The brain is constantly bombarded with sensory stimuli. In order to process and perceive such diverse information streams simultaneously, the brain prioritizes information relevant to an animal's current behavioral needs. In this thesis, I investigate the neural mechanisms that enable the brain to increase or decrease visual signals depending on an animal's behavioral state. In chapter 1, I illustrate a novel mechanism, 3-5 Hz membrane potential (Vm) oscillations, that decreases the responsiveness of neurons in the primary visual cortex (V1) of mice. Using 2-photon guided whole-cell recordings as mice passive viewed and actively engaged drifting sine-wave gratings, I discovered that these visually-evoked phenomena were not influenced by changes in arousal or animal movement, but their timing was influenced by an animal's behavioral state. In addition to uncovering a novel mechanism for reducing the responsiveness of neurons in the brain, this chapter substantially furthers the field's knowledge of how behavior and arousal affect the membrane potential of neurons in the cerebral cortex. In chapter 2, I develop a method to train animals how to perform a visual attention task. I describe the hardware and software tools used to actuate the task and the method used to train the animals. Using the method outlined in this chapter, I was able to routinely train animals to perform a multimodal attention task with approximately one month of training. In chapter 3, I employed this new attention model and, using 2-photon guided whole-cell recordings in behaving animals, I discovered that attention boosts the depolarization associated with visual stimulation in layer 2/3 V1 neurons, illustrating a potential mechanism that causes neurons to be more responsive to visual cues during attention. Finally, using 128 channel silicon nanoprobes chronically implanted in V1, I verified that the attention task increased the responsiveness of V1 neurons and desynchronized the local network in mice, replicating results previously obtained in non-human primate models and setting the groundwork for future study. As a result, my thesis details novel neural mechanisms for enhancing or dampening visual signals and expands our knowledge of how the brain prioritizes information according to an animal's behavioral context.

Decades of extracellular recording in primate, cat and rodent cortex have established that an animal's behavioral state profoundly modulates the spiking response of sensory cortical neurons to external stimuli. Attention and arousal have been shown to affect not only neuronal responsiveness but also psychophysical thresholds, suggesting a direct link between the cortical sensory representation and perception. However, despite this tremendous progress, the cellular mechanisms by which behavioral states modulate the spiking of cortical neurons remain poorly understood. Here I describe two approaches aimed at understanding how the subthreshold activity of cortical cells is modulated across behavioral states. First, I discuss an in vitro study characterizing the ascending basal forebrain cholinergic system, one of the main neuromodulatory systems in the mammalian brain. Cholinergic cells in the basal forebrain project throughout the cortex and are thought to play an important role in state-dependent modulation of cortical activity. By optogenetically labeling and stimulating cholinergic axons in cortical slices, we were able to characterize 1) what cortical cell types are targeted by cholinergic axons, 2) the relevant time course over which endogenous acetylcholine (ACh) release acts on target cells, and 3) the synaptic properties of cholinergic axons in cortex. We found that cholinergic axons target specific subtypes of cortical interneurons. Moreover, we found clear evidence for classical synaptic transmission between cholinergic release sites and specific interneuron classes, challenging the predominant view that the cholinergic system works primarily by nonsynaptic transmission. Next, to better understand how the subthreshold activity of cortical cells is modulated in the intact brain, we performed intracellular recordings from the visual cortex of awake, head-fixed mice. We showed that the membrane potential of neurons in superficial layers is highly variable during quiet wakefulness and that this variability is quenched when the animal moves. In addition, we found that responses to visual stimulation are larger and more reliable during locomotion, which, together with the decrease in baseline variability, drastically improves the signal to noise ratio. Moreover, by recording from pairs of neurons simultaneously, we showed that the membrane potentials of neighboring cells is highly correlated during quiet wakefulness, but that this correlation subsides during active states. Finally, we demonstrated that neurons in the deep cortical layers display similar state-dependent membrane potential dynamics and that correlated membrane potential fluctuations in superficial cells may originate in deep layers.

Over the past decade, mice have emerged as a useful model for studying vision, owing in large part to their genetic tractability. Such studies have also yielded the unexpected and fascinating finding that movement, particularly locomotion, has a striking effect on cortical visual activity in mice. The discovery of so-called state-dependent visual processing suggested that the role of even primary sensory areas is not as simple as previously thought. Many studies showed that locomotion enhances visual neural activity, but few directly examined whether it actually improved sensory perception in a behavioral task. For my dissertation project I addressed this by examining the interactions between locomotion-dependent modulation of brain state and different goal-directed sensory selection brain states. Two groups of mice were trained to visually monitor either one of two locations (selective) or both (non-selective) for a contrast change, and this simple difference produced a spatially selective and non-selective brain state in primary visual cortex (V1), respectively. Locomotion affected the two groups of mice differently, impairing performance and neural representations of visual information of selective mice, while having no effect on non-selective mice. These and other results suggest that these two groups of mice use local versus global mechanisms to perform their respective tasks, and in the case of selective mice, the global influence of locomotion disrupts their locally modulated brain state and impairs performance. Locomotion influences brain state differently, depending on the whether the animal employs a spatially selective state to perform its task. Thus, state-dependence is state-dependent. These findings demonstrate the importance of studying complex interactions, and argue for reducing reductionism in neuroscience as we gain the necessary technology to carry out such studies. Moving forward, this mouse model will do just that, and enable investigation into the cell type and circuit mechanisms underlying these phenomena. Wading into the enormous complexity of the brain may ultimately be the only way to understand how it works as a whole.

Studies of mechanisms in the brain that allow complicated things to happen in a coordinated fashion have produced some of the most spectacular discoveries in neuroscience. This book provides eloquent support for the idea that spontaneous neuron activity, far from being mere noise, is actually the source of our cognitive abilities. It takes a fresh look at the coevolution of structure and function in the mammalian brain, illustrating how self-emerged oscillatory timing is the brain's fundamental organizer of neuronal information. The small-world-like connectivity of the cerebral cortex allows for global computation on multiple spatial and temporal scales. The perpetual interactions among the multiple network oscillators keep cortical systems in a highly sensitive "metastable" state and provide energy-efficient synchronizing mechanisms via weak links. In a sequence of "cycles," György Buzsáki guides the reader from the physics of oscillations through neuronal assembly organization to complex cognitive processing and memory storage. His clear, fluid writing-accessible to any reader with some scientific knowledge-is supplemented by extensive footnotes and references that make it just as gratifying and instructive a read for the specialist. The coherent view of a single author who has been at the forefront of research in this exciting field, this volume is essential reading for anyone interested in our rapidly evolving understanding of the brain.

This book is part of an ongoing history of efforts to understand the nature of waking and sleeping states from a biological point of view. We believe the recent technological revolutions in anatomy and physiology make the present moment especially propitious for this effort. In planning this book we had the choices of producing an edited volume with invited chapter authors or of writing the book ourselves. Edited volumes offer the opportunity for expression of expertise in each chapter but, we felt, would not allow the development of our ideas on the potential and actual unity of the field and would not allow the expression of coherence that can be obtained only with one or two voices, but which may be quite difficult with a chorus assembled and performing together for the first time. (Unlike musical works, there is very little precedent for rehearsals and repeated performances for authors of edited volumes or even for the existence of conductors able to induce a single rhythm and vision of the composition. ) We thus decided on a monograph. The primary goal was to communicate the current realities and the future possibilities of unifying basic studies on anatomy and cellular physiology with investigations of the behavioral and physi ological events of waking and sleep. In keeping with this goal we cross-reference the basic cellular physiology in the latter chapters, and, in the last chapter, we take up possible links to relevant clinical phenomenology.

This book originated at a small and informal workshop held in December of 1992 in Idyllwild, a relatively secluded resort village situated amid forests in the San Jacinto Mountains above Palm Springs in Southern California. Eighteen colleagues from a broad range of disciplines, including biophysics, electrophysiology, neuroanatomy, psychophysics, clinical studies, mathematics and computer vision, discussed 'Large Scale Models of the Brain, ' that is, theories and models that cover a broad range of phenomena, including early and late vision, various memory systems, selective attention, and the neuronal code underlying figure-ground segregation and awareness (for a brief summary of this meeting, see Stevens 1993). The bias in the selection of the speakers toward researchers in the area of visual perception reflects both the academic background of one of the organizers as well as the (relative) more mature status of vision compared with other modalities. This should not be surprising given the emphasis we humans place on'seeing' for orienting ourselves, as well as the intense scrutiny visual processes have received due to their obvious usefullness in military, industrial, and robotic applications. JMD.