Biology subjects

Akerman, C. J.

Publications and source records attributed to Akerman, C. J..

15 recordsLinked to original sources

bioRxiv2026

Opposing intrinsic and synaptic plasticity mechanisms stabilize altered cortical networks during sleep deprivation

Sleep deprivation alters brain activity and impairs performance, yet many aspects of behaviour are preserved in this state. In the cortex for example, sleep deprivation increases neuronal firing rates and low-frequency oscillatory activity, but cortical circuits continue to process information. Recent work has implicated synaptic inhibition in these changes, with sleep deprivation causing cortical GABAA receptor (GABAAR) signalling to become depolarizing due to changes in chloride gradients that determine the GABAAR reversal potential (EGABAAR). The impact in the intact brain remains unclear, however, as both the degree and effects of EGABAAR changes depend on network activity and intrinsic properties of neurons. To address this, we perform in vivo gramicidin recordings from cortical pyramidal neurons in sleep-deprived mice. We reveal that synaptic EGABAAR is depolarised to values sufficient to support bona fide excitatory GABAAR signalling, through combined network-dependent and cell-autonomous effects. In the face of this depolarizing drive, cortical neurons engage spike threshold adaptation mechanisms that limit their excitability. These opposing effects stabilise activity in simulations of sleep-deprived cortical networks and reproduce the increased firing rates and low-frequency oscillatory activity. This interplay between intrinsic and synaptic mechanisms may help maintain network stability during sleep deprivation, while reducing flexibility for subsequent adaptation.

neuroscience↗

bioRxiv2025

Bidirectional modulation of sleep and wakefulness via prefrontal cortical chemogenetics

The cortex is now recognised as a key regulator of sleep. It remains unclear, however, how sleep is affected by changes in cortical activity over different spatial scales. For instance, sleep states are associated with global changes in activity across cortex, but sleep pressure is associated with local variations in cortical activity. Here we use chemogenetic manipulations of a single neuronal population to determine how sleep reflects the spatial scale of cortical activity. Global inhibition of Rbp4-Cre+ neurons increases sleep, but also produces abnormal brief-awakenings and reduces electroencephalogram slow-wave activity, a marker of sleep intensity. In contrast, local inhibition/excitation of Rbp4-Cre+ neurons in the prefrontal but not occipital cortex increases sleep/wake, respectively, whilst preserving normal sleep architecture and electrophysiological features. We conclude that globally altering cortical activity may induce unphysiological sleep due to conflicting sleep-regulatory signals, while locally modulating prefrontal cortex affords bidirectional sleep regulation that leaves naturalistic features intact.

neuroscience↗

bioRxiv2024

Local cortical inhibitory subnetworks are shaped by pyramidal neuron progenitor type

The degree to which cortical neurons share inhibitory synaptic input determines their co-activity within a network. However, the principles by which inhibition is shared between neurons are not known. Here we combine in utero labeling with in vivo two-photon targeted patch-clamp recordings in mature cortex to reveal that a layer 2/3 (L2/3) pyramidal neurons local inhibitory input reflects the embryonic progenitor type from which the neuron is born. In contrast to neighboring neurons, pyramidal neurons derived from intermediate progenitors receive synaptic inhibition that is weakly coupled to local network activity. The underlying mechanisms do not depend upon the amount of inhibitory input received from different interneuron subclasses. Rather, progenitor type defines how much inhibitory input a neuron shares with its neighbors, which is reflected in how individual interneurons target pyramidal neurons according to progenitor type. These findings reveal new significance for progenitor diversity and identify ontogenetic origins of fine-scale inhibitory cortical subnetworks.

neuroscience↗

bioRxiv2023

All-optical reporting of chloride ion driving force in the nervous system.

Ionic driving forces provide the net electromotive force for ion movement across receptors, channels, and transporters, and are a fundamental property of all cells. In the brain for example, fast synaptic inhibition is mediated by chloride permeable GABAA receptors, and single-cell intracellular recordings have been the only method for estimating driving forces across these receptors (DFGABAA). Here we present a new tool for quantifying inhibitory receptor driving force named ORCHID: all-Optical Reporting of CHloride Ion Driving force. We demonstrate ORCHIDs ability to provide accurate, high-throughput measurements of resting and dynamic DFGABAA from genetically targeted cell types over multiple timescales. ORCHID confirms theoretical predictions about the biophysical mechanisms that establish DFGABAA, reveals novel differences in DFGABAA between neurons and astrocytes, and affords the first in vivo measurements of intact DFGABAA. This work extends our understanding of inhibitory synaptic transmission and establishes a precedent for all-optical methods to assess ionic driving forces.

neuroscience↗

bioRxiv2023

Optogenetic determination of dynamic and cell-type-specific chloride equilibrium potentials

Optogenetics has revolutionized neurobiological research by providing tools for modulating neuronal activity. As these tools utilise light-activated ion fluxes, they afford new opportunities to examine the nature of transmembrane ion gradients. Traditional investigation into the equilibrium potential for chloride (ECl) has been limited to studying endogenous chloride-permeable receptors. Here we demonstrate the utility of using a light-activated chloride channel, stGtACR2, to probe somatic ECl in rodent. This agonist-independent optogenetic strategy is validated in vitro and in vivo, captures differences in ECl dynamics following manipulations of endogenous chloride fluxes, and reveals distinct resting ECl across genetically-defined neuronal subpopulations. Using this approach to challenge chloride homeostasis, we uncover cell-specific ECl dynamics that are supported by the differential expression of endogenous handling mechanisms. Our findings establish an optical method for investigating transmembrane chloride gradients and thereby expand the repertoire of optogenetics.

neuroscience↗

bioRxiv2023

Active cortical networks promote shunting fast synaptic inhibition in vivo

Fast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABAARs). Despite their fundamental role, it is still not known how GABAARs signal in the intact brain. Here we use in vivo gramicidin recordings to investigate synaptic GABAAR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anaesthetized cortex, synaptic GABAARs exert classic hyperpolarizing effects. In contrast, GABAAR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABAAR equilibrium potentials (EGABAAR), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. The EGABAAR observed in awake cortex can facilitate the decoupling of local networks, which improves the ability of the network to discriminate stimuli. Our findings therefore suggest that GABAAR signaling adapts to optimize cortical functions.

neuroscience↗

bioRxiv2022

Biologically plausible unsupervised learning in neural networks with sparse and asymmetric connectivity

In the search for biologically plausible but mathematically precise theories of learning in the brain, recent studies have begun to investigate how key assumptions underlying algorithms for supervised learning in artificial neural networks can be relaxed in biologically plausible ways. Turning to unsupervised learning, we develop biologically more plausible variants of the restricted Boltzmann machine (RBM), and benchmark their performance on MNIST. We show that RBMs with asymmetric connectivity can still be successfully trained with contrastive divergence, even if no two units are reciprocally connected. Furthermore, RBMs are able to learn if the forward, visible-to-hidden layer weights are kept constant and only the backward, hidden-to-visible layer weights are updated. These findings indicate that neural networks with biologically plausible connectivity support contrastive learning.

neuroscience↗

bioRxiv2022

Cortical integration of higher-order thalamic inputs is lineage-dependent

Primary sensory cortex receives and integrates inputs from first-order and higher-order thalamic nuclei. First-order inputs convey sensory information from the periphery and exhibit simple response properties, whereas higher-order inputs exhibit more complex response properties, provide contextual feedback, and can modulate first-order inputs. Here we show that the way in which cortical neurons integrate these thalamic inputs, reflects the progenitor cell from which the cortical neurons derive. Within layer 4 of mouse primary somatosensory cortex, excitatory neurons that derive from apical intermediate progenitors exhibit multi-whisker response properties and receive higher-order thalamic input, in a manner consistent with their dendritic morphology. These properties depend upon the expression levels of the transcription factor Lhx2, which when increased, abolishes the higher-order properties of apical intermediate progenitor-derived neurons, and disrupts the induction of sensory-evoked plasticity. These data reveal a lineage-dependent mechanism that establishes the integration and functional contribution of higher-order thalamic inputs within cortex.

neuroscience↗

bioRxiv2022

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye-movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21 or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.

neuroscience↗

bioRxiv2021

Somnotate: A robust automated sleep stage classifier that exceeds human performance and identifies ambiguous states in mice

Electrophysiological recordings from freely behaving animals are a widespread and powerful mode of investigation in sleep research. These recordings generate large amounts of data that require sleep stage annotation (polysomnography), in which the data is parcellated according to three vigilance states: awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. Manual and computational annotation methods currently ignore intermediate states because the classification features become ambiguous. However, these intermediate states contain important information regarding vigilance state dynamics. Here, we present a new classifier, "Somnotate", which produces automated annotation accuracies that exceed human expert performance on mouse electrophysiological data, is robust to errors in the training data, compatible with different recording configurations, and maintains high performance during experimental interventions. Somnotate is a probabilistic classifier based on a combination of linear discriminant analysis (LDA) with a hidden Markov model (HMM). A unique feature of Somnotate is that it quantifies and reports the certainty of its annotations, enabling the experimenter to identify ambiguous recording periods in a principled manner. We leverage this feature to identify epochs that exhibit intermediate vigilance states, revealing that many of these cluster around state transitions, whereas others correspond to failed attempts to transition. We show that the success rates of different transitions can be experimentally manipulated and explain previously observed sleep patterns. Somnotate can thus facilitate the study of sleep stage transitions and offers new insight into the mechanisms underlying sleep-wake dynamics. Author summaryTypically, the three different vigilance states - awake, REM sleep, and non-REM sleep - exhibit distinct features that are readily recognised in electrophysiological recordings. However, particularly around vigilance state transitions, epochs often exhibit features from more than one state. These intermediate vigilance states pose challenges for existing manual and automated classification methods, and are hence often ignored. Here, we present Somnotate - an open-source, highly accurate and robust sleep stage classifier, which supports research into intermediate states and sleep stage dynamics. Somnotate quantifies and reports the certainty of its annotations, enabling the experimenter to identify abnormal epochs in a principled manner. We use this feature to identify intermediate states and to detect unsuccessful attempts to switch between vigilance states. This provides new insights into the mechanisms of vigilance state transitions in mice, and creates new opportunities for future experiments.

neuroscience↗

bioRxiv2020

A role for the cortex in sleep-wake regulation

The cortex and subcortical circuitry are thought to play distinct roles in the generation of sleep oscillations and global control of vigilance states. Here we silenced a subset of cortical layer 5 pyramidal and dentate gyrus granule cells in mice using a cell-specific ablation of the key t-SNARE protein SNAP25. We found a marked increase in wakefulness accompanied by a reduced rebound of EEG slow-wave activity after sleep deprivation. Our data illustrates an important role for the cortex in both global state control and sleep homeostasis.

neuroscience↗

bioRxiv2019

Chloride dynamics alter the input-output properties of neurons

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were entirely mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.\n\nAuthor SummaryThe fundamental unit of computation in the brain is the neuron, whose output reflects information within the brain. A determining factor in the transfer and processing of information in the brain is the modulation of activity by inhibitory synaptic inputs. Fast synaptic inhibition is mediated by the neurotransmitter GABA binding to GABAA receptors, which are permeable to chloride ions. How changes in chloride ion concentration affect neuronal output is an important consideration for information flow in the brain that is currently not being thoroughly investigated. In this research, we used multi-compartmental models of neurons to link the deleterious effects that accumulation of chloride ions can have on inhibitory signalling with changes in neuronal ouput. Together, our results highlight the importance of accounting for changes in chloride concentration in theoretical and computer-based models that seek to explore the computational properties of inhibition.

neuroscience↗

bioRxiv2018

Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

Status epilepticus (SE) is defined as a state of unrelenting seizure activity. It is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as the first line of treatment, but this is ineffective in many cases. We found that 48% of children presenting with SE were unresponsive to benzodiazepine treatment, and critically, that the duration of SE at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of SE. We show that the persistent SE-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during SE-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the SE-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant SE, with relevance to how this life-threatening condition should be managed in the clinic.

neuroscience↗

bioRxiv2018

Fine-scale excitatory cortical circuits reflect embryonic progenitor pools

Introductory paragraph Introductory paragraph Main text Animals In utero electroporation Intrathalamic injections Slice preparation and recording... Stimulation and recording... Analysis of recordings Histological analyses Statistics Methods Author Contributions References The mammalian neocortex is characterised by precise patterns of synaptic connections, which dictate how information flows through cortical circuits. The degree of convergence and divergence of excitatory information results from highly non-random, short-range and long-range glutamatergic synaptic connections1-11. Previous seminal work has shown that c ...

neuroscience↗

bioRxiv2017

Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

neuroscience↗