Current knowledge of thalamocortical interaction comes mainly from studying lemniscal thalamic systems. Less is known about paralemniscal thalamic nuclei function. In the vibrissae system, the posterior medial nucleus (POm) is the corresponding paralemniscal nucleus. POm neurons project to L1 and L5A of the primary somatosensory cortex (S1) in the rat brain. It is known that L1 modifies sensory-evoked responses through control of intracortical excitability suggesting that L1 exerts an influence on whisker responses. Therefore, thalamocortical pathways targeting L1 could modulate cortical firing. Here, using a combination of electrophysiology and pharmacology in vivo, we have sought to determine how POm influences cortical processing. In our experiments, single unit recordings performed in urethane-anesthetized rats showed that POm imposes precise control on the magnitude and duration of supra- and infragranular barrel cortex whisker responses. Our findings demonstrated that L1 inputs from POm imposed a time and intensity dependent regulation on cortical sensory processing. Moreover, we found that blocking L1 GABAergic inhibition or blocking P/Q-type Ca2+ channels in L1 prevents POm adjustment of whisker responses in the barrel cortex. Additionally, we found that POm was also controlling the sensory processing in S2 and this regulation was modulated by corticofugal activity from L5 in S1. Taken together, our data demonstrate the determinant role exerted by the POm in the adjustment of somatosensory cortical processing and in the regulation of cortical processing between S1 and S2. We propose that this adjustment could be a thalamocortical gain regulation mechanism also present in the processing of information between cortical areas.

Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3–4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated pools of neurons that may modulate specific cortical areas.

Previous studies based on the ‘Quantal Model’ for synaptic transmission suggest that neurotransmitter release is mediated by a single release site at individual synaptic contacts in the neocortex. However, recent studies seem to contradict this hypothesis and indicate that multi-vesicular release (MVR) could better explain the synaptic response variability observed in vitro. In this study we present a novel method to estimate the number of release sites per synapse, also known as the size of the readily releasable pool (NRRP), from paired whole-cell recordings of connections between layer 5 thick tufted pyramidal cell (L5_TTPC) in the juvenile rat somatosensory cortex. Our approach extends the work of Loebel et al. (2009) by leveraging a recently published data-driven biophysical model of neocortical tissue. Using this approach, we estimated NRRP to be between two to three for synaptic connections between L5_TTPCs. To constrain NRRP values for other connections in the microcircuit, we developed and validated a generalization approach using published data on the coefficient of variation (CV) of the amplitudes of post-synaptic potentials (PSPs) from literature and comparing them against in silico experiments. Our study predicts that transmitter release at synaptic connections in the neocortex could be mediated by MVR and provides a data-driven approach to constrain the MVR model parameters in the microcircuit.

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Previous studies based on the 'Quantal Model' for synaptic transmission suggested that neurotransmitter release is mediated by a single release site at individual synaptic contacts in the neocortex. However, recent studies seem to contradict this hypothesis and indicate that multi-vesicular release (MVR) could better explain the synaptic response variability observed in vitro. In this study we present a novel method to estimate the number of release sites per synapse, also known as the size of the readily-releasable pool (NRRP), from paired whole-cell recordings of layer 5 thick tufted pyramidal cell (L5_TTPC) connections in the somatosensory neocortex. Our approach extends the work of Loebel and colleagues to take advantage of a recently reported data-driven biophysical model of neocortical tissue. Using this approach, we estimated NRRP to be between two to three for connections between L5-TTPC. To constrain NRRP values for other connections in the microcircuit, we developed and validated a generalization approach using data on post-synaptic potential (PSP) coefficient of variations (CVs) from literature and matching to in silico experiments. Our study shows that synaptic connections in the neocortex generally are mediated by MVR and provides a data-driven approach to constrain the MVR model parameters of the microcircuit.

Rodents use rhythmic whisker movements at frequencies between 4 and 12 Hz to sense the environment that will be disturbed when the animal touches an object. The aim of this work is to study the response adaptation to rhythmic whisker stimulation trains at 4 Hz in the barrel cortex and the sensitivity of cortical neurons to changes in the timing of the stimulation pattern. Longitudinal arrays of four iridium oxide electrodes were used to obtain single-unit recordings in supragranular, granular, and infragranular neurons in urethane anesthetized mice. The stimulation protocol consisted in a stimulation train of three air puffs (20 ms duration each) in which the time interval between the first and the third stimuli was fixed (500 ms) and the time interval between the first and the second stimuli changed (regular: 250 ms; “accelerando”: 375 ms; or “decelerando” stimulation train: 125 ms interval). Cortical neurons adapted strongly their response to regular stimulation trains. Response adaptation was reduced when accelerando or decelerando stimulation trains were applied. This facilitation of the shifted stimulus was mediated by activation of NMDA receptors because the effect was blocked by AP5. The facilitation was not observed in thalamic nuclei. Facilitation increased during periods of EEG activation induced by systemic application of IGF-I, probably by activation of NMDA receptors, as well. We suggest that response adaptation is the outcome of an intrinsic cortical information processing aimed at contributing to improve the detection of “unexpected” stimuli that disturbed the rhythmic behavior of exploration.

According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca2+ spike and Ca2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information.