for Neuroscience
Amsterdam, The Netherlands

Already early in development, before the senses are functional, spontaneous neuronal activity occurs in emerging circuits and determines neuronal connectivity. While experimentally blocking or perturbing spontaneous activity has demonstrated its importance for network development, how early activity patterns shape connectivity on the level of individual synapses is still unclear. We use time-lapse microscopy and electrophysiological recordings to monitor functional neuronal connectivity with single synapse resolution in vitro and in vivo. Mapping spatio-temporal patterns of synaptic activity and plasticity across large populations of synapses on the dendrites of individual neurons showed that functionally correlated synapses are clustered along developing dendrites. Recently, we discovered a local “out of sync – lose your link” plasticity mechanism that can cluster synaptic inputs. These data demonstrate that neuronal connectivity can be tuned with subcellular precision by spontaneous activity.

Neuronal variability, cell types, network homeostasis and pathological compensation from a simple, biologically plausible ion channel expression model
Timothy O'Leary
Volen Center for Complex Systems
Brandeis University

A fundamental question in neuroscience is how neurons develop, control, and maintain their electrical signaling properties in spite of ongoing protein turnover and activity perturbations. In this talk I will summarize efforts to address this question using theory and computational modeling over the past two decades and I will introduce some recent modelling work that has tied together experimental data with long-standing questions about the inherent variability of neuronal properties. I will show how a simple yet robust and flexible model of homeostatic regulation can be derived from generic assumptions about the molecular biology underlying channel expression. The model can generate diverse self-regulating cell types and relates correlations in conductance expression observed in vivo to underlying channel expression rates. Both synaptic as well as intrinsic conductances can be regulated to make a self-assembling central pattern generator network; thus network-level homeostasis can emerge from cell-autonomous regulation rules. Finally, I will demonstrate that homeostatic regulation critically depends on the complement of ion channels expressed in cells: in some cases loss of specific ion channels can be completely compensated, in others the homeostatic mechanisms itself can cause pathological loss of function.

A universal pattern of activity in developing neural networks?
Joel Tabak
Biomedical Research Facility
Florida State University

Developing neuronal networks generate spontaneous activity characterized by episodes of high activity separated by intervals of quiescence. This occurs in the early developmental stage of widely different networks, such as the spinal cord, the retina and cortical tissues. There are striking similarities in the spontaneous activity patterns of these networks. First, the activity may use several excitatory neurotransmitters, so that blocking one neurotransmitter may only block activity temporarily. Second, the duration of an episode is highly correlated with the length of the preceding inter-episode interval, but not with the following interval. This implies that after an episode the network is always “reset” to the same state. To understand this correlation pattern, we have simulated an excitatory network of spiking neurons with slow activity-dependent synaptic depression. Such network produces an episodic activity pattern with the right correlation between episode duration and inter-episode interval. This pattern is robust to changes in network connectivity and in the individual neuron properties, suggesting that the mechanism illustrated here to generate episodic activity may be operating in different developing networks.

Establishing wiring specificity in the fly olfactory system
Alex Ward
Department of Biology
Stanford University

How do complex groups of neurons organize to form a functional circuit? The fly olfactory system provides an excellent model for studying this question. In the olfactory system, primary olfactory receptor neurons (ORNs) expressing the same odorant receptor (OR) converge axons to a discrete target in the central brain called a glomerulus. Mice have 1,000 ORs and each ORN projects to two out of 2000 glomeruli. The fly olfactory system has only 50 ORs with each ORN converging onto one of 50 glomeruli in the antennal lobe (AL). Second-order olfactory neurons, called projection neurons (PNs), are also largely class specific and each projects its dendrites to only a single glomerulus. Because the organization of the olfactory system is largely conserved in insects and mammals, and given the numerical simplicity and abundance of genetic tools in flies, we have focused on studying the developmental mechanisms underlying the assembly of fly olfactory circuits. How are the one-to-one synaptic connections between ORN axons and PN dendrites achieved? A first clue came from our finding that PN dendrites innervate and pattern the developing AL significantly earlier than the arrival of ORN axons, indicating that PNs must target their dendrites to form a proto-map independent of its presynaptic partners. Interestingly, work from our lab also showed that PN dendritic targeting is specified by lineage and birth-order, thus offering some insights into the developmental mechanisms that might regulate formation of a discrete olfactory map. From this we can conclude that patterning of the developing AL occurs in two phases: 1) PNs target their dendrites, independently of ORN-derived cues, to pre-pattern the developing AL; and 2) ORN axons reach the pre-patterned AL where they must find their correct synaptic partners. Much of our recent work has aimed at understanding the molecular mechanisms that regulate target selection and partner matching during these two phases of olfactory system development. In particular, we have focused on the role of cell-surface and secreted molecules in regulating these developmental processes. In my talk, I will present an overview of our work in this area, and also describe new findings from a recently completed high-resolution confocal-based RNAi screen of cell surface and secreted molecules.