Neocortex; calcium; imaging; in vivo; dendrite; dendritic integration; cerebral cortex; dendrites; pyramidal neurons; anesthesia; rats; calcium imaging; inhibition
Palmer Lucy (2014), Dendritic integration in pyramidal neurons during network activity and disease, in Brain Research Bulletin
, 103, 2-10.
Palmer Lucy, Shai Adam, Reeve James, Anderson Harry, Paulsen Ole, Larkum Matthew (2014), NMDA spikes enhance action potential generation during sensory input, in Nature Neuroscience
, 17, 383-390.
Pérez-Garci Enrique, Larkum Matthew, Nevian Thomas (2013), Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o-β-subunit interaction with Cav1 channels, in Journal of Physiology
, 591(7), 1599-1612.
Larkum M. (2012), A cellular mechanism for cortical associations: an organizing principle for the cerebral cortex., in Trends Neurosci.
, 36(3), 141-151.
Granato A, Palmer LM, De Giorgio A, Tavian D, Larkum ME (2012), Early Exposure to Alcohol Leads to Permanent Impairment of Dendritic Excitability in Neocortical Pyramidal Neurons, in JOURNAL OF NEUROSCIENCE
, 32(4), 1377-1382.
Murayama Masanori, Larkum Matthew (2012), Fiber-optic calcium monitoring of dendritic activity in vivo., in Cold Spring Harbor protocols
, 2012(2), 218-25.
Palmer Lucy, Murayama Masanori, Larkum Matthew (2012), Inhibitory Regulation of Dendritic Activity in vivo, in Frontiers in Neural Circuits
, 6, 26-35.
Palmer Lucy, Murayama Masanori, Larkum Matthew (2012), Inhibitory Regulation of Dendritic Activity in vivo., in Frontiers in neural circuits
, 6, 26-26.
Palmer LM, Schulz JM, Murphy SC, Ledergerber D, Murayama M, Larkum ME (2012), The Cellular Basis of GABA(B)-Mediated Interhemispheric Inhibition, in SCIENCE
, 335(6071), 989-993.
Ledergerber D, Larkum ME (2012), The Time Window for Generation of Dendritic Spikes by Coincidence of Action Potentials and EPSPs is Layer Specific in Somatosensory Cortex, in PLOS ONE
, 7(3), 1-5.
Ledergerber D, Larkum ME (2010), Properties of Layer 6 Pyramidal Neuron Apical Dendrites, in JOURNAL OF NEUROSCIENCE
, 30(39), 13031-13044.
The neocortex and its interaction with the thalamus lie at the heart of what makes mammals intelligent. The neocortex is particularly adept at making associations and predictions about the world. But how does the cortex achieve this? Although this is an enormous question, per se, it is highly probable that the answer depends at least in part on the architecture of the cortex itself - both in terms of the individual elements and their connectivity. Surprisingly, treatment of the former (understanding the intrinsic properties of neurons) is still a largely open question and is rarely posed in relation to the latter (the functional connectivity of the cortex). Since the cortex is predominantly made up of pyramidal neurons, it would appear absolutely fundamental to understand synaptic integration in these neurons in the context of the network in which they are embedded.This proposal examines the hypothesis that, for all their complexities, the salient feature about the main output neurons of the cortex, the large layer 5 (L5) pyramidal neurons, is that their dendrites function as a point of intersection for the integration of bottom-up and top-down information in the cortex. This makes sense both in terms of the intrinsic properties of L5 pyramidal dendrites and the connectivity of the cortex. Firstly, a specific set of ion channels in the apical dendrite lead to Ca2+ plateau potentials (Ca2+ spikes) which convert the firing mode of the neurons to bursting. This tendency to go into dendritic spike/burst mode is greatly increased by coincident input to both the proximal and distal parts of the neurons. Secondly, the tuft dendrites of layer 5 (L5) pyramidal neurons lie in layer 1 where long-range axons from secondary thalamic nuclei and higher cortical areas arrive. This class of input is very dependent on active thalamo-cortical loops and activity in higher brain areas and so is likely to be heavily influenced by the conscious state of the animal. So far, this hypothesis has been well tested at the single cell level in vitro but has yet to be observed in vivo. If true in vivo, it should at a minimum be possible to observe dendritic Ca2+ increases during circumstances that lead to simultaneous bottom-up and top-down input. Therefore, the planned experiments in this proposal aim to look for the presence of Ca2+ electrogenesis in the dendrites of L5 pyramidal neurons in more physiological experiments in vivo and even recordings from the dendrites in freely moving rats during a behavioural task.The complexity of the active properties of L5 pyramidal apical dendrites makes this project particularly interesting and leads to possibilities for translational research. Most of the different voltage-sensitive ion channels, receptors and intracellular molecular machinery involved in dendritic spikes are influenced by one or more clinically used pharmaceutical interventions. There is also abundant evidence that inhibition has a disproportionately strong influence in blocking dendritic activity and that specialized inhibitory circuits and intracellular mechanisms are involved. We have also shown recently that the action of anesthetics and therefore the conscious state of the animal have direct and indirect affects on dendritic spiking in vivo. The proposed research project will examine all of these factors with the aim of describing the circumstances and conditions that lead to Ca2+ spike firing in the neocortex. Experiments in vitro will look in detail at the mechanisms underlying dendritic Ca2+ and NMDA spikes. Experiments in vivo will look at physiological conditions leading to dendritic activity as well as testing ways to artificially influence this activity to derive the causal relationship between dendritic activity, network activity and physiological input/output. Lastly, experiments in behaving rats will establish the behavioural correlates of dendritic activity.