Yann Sweeney PhD

Yann Sweeney


Research Interests

I am interested in homeostasis and how regulation of single neuron characteristics affects the behaviour and stability of networks. I am currently modelling the effect of Nitric Oxide (NO), a signalling molecule generated by MNTB neurons following synaptic stimulation and which modulates ion channels. I am interested in developing a biologically grounded model of how neurons sense and respond to changes in activity. 

Publications:
2015
  Homeostatic intrinsic plasticity, neural heterogeneity and memory maintenance
Sweeney, Y, Hellgren-Kotaleski, J & Hennig, M 2015, 'Homeostatic intrinsic plasticity, neural heterogeneity and memory maintenance' BMC Neuroscience, vol 16, no. 1, pp. 1-2. DOI: 10.1186/1471-2202-16-S1-P98
Neural firing rates must be maintained within a stable range in the face of ongoing fluctuations in synaptic activity. This can be achieved through homeostatic intrinsic plasticity. However, here we show that such a mechanism, while successfully regulating neural firing rates, has an adverse effect on a network's ability to encode and retain memories. This is due to its interactions with Hebbian plasticity; neurons whose firing rates change following potentiation or depression of synaptic inputs will experience modifications in intrinsic excitability toward their homeostatic target, which can cause subsequent synaptic weight variations and disrupt learning. Essentially, this failure is a direct consequence of homeostasis preventing neural heterogeneity in order to maintain stable activity.

We propose a new mechanism, diffusive homeostasis, in which neural excitability is modulated by a diffuse messenger, specifically nitric oxide, which is known to freely cross cell membranes and homeostatically regulate neural excitability [1]. Information about a neuron's firing rate can be carried by nitric oxide, meaning that an individual neuron's excitability is affected by neighbouring neurons' firing rates as well as its own. We find that this allows a neuron to deviate from the target population activity, as its neighbours will counteract this deviation, thus maintaining stable average activity. We show that this form of neural heterogeneity endows a network with more flexibility than heterogeneity through variable target firing rates in individual neurons, which in turn leads to networks that are more responsiveness to changes in synaptic inputs (Figure 1) [2]. The increased flexibility in firing rates conferred by diffusive homeostasis resolves the conflict between homeostatic intrinsic plasticity and Hebbian plasticity by limiting the impact of homeostasis on individual synaptic modifications. Consequently, networks endowed with this diffusive mechanism have an improved learning capability compared to canonical, local homeostatic mechanisms, exhibit more stable synaptic weights, and allow for more efficient use of neural resources.
General Information
Organisations: Edinburgh Neuroscience.
Authors: Sweeney, Yann, Hellgren-Kotaleski, Jeanette & Hennig, Matthias.
Number of pages: 2
Pages: 1-2
Publication Date: Dec 2015
Publication Information
Category: Article
Journal: BMC Neuroscience
Volume: 16
Issue number: 1
ISSN: 1471-2202
Original Language: English
DOIs: 10.1186/1471-2202-16-S1-P98
  A Diffusive Homeostatic Signal Maintains Neural Heterogeneity and Responsiveness in Cortical Networks
Sweeney, Y, Hellgren Kotaleski, J & Hennig, MH 2015, 'A Diffusive Homeostatic Signal Maintains Neural Heterogeneity and Responsiveness in Cortical Networks' PLoS Computational Biology, vol 11, no. 7, e1004389. DOI: 10.1371/journal.pcbi.1004389

Gaseous neurotransmitters such as nitric oxide (NO) provide a unique and often overlooked mechanism for neurons to communicate through diffusion within a network, independent of synaptic connectivity. NO provides homeostatic control of intrinsic excitability. Here we conduct a theoretical investigation of the distinguishing roles of NO-mediated diffusive homeostasis in comparison with canonical non-diffusive homeostasis in cortical networks. We find that both forms of homeostasis provide a robust mechanism for maintaining stable activity following perturbations. However, the resulting networks differ, with diffusive homeostasis maintaining substantial heterogeneity in activity levels of individual neurons, a feature disrupted in networks with non-diffusive homeostasis. This results in networks capable of representing input heterogeneity, and linearly responding over a broader range of inputs than those undergoing non-diffusive homeostasis. We further show that these properties are preserved when homeostatic and Hebbian plasticity are combined. These results suggest a mechanism for dynamically maintaining neural heterogeneity, and expose computational advantages of non-local homeostatic processes.


General Information
Organisations: Edinburgh Neuroscience.
Authors: Sweeney, Yann, Hellgren Kotaleski, Jeanette & Hennig, Matthias H.
Publication Date: Jul 2015
Publication Information
Category: Article
Journal: PLoS Computational Biology
Volume: 11
Issue number: 7
ISSN: 1553-734X
Original Language: English
DOIs: 10.1371/journal.pcbi.1004389
2013
  Volume transmission as a new homeostatic mechanism
Sweeney, YA, Hellgren-Kotaleski, J & Hennig, M 2013, 'Volume transmission as a new homeostatic mechanism' Champalimaud Neuro Science Symposium 2013, Lisboa, Portugal, 25/09/13 - 28/09/13, .
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Sweeney, Yann A., Hellgren-Kotaleski, Jeanette & Hennig, Matthias.
Publication Date: 2013
Publication Information
Category: Poster
Original Language: English
  Nitric oxide volume transmission mediates a novel homeostatic mechanism in cortical networks
Sweeney, YA, Hellgren-Kotaleski, J & Hennig, M 2013, 'Nitric oxide volume transmission mediates a novel homeostatic mechanism in cortical networks' Society for Neuroscience (SfN) 2013, San Diego, CA, United States, 9/11/13 - 13/11/13, .
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Sweeney, Yann A., Hellgren-Kotaleski, Jeanette & Hennig, Matthias.
Publication Date: 2013
Publication Information
Category: Poster
Original Language: English
  Modelling homeostatic control of high-frequency post-synaptic transmission and its effect on metabolic efficiency in the auditory brainstem
Sweeney, Y, Hellgren-kotaleski, J & Hennig, M 2013, 'Modelling homeostatic control of high-frequency post-synaptic transmission and its effect on metabolic efficiency in the auditory brainstem' pp. P167. DOI: 10.1186/1471-2202-14-S1-P167
Intrinsic electrical properties of neurons are controlled by a number of homeostatic mechanisms, among which is the modulation of conductances of voltage-dependent ion channels. One such example is mediated by Nitric Oxide (NO) in principal neurons of the Medial Nucleus of the Trapezoid Body (MNTB) in the auditory brainstem. These act as relay neurons, receiving excitatory input and transmitting inhibitory signals to the auditory nuclei involved in sound localisation. NO is released here in an activity-dependent manner and switches the basis of action potential (AP) repolarisation from Kv3 to Kv2, decreasing intrinsic excitability and improving faithful following of high frequency input trains [1]. We have replicated these effects in a biophysically detailed neuron model and have measured both transmission fidelity and metabolic efficiency of AP generation, quantified by the Na+/K+ charge overlap ratio [3], across varying states of NO activation.

It is observed that increasing Kv2 conductance leads to improved post-synaptic transmission at high frequencies, while also decreasing the metabolic efficiency of an action potential. The location of Kv2 channels adjacent to Nav channels at the axon initial segment (AIS), as opposed to Kv3, which is located at the soma, is found to be crucial in determining how it affects metabolic efficiency. Figure 1 illustrates that NO mediates transition between a metabolically efficient state sufficient to perform its function at low activity and a metabolically inefficient state required in order to sustain transmission fidelity at high frequencies. This finding provides a plausible justification for the presence of an activity-dependent switch of dominant potassium channel in the MNTB. This effect has subsequently been observed in a CA3 pyramidal cell model [3], a more generic neuron morphology in which NO is also known to act on Kv conductances [1].
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Sweeney, Yann, Hellgren-kotaleski, Jeanette & Hennig, Matthias.
Publication Date: 1 Jan 2013
Publication Information
Category: Poster
Original Language: English
DOIs: 10.1186/1471-2202-14-S1-P167
2012
  Modelling homeostatic control of intrinsic excitability in single neurons
Sweeney, YA, Hennig, M & Hellgren-Kotaleski, J 2012, 'Modelling homeostatic control of intrinsic excitability in single neurons' Society for Neuroscience Annual Meeting 2012, New Orleans, 13/10/12 - 17/10/12, .
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Sweeney, Yann A., Hennig, Matthias & Hellgren-Kotaleski, Jeanette.
Publication Date: 2012
Publication Information
Category: Poster
Original Language: English
  Modelling homeostatic control of intrinsic excitability in single neurons
Sweeney, YA, Hellgren-Kotaleski, J & Hennig, M 2012, 'Modelling homeostatic control of intrinsic excitability in single neurons' The Bernstein Conference on Computational Neuroscience 2012, Munich, Germany, 12/09/12 - 14/09/12, .
Intrinsic excitability in neurons is controlled by a number of homeostatic mechanisms, among which are the modulation of conductances in voltage-dependent ion channels and the modulation of the distance of the axon initial segment (AIS) from the soma. Due to their large size and good accessibility in slice experiments, a useful model system for these forms of homeostatic regulation are principal neurons of the medial nucleus of trapezoid body (MNTB) in the auditory brainstem. These act as relay neurons, receiving excitatory input and transmitting inhibitory signals to the auditory nuclei involved in sound localisation. One form of homeostasis of intrinsic excitability has been shown to be mediated by Nitric Oxide (NO), which is released by MNTB neurons in an activity-dependent manner and modulates Kv3 and Kv2 potassium channels conductance. We have investigated this homeostatic regulation in a multi-compartment MNTB neuron model, incorporating the localisation of ion channels in the soma and the AIS. The analysis of the model showed that the main effects of NO synthesis, a reduction of excitability and concomitant changes in action potential shape as observed in vitro (Steinert et al., Neuron, 2008, 2011), can be accounted for by increasing Kv2 conductances. Moreover, we found that the localisation of ion channels in the AIS, as opposed to the soma, results in a significantly faster action potential onset, with this effect increasing as the AIS is located more distally to the soma. Consistent with previous reports (Grubb Burrone, Nature, 2010), the latter also increased neural excitability. We currently investigate how NO synthesis and AIS location affect the integration of synaptic inputs for different average activity levels and other statistical features of the input.
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Sweeney, Yann A., Hellgren-Kotaleski, Jeanette & Hennig, Matthias.
Publication Date: 2012
Publication Information
Category: Poster
Original Language: English

Projects:
Functional relevance of homeostatic intrinsic plasticity in neurons and networks (PhD)