Search bioRxiv⌕ Search

Biology subjects

Bacci, A.

Publications and source records attributed to Bacci, A..

9 recordsLinked to original sources

A dendritic substrate for temporal diversity of cortical inhibition

In the mammalian neocortex, GABAergic interneurons (INs) inhibit cortical networks in profoundly different ways. The extent to which this depends on how different INs process excitatory signals along their dendrites is poorly understood. Here, we reveal that the functional specialization of two major populations of cortical INs is determined by the unique association of different dendritic integration modes with distinct synaptic organization motifs. We found that somatostatin (SST)-INs exhibit NMDAR-dependent dendritic integration and uniform synapse density along the dendritic tree. In contrast, dendrites of parvalbumin (PV)-INs exhibit passive synaptic integration coupled with proximally enriched synaptic distributions. Theoretical analysis shows that these two dendritic configurations result in different strategies to optimize synaptic efficacy in thin dendritic structures. Yet, the two configurations lead to distinct temporal engagement of each IN during network activity. We confirmed these predictions with in vivo recordings of IN activity in the visual cortex of awake mice, revealing a rapid and linear recruitment of PV-INs as opposed to a long-lasting integrative activation of SST-INs. Our work reveals the existence of distinct dendritic strategies that confer distinct temporal representations for the two major classes of neocortical INs and thus dynamics of inhibition.

neuroscience↗

Alterations of adult prefrontal circuits induced by early postnatal fluoxetine treatment mediated by 5-HT7 receptors.

The prefrontal cortex (PFC) plays a key role in high-level cognitive functions and emotional behaviors, and PFC alterations correlate with different brain disorders including major depression and anxiety. In mice, the first two postnatal weeks represent a critical period of high sensitivity to environmental changes. In this temporal window, serotonin (5- HT) levels regulate the wiring of PFC cortical neurons. Early life insults and postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) affect PFC development leading to depressive and anxiety-like phenotypes in adult mice. However, the mechanisms responsible for these dysfunctions remain obscure. We found that postnatal FLX exposure (PNFLX) results in reduced overall firing, and high-frequency bursting of putative pyramidal neurons (PNs) of deep layers of the medial PFC (mPFC) of adult mice in vivo. Ex-vivo, patch-clamp recordings revealed that PNFLX abolished high-frequency firing in a distinct subpopulation of deep-layer mPFC PNs, which transiently express the serotonin transporter SERT. SERT+ and SERT- PNs exhibit distinct morpho-functional properties. Genetic deletion of 5-HT7Rs prevented the PNFLX-induced reduction of PN firing in vivo and pharmacological 5-HT7R blockade precluded altered firing of SERT+ PNs in vitro. This indicates a pivotal role of this 5-HTR subtype in mediating 5-HT-dependent maturation of PFC circuits that are susceptible to early-life insults. Overall, our results suggest potential novel neurobiological mechanisms, underlying detrimental neurodevelopmental consequences induced by early-life alterations of 5-HT levels.

neuroscience↗

An unconventional GABAergic circuit differently controls pyramidal neuron activity in two visual cortical areas via endocannabinoids

Perisomatic inhibition of neocortical pyramidal neurons (PNs) coordinates cortical network activity during sensory processing, and it has been mainly attributed to parvalbumin-expressing basket cells (BCs). However, cannabinoid receptor type 1 (CB1)-expressing interneurons also inhibit the perisomatic region of PNs but the connectivity and function of these elusive - yet prominent - neocortical GABAergic cells is unknown. We found that the connectivity pattern of CB1-positive BCs strongly differs between primary and high-order cortical visual areas. Moreover, persistently active CB1 signaling suppresses GABA release from CB1 BCs in the medial secondary visual cortex (V2M), but not in the primary (V1) visual area. Accordingly, in vivo, tonic CB1 signaling is responsible for higher but less coordinated PN activity in V2M than in V1. Our results indicate a differential CB1-mediated mechanism controlling PN activity, and suggest an alternative connectivity schemes of a specific GABAergic circuit in different cortical areas

neuroscience↗

Molecular signature and target-specificity of inhibitory circuits formed by Martinotti cells in the mouse barrel cortex

In the neocortex, fast synaptic inhibition orchestrates both spontaneous and sensory-evoked activity. GABAergic interneurons (INs) inhibit pyramidal neurons (PNs) directly, modulating their output activity and thus contributing to balance cortical networks. Moreover, several IN subtypes also inhibit other INs, forming specific disinhibitory circuits, which play crucial roles in several cognitive functions. Here, we studied a homogeneous subpopulation of somatostatin (SST)-positive INs, the Martinotti cells (MCs) in layer 2/3 of the mouse barrel cortex (both sexes). MCs are a prominent IN subclass inhibiting the distal portion of PN apical dendrites, thus controlling dendrite electrogenesis and synaptic integration. Yet, it is poorly understood whether MCs inhibit other elements of the cortical circuits, and the connectivity properties with non-PN targets are unknown. We found that MCs have a strong preference for PN dendrites, but they also considerably connect with parvalbumin (PV)-positive, vasoactive intestinal peptide (VIP)-expressing and layer 1 (L1) INs. Remarkably, GABAergic synapses from MCs exhibited clear cell-type-specific short-term plasticity. Moreover, whereas the biophysical properties of MC-PN synapses were consistent with distal dendritic inhibition, MC-IN synapses exhibited characteristics of fast perisomatic inhibition. Finally, MC-PN connections used 5-containing GABAARs, but this subunit was not expressed by the other INs targeted by MCs. We reveal a specialized connectivity blueprint of MCs within different elements of superficial cortical layers. In addition, our results identify 5-GABAARs as the molecular fingerprint of MC-PN dendritic inhibition. This is of critical importance, given the role of 5-GABAARs in cognitive performance and their involvement in several brain diseases. Significance statementMartinotti cells (MCs) are a prominent subclass of SST-expressing GABAergic INs, specialized in controlling distal dendrites of PNs and taking part in several cognitive functions. Here we characterize the connectivity pattern of MCs with other INs in the superficial layers (L1 and L2/3) of the mouse barrel cortex. We found that the connectivity pattern of MCs with PNs as well as PV, VIP and L1 INs exhibit target-specific plasticity and biophysical properties. The stark specificity of 5-GABAARs at MC-PN synapses, and the lack or functional expression of this subunit by other cell types, define the molecular identity of MC-PN connections and the exclusive involvement of this outstanding inhibitory circuits in 5-dependent cognitive tasks.

neuroscience↗

Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

neuroscience↗

Modulation of coordinated activity across cortical layers by plasticity of inhibitory synapses onto layer 5 pyramidal neurons

In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory-evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer 2/3 PNs elicited strong feed-forward perisomatic inhibition (FFI) onto layer 5 PNs. We found that FFI involving PV cells was strongly potentiated by postsynaptic PN burst firing. FFI plasticity modified PN excitation-to-inhibition (E/I) ratio, strongly modulated PN gain and altered information transfer across cortical layers. Moreover, our LTPi-inducing protocol modified the firing of layer 5 PNs and altered the temporal association of PN spikes to {gamma}-oscillations both in vitro and in vivo. All these effects were captured by unbalancing the E/I ratio in a feed-forward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognitive-relevant network activity.\n\nImpact StatementLong-term potentiation of feed-forward perisomatic inhibition effectively alters the computational properties of single layer 5 pyramidal neurons and their association to network activity.

neuroscience↗

Strong preference for autaptic self-connectivity of neocortical PV interneurons entrains them to γ-oscillations

Parvalbumin (PV) positive interneurons modulate cortical activity through highly specialized connectivity patterns onto excitatory pyramidal neurons (PNs) and other inhibitory cells. PV cells are auto-connected through powerful autapses, but the contribution of this form of fast disinhibition to cortical function is unknown. We found that autaptic transmission represents the most powerful input of PV cells in neocortical Layer V. Autaptic strength was greater than synaptic strength onto PNs as result of a larger quantal size, whereas autaptic and heterosynaptic PV-PV synapses differed in the number of release sites. Overall, single-axon autaptic transmission contributed to ~40% of the total perisomatic inhibition that PV interneurons received. The strength of autaptic transmission modulated the coupling of PV-cell firing with optogenetically-induced {gamma}-oscillations preventing high frequency bursts of spikes. Autaptic self-inhibition represents an exceptionally large and fast disinhibitory mechanism to synchronize the output of PV cells during cognitive-relevant cortical network activity.

neuroscience↗

Perineuronal nets set the strength of thalamic recruitment of interneurons in the adult visual cortex

In the neocortex, the closure of critical periods (CPs) of plasticity is paralleled by the accumulation of perineuronal nets (PNNs) around parvalbumin (PV)-positive inhibitory interneurons. Accordingly, PNN degradation in adult mammals re-opens cortical plasticity. However, how PNNs tune cortical function and plasticity is unknown. We found that PNNs modulated the gain of visual responses in the adult mouse visual cortex in vivo. Removal of PNNs in adult V1 strongly increased thalamic neurotransmission selectively on layer 4 PV cells. This produced a differential gating of feed-forward inhibition on principal neurons and other PV cells, with no alterations of unitary inhibitory synaptic transmission and neuronal excitability. These effects depended on visual input, as they were strongly attenuated by monocular deprivation in PNN-depleted adult mice. Thus, PNNs control visual processing and plasticity by selectively setting the strength of thalamic recruitment of PV cells. We conclude that PNN accumulation during circuit maturation likely prevents excessive thalamic excitation of PV cells at the expense of cortical plasticity.

neuroscience↗

Early life stress impairs postnatal oligodendrogenesis and adult behavior through activity-dependent mechanisms

Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC) and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here we focused on changes induced by chronic maternal separation during the first two weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first two postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalized it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviors.

animal behavior and cognition↗