Biology subjects

Aggleton, J.

Publications and source records attributed to Aggleton, J..

9 recordsLinked to original sources

bioRxiv2025

Anterior thalamic nucleus inputs to the retrosplenial cortex are unperturbed in the hAPP-J20 mouse model of Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative condition characterised by progressive loss of memory and general decline in cognitive function. Although research has traditionally focused on the hippocampus and entorhinal cortex, other regions important for memory and spatial navigation, such as the anterior thalamic nuclei (ATN) and retrosplenial cortex (RSC), are also affected. The RSC is an important brain region for both memory and spatial navigation, and displays dysfunction in humans during prodromal phases of AD. The ATN provide a major input to RSC, with loss of this input to RSC causing a dramatic reduction in the expression of the immediate early gene product c-Fos. The ATN to RSC connection may thus present a new target for therapeutic intervention in AD. Here, we set out to determine whether AD-like pathology perturbed projections from ATN to RSC using the hAPP-J20 amyloidopathy mouse model, using optogenetic activation of thalamic inputs combined with ex vivo patch clamp electrophysiology. We found that RSC displayed an age-dependent decline in basal c-Fos activity, with no additional effect of amyloid pathology on c-Fos expression. At all time points (3, 6 and 9 months) measured, we found no evidence of impairments in the synaptic strength or efficacy of the ATN projections to either granular or dysgranular subdivisions of RSC. We conclude that, in the hAPP-J20 mouse model, this pathway is unaffected by amyloid-{beta} overexpression.

neuroscience↗

bioRxiv2022

No evidence from complementary data sources of a direct projection from the mouse anterior cingulate area to the hippocampal formation

The connectivity and interplay between the prefrontal cortex and hippocampus underpin a number of key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental as well as neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate cortex to hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using both anterograde and retrograde AAVs and monosynaptic rabies tracing. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies, as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic projection from mouse anterior cingulate cortex to the hippocampus proper.

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bioRxiv2021

Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults.

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-{varepsilon}4, a family history of dementia, and central obesity, on CA1, CA2/3, dentate gyrus (DG) and subiculum in 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields (ASHS) and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and FH status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE {varepsilon}4 carriers showed lower size/complexity than non-carriers. Protocol type did not affect this risk pattern. These findings provide novel evidence for interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults. HighlightsO_LIAge-related inverted U-shaped curve of hippocampal myelin/neurite packing C_LIO_LIObesity-related reductions of hippocampal myelin/neurite packing and size/complexity C_LIO_LIAPOE modifies the effects of obesity on hippocampal size/complexity C_LIO_LIAge-related slowing of spatial navigation C_LIO_LINo APOE, family history, or obesity effects on cognition C_LI

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bioRxiv2020

Can we conjointly record direct interactions between neurons in vivo in anatomically-connected brain areas? Probabilistic analyses and further implications.

Large-scale simultaneous in vivo recordings of neurons in multiple brain regions raises the question of the probability of recording direct interactions of neurons within, and between, multiple brain regions. In turn, identifying inter-regional communication rules between neurons during behavioural tasks might be possible, assuming conjoint activity between neurons in connected brain regions can be detected. Using the hypergeometric distribution, and employing anatomically-tractable connection mapping between regions, we derive a method to calculate the probability distribution of recordable connections between groups of neurons. This mathematically-derived distribution is validated by Monte Carlo simulations of directed graphs representing the underlying anatomical connectivity structure. We apply this method to simulated graphs with multiple neurons, based on counts in rat brain regions, and to connection matrices from the Blue Brain model of the mouse neocortex connectome. Overall, we find low probabilities of simultaneously-recording directly interacting neurons in vivo in anatomically-connected regions with standard (tetrode-based) approaches. We suggest alternative approaches, including new recording technologies and summing neuronal activity over larger scales, offer promise for testing hypothesised interregional communication and source transformation rules.

neuroscience↗

bioRxiv2020

Chemogenetics reveal an anterior cingulate-thalamic pathway for attending to task-relevant information

In a changing environment, we need to decide when to select items that resemble previously rewarded stimuli and when it is best to switch to other stimulus types. Here, we used chemogenetic techniques to provide causal evidence that activity in the rodent anterior cingulate cortex and its efferents to the anterior thalamic nuclei modulate the ability to attend to reliable predictors of important outcomes. Rats were tested on an attentional set-shifting paradigm that first measures the ability to master serial discriminations involving a constant stimulus dimension that reliably predicts reinforcement (intradimensional-shift), followed by the ability to shift attention to a previously irrelevant class of stimuli when reinforcement contingencies change (extradimensional-shift). Chemogenetic silencing of the anterior cingulate cortex (Experiment 1) as well as selective inactivation of anterior cingulate efferents to the anterior thalamic nuclei (Experiment 2) impaired intradimensional learning but, facilitated two sets of extradimensional-shifts. This pattern of results signals the loss of a cortico-thalamic system for cognitive control that preferentially processes stimuli resembling those previously associated with reward. Previous studies highlight a separate prefrontal system that promotes switching to hitherto inconsistent predictors of reward when contingencies change. Competition between these two systems regulates cognitive flexibility and choice.

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bioRxiv2020

Spatial Coding in the Subiculum Requires Anterior Thalamic Inputs

Hippocampal function relies on the anterior thalamic nuclei, but the reasons remain poorly understood. While anterior thalamic lesions disrupt parahippocampal spatial signalling, their impact on the subiculum is unknown, despite the importance of this area for hippocampal networks. We recorded subicular cells in rats with either permanent (N-methyl-D-aspartic acid) or reversible (muscimol) anterior thalamic lesions. Bayesian and other statistical analyses underscored the notable absence of the diverse spatial signals normally found in the subiculum, including place cells, following permanent anterior thalamic lesions. Likewise, there was marked disruption of these diverse spatial signals during transient lesions. By contrast, permanent anterior thalamic lesions had no discernible impact on CA1 place fields. Anterior thalamic lesions reduced spatial alternation performance (permanently or reversibly) to chance, while leaving a non-spatial recognition memory task unaffected. These findings, which help explain why anterior thalamic damage is so deleterious for spatial memory, cast a new spotlight on the importance of subiculum function and reveal its dependence on anterior thalamic signalling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/928762v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@9ae754org.highwire.dtl.DTLVardef@1c96837org.highwire.dtl.DTLVardef@1d91ddaorg.highwire.dtl.DTLVardef@136fa1d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2019

Stable encoding of visual cues in the mouse retrosplenial cortex

The rodent retrosplenial cortex functions as an integrative hub for sensory and motor signals, serving roles in both navigation and memory. While retrosplenial cortex (RSC) is reciprocally connected with the sensory cortex, the form in which sensory information is represented in the retrosplenial cortex and how it interacts with behavioural state is unclear. Here, we used 2-photon cellular imaging of neural activity of putative excitatory (CaMKII expressing) and inhibitory (parvalbumin expressing) neurons to measure visual and running evoked activity in RSC and compare it to primary visual cortex (V1). We found that stimulus position and orientation information was preserved between V1 and RSC, and additionally that positional information was organised topographically. Stimulus directional preference was biased towards nasal-temporal flow. Locomotion modulation of activity of single neurons, both in darkness and light, was also more pronounced in RSC than V1, and strongest in parvalbumin-positive neurons. Longitudinal measurements of single neurons showed that these response features were stably maintained over many weeks. These data provide evidence for stable representations of visual cues in retrosplenial cortex which are highly spatially selective. These may provide sensory data to contribute to the formation of memories of spatial information.

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bioRxiv2018

Proximal perimeter encoding in the rat rostral thalamus

Perimeters are an important part of the environment, delimiting its geometry. Here, we investigated how perimeters (vertical walls; vertical drops) affect neuronal responses in the rostral thalamus (the anteromedial and parataenial nuclei in particular). We found neurons whose firing patterns reflected the presence of walls and drops, irrespective of arena shape. Their firing patterns were stable across multiple sleep-wake cycles and were independent of ambient lighting conditions. Thus, rostral thalamic nuclei may participate in spatial representation by encoding the perimeters of environments.

neuroscience↗

bioRxiv2018

Uncovering a role for the dorsal hippocampal commissure in episodic memory

The dorsal hippocampal commissure (DHC) is a white matter tract that provides inter-hemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted MRI (DW-MRI) and white matter tractography to reconstruct the DHC across both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived Diffusion Tensor MRI (DT-MRI) metrics from the DHC in a large sample of human subjects to investigate whether inter-individual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC was correlated with performance in a standardised episodic memory task; an effect that was not reproduced in a comparison commissure tract - the anterior commissure. These findings highlight a role for the DHC in episodic memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

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