In our daily lives we have to process sensory information at different speeds and in a sensory specific manner. For example, if we go for a walk in the park we will need to be aware of the relatively slow pace of changes in the environment, but as we read this text we will need to process the characters that pass through our fovea in rapid succession. A child might be aware of her teacher starting or finishing a discussion, but only if she is interested will she follow the ongoing flow of details. Because of its anatomical characteristics and its well established role in the control of global brain activity, the neurotransmitter acetylcholine is likely to play a large role in such temporal processing of information. This work deals with two aspects of the sensory processing of time modulated stimuli, particularly as it relates to acetylcholine. Chapters 1 and 2 analyze acetylcholine's influence on an animal's ability to discriminate between time modulated flashes of light (chapter 1) or trains of sounds (chapter 2). Chapter 3 analyzes the influence of brain state, a phenomenon tightly related to cholinergic activity, on the neural processing of trains of sounds, both at the thalamic and cortical levels. Finally, chapter 4 undertakes the problem of the influence of mean neuronal firing rate on measures of neural representation. The mean firing rate in the thalamus differs dramatically between states, and analysis of correlative activity must take this into consideration. Our theoretical results can explain various aspects of the current literature on the subject

A primary function of the brain is to form representations of the sensory world. Its capacity to do so depends on the relationship between signal correlations, associated with neuronal receptive fields, and noise correlations, associated with neuronal response variability. It was recently shown that the behavioral relevance of sensory stimuli can modify the relationship between signal and noise correlations, presumably increasing the encoding capacity of the brain. In this work, we use data from the visual cortex of the awake mouse watching naturalistic stimuli and show that a similar modification is observed under heightened cholinergic modulation. Increasing cholinergic levels in the cortex through optogenetic stimulation of basal forebrain cholinergic neurons decreases the dependency that is commonly observed between signal and noise correlations. Simulations of correlated neural networks with realistic firing statistics indicate that this change in the correlation structure increases the encoding capacity of the network.

Neurons in the CA1 area of the mouse hippocampus encode the position of the animal in an environment. However, given the variability in individual neurons responses, the accuracy of this code is still poorly understood. It was proposed that downstream areas could achieve high spatial accuracy by integrating the activity of thousands of neurons, but theoretical studies point to shared fluctuations in the firing rate as a potential limitation. Using high-throughput calcium imaging in freely moving mice, we demonstrated the limiting factors in the accuracy of the CA1 spatial code. We found that noise correlations in the hippocampus bound the estimation error of spatial coding to ~10 cm (the size of a mouse). Maximal accuracy was obtained using approximately [300-1400] neurons, depending on the animal. These findings reveal intrinsic limits in the brain's representations of space and suggest that single neurons downstream of the hippocampus can extract maximal spatial information from several hundred inputs.

The ability to integrate our perceptions across sensory modalities and across time, to execute and coordinate movements, and to adapt to a changing environment rests on temporal processing. Timing is essential for basic daily tasks, such as walking, social interaction, speech and language comprehension, and attention. Impaired temporal processing may contribute to various disorders, from attention-deficit hyperactivity disorder and schizophrenia to Parkinson's disease and dementia. The foundational importance of timing ability has yet to be fully understood; and popular tasks used to investigate behavioral timing ability, such as sensorimotor synchronization (SMS), engage a variety of processes in addition to the neural processing of time. The present study utilizes SMS in conjunction with a separate passive listening task that manipulates temporal expectancy while recording electroencephalographic data. Participants display a larger N1-P2 evoked potential complex to unexpected beats relative to temporally predictable beats, a differential we call the timing response index (TRI). The TRI correlates with performance on the SMS task: better synchronizers show a larger brain response to unexpected beats. The TRI, derived from the perceptually driven N1-P2 complex, disentangles the perceptual and motor components inherent in SMS and thus may serve as a neural marker of a more general temporal processing.

Based on recent molecular genetics, as well as functional and quantitative anatomical studies, the basal forebrain (BF) cholinergic projections, once viewed as a diffuse system, are emerging as being remarkably specific in connectivity. Acetylcholine (ACh) can rapidly and selectively modulate activity of specific circuits and ACh release can be coordinated in multiple areas that are related to particular aspects of cognitive processing. This review discusses how a combination of multiple new approaches with more established techniques are being used to finally reveal how cholinergic neurons, together with other BF neurons, provide temporal structure for behavior, contribute to local cortical state regulation, and coordinate activity between different functionally related cortical circuits. ACh selectively modulates dynamics for encoding and attention within individual cortical circuits, allows for important transitions during sleep, and shapes the fidelity of sensory processing by changing the correlation structure of neural firing. The importance of this system for integrated and fluid behavioral function is underscored by its disease-modifying role; the demise of BF cholinergic neurons has long been established in Alzheimers disease and recent studies have revealed the involvement of the cholinergic system in modulation of anxiety-related circuits. Therefore, the BF cholinergic system plays a pivotal role in modulating the dynamics of the brain during sleep and behavior, as foretold by the intricacies of its anatomical map.