Thalamic microcircuitry: neurons, synapses, and circuit motifs in receptive field structure and sensory processing

Our perception of the world is first shaped by the thalamus, a structure composed of many nuclei in the center of our brains. Different nuclei hold different responsibilities - vision (dorsal lateral genicular nucleus; dLGN), audition (medial geniculate nucleus; MGN), somatosensation (ventro-basal nuclei; VB), though many properties across these sensory modalities appear to be universal. In this thesis, we completed a comprehensive characterization of the neurons, connections, and microcircuitries within the rodent VB thalamus. Our most prominent finding is the confirmation of the existence of local interneurons in the VB and the discovery of their profoundly active and diverse role in thalamic processes. Thus, we have observed that the fundamental excitatory and inhibitory neurons of dLGN and VB nuclei and their intrinsic circuit motifs are indistinguishable. Only a few notable differences are, however, present. (1), Principal excitatory neurons of the VB, the thalamocortical (TC) relays, have morphological types that appear to be distributed heteroge-neously throughout the VB whereas dLGN TC morphological types have regional preferences. (2), VB inhibitory local interneurons represent a smaller proportion of the total neuronal popula-tion compared to their dLGN counterparts. The similarities between these thalamic regions great-ly outnumber the differences. It then introduces new questions of how different vision and soma-tosensation of the physical world are when these senses are ultimately represented as binary sig-nals and are processed in similar manners in the thalamus. Following these questions may lead to new therapeutic solutions for retinally blind patients, tactile prostheses, or neurological disorders of sensory perception like schizophrenia.

Target cell-type specificity of a cortico-amygdala long range synaptic connection

Ayah Khubieh

An important function of the brain is to analyze sensory information, and to modulate animal behaviour according to previous experience. During processes of emotional learning, sensory percepts with a reinforcing quality, also called unconditioned stimuli (US), influence the quality of innocuous sensory stimuli. A brain structure involved in the integration of innocuous and reinforcing sensory stimuli is the lateral amygdala (LA), an input station to further amygdalar circuits. Little is known about which upstream brain regions convey US-information to the LA; however, evidence indicates that the posterior insular cortex, which processes nociceptive somatosensory information, might be a candidate. The LA microcircuit is composed of principal neurons and inhibitory interneurons; the latter play a prominent role in the control of local activity and plasticity. To investigate how the posterior insular cortex might recruit LA neurons, we used optogenetically-assisted circuit mapping in combination with genetic identification of cell types with Cre-mouse lines. Specifically, a VGluT2-Cre mouse line, producing a marker for excitatory neurons, and VIP-Cre and SOM-Cre mice as markers for two classes of inhibitory interneurons, were used. We found that VGluT2-Cre+ neurons received strong excitatory and feedforward inhibitory inputs from the posterior insular cortex. The excitatory input was sufficient to induce action potential firing, hence engaging the local circuit. VIP-Cre+ interneurons were moderately excited by posterior insular cortex input, and received strong feedforward inhibition. Both VIP-Cre+ and SOM-Cre+ interneurons also received feedforward, polysynaptic excitation, likely the result of the activity of local principal neurons. Finally, SOM-Cre+ interneurons received moderate excitatory and feedforward inhibitory input from the posterior insular cortex, and their connectivity probability was high. This study supports the notion that the posterior insular cortex can convey US-information to the LA, with the potential to strongly activate LA principal neurons. However, it suggests that a disinhibition of LA principal neurons through VIP interneurons, which has been observed in previous studies, might be shaped by additional afferents, possibly including neuromodulatory inputs. Through systematic recordings of input connections to defined neuron types in the LA, this study provides an entry point to the understanding of the synaptic connectivity rules that govern the activation of amygdalar circuits by incoming long-range cortical inputs.

EPFL2021

Structure and dynamics of the neocortical microcircuit connectivity

Jean-Vincent Le Bé

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.

EPFL2007

Long-range connectivity of mouse primary somatosensory barrel cortex

Rachel Aronoff, Céline Matéo, Ferenc Mátyás, Carl Petersen, Bernard Schneider

The primary somatosensory barrel cortex processes tactile vibrissae information, allowing rodents to actively perceive spatial and textural features of their immediate surroundings. Each whisker on the snout is individually represented in the neocortex by an anatomically identifiable 'barrel' specified by the segregated termination zones of thalamocortical axons of the ventroposterior medial nucleus, which provide the primary sensory input to the neocortex. The sensory information is subsequently processed within local synaptically connected neocortical microcircuits, which have begun to be investigated in quantitative detail. In addition to these local synaptic microcircuits, the excitatory pyramidal neurons of the barrel cortex send and receive long-range glutamatergic axonal projections to and from a wide variety of specific brain regions. Much less is known about these long-range connections and their contribution to sensory processing. Here, we review current knowledge of the long-range axonal input and output of the mouse primary somatosensory barrel cortex. Prominent reciprocal projections are found between primary somatosensory cortex and secondary somatosensory cortex, motor cortex, perirhinal cortex and thalamus. Primary somatosensory barrel cortex also projects strongly to striatum, thalamic reticular nucleus, zona incerta, anterior pretectal nucleus, superior colliculus, pons, red nucleus and spinal trigeminal brain stem nuclei. These long-range connections of the barrel cortex with other specific cortical and subcortical brain regions are likely to play a crucial role in sensorimotor integration, sensory perception and associative learning.