The role of developmental cell death in the formation of brain circuits is not well understood. Cajal-Retzius cells constitute a major transient neuronal population in the mammalian neocortex, which largely disappears at the time of postnatal somatosensory maturation. In this study, we used mouse genetics, anatomical, functional, and behavioral approaches to explore the impact of the early postnatal death of Cajal-Retzius cells in the maturation of the cortical circuit. We find that before their death, Cajal-Retzius cells mainly receive inputs from layer 1 neurons, which can only develop their mature connectivity onto layer 2/3 pyramidal cells after Cajal-Retzius cells disappear. This developmental connectivity progression from layer 1 GABAergic to layer 2/3 pyramidal cells regulates sensory-driven inhibition within, and more so, across cortical columns. Here we show that Cajal-Retzius cell death prevention leads to layer 2/3 hyper-excitability, delayed learning and reduced performance in a multi-whisker-dependent texture discrimination task.

Sustained attention, as the basis of general cognitive ability, naturally varies across different time scales, spanning from hours, e.g. from wakefulness to drowsiness state, to seconds, e.g. trial-by-trail fluctuation in a task session. Whether there is a unified mechanism underneath such trans-scale variability remains unclear. Here we show that fluctuation of cortical excitation/inhibition (E/I) is a strong modulator to sustained attention in humans across time scales. First, we observed the ability to attend varied across different brain states (wakefulness, postprandial somnolence, sleep deprived), as well as within any single state with larger swings. Second, regardless of the time scale involved, we found highly attentive state was always linked to more balanced cortical E/I characterized by electroencephalography (EEG) features, while deviations from the balanced state led to temporal decline in attention, suggesting the fluctuation of cortical E/I as a common mechanism underneath trans-scale attentional variability. Furthermore, we found the variations of both sustained attention and cortical E/I indices exhibited fractal structure in the temporal domain, exhibiting features of self-similarity. Taken together, these results demonstrate that sustained attention naturally varies across different time scales in a more complex way than previously appreciated, with the cortical E/I as a shared neurophysiological modulator.

Interhemispheric inhibition of the homotopic motor cortex is believed to be effective for accurate unilateral motor function. However, the cellular mechanisms underlying interhemispheric inhibition during unilateral motor behavior remain unclear. Furthermore, the impact of the neuromodulator acetylcholine on interhemispheric inhibition and the associated cellular mechanisms are not well understood. To address this knowledge gap, we conducted recordings of neuronal activity from the bilateral motor cortex of mice during the paw-reaching task. Subsequently, we analyzed interhemispheric spike correlation at the cell-pair level, classifying putative cell types to explore the underlying cellular circuitry mechanisms of interhemispheric inhibition. We found a cell-type pair-specific enhancement of the interhemispheric spike correlation when the mice were engaged in the reaching task. We also found that the interhemispheric spike correlation was modulated by pharmacological acetylcholine manipulation. The local field responses to contralateral excitation differed along the cortical depths, and muscarinic receptor antagonism enhanced the inhibitory component of the field response in deep layers. The muscarinic subtype M2 receptor is predominantly expressed in deep cortical neurons, including GABAergic interneurons. These results suggest that GABAergic interneurons expressing muscarinic receptors in deep layers mediate the neuromodulation of interhemispheric inhibition in the homotopic motor cortex.

OBJECTIVE: This study aimed at investigating the effect of median nerve stimulation on ipsilateral cortical potentials evoked by contralateral median nerve electrical stimulation.
METHODS: We recorded somatosensory-evoked potentials (SEPs) from the left parietal cortex in 15 right-handed, healthy subjects. We administered bilateral median nerve stimulation, with the ipsilateral stimulation preceding the stimulation on the contralateral by intervals of 5, 10, 20, or 40 ms. We adjusted these intervals based on each individual\'s N20 latency. As a measure of S1 excitability, the amplitude of the N20 and the area of the High Frequency Oscillation (HFO) burst were analyzed for each condition.
RESULTS: The results revealed significant inhibition of N20 amplitude by ipsilateral median nerve stimulation at interstimulus intervals (ISIs) between 5 and 40 ms. Late HFO burst was suppressed at short ISIs of 5 and 10 ms, pointing to a transcallosal inhibitory effect on S1 intracortical circuits.
CONCLUSIONS: Findings suggest interhemispheric interaction between the primary somatosensory areas, supporting the existence of transcallosal transfer of tactile information.
CONCLUSIONS: This study provides valuable insights into the interhemispheric connections between primary sensory areas and underscore the potential role of interhemispheric interactions in somatosensory processing.

A fundamental task for the brain is to generate predictions of future sensory inputs, and signal errors in these predictions. Many neurons have been shown to signal omitted stimuli during periodic stimulation, even in the retina. However, the mechanisms of this error signaling are unclear. Here we show that depressing inhibitory synapses shape the timing of the response to an omitted stimulus in the retina. While ganglion cells, the retinal output, responded to an omitted flash with a constant latency over many frequencies of the flash sequence, we found that this was not the case once inhibition was blocked. We built a simple circuit model and showed that depressing inhibitory synapses were a necessary component to reproduce our experimental findings. A new prediction of our model is that the accuracy of the constant latency requires a sufficient amount of flashes in the stimulus, which we could confirm experimentally. Depressing inhibitory synapses could thus be a key component to generate the predictive responses observed in the retina, and potentially in many brain areas.

Aftereffects of non-invasive brain stimulation techniques may be brain state-dependent. Either continuous theta-burst stimulation (cTBS) as transcranial static magnetic field stimulation (tSMS) reduce cortical excitability. Our objective was to explore the aftereffects of tSMS on a M1 previously stimulated with cTBS. The interaction effect of two inhibitory protocols on cortical excitability was tested on healthy volunteers (n = 20), in two different sessions. A first application cTBS was followed by real-tSMS in one session, or sham-tSMS in the other session. When intracortical inhibition was tested with paired-pulse transcranial magnetic stimulation, LICI (ie., long intracortical inhibition) increased, although the unconditioned motor-evoked potential (MEP) remained stable. These effects were observed in the whole sample of participants regardless of the type of static magnetic field stimulation (real or sham) applied after cTBS. Subsequently, we defined a group of good-responders to cTBS (n = 9) on whom the unconditioned MEP amplitude reduced after cTBS and found that application of real-tSMS (subsequent to cTBS) increased the unconditioned MEP. This MEP increase was not found when sham-tSMS followed cTBS. The interaction of tSMS with cTBS seems not to take place at inhibitory cortical interneurons tested by LICI, since LICI was not differently affected after real and sham tSMS. Our results indicate the existence of a process of homeostatic plasticity when tSMS is applied after cTBS. This work suggests that tSMS aftereffects arise at the synaptic level and supports further investigation into tSMS as a useful tool to restore pathological conditions with altered cortical excitability.

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus and ventral pallidum afferents. We next determined the phase resetting curve, the reversal potential for GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs), and the average interspike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the interspike interval or phase. Simulations were performed to predict the pause duration resulting from the synchronous arrival of multiple uIPSGs and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns, including pauses that have been implicated in reinforcement.

OBJECTIVE: Investigating the optimal interstimulus interval (ISI) and the 24-hour test-retest reliability for intrahemispheric dorsal premotor cortex (PMd) - primary motor cortex (M1) connectivity using dual-site transcranial magnetic stimulation (dsTMS).
METHODS: In 21 right-handed adults, left intrahemispheric PMd-M1 connectivity has been investigated with a stacked-coil dsTMS setup (conditioning stimulus: 75% of resting motor threshold; test stimulus: eliciting MEPs of 1-1.5 mV) at ISIs of 3, 5-8, and 10 ms. Additionally, M1-M1 short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were investigated to assess comparability to standard paired-pulse setups.
RESULTS: Conditioning PMd led to significant inhibition of M1 output at ISIs of 3 and 5 ms, whereas 10 ms resulted in facilitation (all, p < 0.001), with a fair test-retest reliability for 3 (ICC: 0.47) and 6 ms (ICC: 0.44) ISIs. Replication of SICI (p < 0.001) and ICF (p = 0.017) was successful, with excellent test-retest reliability for SICI (ICC: 0.81).
CONCLUSIONS: This dsTMS setup can probe the inhibitory and facilitatory PMd-M1 connections, as well as reliably replicate SICI and ICF paradigms.
CONCLUSIONS: The stacked-coil dsTMS setup for investigating intrahemispheric PMd-M1 connectivity offers promising possibilities to better understand motor control.

Ageing induces a decline in GABAergic intracortical inhibition, which seems to be associated not only with decremental changes in well-being, sleep quality, cognition and pain management but also with impaired motor control. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. Therefore, the present study investigated whether age-related cortical dis-inhibition could be reversed after 6 months of balance learning and whether improvements in postural control correlated with the extent of reversed dis-inhibition. The results demonstrated that intracortical inhibition can be upregulated in elderly subjects after long-term balance learning and revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity-related upregulation of GABAergic inhibition in a population with chronic dis-inhibition and may therefore be seminal for many pathologies in which the equilibrium between inhibitory and excitatory neurotransmitters is disturbed. KEY POINTS: Ageing induces a decline in GABAergic intracortical inhibition. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. After 6 months of balance learning, intracortical inhibition can be upregulated in elderly subjects. The results of this study also revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity-related upregulation of GABAergic inhibition in a population with chronic dis-inhibition.

The mechanisms utilized by neurons to regulate the efficacy of phasic and tonic inhibition and their impacts on synaptic plasticity and behavior are incompletely understood. Cleft lip and palate transmembrane protein 1 (Clptm1) is a membrane-spanning protein that interacts with multiple γ-aminobutyric acid type A receptor (GABAAR) subunits, trapping them in the endoplasmic reticulum and Golgi network. Overexpression and knock-down studies suggest that Clptm1 modulates GABAAR-mediated phasic inhibition and tonic inhibition as well as activity-induced inhibitory synaptic homeostasis in cultured hippocampal neurons. To investigate the role of Clptm1 in the modulation of GABAARs in vivo, we generated Clptm1 knock-out (KO) mice. Here, we show that genetic KO of Clptm1 elevated phasic and tonic inhibitory transmission in both male and female heterozygous mice. Although basal excitatory synaptic transmission was not affected, Clptm1 haploinsufficiency significantly blocked high-frequency stimulation-induced long-term potentiation (LTP) in hippocampal CA3→CA1 synapses. In the hippocampus-dependent contextual fear-conditioning behavior task, both male and female Clptm1 heterozygous KO mice exhibited impairment in contextual fear memory. In addition, LTP and contextual fear memory were rescued by application of L-655,708, a negative allosteric modulator of the extrasynaptic GABAAR α5 subunit. These results suggest that haploinsufficiency of Clptm1 contributes to cognitive deficits through altered synaptic transmission and plasticity by elevation of inhibitory neurotransmission, with tonic inhibition playing a major role.