Deep within the brain resides a set of neurons that have inherent time-keeping capacity. The electrical firing properties of this cell population (referred to as the suprachiasmatic nucleus, or SCN) generates a 24 hour oscillation (referred to as a circadian rhythm) that functions as a timing cue to ancillary neuronal oscillator populations found throughout the rest of the brain. This circadian timing circuit has remarkable power over the nervous system. For example, key functions of the nervous system, such as the sleep/wake cycle, and complex cognitive processes (e.g., learning, memory and critical thinking skills) are modulated by this circadian rhythm. Further, the disruption of this circadian timekeeping system has profound effects on mood, cognitive capacity and sleep. Notably, the disruption of circadian timing can result from alterations in one's work schedule (often seen in night shift workers), or from a number of acquired and congenital disorders of the brain (e.g., depression, Alzheimer's disease and Huntington's disease). In fact, the disruption of circadian timing in individuals with Alzheimer's disease is considered to be one of the most pressing issues for health care workers. This rich series of observations raises questions about the functional relationship between the SCN and ancillary neuronal oscillator populations, and, relatedly, about the underlying neuronal circuits that modulate cognitive capacity over the circadian cycle. In this application, the researchers propose to employ a wide array of innovative interdisciplinary approaches to determine the functional significance and mechanistic underpinnings by which circadian clock timing in brain circuits modulate complex cognitive processes, such as learning and memory. The research will also provide an opportunity for direct student involvement in research and the data from the study will be used to generate an interactive website for outreach to the public and included in the Brain Awareness Program that presents research findings to elementary and middle schools.
Within the central nervous system, rhythmicity is not restricted to the SCN, but rather, is found in a diversity of brain regions. In line with this, forebrain structures, including the cortex and hippocampus, express all of the molecular components required to drive clock timing. Here, the researchers propose to systematically test the contribution of forebrain clocks to the circadian regulation of learning and memory. This application is predicated on the hypothesis that the SCN clock works in a coordinated manner with ancillary hippocampal/forebrain oscillators to regulate cognitive capacity as a function of the time of day. To test this idea, the researchers propose to use an innovative set of transgenic animal models that will allow them to resolve clock timing at a single cell level, and thus, create a systems and cellular level blueprint of hippocampal timing (Objectives 1 and 2). This aim will allow the researchers to identify the cycling cell types (e.g., glutamatergic excitatory neurons, GABAergic inhibitory neurons, astrocytes and microglia) and to assess the phase relationship of discrete oscillator populations. Addressing these questions is key to the understanding of the tightly intertwined relationship between circadian timing and cognition. In Objectives 3 and 4, the researchers will use conditional knockout technology to disrupt forebrain circadian timing and assess the effects on learning and memory. Importantly, with this approach, SCN timing will be intact, and thus, the scientists will be able to specifically test the contribution of forebrain oscillators to learning and memory. These data sets will provide new insights into the complex processes by which the clock shapes cognition, and in turn provide a foundation for further experimental approaches designed to reveal clock functionality in a broad range of physiological and psychological processes.
