Multi-functional feedforward inhibitory circuits for cortical odor processing

Feedforward inhibitory circuits are key contributors to the complex interplay between excitation and inhibition in the brain. Little is known about the function of feedforward inhibition in the primary olfactory (piriform) cortex. Using in vivo two-photon targeted patch clamping and calcium imaging in mice, we find that odors evoke strong excitation in two classes of interneurons – neurogliaform (NG) cells and horizontal (HZ) cells – that provide feedforward inhibition in layer 1 of the piriform cortex. NG cells fire much earlier than HZ cells following odor onset, a difference that can be attributed to the faster odor-driven excitatory synaptic drive that NG cells receive from the olfactory bulb. As a consequence, NG cells strongly but transiently inhibit odor-evoked excitation in layer 2 principal cells, whereas HZ cells provide more diffuse and prolonged feedforward inhibition. Our findings reveal unexpected complexity in the operation of inhibition in the piriform cortex.

Hippocampal β2-GABAA receptors mediate LTP suppression by etomidate and contribute to long-lasting feedback but not feedforward inhibition of pyramidal neurons

The general anesthetic etomidate, which acts through GABAA receptors, impairs the formation of new memories under anesthesia. This study addresses the molecular and cellular mechanisms by which this occurs. Here, using a new line of genetically engineered mice carrying the GABAAR β2-N265M mutation, we tested the roles of receptors that incorporate GABAA receptor β2 vs. β3 subunits to suppression of long-term potentiation (LTP), a cellular model of learning and memory. We found that brain slices from β2-N265M mice resisted etomidate suppression of LTP, indicating that the β2-GABAARs are an essential target in this model. As these receptors are most heavily expressed by interneurons in the hippocampus, this finding supports a role for interneuron modulation in etomidate control of synaptic plasticity. Nevertheless, β2 subunits are also expressed by pyramidal neurons, so they might also contribute. Therefore, using a previously established line of β3-N265M mice, we also examined the contributions of β2- vs. β3-GABAARs to GABAA,slow dendritic inhibition, because dendritic inhibition is particularly well suited to controlling synaptic plasticity. We also examined their roles in long-lasting suppression of population activity through feedforward and feedback inhibition. We found both β2- and β3-GABAARs contribute to GABAA,slow inhibition, and that both β2- and β3-GABAARs contribute to feedback inhibition, whereas only β3-GABAARs contribute to feedforward inhibition. We conclude that modulation of β2-GABAARs is essential to etomidate suppression of LTP. Furthermore, to the extent that this occurs through GABAARs on pyramidal neurons, it is through modulation of feedback inhibition.

Organization of cortical and thalamic input to inhibitory neurons in mouse motor cortex

Understanding how feedforward inhibition regulates movement requires knowing how cortical and thalamic projections connect to inhibitory interneurons in primary motor cortex (M1). We quantified excitatory synaptic input from sensory cortex and thalamus onto two main classes of M1 inhibitory interneurons across all cortical layers: parvalbumin (PV) expressing fast-spiking cells and somatostatin (SOM) expressing low-threshold-spiking cells. Each projection innervated M1 interneurons with a unique laminar profile. While pyramidal neurons were excited by these cortical and thalamic inputs in the same layers, different interneuron types were excited in a distinct, complementary manner, suggesting feedforward inhibition from different inputs proceeds selectively via distinct circuits. Specifically, somatosensory cortex (S1) inputs primarily targeted PV+ neurons in upper layers (L2/3) but SOM+ neurons in middle layers (L5). Somatosensory thalamus (PO) inputs primarily targeted PV+ neurons in middle layers (L5). Our results show that long-range excitatory inputs target inhibitory neurons in a cell type-specific manner which contrasts with input to neighboring pyramidal cells. In contrast to feedforward inhibition providing generic inhibitory tone in cortex, circuits are selectively organized to recruit inhibition matched to incoming excitatory circuits.

Gated feedforward inhibition in the frontal cortex releases goal-directed action

Cortical circuits process sensory information and generate motor signals in animals performing perceptual tasks. However, it is still unclear how sensory inputs generate motor signals in the cortex to initiate goal-directed action. Here, we identified a visual-to-motor inhibitory circuit in the anterior cingulate cortex (ACC) that induced action initiation in mice performing visual Go/No-go tasks. Interestingly, higher activity in sensory neurons and faster suppression in motor neurons of the ACC predicted faster reaction times. Notably, optogenetic activation of visual inputs in the ACC evoked strong suppression of neighboring motor neurons by activating fast-spiking sensory neurons and drove task-relevant actions in mice via activating striatal neurons. Finally, the ACC network activity maintained low during spontaneous and perceptual actions and increased during action cancellation in response to the stop signals. Collectively, our data demonstrate that visual salience in the frontal cortex exerts gated feedforward inhibition to release goal-directed actions.

Dynamic Transitions of Epilepsy Waveforms Induced by Astrocyte Dysfunction and Electrical Stimulation

Experimental studies have shown that astrocytes participate in epilepsy through inducing the release of glutamate. Meanwhile, considering the disinhibition circuit among inhibitory neuronal populations with different time scales and the feedforward inhibition connection from thalamic relay nucleus to cortical inhibitory neuronal population, here, we propose a modified thalamocortical field model to systematically investigate the mechanism of epilepsy. Firstly, our results show that rich firing activities can be induced by astrocyte dysfunction, including high or low saturated state, high- or low-frequency clonic, spike-wave discharge (SWD), and tonic. More importantly, with the enhancement of feedforward inhibition connection, SWD and tonic oscillations will disappear. In other words, all these pathological waveforms can be suppressed or eliminated. Then, we explore the control effects after different external stimulations applying to thalamic neuronal population. We find that single-pulse stimulation can not only suppress but also induce pathological firing patterns, such as SWD, tonic, and clonic oscillations. And we further verify that deep brain stimulation can control absence epilepsy by regulating the amplitude and pulse width of stimulation. In addition, based on our modified model, 3 : 2 coordinated reset stimulation strategies with different intensities are compared and a more effective and safer stimulation mode is proposed. Our conclusions are expected to give more theoretical insights into the treatment of epilepsy.

Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

Excitatory and inhibitory neurons are connected into microcircuits that generate circuit output. Central in the hippocampal CA3 microcircuit is the mossy fiber (MF) synapse, which provides powerful direct excitatory input and indirect feedforward inhibition to CA3 pyramidal neurons. Here, we dissect its cell-surface protein (CSP) composition to discover novel regulators of MF synaptic connectivity. Proteomic profiling of isolated MF synaptosomes uncovers a rich CSP composition, including many CSPs without synaptic function and several that are uncharacterized. Cell-surface interactome screening identifies IgSF8 as a neuronal receptor enriched in the MF pathway. Presynaptic Igsf8 deletion impairs MF synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition. Consequently, IgSF8 loss impairs excitation/inhibition balance and increases excitability of CA3 pyramidal neurons. Our results provide insight into the CSP landscape and interactome of a specific excitatory synapse and reveal IgSF8 as a critical regulator of CA3 microcircuit connectivity and function.