Life has evolved within a dynamic environment. In order to anticipate and prepare for recurrent environmental changes, organisms have internalized biological solutions to challenges imposed through sensory stimuli. Circadian rhythms have evolved to provide synchrony with the predictable daily oscillators of environmental cues, and interactions among circadian oscillators throughout the brain and the body influence the adaptive coordination of the organism as a whole. To abstract relevant information, organisms must constantly sample not only rhythmic features from the environment— such as light— but also more transient stimuli— such as olfactory cues. Olfaction allows for active sampling of crucial survival information including predator identification, social recognition, and sourcing of food. Importantly, odor stimuli exert powerful control over learning and memory networks through the unique anatomical structure of olfactory pathways, which in turn predispose the olfactory system to be more vulnerable to neurodegenerative diseases. This research examines how desynchrony between internal biology and external cues can impact overall organismal health, and in turn how neurodegenerative disease alters perception of environmental stimuli. First, I examine how internal desynchrony within the molecular machinery of the circadian clock affects behavior in the face of environmental challenge by testing the hypothesis that a core circadian clock gene, per2, is responsible for circadian clock responses to light. Lack of functional per2 prevents the normal circadian period lengthening and compression of active period in response to light by increasing the magnitude of phase advance in response to late evening/early morning light and decreasing the magnitude of phase delay in response to early evening light (Chapter 3). In this way, destabilization of the internal biological clock machinery through the functional mutation of the per2 gene can affect the behavioral response to environmental stimuli. Experiments in Chapter 4 disrupted circadian rhythms by manipulating exogenous stimuli: the timing of light and food, to examine whether circadian disruption exacerbated symptoms of neurodegenerative disease. In the APP/PS1-21 mouse model of Alzheimer’s Disease (AD), mice were fed either only at night or only during the day, the latter of which induced internal circadian desynchrony. Circadian desynchrony itself idiosyncratically altered performance in some behavioral cognitive and emotional tests, but it did not clearly exacerbate AD behavioral pathology. Finally, in Chapter 5, I aimed to characterize how neurodegenerative disease alters perception of environmental cues, by characterizing olfactory dysfunction in this same model of AD during the initial stage of disease. An objective of this study was to identify behavioral markers for diagnosis of AD early in development (Chapter 5). APP/PS1-21 mice at the initial stages of pathology show reduced discrimination between odorants in a non-rewarded paradigm. However, discrimination was recovered under conditions of reward, indicating that mice may be able to recruit other neural systems to compensate for impaired olfaction, when sufficiently motivated by appetitive stimuli. This presents olfactory discrimination as a potential site for behavioral diagnosis of early-stage AD. Together, these experiments identify novel interactions among sensory features of the environment and their influence on brain function, behavior, and symptoms of disease.