Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is poorly understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. We found that sleep deprivation increases cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta oscillations due to sleep pressure. Motor learning, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are also impaired during sleep deprivation. Our study indicates that upscaled brain excitability and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance. Besides showing how brain physiology and cognition undergo changes (from neurophysiology to higher-order cognition) under sleep pressure, the findings have implications for variability and optimal application of noninvasive brain stimulation.

The David Smith Lectures in Anatomical Neuropharmacology, Part of the 'Pharmacology, Anatomical Neuropharmacology and Drug Discovery Seminars Series', Department of Pharmacology, University of Oxford. The 15th David Smith Award Lecture in Anatomical Neuropharmacology will be delivered by Professor Tim Bliss, Visiting Professor at UCL and the Frontier Institutes of Science and Technology, Xi’an Jiaotong University, China, and is hosted by Professor Nigel Emptage. This award lecture was set up to celebrate the vision of Professor A David Smith, namely, that explanations of the action of drugs on the brain requires the definition of neuronal circuits, the location and interactions of molecules. Tim Bliss gained his PhD at McGill University in Canada. He joined the MRC National Institute for Medical Research in Mill Hill, London in 1967, where he remained throughout his career. His work with Terje Lømo in the late 1960’s established the phenomenon of long-term potentiation (LTP) as the dominant synaptic model of how the mammalian brain stores memories. He was elected as a Fellow of the Royal Society in 1994 and is a founding fellow of the Academy of Medical Sciences. He shared the Bristol Myers Squibb award for Neuroscience with Eric Kandel in 1991, the Ipsen Prize for Neural Plasticity with Richard Morris and Yadin Dudai in 2013. In May 2012 he gave the annual Croonian Lecture at the Royal Society on ‘The Mechanics of Memory’. In 2016 Tim, with Graham Collingridge and Richard Morris shared the Brain Prize, one of the world's most coveted science prizes. Abstract: In 1966 there appeared in Acta Physiologica Scandinavica an abstract of a talk given by Terje Lømo, a PhD student in Per Andersen’s laboratory at the University of Oslo. In it Lømo described the long-lasting potentiation of synaptic responses in the dentate gyrus of the anaesthetised rabbit that followed repeated episodes of 10-20Hz stimulation of the perforant path. Thus, heralded and almost entirely unnoticed, one of the most consequential discoveries of 20th century neuroscience was ushered into the world. Two years later I arrived in Oslo as a visiting post-doc from the National Institute for Medical Research in Mill Hill, London. In this talk I recall the events that led us to embark on a systematic reinvestigation of the phenomenon now known as long-term potentiation (LTP) and will then go on to describe the discoveries and controversies that enlivened the early decades of research into synaptic plasticity in the mammalian brain. I will end with an observer’s view of the current state of research in the field, and what we might expect from it in the future.

Activity dependent synaptic plasticity is considered to be a primary mechanism underlying learning and memory. Yet it is unclear whether plasticity rules such as STDP measured in vitro apply in vivo. Network models with STDP predict that activity patterns (e.g., place-cell spatial selectivity) should change much faster than observed experimentally. We address this gap by investigating a nonlinear calcium-based plasticity rule fit to experiments done in physiological conditions. In this model, LTP and LTD result from intracellular calcium transients arising almost exclusively from synchronous coactivation of pre- and postsynaptic neurons. We analytically approximate the full distribution of nonlinear calcium transients as a function of pre- and postsynaptic firing rates, and temporal correlations. This analysis directly relates activity statistics that can be measured in vivo to the changes in synaptic efficacy they cause. Our results highlight that both high-firing rates and temporal correlations can lead to significant changes to synaptic efficacy. Using a mean-field theory, we show that the nonlinear plasticity rule, without any fine-tuning, gives a stable, unimodal synaptic weight distribution characterized by many strong synapses which remain stable over long periods of time, consistent with electrophysiological and behavioral studies. Moreover, our theory explains how memories encoded by strong synapses can be preferentially stabilized by the plasticity rule. We confirmed our analytical results in a spiking recurrent network. Interestingly, although most synapses are weak and undergo rapid turnover, the fraction of strong synapses are sufficient for supporting realistic spiking dynamics and serve to maintain the network’s cluster structure. Our results provide a mechanistic understanding of how stable memories may emerge on the behavioral level from an STDP rule measured in physiological conditions. Furthermore, the plasticity rule we investigate is mathematically equivalent to other learning rules which rely on the statistics of coincidences, so we expect that our formalism will be useful to study other learning processes beyond the calcium-based plasticity rule.

Spike Timing Dependent Plasticity (STDP) is argued to modulate synaptic strength depending on the timing of pre- and postsynaptic spikes. Physiological experiments identified a variety of temporal kernels: Hebbian, anti-Hebbian and symmetrical LTP/LTD. In this work we present a novel plasticity model, the Voltage-Dependent Pathway Model (VDP), which is able to replicate those distinct kernel types and intermediate versions with varying LTP/LTD ratios and symmetry features. In addition, unlike previous models it retains these characteristics for different neuron models, which allows for comparison of plasticity in different neuron types. The plastic updates depend on the relative strength and activation of separately modeled LTP and LTD pathways, which are modulated by glutamate release and postsynaptic voltage. We used the 15 neuron type parametrizations in the GLIF5 model presented by Teeter et al. (2018) in combination with the VDP to simulate a range of standard plasticity protocols including standard STDP experiments, frequency dependency experiments and low frequency stimulation protocols. Slight variation in kernel stability and frequency effects can be identified between the neuron types, suggesting that the neuron type may have an effect on the effective learning rule. This plasticity model builds a middle ground between biophysical and phenomenological models allowing not just for the combination with more complex and biophysical neuron models, but is also computationally efficient so can be used in network simulations. Therefore it offers the possibility to explore the functional role of the different kernel types and electrophysiological differences in heterogeneous networks in future work.

Ever since Bliss and Lømo discovered the phenomenon of long-term potentiation (LTP) in rabbit dentate gyrus in the 1960s, Hebb’s rule—neurons that fire together wire together—gained popularity to explain learning and memory. Accumulating evidence, however, suggests that neural activity is homeostatically regulated. Homeostatic mechanisms are mostly interpreted to stabilize network dynamics. However, recent theoretical work has shown that linking the activity of a neuron to its connectivity within the network provides a robust alternative implementation of Hebb’s rule, although entirely based on negative feedback. In this setting, both natural and artificial stimulation of neurons can robustly trigger network rewiring. We used computational models of plastic networks to simulate the complex temporal dynamics of network rewiring in response to external stimuli. In parallel, we performed optogenetic stimulation experiments in the mouse anterior cingulate cortex (ACC) and subsequently analyzed the temporal profile of morphological changes in the stimulated tissue. Our results suggest that the new theoretical framework combining neural activity homeostasis and structural plasticity provides a consistent explanation of our experimental observations.

The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Recent experiments showed that repeated cholinergic activation of 𝛼7 nACh receptors expressed in oriens-lacunosum-moleculare (OLM𝛼2) interneurons could induce LTP in SC-CA1 synapses. We used a biophysically realistic computational model to examine mechanistically how cholinergic activation of OLMa2 interneurons increases SC to CA1 transmission. Our results suggest that, when properly timed, activation of OLMa2 interneurons cancels the feedforward inhibition onto CA1 pyramidal cells by inhibiting fast-spiking interneurons that synapse on the same dendritic compartment as the SC, i.e., by disinhibiting the pyramidal cell dendritic compartment. Our work further describes the pairing of disinhibition with SC stimulation as a general mechanism for the induction of synaptic plasticity. We found that locally-reduced GABA release (disinhibition) paired with SC stimulation could lead to increased NMDAR activation and intracellular calcium concentration sufficient to upregulate AMPAR permeability and potentiate the excitatory synapse. Our work suggests that inhibitory synapses critically modulate excitatory neurotransmission and induction of plasticity at excitatory synapses. Our work also shows how cholinergic action on OLM interneurons, a mechanism whose disruption is associated with memory impairment, can down-regulate the GABAergic signaling into CA1 pyramidal cells and facilitate potentiation of the SC-CA1 synapse.

CA3-CA1 synapses in the hippocampus are the initial locus of episodic memory. The action of acetylcholine alters cellular excitability, modifies neuronal networks, and triggers secondary signaling that directly affects long-term plasticity (LTP) (the cellular underpinning of memory). It is therefore considered a critical regulator of learning and memory in the brain. Its action via M4 metabotropic receptors in the presynaptic terminal of the CA3 neurons and M1 metabotropic receptors in the postsynaptic spines of CA1 neurons produce rich dynamics across multiple timescales. We developed a model to describe the activation of postsynaptic M1 receptors that leads to IP3 production from membrane PIP2 molecules. The binding of IP3 to IP3 receptors in the endoplasmic reticulum (ER) ultimately causes calcium release. This calcium release from the ER activates potassium channels like the calcium-activated SK channels and alters different aspects of synaptic signaling. In an independent signaling cascade, M1 receptors also directly suppress SK channels and the voltage-activated KCNQ2/3 channels, enhancing post-synaptic excitability. In the CA3 presynaptic terminal, we model the reduction of the voltage sensitivity of voltage-gated calcium channels (VGCCs) and the resulting suppression of neurotransmitter release by the action of the M4 receptors. Our results show that the reduced initial release probability because of acetylcholine alters short-term plasticity (STP) dynamics. We characterize the dichotomy of suppressing neurotransmitter release from CA3 neurons and the enhanced excitability of the postsynaptic CA1 spine. Mechanisms underlying STP operate over a few seconds, while those responsible for LTP last for hours, and both forms of plasticity have been linked with very distinct functions in the brain. We show that the concurrent suppression of neurotransmitter release and increased sensitivity conserves neurotransmitter vesicles and enhances the reliability in plasticity. Our work establishes a relationship between STP and LTP coordinated by neuromodulation with acetylcholine.

Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons possibly mediated by long-term potentiation (LTP) of synapses. We have previously shown in the mouse somatosensory cortex (S1) that sensory-driven LTP in layer (L) 2/3 pyramidal neurons is dependent on higher order thalamic feedback from the posteromedial nucleus (POm), which is thought to convey contextual information from various cortical regions integrated with sensory input. We have followed up on this work by dissecting the cortical microcircuitry that underlies this form of LTP. We found that repeated pairing of Pom thalamocortical and intracortical pathway activity in brain slices induces NMDAr-dependent LTP of the L2/3 synapses that are driven by the intracortical pathway. Repeated pairing also recruits activity of vasoactive intestinal peptide (VIP) interneurons, whereas it reduces the activity of somatostatin (SST) interneurons. VIP interneuron-mediated inhibition of SST interneurons has been established as a motif for the disinhibition of pyramidal neurons. By chemogenetic interrogation we found that activation of this disinhibitory microcircuit motif by higher-order thalamic feedback is indispensable for eliciting LTP. Preliminary results in vivo suggest that VIP neuron activity also increases during sensory-evoked LTP. Together, this suggests that the higherorder thalamocortical feedback may help modifying the strength of synaptic circuits that process first-order sensory information in S1. To start characterizing the relationship between higher-order feedback and cortical plasticity during learning in vivo, we adapted a perceptual learning paradigm in which head-fixed mice have to discriminate two types of textures in order to obtain a reward. POm axons or L2/3 pyramidal neurons labeled with the genetically encoded calcium indicator GCaMP6s were imaged during the acquisition of this task as well as the subsequent learning of a new discrimination rule. We found that a subpopulation of the POm axons and L2/3 neurons dynamically represent textures. Moreover, upon a change in reward contingencies, a fraction of the L2/3 neurons re-tune their selectivity to the texture that is newly associated with the reward. Altogether, our data indicates that higher-order thalamic feedback can facilitate synaptic plasticity and may be implicated in dynamic sensory stimulus representations in S1, which depends on higher-order features that are associated with the stimuli.