Structure and dynamics of the neocortical microcircuit connectivity

The neocortex is the most computationally advanced portion of the brain. It is currently assumed to be composed of a large number of "cortical columns" – intricate arrangements of cortical neurons approximately 300-500 µm in diameter and 2-5 mm in height in humans – that might serve as the elementary computational unit of the neocortex. Understanding the computation performed by this microcircuit is one of the keys to our comprehension of the brain. The so-called cortical column is not a static entity, however, and it evolves throughout a lifetime and continually adapts to the information from its cortical environment. Despite the differences between cortical columns across the cortex, a number of common features have been identified: a laminar structure, the dynamics of connections between identified neurons or the mechanisms for these connections to be modified (that give its specificity to each microcircuit). This thesis presents the description of the differential connectivity and synaptic dynamics across cell populations and the long term neuronal rewiring in a particular neuronal population within the cortical column. Somatic whole cell recordings have been performed to probe the connectivity, synaptic dynamics and plasticity of the connections in the rat neocortex. Two populations of layer V pyramidal neurons were studied in particular: cortico-callosally projecting pyramidal cells (CCPs) and thick tufted pyramidal cells (TTCs). The first major results from this work revealed the degree of connectivity and the linear dynamics of the CCPs population when compared to the TTCs. CCPs have nearly 4 times fewer interconnections and subsequent post-synaptic potentials were less decreasing in amplitude along a pre-synaptic series of action potentials. Long term configuration of TTC networks was explored. These experiments show for the first time the emergence of new functional synaptic connections between TTCs within hours. Activation of the slice by glutamate greatly increases their rate of emergence and this work demonstrated that metabotropic glutamate receptor 5 (mGluR5) activation and action potential firing are required for new connections to be formed in this experimental protocol. Newly formed connections respond in a more linear fashion and have weaker post-synaptic influence than already existing connections. Pre-existing connections are also modified after stimulation, requiring mGluR5, action potentials as well as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors activation. The activation of group III metabotropic glutamate receptors (mGluRs) however results in a decrease in the strength of connections. Finally, the influence of inhibitory interneurons on the activity and connectivity between TTCs was also investigated. The results of this study show that firing of inhibitory interneurons can be triggered by the input of only one pyramidal cell. They further show that stimulation of a single TTC can result in an hyperpolarization of the post-synaptic TTC mediated by an interneurone. When the pre-synaptic neuron is also directly connected to the post-synaptic neuron with an excitatory synapse, the indirect inhibitory connection serves to curtail the excitatory response. This work has provided a new insight into the dynamic nature of the cortical microcircuitry, showing that it evolves rapidly and can adapt, reconfigure and rewire itself in remarkably short time-spans. It also describes the variety of dynamics exhibited by the different types of pyramidal cells, due to either the projecting site specificity or to the action of an intermediate interneuron

Morphological, Electrophysiological, and Synaptic Properties of Corticocallosal Pyramidal Cells in the Neonatal Rat Neocortex

Neocortical pyramidal cells (PCs) project to various cortical and subcortical targets. In layer V, the population of thick tufted PCs (TTCs) projects to subcortical targets such as the tectum, brainstem, and spinal cord. Another population of layer V PCs projects via the corpus callosum to the contralateral neocortical hemisphere mediating information transfer between the hemispheres. This subpopulation (corticocallosally projecting cells [CCPs]) has been previously described in terms of their morphological properties, but less is known about their electrophysiological properties, and their synaptic connectivity is unknown. We studied the morphological, electrophysiological, and synaptic properties of CCPs by retrograde labeling with fluorescent microbeads in P13-P16 Wistar rats. CCPs were characterized by shorter, untufted apical dendrites, which reached only up to layers II/III, confirming previous reports. Synaptic connections between CCPs were different from those observed between TTCs, both in probability of occurrence and dynamic properties. We found that the CCP network is about 4 times less interconnected than the TTC network and the probability of release is 24% smaller, resulting in a more linear synaptic transmission. The study shows that layer V pyramidal neurons projecting to different targets form subnetworks with specialized connectivity profiles, in addition to the specialized morphological and electrophysiological intrinsic propertie

Enhanced Long-Term Microcircuit Plasticity in the Valproic Acid Animal Model of Autism

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 μm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12–15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism

Reconstruction and simulation of neocortical microcircuitry

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies

The modular cross-synaptic nature of LTP/LTD following on-going neural activity

While synaptic efficacies are modified continuously by on-going spiking activity, it is yet unclear whether the underlying pre- and post-synaptic processes occur independently, or in accordance