Biology subjects

Randall, A. D.

Publications and source records attributed to Randall, A. D..

7 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↗

bioRxiv2025

Dissection of retrosplenial cortex inputs: ubiquitous drive from anterior thalamus

The retrosplenial cortex (RSC) is a highly interconnected brain region involved in spatial navigation and associative learning. It forms extensive, reciprocal connections with sensory, hippocampal, parahippocampal, prefrontal, and thalamic areas. RSC comprises granular (gRSC) and dysgranular (dRSC) subdivisions with distinct connectivity and functions. Despite its emerging role in behaviour and its implication in memory-related disorders such as Alzheimers disease, the nature of its synaptic inputs remains poorly understood. Here, we combined viral anatomical tracing, optogenetic stimulation, and patch-clamp electrophysiology to investigate inputs from the anterior cingulate cortex (ACC), dorsal subiculum (dSub), and anterior thalamic nuclei (ATN) to gRSC and dRSC. Strikingly, all recorded RSC pyramidal neurons received ATN input, regardless of subdivision or cortical layer. Activation of ATN inputs evoked significantly larger post-synaptic responses than those from dSub or ACC, though both regions maintained substantial connectivity with RSC. While dSub projections appeared denser in gRSC, synaptic responses were larger in dRSC, albeit with lower input probability. Notably, NMDA receptor-mediated components of RSC excitatory inputs were weaker than expected, potentially explaining the reported inability to induce long-term potentiation in RSC in ex vivo neurophysiology experiments. This is the first study to characterise the synaptic properties of retrosplenial afferents. Our findings highlight the dominant influence of ATN inputs and raise important questions about how RSCs long-range connectivity supports its roles in memory and spatial navigation.

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bioRxiv2022

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in APPNL-G-F mice

In the early stages of Alzheimers disease (AD), the accumulation of the peptide amyloid-{beta} (A{beta}) damages synapses and disrupts neuronal activity and leads to disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of A{beta}-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampal - medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the amplitude of mPFC spindles and decrease in the power of hippocampal SWRs was identified. The former was associated with a decrease in the density of mPFC PV-expressing interneurons and the latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.

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bioRxiv2021

Beta bursting in the retrosplenial cortex is a neurophysiological correlate of environmental novelty which is disrupted in a mouse model of Alzheimer's disease.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory, and is functionally disrupted in the early stages of Alzheimers disease. In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake, behaving mice, comparing neural activity between wild-type and J20 mice, a mouse model of Alzheimers disease-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of beta (20-30 Hz) oscillations (beta bursts) which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of beta bursts. Additionally, theta-beta cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during beta bursts. Finally, aberrant beta bursting was seen in J20 mice, including increased beta bursting during novelty and familiarity, yet a loss of coupling between beta bursts and spiking activity. These findings, support the concept that beta bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.

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bioRxiv2019

Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer’s disease

Transgenic mice that overproduce beta-amyloid (A{beta}) peptides exhibit neurophysiological alterations at the cellular, synaptic and network levels. Recently, increased neuronal activity in nucleus reuniens (Re), has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether alterations to the intrinsic electrophysiological properties of Re neurons could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons displayed a hyperpolarised membrane potential in J20 mice without changes to the incidence or frequency of spontaneous action potential (AP) generation. Passive membrane properties were independent of transgene expression. Re neurons recorded from J20 mice did not exhibit increased AP generation in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increase in rebound firing does not appear to result from alterations to T-type calcium channels. Finally, in J20 mice there was an [~]8% reduction in spike width, similar to what we and others have reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to the hyperexcitability observed in hippocampal-thalmo-cortical circuits under pathological A{beta} load.\n\nKey PointsO_LIAlterations in the neurophysiology of hippocampal and cortical neurons has been linked to network hyperexcitability in mouse models of amyloidopathy.\nC_LIO_LIThe nucleus reuniens (Re) is part of a cognitive network involving the hippocampal formation and prefrontal cortex. Increased cellular activity in Re has been linked to the generation of hippocampal-thalamo-cortical seizure activity in J20 mice.\nC_LIO_LIRe neurons display hyperpolarised resting membrane potentials in J20 mice. Passive membrane properties are unaffected by transgene expression. Re neurons recorded from J20 mice did not exhibit increased excitability in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increased rebound firing was not a result of changes in T-type Ca2+ conductances. Finally we observed a decrease in AP width.\nC_LIO_LIThese results help us understand how altered Re cellular neurophysiology may contribute to hippocampal-thalamo-cortical hyperexcitability in J20 mice.\nC_LI

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bioRxiv2019

Impaired speed encoding is associated with reduced grid cell periodicity in a mouse model of tauopathy

Dementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially-sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wildtype mice are tightly linked to running speed, was invariant in rTg4510 mice. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.

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bioRxiv2018

Human primary astrocytes increase basal fatty acid oxidation following recurrent low glucose to maintain intracellular nucleotide levels

Hypoglycemia is a major barrier to good glucose control in type 1 diabetes and frequent exposure to hypoglycemia can impair awareness to subsequent bouts of hypoglycemia. The neural changes that occur to reduce a persons awareness of hypoglycemia are poorly defined. Moreover, the molecular mechanisms by which glial cells contribute to hypoglycemia sensing and glucose counterregulation require further investigation. To test whether glia, specifically astrocytes, could detect changes in glucose, we utilized human primary astrocytes (HPA) and U373 astrocytoma cells and exposed them to recurrent low glucose (RLG) in vitro. This allowed measurement, with high specificity and sensitivity, of changes in cellular metabolism following RLG. We report that the AMP-activated protein kinase (AMPK) is activated over a pathophysiologically-relevant glucose concentration range. We observed an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and hallmarks of mitochondrial stress including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG, nor were glucose uptake or glycogen levels. Taken together, these data indicate that astrocyte mitochondria are dysfunctional following recurrent low glucose exposure, which could have implications for hypoglycemia glucose counterregulation and/or hypoglycemia awareness.

neuroscience↗