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.
Abstract There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre‐ or post‐training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non‐HPC system that can acquire long‐term memories that support context fear discrimination. Post‐training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long‐term memory.
Alzheimer's disease (AD) is characterized by the prion-like propagation of amyloid-β (Aβ). However, the role of Aβ in cognitive impairment is still unclear. To determine the causal role of Aβ in AD, we intracerebrally seeded the entorhinal cortex of a 2-month-old App NL − G − F mouse model with an Aβ peptide derived from patients who died from rapidly progressing AD. When the mice were 3 months of age or 1 month following seeding, spatial learning and memory were tested using the Morris water task. Immunohistochemical labeling showed seeding with the Aβ was found accelerate Aβ plaque deposition and microgliosis in the App NL − G − F mice, but this was dependent on the presence of the knocked-in genes. However, we found no correlation between pathology and spatial performance. The results of the present study show the seeding effects in the App NL − G − F knock-in model, and how these are dependent on the presence of a humanized App gene. But these pathological changes were not initially causal in memory impairment.
Blood samples were collected from the first calves of 48 four-breed composite cows and postpartum hours 0 and 24 (group 1) and heparinized blood samples were collected from the 263 calves born to 203 cows at postpartum hours 10 (±2) and 24 (±2) (group 2). For group 1, at birth, the mean serum concentrations of IgG and protein were 131 mg/di and 3.9 g/dl, respectively, and serum activity of GGT was 28 IU/L. After 24 hours, these values had increased to 1,400 mg/di, 5.0 g/dl, and 734 IU/L, respectively. The calves with failure of passive transfer (FPT) had a 9.5 times greater risk of becoming classified as sick prior to weaning compared with calves with partial FPT and normal passive transfer <£=0.0004). The retrospective sensitivity and specificity of a cut-off value of 200 IU of GGT/L of serum for diagnosing FPT were 80 and 97%, respectively. The retrospective sensitivity and specificity of a cutoff value of 4.2 g of protein/di of serum for diagnosing FPT were 80 and 100%, respectively. The Kappa values for diagnosis of FPT using serum concentrations of lgG vs serum activity of GGT, IgG vs protein, and GGT vs protein were 0. 72, 0.86, and 0. 79, respectively. For group 2, the prospective sensitivity and specificity of a cut-off value of 4.8 g of protein/di of plasma, measured at 10 hours, for diagnosing FPT at 10 hours were 78 and 94%, and for diagnosing FPT at 24 hours were 88 and 73%, respectively. Colostrum supplement administered to calves with low PP concentration at 10 hours had no effect on PP or IgG values at 24 hours or on preweaning morbidity and mortality. Total PP and IgG concentrations were similar for single and twin calves at 10 hours, but IgG values at 24 hours were higher (£ < 0.01) in twin calves. Calves born to dams that had dystocia had consistently lower mean PP and lgG values. However, observed differences were small, and after adjustment for other important factors, these differences were not significant. Calves of dams diagnosed with mastitis had lower mean PP and IgG values at 10 (£ < 0.05) and 24 (£ < 0.01) hours. Results of logistic regression analysis indicated that IgG concentration at 24 hours was associated with morbidity and mortality outcomes prior to weaning. Calves classified as having inadequate IgG concentration at 24 hours were at greater risk of mortality from birth to weaning (odds ratio [OR]= 5.4), morbidity in the first 28 days of life (OR= 6.4), and morbidity from birth to weaning (OR = 3.2), compared with calves classified as having adequate IgG concentration at 24 hours. Calves classified as having marginal IgG concentration at 24 hours also had a greater risk of preweaning morbidity (OR= 3.6), compared with calves that had adequate IgG concentration. Calf PP concentration at 24 hours was associated with morbidity in the feedlot. Calves classified as having inadequate PP concentration were at greater risk of feedlot morbidity (OR= 3.0) and feedlot respiratory tract morbidity (OR= 3.1). The lowest calf weaning weights were observed among calves classified as having inadequate lgG or PP concentration at 24 hours. However, multivariable modeling indicated that the effect of passive transfer on weaning weight was indirect through its effect on neonatal morbidity. Morbidity during the first 28 days of life resulted in a 16-kg lower expected weaning weight. Similar to weaning weight, passive immune status at 24 hours was not directly associated with feedlot growth rate. There was, however, an indirect association through the effect of PP concentration at 24 hours on morbidity in the feedlot. Adjusted mean MDG for calves with respiratory tract morbidity while in the feedlot was 0.04 kg less than that for noncases. The magnitude of the effects of passive immune status on the health and growth performance of calves in this study emphasize the importance of producer management strategies to identify calves at risk of failing to acquire passive immunity and to provide appropriate intervention.
Automated touchscreen systems have become increasingly prevalent in rodent model screening. This technology has significantly enhanced cognitive and behavioral assessments in mice and has bridged the translational gap between basic research using rodent models and human clinical research. Our study introduces a custom-built touchscreen operant conditioning chamber powered by a Raspberry Pi and a commercially available computer tablet, which effectively addresses the significant cost barriers traditionally associated with this technology. In order to test our prototype, we decided to train C57BL/6 mice on a visual discrimination serial-reversal task, and both C57BL/6 and App NL−G−F strain - an Alzheimer’s Disease (AD) mouse model - on a new location discrimination serial-reversal task. The results demonstrated a clear progression toward asymptotic performance, particularly in the location discrimination task, which also revealed potential genotype-specific deficits, with App NL−G−F mice displaying an increase in the average number of errors in the first reversal as well as in perseverative errors, compared to wild-type mice. These results validate the practical utility of our touchscreen apparatus and underline its potential to provide insights into the behavioral and cognitive markers of neurobiological disorders.
ABSTRACT 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 67-97% 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, does not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories.
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