Biology subjects

Graham, B. P.

Publications and source records attributed to Graham, B. P..

4 recordsLinked to original sources

bioRxiv2025

Control of two-pathway signal integration in a model neocortical pyramidal cell

We demonstrate how neuromodulation and spatially targetted inhibition can alter the integration of the two streams of excitatory input in a thick-tufted layer 5 pyramidal cell, using a computational reduced-compartmental cell models. Choosing suitable ranges of brief current stimulus amplitudes, applied basally to either the soma or basal dendrites (basal stimulation) and to the apical tuft (apical stimulation) results in burst firing due to either stimulus alone, if strong enough, or by a combination of the stimuli at lower amplitudes. Applying tonic inhibition to the apical tuft removes the ability of apical input alone to generate a burst over the chosen amplitude range. A similar effect is achieved by reducing the tuft calcium channel conductance as an outcome of neuromodulation. Similarly, tonic inhibition to the basal dendrites removes the ability of basal stimulation alone to generate a burst, without blocking bursts resulting from apical calcium spikes. HCN channels in the apical dendrites may amplify or reduce bursting probability, depending on other active and passive properties of dendrites. So neuromodulation that decreases the conductance of these channels may act to reduce or increase bursting probability across the across the ranges of basal and apical inputs, depending on cell properties. These effects mimic those found previously by simply limiting the range of stimulus amplitudes (Graham et al., 2025) but now show that such changes in two-stream signal integration can happen through network inhibition and neuromodulation with no change in the excitatory driving stimulus strengths. These changes in signal integration also lead to changes in information transmitted by the cells bursting probability about the two input streams, as shown in Graham et al. (2025). Changes in cell morphology are also investigated by reducing the apical trunk length and are revealed to alter this two-stream signal integration through differential effects on passive and active interaction between the soma and apical tuft.

neuroscience↗

bioRxiv2024

Transfer functions for burst firing probability in a model neocortical pyramidal cell

Neocortical layer 5 thick-tufted pyramidal cells are prone to exhibiting burst firing on receipt of coincident basal and apical dendritic inputs. These inputs carry different information, with basal inputs coming from feedforward sensory pathways and apical inputs coming from diverse sources that provide context in the cortical hierarchy. We explore the information processing possibilities of this burst firing using computer simulations of a noisy compartmental cell model. Simulated data on stochastic burst firing due to brief, simultaneously injected basal and apical currents allows estimation of burst firing probability for different stimulus current amplitudes. Information-theory-based partial information decomposition (PID) is used to quantify the contributions of the apical and basal input streams to the information in the cell output bursting probability. Four different operating regimes are apparent, depending on the relative strengths of the input streams, with output burst probability carrying more or less information that is uniquely contributed by either the basal or apical input, or shared and synergistic information due to the combined streams. We derive and fit transfer functions for these different regimes that describe burst probability over the different ranges of basal and apical input amplitudes. The operating regimes can be classified into distinct modes of information processing, depending on the contribution of apical input to out-put bursting: apical cooperation, in which both basal and apical inputs are required to generate a burst; apical amplification, in which basal input alone can generate a burst but the burst probability is modulated by apical input; apical drive, in which apical input alone can produce a burst; and apical integration, in which strong apical or basal inputs alone, as well as their combination, can generate bursting. In particular, PID and the transfer function clarify that the apical amplification mode has the features required for contextually-modulated information processing.

neuroscience↗

bioRxiv2021

Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse

Kv3 potassium currents mediate rapid repolarization of action potentials (AP), supporting fast spikes and high repetition rates. Of the four Kv3 gene family members, Kv3.1 and Kv3.3 are highly expressed in the auditory brainstem and we exploited this to test for subunit-specific roles at the calyx of Held presynaptic terminal. Deletion of Kv3.3 (but not Kv3.1) increased presynaptic AP duration and facilitated transmitter release, which in turn enhanced short-term depression during high frequency transmission. The response to sound was delayed in the Kv3.3KO, with higher spontaneous and lower evoked firing, thereby reducing signal-to-noise ratio. Computational modelling showed that the enhanced EPSC and short-term depression in the Kv3.3KO reflected increased vesicle release probability and accelerated activity-dependent vesicle replenishment. We conclude that Kv3.3 is the presynaptic delayed rectifier, enabling short duration, precisely timed APs to maintain transmission at high frequencies and during sustained synaptic activity.

neuroscience↗

bioRxiv2018

A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity

Neurons in the medial vestibular nucleus (MVN) display hyperpolarisation-gated synaptic plasticity, where inhibition believed to come from cerebellar cortical Purkinje cells can induce long-term potentiation (LTP) or long-term depression (LTD) of vestibular nerve afferent synapses. This phenomenon is thought to underlie the plasticity of the vestibulo-ocular reflex (VOR). The molecular and cellular mechanisms involved are largely unknown. Here we present a novel multi-scale computational model, which captures both electrophysiological and biochemical signalling at vestibular nerve synapses on proximal dendrites of the MVN neuron. We show that AMPA receptor phosphorylation at the vestibular synapse depends in complex ways on dendritic calcium influx, which is in turn shaped by patterns of post-synaptic hyperpolarisation and vestibular nerve stimulation. Hyperpolarisation-gated synaptic plasticity critically depends on the activation of LVA calcium channels and on the interplay between CaMKII and PP2B in dendrites of the post-synaptic MVN cell. The extent and direction of synaptic plasticity depend on the strength and duration of hyperpolarisation, and on the relative timing of hyperpolarisation and vestibular nerve stimulation. The multi-scale model thus enables us to explore in detail the interactions between electrophysiological activation and post-synaptic biochemical reaction systems. More generally, this model has the potential to address a wide range of questions about neural signal integration, post-synaptic biochemical reaction systems and plasticity.

neuroscience↗