Wireless monitoring of respiration with EEG reveals relationships between respiration, behavior, and brain activity in freely moving mice.

Active sampling in the olfactory domain is a fundamental aspect of mouse behavior, and there is increasing evidence that respiration-entrained neural activity outside of the olfactory system sets an important global brain rhythm. It is therefore crucial to accurately measure breathing during natural behaviors. We develop a new approach to do this in freely moving animals, by implanting a telemetry-based pressure sensor into the right jugular vein, which allows for wireless monitoring of thoracic pressure. After verifying this technique against standard head-fixed respiration measurements, we combined it with EEG and EMG recording and used evolving partial coherence analysis to investigate the relationship between respiration and brain activity across a range of experiments in which the mice could move freely. During voluntary exploration of odors and objects, we found that the association between respiration and cortical activity in the delta and theta frequency range decreased, whereas the association between respiration and cortical activity in the alpha range increased. During sleep, however, the presentation of an odor was able to cause a transient increase in sniffing without changing dominant sleep rhythms (delta and theta) in the cortex. Our data align with the emerging idea that the respiration rhythm could act as a synchronizing scaffold for specific brain rhythms during wakefulness and exploration, but suggest that respiratory changes are less able to impact brain activity during sleep. Combining wireless respiration monitoring with different types of brain recording across a variety of behaviors will further increase our understanding of the important links between active sampling, passive respiration, and neural activity.NEW & NOTEWORTHY Animals can alter their respiration rate to actively sample their environment, and increasing evidence suggests that neurons across the brain align their firing to this changing rhythm. We developed a new approach to measure sniffing in freely moving mice while simultaneously recording brain activity, and uncovered how specific cortical rhythms changed their coherence with respiration rhythm during natural behaviors and across arousal states.

A role for MCH neuron firing in modulating hippocampal plasticity threshold.

It has been revealed that hypothalamic neurons containing the peptide, melanin-concentrating hormone (MCH) can influence learning [1] and memory formation [2], but the cellular mechanisms by which they perform this function are not well understood. Here, we examine the role of MCH neural input to the hippocampus, and show in vitro that optogenetically increasing MCH axon activity facilitates hippocampal plasticity by lowering the threshold for synaptic potentiation. These results align with increasing evidence that MCH neurons play a regulatory role in learning, and reveal that this could be achieved by modulating plasticity thresholds in the hippocampus.

Natural VTA activity during NREM sleep influences future exploratory behavior.

During wakefulness, the VTA represents the valence of experiences and mediates affective response to the outside world. Recent work revealed that two major VTA populations - dopamine and GABA neurons - are highly active during REM sleep and less active during NREM sleep. Using long-term cell type and brain state-specific recordings, machine learning, and optogenetics, we examined the role that the sleep-activity of these neurons plays in subsequent awake behavior. We found that VTA activity during NREM (but not REM) sleep correlated with exploratory features of the next day's behavior. Disrupting natural VTA activity during NREM (but not REM) sleep reduced future tendency to explore and increased preferences for familiarity and goal-directed actions, with no direct effect on learning or memory. Our data suggest that, during deep sleep, VTA neurons engage in offline processing, consolidating not memories but affective responses to remembered environments, shaping the way that animals respond to future experiences.

Optimising the energetic cost of the glutamatergic synapse.

As for electronic computation, neural information processing is energetically expensive. This is because information is coded in the brain as membrane voltage changes, which are generated largely by passive ion movements down electrochemical gradients, and these ion movements later need to be reversed by active ATP-dependent ion pumping. This article will review how much of the energetic cost of the brain reflects the activity of glutamatergic synapses, consider the relative amount of energy used pre- and postsynaptically, outline how evolution has energetically optimised synapse function by adjusting the presynaptic release probability and the postsynaptic number of glutamate receptors, and speculate on how energy use by synapses may be sensed and adjusted. This article is part of the special Issue on 'Glutamate Receptors - The Glutamatergic Synapse'.

Fast odour dynamics are encoded in the olfactory system and guide behaviour.

Odours are transported in turbulent plumes, which result in rapid concentration fluctuations1,2 that contain rich information about the olfactory scenery, such as the composition and location of an odour source2-4. However, it is unclear whether the mammalian olfactory system can use the underlying temporal structure to extract information about the environment. Here we show that ten-millisecond odour pulse patterns produce distinct responses in olfactory receptor neurons. In operant conditioning experiments, mice discriminated temporal correlations of rapidly fluctuating odours at frequencies of up to 40 Hz. In imaging and electrophysiological recordings, such correlation information could be readily extracted from the activity of mitral and tufted cells-the output neurons of the olfactory bulb. Furthermore, temporal correlation of odour concentrations5 reliably predicted whether odorants emerged from the same or different sources in naturalistic environments with complex airflow. Experiments in which mice were trained on such tasks and probed using synthetic correlated stimuli at different frequencies suggest that mice can use the temporal structure of odours to extract information about space. Thus, the mammalian olfactory system has access to unexpectedly fast temporal features in odour stimuli. This endows animals with the capacity to overcome key behavioural challenges such as odour source separation5, figure-ground segregation6 and odour localization7 by extracting information about space from temporal odour dynamics.

GABA and glutamate neurons in the VTA regulate sleep and wakefulness.

We screened for novel circuits in the mouse brain that promote wakefulness. Chemogenetic activation experiments and electroencephalogram recordings pointed to glutamatergic/nitrergic (NOS1) and GABAergic neurons in the ventral tegmental area (VTA). Activating glutamatergic/NOS1 neurons, which were wake- and rapid eye movement (REM) sleep-active, produced wakefulness through projections to the nucleus accumbens and the lateral hypothalamus. Lesioning the glutamate cells impaired the consolidation of wakefulness. By contrast, activation of GABAergic VTA neurons elicited long-lasting non-rapid-eye-movement-like sleep resembling sedation. Lesioning these neurons produced an increase in wakefulness that persisted for at least 4 months. Surprisingly, these VTA GABAergic neurons were wake- and REM sleep-active. We suggest that GABAergic VTA neurons may limit wakefulness by inhibiting the arousal-promoting VTA glutamatergic and/or dopaminergic neurons and through projections to the lateral hypothalamus. Thus, in addition to its contribution to goal- and reward-directed behaviors, the VTA has a role in regulating sleep and wakefulness.

How do antidepressants influence the BOLD signal in the developing brain?

Depression is a highly prevalent life-threatening disorder, with its first onset commonly occurring during adolescence. Adolescent depression is increasingly being treated with antidepressants, such as fluoxetine. The use of medication during this sensitive period of physiological and cognitive brain development produces neurobiological changes, some of which may outlast the course of treatment. In this review, we look at how antidepressant treatment in adolescence is likely to alter neurovascular coupling and brain energy use and how these changes, in turn, affect our ability to identify neuronal activity changes between participant groups. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), the method most commonly used to record brain activity in humans, is an indirect measure of neuronal activity. This means that between-group comparisons - adolescent versus adult, depressed versus healthy, medicated versus non-medicated - rely upon a stable relationship existing between neuronal activity and the BOLD response across these groups. We use data from animal studies to detail the ways in which fluoxetine may alter this relationship, and explore how these alterations may influence the interpretation of BOLD signal differences between groups that have been treated with fluoxetine and those that have not.

Energy-Efficient Information Transfer by Visual Pathway Synapses.

The architecture of computational devices is shaped by their energy consumption. Energetic constraints are used to design silicon-based computers but are poorly understood for neural computation. In the brain, most energy is used to reverse ion influxes generating excitatory postsynaptic currents (EPSCs) and action potentials. Thus, EPSCs should be small to minimize energy use, but not so small as to impair information transmission. We quantified information flow through the retinothalamic synapse in the visual pathway in brain slices, with cortical and inhibitory input to the postsynaptic cell blocked. Altering EPSC size with dynamic clamp, we found that a larger-than-normal EPSC increased information flow through the synapse. Thus, the evolutionarily selected EPSC size does not maximize retinal information flow to the cortex. By assessing the energy used on postsynaptic ion pumping and action potentials, we show that, instead, the EPSC size optimizes the ratio of retinal information transmitted to energy consumed. These data suggest maximization of information transmission per energy used as a synaptic design principle.

The BOLD signal and neurovascular coupling in autism.

BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging) is commonly used to study differences in neuronal activity between human populations. As the BOLD response is an indirect measure of neuronal activity, meaningful interpretation of differences in BOLD responses between groups relies upon a stable relationship existing between neuronal activity and the BOLD response across these groups. However, this relationship can be altered by changes in neurovascular coupling or energy consumption, which would lead to problems in identifying differences in neuronal activity. In this review, we focus on fMRI studies of people with autism, and comparisons that are made of their BOLD responses with those of control groups. We examine neurophysiological differences in autism that may alter neurovascular coupling or energy use, discuss recent studies that have used fMRI to identify differences between participants with autism and control participants, and explore experimental approaches that could help attribute between-group differences in BOLD signals to either neuronal or neurovascular factors.

Is myelin a mitochondrion?

It has been hypothesized that myelin acts like a mitochondrion, generating ATP across the membranes of its sheath. By calculating the proton motive force across the myelin membrane based on known values for the pH and membrane potential of the oligodendrocyte, we find that insufficient energy could be harvested from proton flow across the myelin membrane to synthesize ATP. In fact, if the respiratory chain were present in the myelin membrane, then the ATP synthase would function in reverse, hydrolyzing rather than synthesizing ATP. This calculation places the hypothesis of an energy-producing role for myelin in considerable doubt.

Synaptic energy use and supply.

Neuronal computation is energetically expensive. Consequently, the brain's limited energy supply imposes constraints on its information processing capability. Most brain energy is used on synaptic transmission, making it important to understand how energy is provided to and used by synapses. We describe how information transmission through presynaptic terminals and postsynaptic spines is related to their energy consumption, assess which mechanisms normally ensure an adequate supply of ATP to these structures, consider the influence of synaptic plasticity and changing brain state on synaptic energy use, and explain how disruption of the energy supply to synapses leads to neuropathology.

Metabolic differentiation in the embryonic retina.

Unlike healthy adult tissues, cancers produce energy mainly by aerobic glycolysis instead of oxidative phosphorylation. This adaptation, called the Warburg effect, may be a feature of all dividing cells, both normal and cancerous, or it may be specific to cancers. It is not known whether, in a normally growing tissue during development, proliferating and postmitotic cells produce energy in fundamentally different ways. Here we show in the embryonic Xenopus retina in vivo, that dividing progenitor cells depend less on oxidative phosphorylation for ATP production than non-dividing differentiated cells, and instead use glycogen to fuel aerobic glycolysis. The transition from glycolysis to oxidative phosphorylation is connected to the cell differentiation process. Glycolysis is indispensable for progenitor proliferation and biosynthesis, even when it is not used for ATP production. These results suggest that the Warburg effect can be a feature of normal proliferation in vivo, and that the regulation of glycolysis and oxidative phosphorylation is critical for normal development.

The energetics of CNS white matter.

The energetics of CNS white matter are poorly understood. We derive a signaling energy budget for the white matter (based on data from the rodent optic nerve and corpus callosum) which can be compared with previous energy budgets for the gray matter regions of the brain, perform a cost-benefit analysis of the energetics of myelination, and assess mechanisms for energy production and glucose supply in myelinated axons. We show that white matter synapses consume ≤0.5% of the energy of gray matter synapses and that this, rather than more energy-efficient action potentials, is the main reason why CNS white matter uses less energy than gray matter. Surprisingly, while the energetic cost of building myelin could be repaid within months by the reduced ATP cost of neuronal action potentials, the energetic cost of maintaining the oligodendrocyte resting potential usually outweighs the saving on action potentials. Thus, although it dramatically speeds action potential propagation, myelination need not save energy. Finally, we show that mitochondria in optic nerve axons could sustain measured firing rates with a plausible density of glucose transporters in the nodal membrane, without the need for energy transfer from oligodendrocytes.

Contextual illusions reveal the limit of unconscious visual processing.

The perception of even the most elementary features of the visual environment depends strongly on their spatial context. In the study reported here, we asked at what level of abstraction such effects require conscious processing of the context. We compared two visual illusions that alter subjective judgments of brightness: the simultaneous brightness contrast illusion, in which two circles of identical physical brightness appear different because of different surround luminance, and the Kanizsa triangle illusion, which occurs when the visual system extrapolates a surface without actual physical stimulation. We used a novel interocular masking technique that allowed us to selectively render only the context invisible. Simultaneous brightness contrast persisted even when the surround was masked from awareness. In contrast, participants did not experience illusory contours when the inducing context was masked. Our findings show that invisible context is resolvable by low-level processes involved in surface-brightness perception, but not by high-level processes that assign surface borders through perceptual completion.

The physiology of developmental changes in BOLD functional imaging signals.

BOLD fMRI (blood oxygenation level dependent functional magnetic resonance imaging) is increasingly used to detect developmental changes of human brain function that are hypothesized to underlie the maturation of cognitive processes. BOLD signals depend on neuronal activity increasing cerebral blood flow, and are reduced by neural oxygen consumption. Thus, developmental changes of BOLD signals may not reflect altered information processing if there are concomitant changes in neurovascular coupling (the mechanism by which neuronal activity increases blood flow) or neural energy use (and hence oxygen consumption). We review how BOLD signals are generated, and explain the signalling pathways which convert neuronal activity into increased blood flow. We then summarize in broad terms the developmental changes that the brain's neural circuitry undergoes during growth from childhood through adolescence to adulthood, and present the changes in neurovascular coupling mechanisms and energy use which occur over the same period. This information provides a framework for assessing whether the BOLD changes observed during human development reflect altered cognitive processing or changes in neurovascular coupling and energy use.