Robert J. Sutherland

1 Food carrying is an adaptive component of foraging that integrates resource evaluation with home-directed navigation, providing a naturalistic model for investigating how the brain organizes goal-directed behaviour. Despite extensive work on hippocampal coding during navigation and homing, how CA1 representations are reorganized when animals spontaneously transport acquired food home remains largely unexplored. We recorded dorsal CA1 population activity using one-photon calcium imaging with a V4 Miniscope while mice performed a self-paced foraging task in which food could be consumed at the acquisition site followed by a homeward return or carried to the home for consumption. Mice preferentially carried larger pellets, indicating that transport behaviour was sensitive to resource value. CA1 spatial coding differed systematically across behavioural outcomes. During carry-homeward runs, spatial representations were sparser, conveyed more spatial information, and showed greater trial-to-trial stability than during eat-inward runs, indicating a more precise and reliable place code during home-directed transport. Place fields also shifted forward during carrying, consistent with a retrospective bias toward recently traversed locations. By linking a self-generated food-handling decision to coordinated changes in the precision, stability, and temporal organization of CA1 activity, these findings extend hippocampal spatial-coding frameworks from trained navigation to ecologically grounded foraging behaviour.

Pyruvate kinase M2 (PKM2) has emerged as a critical regulator of Alzheimer’s disease pathophysiology. This review synthesizes current evidence demonstrating how PKM2 dysregulation contributes to cognitive decline by driving Warburg-like metabolic reprogramming, altering post-translational modifications and modulating protein–protein interactions. These processes collectively impair cell-cycle control, transcriptional regulation and cytoskeletal stability in neuronal cells. We further examine the impact of PKM2 on neuroinflammation, highlighting its context-dependent roles in microglia and astrocytes. In addition, we provide a comprehensive evaluation of natural and synthetic PKM2 modulators with therapeutic potential in Alzheimer’s disease, summarizing their mechanisms and reported outcomes. Clarifying the molecular basis of PKM2-mediated neurodegeneration and rigorously testing these modulators in preclinical models will be essential steps towards developing PKM2-targeted strategies for Alzheimer’s disease intervention.

Foraging requires animals to integrate spatial, temporal, and reward-related costs to guide adaptive action selection, yet how neurodegenerative pathology alters this process remains poorly understood. We compared foraging behavior in control (C57BL/6J) and APP ^NL-G-F transgenic mice, a knock-in mouse model of Alzheimer disease. The foraging task was structured such that distance to home, the size of food-pellet rewards, and food texture jointly shaped choices. These task variables implicitly imposed time costs related to travel, handling, and inter trial intervals. While control mice adjusted foraging behavior in relation to task demands across conditions, APP ^NL-G-F mice showed systematic deviations from control patterns. Their choices were characterized by increased withdrawal and reduced flexibility as spatial and temporal costs increased. Using a normative rate-maximization framework grounded in classical foraging theory, we quantified optimality and found marked suboptimality in both groups: control mice achieved 53% of the optimal reward rate, whereas APP ^NL-G-F mice achieved 45%. This suboptimality indicates that naturalistic decision making operates under context-dependent constraints rather than adhering to strict theoretical optimality. Within this constrained landscape, APP ^NL-G-F mice deviated more strongly from optimality than control mice, particularly under conditions requiring fine-grained integration of time-based costs. Group differences were most pronounced when optimal policies were highly sensitive to small errors in the estimation of temporal and spatial trade-offs. These findings suggest that Alzheimer-related pathology selectively amplified normative decision deficits rather than producing qualitatively distinct foraging strategies.

This paper describes my history of exposure and contributions to behavioral neuroscience, especially to the role of the hippocampus in learning and memory. Through a series of accidents and opportunities, and after priming in the graduate student environment of hippocampus and memory at Dalhousie University in the Department of Psychology, my work on the topic started at the University of Lethbridge, evaluating place navigation in Richard Morris' swimming pool task with Bryan Kolb and Ian Whishaw. We made a number of experimental and theoretical contributions, most important among these was the evaluation of the deficits caused by hippocampal damage on place learning and memory, recent versus remote memory, configural associations, and extensions to human memory. We describe some missteps and how we picked ourselves up and continued on.

Evidence from neurophysiological and genetic studies demonstrates that activity sparsity—the proportion of neurons that are active at a given time in a population—systematically varies across the canonical trisynaptic circuit of the hippocampus. Recent work has also shown that sparsity varies across the hippocampal dorsoventral (long) axis, wherein activity is sparser in ventral than dorsal regions. While the hippocampus has a critical role in long‐term memory (LTM), whether sparsity across the trisynaptic circuit and hippocampal long axis is task‐dependent or invariant remains unknown. Importantly, representational sparsity has significant implications for neural computation and theoretical models of learning and memory within and beyond the hippocampus. Here we used functional molecular imaging to quantify sparsity in the rat hippocampus during performance of the Morris water task (MWT) and contextual fear discrimination (CFD) – two popular and distinct assays of LTM. We found that activity sparsity is highly reliable across memory tasks, wherein activity increases sequentially across the trisynaptic circuit (DG < CA3 < CA1) and decreases across the long axis (ventral<dorsal). These results have important implications for models of hippocampal function and suggest that activity sparsity is a preserved property in the hippocampal system across cognitive settings.

Evidence from neurophysiological and genetic studies demonstrates that activity sparsity – the proportion of neurons that are active at a given time in a population – systematically varies across the canonical trisynaptic circuit of the hippocampus. Recent work has also shown that sparsity varies across the hippocampal dorsoventral (long) axis, wherein activity is sparser in ventral than dorsal regions. While the hippocampus has a critical role in long-term memory (LTM), whether sparsity across the trisynaptic circuit and hippocampal long axis is task-dependent or invariant remains unknown. Importantly, representational sparsity has significant implications for neural computation and theoretical models of learning and memory within and beyond the hippocampus. Here we used functional molecular imaging to quantify sparsity in the rat hippocampus during performance of the Morris water task (MWT) and contextual fear discrimination (CFD) – two popular and distinct assays of LTM. We found that activity sparsity is highly reliable across memory tasks, wherein activity increases sequentially across the trisynaptic circuit (DG < CA3 < CA1) and decreases across the long axis (ventral < dorsal). These results have important implications for models of hippocampal function and suggest that activity sparsity is a preserved property in the hippocampal system across cognitive settings.

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made using N-methyl-D-aspartate (NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67% to 97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, do not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories. Rats were trained to discriminate between objects with distinct visual features and odours, after which they received near-complete lesions of the hippocampus. Post-surgery, the rats exhibited no amnesia for the discrimination when tested in the dark but marked retrograde amnesia when the odours were eliminated from the objects, forcing the rats to rely on non-odour information. This suggests that long-term memories for odours are not dependent on the hippocampus.image

In contrast to most transgenic mouse models of Alzheimer disease (AD), knock-in mice expressing familial AD-linked mutations of the amyloid precursor protein ( App ) gene exhibit stereotypical age-dependent amyloid beta (Aβ) pathology and cognitive impairment without physiologically unrealistic App overexpression. This study investigated the effect of familial AD-linked App mutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity, App ^{NL-G-F/NL-G-F} knock-in (APPki) mice were crossed with Thy1 -GCaMP6s ^+/- (C-TG) mice to generate App ^{NL-G-F/NL-G-F} × Thy1 -GCaMP6s ^+/- (A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited Aβ pathology in the hippocampus. In several configurations of an air-induced running task, A-TG mice and C-TG mice were equally successful in learning to run or to stay immobile. In the Morris water place test, A-TG mice were impaired, but learned the task. Comparisons of hippocampal CA1 neuronal activity in the air-induced running task showed that A-TG mice displayed neuronal hypoactivity both during movement and immobility. A-TG mice and C-TG CA1 neuronal encoding of distance or time in the air induced running task were not different. These results suggest that knock-in of familial AD-linked mutations in A-TG mice results in Aβ pathology, neuronal hypoactivity, and cognitive impairment without severely affecting CA1 neuronal encoding. In comparison to APPki mice, A-TG mice had less severe AD-like memory impairments at 12 months of age (Saito et al., 2014; Mehla et al., 2019), suggesting that the disease onset was delayed in A-TG mice. The effect of APP mutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.

Background. Alzheimer’s disease (AD) is characterized by the prion-like propagation of amyloid-β (Aβ). However, the role of Ab in cognitive impairment is still unclear. Methods. Two-month-old App^NL-G-F were intracerebrally seeded with three conformationally distinct Aβ seeds. The mice were trained in a multi-model paradigm using multiple behavioural tests. Immunohistochemical techniques were used to assess Ab deposition, microgliosis, and cholinergic tone. Results. Seeding accelerated AD pathology throughout the brain in a region-dependent manner. Microgliosis was elevated in the substantia nigra reticular area. The cholinergic tone was found to be significantly reduced in the medial septal band. No impairment in learning and memory was found. Conclusion. These results suggest seeding accelerates microglial and Ab plaque progression in a regional distinct manner with the seed having no unique effect on behaviour or histological markers.