While the link between amyloid β (Aβ) accumulation and synaptic degradation in Alzheimer's disease (AD) is known, the consequences of this pathology on population coding remain unknown. We found that the entropy, a measure of the diversity of network firing patterns, was lower in the dorsal CA1 region in the APP/PS1 mouse model of Aβ pathology, relative to controls, thereby reducing the population's coding capacity. Our results reveal a network level signature of the deficits Aβ accumulation causes to the computations performed by neural circuits. Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline that is thought to arise in part from the pathological accumulation of amyloid β (Aβ) plaques 1 throughout the neocortex and hippocampus. Plaques cause a constellation of changes in neural circuits including, but not limited to, degradation of dendritic spines 2 , reductions in synapse density 2,3 , and increases in the intrinsic excitability of neurons 3. Aβ pathology has been linked to various behavioral and cognitive changes 4,5 ; for example in mouse models, plaque burden correlates with degradation of place fields in the dorsal CA1 (dCA1) subfield of the hippocampus, and is associated with poor performance on spatial memory tasks 4. Such behaviors require the orchestration of activity across large groups of neurons, or ensembles, whose dynamics are governed by the structure of neural circuits 6. However, although Aβ pathology disrupts multiple features of these circuits 2,7,8 , the net effect of these changes on the structure of population activity and the resulting disruptions in neural computation remains unknown. To address this question, we performed electrophysiological recordings in the hippocampus of awake APP/ PS1 mice (model of Aβ pathology 9), where amyloid plaques can be seen at 12 months of age 10 and plaque burden corresponds to poor performance on spatial cognition and memory tasks, such as the T-maze alternation task 4,5. We found a reduction in the pair-wise correlations between neurons in APP/PS1 animals as compared to controls. Additionally, we identified a reduction in the entropy of population activity across a large array of ensemble sizes, suggesting that the coding vocabulary of populations of neurons in the dCA1 region of hippocampus is compromised in this mouse model of amyloid pathology. Materials and Methods Animals. All protocols and procedures were approved by the University Committee on Animal Resources (UCAR) at the University of Rochester and were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at the University of Rochester. 4 APP/PS1 double transgenic mice and 4 littermate control mice were used in this study. The APP/PS1 mice expressed chimeric mouse/human amyloid precursor protein (Mo/HuApp695swe) 11 and mutant human presenilin-1 (PS1-dE9) 12 under the control of the neuron-specific prion protein promotor element 9. All mice were males aged 11 to 13 months. By this age, amyl...

Sex differences in running behaviors between female and male mice occur naturally in the wild. Recent experiments using head‐fixed mice on a voluntary running wheel have exploited analogous locomotor activity to gain insight into the neural underpinnings of a number of behaviors ranging from spatial navigation to decision‐making. It is however largely unknown if sex differences exist between females and males in a head‐fixed experimental paradigm. To address this, we characterized locomotor activity in head‐fixed female and male C57BL/6J mice on a voluntary running wheel. First, we found that over the initial 7‐day period, on average, animals increased both the velocity and the time spent running. Furthermore, we found that female mice habituated to running forward over the initial 2 days of encountering the wheel, while male mice took up to 4 days to habituate to running forward. Taken together, we characterized features of a sexually divergent behavior in head‐fixed running that should be considered in experiments employing female and male mice.

73 15 Text: 1375 words 16 Main figure legends: 320 Abstract 25 While the link between amyloid β (Aβ) accumulation and synaptic degradation in 26 Alzheimer's disease (AD) is known, the consequences of this pathology on coding remain 157

No abstract

Sex differences in running behaviors between male and female mice occur naturally in the wild. Recent experiments using head restrained mice on a running wheel have exploited locomotion to provide insight in the neural underpinnings of a number of behaviors ranging from spatial navigation to decision making. However, it is largely unknown how males and females behave differently in this experimental paradigm. We found that in head-fixed mice that were initially exposed to a running wheel, all female mice ran forward naturally within the first two days, while almost all male mice scurried backward for up to 4 days. With daily exposure, male mice progressively learned to naturally run forward, with this transition occurring over the course of a 7-day period. Taken together, we have identified a sexually divergent behavior in head-fixed running that should be considered in experiments that use this experimental design.Furthermore, this sex-specific difference could serve as a new way to interrogate the neural underpinnings of a number of behaviors such as anxiety or fear.