Fragmented sleep is a common and troubling symptom in ageing and Alzheimer's disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer's disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer's disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer's disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate -0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer's disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer's disease.

A method for capturing gait signatures in neurological conditions that allows comparison of human gait with animal models would be of great value in translational research. However, the velocity dependence of gait parameters and differences between quadruped and biped gait have made this comparison challenging. Here we present an approach that accounts for changes in velocity during walking and allows for translation across species. In mice, we represented spatial and temporal gait parameters as a function of velocity and established regression models that reproducibly capture the signatures of these relationships during walking. In experimental parkinsonism models, regression curves representing these relationships shifted from baseline, implicating changes in gait signatures, but with marked differences between models. Gait parameters in healthy human subjects followed similar strict velocity dependent relationships which were altered in Parkinson's patients in ways that resemble some but not all mouse models. This novel approach is suitable to quantify qualitative walking abnormalities related to CNS circuit dysfunction across species, identify appropriate animal models, and it provides important translational opportunities.Walking is a complex behavior that requires not only control of initiation and termination of locomotion, but also ongoing adjustments of speed, stride length, cadence, direction, and posture in response to dynamic internal and external cues. Walking can be affected in many different ways secondary to musculoskeletal or cardiovascular problems, as well as dysfunction of the peripheral or the central nervous system (CNS). Gait disorders due to specific CNS circuit pathologies can be clinically recognized based upon phenomenology, such as shuffling gait or festination in Parkinson's disease or ataxic gait in cerebellar disorders 1, 2 . The wide variety of causal conditions and subtypes of gait disorders illustrate that abnormal function or pathology in multiple CNS networks differentially affect gait.Human gait can be objectively measured using direct or indirect kinematic, spatial or temporal measures via video-analysis, footfall studies, or wearable devices. Advances in imaging technology have allowed visualization of putative supratentorial circuitries involved in gait control [3][4][5][6][7][8][9] . However, the functional-anatomical basis for the various gait abnormalities so readily recognized in clinical settings remains poorly understood as approaches to isolate relevant networks during life are relatively limited. This gap in knowledge stands in the way of the development of specific, circuit based treatment strategies targeted to the various specific gait abnormalities.Animal models offer a means to circumvent current barriers of studying gait in humans. In mice, highly selective approaches are now available to identify components of CNS circuits from cortex to spinal cord that mediate or modulate locomotion, including walking 10-13 . Effects of interventions can then be measured u...

Theories about subsystem activity typically focus on policy formulation processes. One causal model of public policymaking, the advocacy coalition framework, offers a potentially useful way to bridge the gap between policy formulation and implementation in examining subsystem activity. The purpose of this paper is to assess the analytical utility of the advocacy coalition framework by examining the stability of policy‐producing coalitions over time in the face of implementation complexities. An analysis of the policy changes that occurred during the implementation of the Endangered Species Act vis‐à‐vis planning for the construction of the Bureau of Reclamation's Animas‐La Plata water project is conducted. The analysis reveals how coalitions protect their policy core beliefs during technical disputes through the acquiescence of secondary aspects of belief systems.