Jonathan T. Brown

Accurate learning underpins optimal predictions and requires the brain to navigate uncertainty, identifying important information and distinguishing between expected and unexpected uncertainties. Theoretical models propose that the neuromodulator acetylcholine positively correlates with expected uncertainty, priming neuronal networks for learning. We tested this hypothesis by measuring acetylcholine release and neuronal representations in the retrosplenial cortex of mice whilst challenging them with expected and unexpected uncertainties of reward location. Acetylcholine release did not directly correlate with expected or unexpected uncertainty but instead increased with changes in expected uncertainty. In tandem, increased expected uncertainty shifted neuronal representations from a positional reference frame to focus on salient landmarks, such as reward location. Transitions in expected uncertainty also accelerated remapping of neuronal representations and behavioural adaptation when unexpected uncertainty was experienced. Thus, we demonstrate acetylcholine release in retrosplenial cortex discerns types of uncertainty and correlates with learning speed in uncertain environments.

Within the brain, neurons and glial cells engage in dynamic crosstalk to maintain homeostasis and regulate neuroimmune responses. Recent studies have implicated rhythmic neuronal network activity, most notably at gamma oscillation frequencies (approx. 25-100 Hz), in modulating the morphology and function of microglia, the brain’s primary immune cells. Little is known, however, about the cellular mechanisms underlying this form of neuroimmune communication. Using pharmacological and optogenetic models of gamma oscillations in mouse brain slices, we found that gamma oscillations stimulate microglia to adopt a reactive morphological phenotype via activation of colony stimulation factor 1 receptor (CSF1R) and nuclear factor κB-mediated signalling. Surprisingly, inhibition of two downstream mediators of CSF1R signalling – phosphoinositide-3-kinase or phospholipase C – did not prevent this effect, suggesting that neuron-microglia interactions in this context may occur via compensatory or alternative CSF1R-linked pathways. These findings provide important insights into how rhythmic brain activity regulates neuroimmune function, with potential implications for neurological health and disease.

Beta-frequency oscillations (20-30 Hz) are prominent in both human and rodent electroencephalogram (EEG) recordings. Discrete epochs of beta (or Beta2) oscillations are prevalent in the hippocampus and other brain areas during exploration of novel environments. However, little is known about the spatial distribution and temporal relationships of beta oscillations across the cortex in response to novelty. To investigate this, mice fitted with 30-channel EEG-style multi-electrode arrays underwent a single recording session in a novel environment. While changes to spectral properties of cortical oscillations were minimal, there was a profound increase in the rate of beta bursts during the initial part of the recording session, when the environment was most novel. This was true across the cortex but most notable in recording channels situated above the retrosplenial cortex. Additionally, novelty was associated with greater connectivity between retrosplenial areas and the rest of the cortex, specifically in the beta frequency range. However, it was also found that the cortex in general, is highly modulated by environmental novelty. This data further suggests the retrosplenial cortex is an important hub for distinguishing environmental context and highlights the diversity of functions for beta oscillations across the brain, which can be observed using high-density EEG.

Ridler T, Witton J, Phillips KG, Randall AD, Brown JT. 2020. Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy. eLife 9:e59045. doi: 10.7554/eLife.59045.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer9s disease (AD). In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of AD-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials (LFPs) were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of β (20–30 Hz) oscillations (β 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 β bursts. Additionally, θ-α/β cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during β bursts. Finally, excessive β bursting was seen in J20 mice, including increased β bursting during novelty and familiarity, yet a loss of coupling between β bursts and spiking activity. These findings support the concept that β 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. SIGNIFICANCE STATEMENT The retrosplenial cortex (RSC) is thought to be involved in the formation, recall and consolidation of contextual memory. The discovery of bursts of β oscillations in this region, which are associated with increased neuronal spiking and strongly upregulated while mice explore novel environments, provides a potential mechanism for the activation of neuronal ensembles, which may underlie the formation of cortical representations of context. Excessive β bursting in the RSC of J20 mice, a mouse model of Alzheimer9s disease (AD), alongside the disassociation of β bursting from neuronal spiking, may underlie spatial memory impairments previously shown in these mice. These findings introduce a novel neurophysiological correlate of spatial learning and memory, and a potentially new form of AD-related cortical dysfunction.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory, and is functionally disrupted in the early stages of Alzheimer’s 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 Alzheimer’s 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.

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 wild-type mice are tightly linked to running speed, was invariant in rTg4510 mice during locomotion. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.

The International League Against Epilepsy (ILAE) groups seizures into “focal”, “generalized” and “unknown” based on whether the seizure onset is confined to a brain region in one hemisphere, arises in several brain region simultaneously, or is not known, respectively. This separation fails to account for the rich diversity of clinically and experimentally observed spatiotemporal patterns of seizure onset and even less so for the properties of the brain networks generating them. We consider three different patterns of domino-like seizure onset in Idiopathic Generalized Epilepsy (IGE) and present a novel approach to classification of seizures. To understand how these patterns are generated on networks requires understanding of the relationship between intrinsic node dynamics and coupling between nodes in the presence of noise, which currently is unknown. We investigate this interplay here in the framework of domino-like recruitment across a network. In particular, we use a phenomenological model of seizure onset with heterogeneous coupling and node properties, and show that in combination they generate a range of domino-like onset patterns observed in the IGE seizures. We further explore the individual contribution of heterogeneous node dynamics and coupling by interpreting in-vitro experimental data in which the speed of onset can be chemically modulated. This work contributes to a better understanding of possible drivers for the spatiotemporal patterns observed at seizure onset and may ultimately contribute to a more personalized approach to classification of seizure types in clinical practice. Epilepsy is a serious neurological condition encompassing a variety of syndromes that affect around 65 million people worldwide. Seizure type in epilepsy is characterized by onset pattern and brain network involved into three categories that do not fully capture the complexity of observed onset patterns. Ambiguity of seizure onset observed in the clinic could result in significant diagnostic delay and inappropriate treatment for an individual. We show how a variety of recruitment patterns across a network arise as the result of interplay between heterogeneous node dynamics and heterogeneous coupling among nodes. Our results demonstrate the important role of brain network dynamics in driving spatiotemporal patterns of seizure onset and provide a dynamic mechanism that could inform novel classifications of seizure types in clinical practice.

Transgenic mice that overproduce beta-amyloid (Aβ) 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 Aβ load. Key Points: Alterations in the neurophysiology of hippocampal and cortical neurons has been linked to network hyperexcitability in mouse models of amyloidopathy. The 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. Re 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 Ca ²⁺ conductances. Finally we observed a decrease in AP width. These results help us understand how altered Re cellular neurophysiology may contribute to hippocampal-thalamo-cortical hyperexcitability in J20 mice.

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.