Artificial neural networks simplify complex biological circuits into tractable models for computational exploration and experimentation. However, the simplification of artificial models also undermines their applicability to real brain dynamics. Typical efforts to address this mismatch add complexity to increasingly unwieldy models. Here, we take a different approach; by reducing the complexity of a biological cortical culture, we aim to distil the essential factors of neuronal dynamics and plasticity. We leverage recent advances in growing neurons from human induced pluripotent stem cells (hiPSCs) to analyse ex vivo cortical cultures with only two distinct excitatory and inhibitory neuron populations. Over 6 weeks of development, we record from thousands of neurons using high-density microelectrode arrays (HD-MEAs) that allow access to individual neurons and the broader population dynamics. We compare these dynamics to two-population artificial networks of single-compartment neurons with random sparse connections and show that they produce similar dynamics. Specifically, our model captures the firing and bursting statistics of the cultures. Moreover, tightly integrating models and cultures allows us to evaluate the impact of changing architectures over weeks of development, with and without external stimuli. Broadly, the use of simplified cortical cultures enables us to use the repertoire of theoretical neuroscience techniques established over the past decades on artificial network models. Our approach of deriving neural networks from human cells also allows us, for the first time, to directly compare neural dynamics of disease and control. We found that cultures e.g. from epilepsy patients tended to have increasingly more avalanches of synchronous activity over weeks of development, in contrast to the control cultures. Next, we will test possible interventions, in silico and in vitro, in a drive for personalised approaches to medical care. This work starts bridging an important theoretical-experimental neuroscience gap for advancing our understanding of mammalian neuron dynamics.

Low-dimensional population dynamics can be observed in neural activity recorded from the prefrontal cortex (PFC) of subjects performing simple cognitive tasks. Many studies have shown that recurrent neural networks (RNNs) trained on the same tasks can reproduce qualitatively these state space trajectories, and have used them as models of how neuronal dynamics implement task computations. The PFC is also viewed as a conductor that organizes the communication between cortical areas and provides contextual information. It is then not clear what is its role in solving simple cognitive tasks. Do the low-dimensional trajectories observed in the PFC really correspond to the computations that it performs? Or do they indirectly reflect the computations occurring within the cortical areas projecting to the PFC? To address these questions, we modelled cortical areas with a modular RNN and equipped it with a PFC-like cognitive system. When trained on cognitive tasks, this multi-system brain model can reproduce the low-dimensional population responses observed in neuronal activity as well as classical RNNs. Qualitatively different mechanisms can emerge from the training process when varying some details of the architecture such as the time constants. In particular, there is one class of models where it is the dynamics of the cognitive system that is implementing the task computations, and another where the cognitive system is only necessary to provide contextual information about the task rule as task performance is not impaired when preventing the system from accessing the task inputs. These constitute two different hypotheses about the causal role of the PFC in solving simple cognitive tasks, which could motivate further experiments on the brain.

Distinct synapses influence one another when they undergo changes, with unclear consequences for neuronal dynamics and function. Here we show that synapses can interact such that excitatory currents are naturally normalised and balanced by inhibitory inputs. This happens when classical spike-timing dependent synaptic plasticity rules are extended by additional mechanisms that incorporate the influence of neighbouring synaptic currents and regulate the amplitude of efficacy changes accordingly. The resulting control of excitatory plasticity by inhibitory activation, and vice versa, gives rise to quick and long-lasting memories as seen experimentally in receptive field plasticity paradigms. In models with additional dendritic structure, we observe experimentally reported clustering of co-active synapses that depends on initial connectivity and morphology. Finally, in recurrent neural networks, rich and stable dynamics with high input sensitivity emerge, providing transient activity that resembles recordings from the motor cortex. Our model provides a general framework for codependent plasticity that frames individual synaptic modifications in the context of population-wide changes, allowing us to connect micro-level physiology with behavioural phenomena.

Spike trains recorded from the cortex of behaving animals can be complex, highly variable from trial to trial, and therefore challenging to interpret. A fraction of cells exhibit trial-averaged responses with obvious task-related features such as pure tone frequency tuning in auditory cortex. However, a substantial number of cells (including cells in primary sensory cortex) do not appear to fire in a task-related manner and are often neglected from analysis. We recently used a novel single-trial, spike-timing-based analysis to show that both classically responsive and non-classically responsive cortical neurons contain significant information about sensory stimuli and behavioral decisions suggesting that non-classically responsive cells may play an underappreciated role in perception and behavior. We now expand this investigation to explore the synaptic origins and potential contribution of these cells to network function. To do so, we trained a novel spiking recurrent neural network model that incorporates spike-timing-dependent plasticity (STDP) mechanisms to perform the same task as behaving animals. By leveraging excitatory and inhibitory plasticity rules this model reproduces neurons with response profiles that are consistent with previously published experimental data, including classically responsive and non-classically responsive neurons. We found that both classically responsive and non-classically responsive neurons encode behavioral variables in their spike times as seen in vivo. Interestingly, plasticity in excitatory-to-excitatory synapses increased the proportion of non-classically responsive neurons and may play a significant role in determining response profiles. Finally, our model also makes predictions about the synaptic origins of classically and non-classically responsive neurons which we can compare to in vivo whole-cell recordings taken from the auditory cortex of behaving animals. This approach successfully recapitulates heterogeneous response profiles measured from behaving animals and provides a powerful lens for exploring large-scale neuronal dynamics and the plasticity rules that shape them.

Historically, research on the brain has been working its way in from the outside world, hoping that such systematic exploration will take us some day to the middle and on through the middle to the output. Ever since the time of Aristotle, philosophers and scientists have assumed that the brain (or, more precisely, the mind) is initially a blank slate filled up gradually with experience in an outside-in manner. An alternative, brain-centric view, the one I am promoting, is that self-organized brain networks induce a vast repertoire of preformed neuronal patterns. While interacting with the world, some of these initially ‘nonsensical’ patterns acquire behavioral significance or meaning. Thus, experience is primarily a process of matching preexisting neuronal dynamics to events in the world. I suggest that perpetually active, internal dynamic is the source of cognition, a neuronal operation disengaged from immediate senses.

Engineered pattern-recognition systems strive for short time-to-solution and low energy-to-solution characteristics. This represents one of the main driving forces behind the development of neuromorphic devices. For both them and their biological archetypes, this corresponds to using as few spikes as early as possible. The concept of few and early spikes is used as the founding principle in the time-to-first-spike coding scheme. Within this framework, we have developed a spike-timing-based learning algorithm, which we used to train neuronal networks on the mixed-signal neuromorphic platform BrainScaleS-2. We derive, from first principles, error-backpropagation-based learning in networks of leaky integrate-and-fire (LIF) neurons relying only on spike times, for specific configurations of neuronal and synaptic time constants. We explicitly examine applicability to neuromorphic substrates by studying the effects of reduced weight precision and range, as well as of parameter noise. We demonstrate the feasibility of our approach on continuous and discrete data spaces, both in software simulations and on BrainScaleS-2. This narrows the gap between previous models of first-spike-time learning and biological neuronal dynamics and paves the way for fast and energy-efficient neuromorphic applications.