Dendritic Inhibition Research Articles

Inhibition of Zinc Dendrites in Zinc-Based Flow Batteries.

Zinc-based flow batteries have gained widespread attention and are considered to be one of the most promising large-scale energy storage devices for increasing the utilization of intermittently sustainable energy. However, the formation of zinc dendrites at anodes has seriously depressed their cycling life, security, coulombic efficiency, and charging capacity. Inhibition of zinc dendrites is thus the bottleneck to further improving the performance of zinc-based flow batteries, but it remains a major challenge. Considering recent developments, this mini review analyzes the formation mechanism and growth process of zinc dendrites and presents and summarizes the strategies for preventing zinc dendrites by regulating the interfaces between anodes and electrolytes. Four typical strategies, namely electrolyte modification, anode engineering, electric field regulation, and ion transfer control, are comprehensively highlighted. Finally, remaining challenges and promising directions are outlined and anticipated for zinc dendrites in zinc-based flow batteries.

The interplay between somatic and dendritic inhibition promotes the emergence and stabilization of place fields.

During the exploration of novel environments, place fields are rapidly formed in hippocampal CA1 neurons. Place cell firing rate increases in early stages of exploration of novel environments but returns to baseline levels in familiar environments. Although similar in amplitude and width, place fields in familiar environments are more stable than in novel environments. We propose a computational model of the hippocampal CA1 network, which describes the formation, dynamics and stabilization of place fields. We show that although somatic disinhibition is sufficient to form place fields, dendritic inhibition along with synaptic plasticity is necessary for place field stabilization. Our model suggests that place cell stability can be attributed to strong excitatory synaptic weights and strong dendritic inhibition. We show that the interplay between somatic and dendritic inhibition balances the increased excitatory weights, such that place cells return to their baseline firing rate after exploration. Our model suggests that different types of interneurons are essential to unravel the mechanisms underlying place field plasticity. Finally, we predict that artificially induced dendritic events can shift place fields even after place field stabilization.

Hybrid solid electrolyte enabled dendrite-free Li anodes for high-performance quasi-solid-state lithium-oxygen batteries.

The dendrite growth of Li anodes severely degrades the performance of lithium-oxygen (Li-O2) batteries. Recently, hybrid solid electrolyte (HSE) has been regarded as one of the most promising routes to tackle this problem. However, before this is realized, the HSE needs to simultaneously satisfy contradictory requirements of high modulus and even, flexible contact with Li anode, while ensuring uniform Li+ distribution. To tackle this complex dilemma, here, an HSE with rigid Li1.5Al0.5Ge1.5(PO4)3 (LAGP) core@ultrathin flexible poly (vinylidene fluoride-hexafluoropropylene) (PVDF-HFP) shell interface has been developed. The introduced large amount of nanometer-sized LAGP cores can not only act as structural enhancer to achieve high Young's modulus but can also construct Li+ diffusion network to homogenize Li+ distribution. The ultrathin flexible PVDF-HFP shell provides soft and stable contact between the rigid core and Li metal without affecting the Li+ distribution, meanwhile suppressing the reduction of LAGP induced by direct contact with Li metal. Thanks to these advantages, this ingenious HSE with ultra-high Young's modulus of 25 GPa endows dendrite-free Li deposition even at a deposition capacity of 23.6 mAh. Moreover, with the successful inhibition of Li dendrites, the HSE-based quasi-solid-state Li-O2 battery delivers a long cycling stability of 146 cycles, which is more than three times that of gel polymer electrolyte-based Li-O2 battery. This new insight may serve as a starting point for further designing of HSE in Li-O2 batteries, and can also be extended to various battery systems such as sodium-oxygen batteries.

Chloride dynamics alter the input-output properties of neurons.

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.

Optopharmacology reveals a differential contribution of native GABAA receptors to dendritic and somatic inhibition using azogabazine

γ-aminobutyric acid type-A receptors (GABAARs) are inhibitory ligand-gated ion channels in the brain that are crucial for controlling neuronal excitation. To explore their physiological roles in cellular and neural network activity, it is important to understand why specific GABAAR isoforms are distributed not only to various brain regions and cell types, but also to specific areas of the membrane in individual neurons. To address this aim we have developed a novel photosensitive compound, azogabazine, that targets and reversibly inhibits GABAARs. The receptor selectivity of the compound is based on the competitive antagonist, gabazine, and photosensitivity is conferred by a photoisomerisable azobenzene group. Azogabazine can exist in either cis or trans conformations that are controlled by UV and blue light respectively, to affect receptor inhibition. We report that the trans-isomer preferentially binds and inhibits GABAAR function, whilst promotion of the cis-isomer caused unbinding of azogabazine from GABAARs. Using cultured cerebellar granule cells, azogabazine in conjunction with UV light applied to defined membrane domains, revealed higher densities of GABAARs at somatic inhibitory synapses compared to those populating proximal dendritic zones, even though the latter displayed a higher number of synapses per unit area of membrane. Azogabazine also revealed more pronounced GABA-mediated inhibition of action potential firing in proximal dendrites compared to the soma. Overall, azogabazine is a valuable addition to the photochemical toolkit that can be used to interrogate GABAAR function and inhibition.

Treatment with Mesenchymal-Derived Extracellular Vesicles Reduces Injury-Related Pathology in Pyramidal Neurons of Monkey Perilesional Ventral Premotor Cortex.

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

Hyperactivated PTP1B phosphatase in parvalbumin neurons alters anterior cingulate inhibitory circuits and induces autism-like behaviors

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. Humans with deletions including LMO4, an endogenous inhibitor of PTP1B, display intellectual disabilities and occasionally autism. PV-Lmo4KO mice ablate Lmo4 in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Surprisingly, increased PV neuron-mediated peri-somatic feedforward inhibition to the pyramidal neurons causes a compensatory reduction in (somatostatin neuron-mediated) dendritic inhibition. These homeostatic changes increase filtering of mediodorsal-thalamocortical inputs but reduce filtering of cortico-cortical inputs and narrow the range of stimuli ACC pyramidal neurons can distinguish. Simultaneous ablation of PTP1B in PV-Lmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD.

Toward Stable Lithium Plating/Stripping by Successive Desolvation and Exclusive Transport of Li Ions.

Li has been regarded as the most attractive anode for next-generation high-energy-density batteries due to its high specific capacity and low electrochemical potential. However, its low electrochemical potential leads to the side reaction of Li with the solvent of the electrolyte (the solvation of Li ions exacerbates the reaction). This adverse side reaction results in uneven Li distribution and deposition, low Coulombic efficiency, and the formation of Li dendrites. Herein, we demonstrate an efficient method for achieving successive desolvation and homogeneous distribution of Li ions by using a double-layer membrane. The first layer is designed to enable the desolvation of Li ions. The second layer with controllable and ordered nanopores is expected to facilitate the homogeneous and exclusive transport of Li ions. The efficiency of the double-layer membrane on desolvation and exclusive transport of Li ions is confirmed by theoretical calculations, the significantly enhanced Li-ion transference number, improved Coulombic efficiency, and the inhibition of Li dendrites. These results will deepen our understanding of the modulation of ions and pave a way to the next-generation high-energy-density Li-metal batteries.

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

Reduction of Dendritic Inhibition in CA1 Pyramidal Neurons in Amyloidosis Models of Early Alzheimer's Disease.

Background:In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition.Objective:In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels.Methods:We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in hippocampal brain slices from AppNL-F-G mice (APP-KI).Results:We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24 h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent transmission after Aβ treatment. We observed a similar, although weaker, reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices.Conclusion:Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD.

Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition.

There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.

A Multifunctional Separator Enables Safe and Durable Lithium/Magnesium–Sulfur Batteries under Elevated Temperature

AbstractRechargeable metal–sulfur batteries encounter severe safety hazards and fast capacity decay, caused by the flammable and shrinkable separator and unwanted polysulfide dissolution under elevated temperatures. Herein, a multifunctional Janus separator is designed by integrating temperature endurable electrospinning polyimide nonwovens with a copper nanowire‐graphene nanosheet functional layer and a rigid lithium lanthanum zirconium oxide‐polyethylene oxide matrix. Such architecture offers multifold advantages: i) intrinsically high dimensional stability and flame‐retardant capability, ii) excellent electrolyte wettability and effective metal dendritic growth inhibition, and iii) powerful physical blockage/chemical anchoring capability for the shuttled polysulfides. As a consequence, the as constructed lithium–sulfur battery using a pure sulfur cathode displays an outstandingly high discharge capacity of 1402.1 mAh g−1and a record high cycling stability (approximately average 0.24% capacity decay per cycle within 300 cycles) at 80 °C, outperforming the state‐of‐the‐art results in the literature. Promisingly, a high sulfur mass loading of ≈3.0 mg cm−2and a record low electrolyte/sulfur ratio of 6.0 are achieved. This functional separator also performs well for a high temperature magnesium–sulfur battery. This work demonstrates a new concept for high performance metal–sulfur battery design and promises safe and durable operation of the next generation energy storage systems.

Dendritic inhibition differentially regulates excitability of dentate gyrus parvalbumin-expressing interneurons and granule cells

Fast-spiking parvalbumin-expressing interneurons (PVIs) and granule cells (GCs) of the dentate gyrus receive layer-specific dendritic inhibition. Its impact on PVI and GC excitability is, however, unknown. By applying whole-cell recordings, GABA uncaging and single-cell-modeling, we show that proximal dendritic inhibition in PVIs is less efficient in lowering perforant path-mediated subthreshold depolarization than distal inhibition but both are highly efficient in silencing PVIs. These inhibitory effects can be explained by proximal shunting and distal strong hyperpolarizing inhibition. In contrast, GC proximal but not distal inhibition is the primary regulator of their excitability and recruitment. In GCs inhibition is hyperpolarizing along the entire somato-dendritic axis with similar strength. Thus, dendritic inhibition differentially controls input-output transformations in PVIs and GCs. Dendritic inhibition in PVIs is suited to balance PVI discharges in dependence on global network activity thereby providing strong and tuned perisomatic inhibition that contributes to the sparse representation of information in GC assemblies.

Performance improvement of lithium-ion battery by pulse current

Abstract Periodically changed current is called pulse current. It has been found that using the pulse current to charge/discharge lithium-ion batteries can improve the safety and cycle stability of the battery. In this short review, the mechanisms of pulse current improving the performance of lithium-ion batteries are summarized from four aspects: activation, warming up, fast charging and inhibition of lithium dendrites. Related content may help us use the pulse current to improve the performance of lithium-ion batteries and further optimize pulse current technology.

Highly multiscale structural Poly(vinylidene fluoridehexafluoropropylene) / poly-m-phenyleneisophthalamide separator with enhanced interface compatibility and uniform lithium-ion flux distribution for dendrite-proof lithium-metal batteries

In this paper, a novel multiscale structural poly(vinylidene fluoridehExafluoropropyl-ene) (PVDF-HFP)/poly-m-phenyleneisophthalamide (PMIA)-based gel polymer electrolyte (GPE) including tetrabutylammonium hexafluorophosphate (TBAHP) was prepared for lithium-metal batteries via electrospinning technology. Under the synergistic regulation of PVDF-HFP and TBAHP, the TBAHP/PVDF-HFP-PMIA (T/F-P) membrane was yielded distinct multiscale structure accompanied by extremely high porosity, reduced aperture and well-distributed pore structure, leading to exceedingly good electrolyte affinity and enhanced interfacial compatibility. Especially, the homogeneous lithium-ions flux distribution above lithium electrodes from the multiscale structure confinement could account for the uniform lithium nucleation and nondendrite growth. Meanwhile, the as-fabricated T/F-P separator exhibited admirable thermal stability and ultra-strong tensile strength, which also contributed to the inhibition of lithium dendrites and guarantee of battery safety. More significantly, the lithium/LCO (Li/LCO) cell with T/F-P separator obtained a pronounced improvement in cycle stability and rate capability thanks to the outstanding ionic conductivity, inferior interface impedance and reduced polarization. Moreover, the T/F-P-based lithium-sulfur (Li–S) battery also delivered the superior cycle performance due to prominent anti-self-discharge capability and forceful adsorption or captured ability to dissolved polysulfide species. Consequently, the highly multiscale structural T/F-P separator can be identified as a dependable candidate for the enhanced safety and electrochemical performance of lithium-metal cells.

Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model

Overinhibition is assumed one of the main causes of cognitive deficits (e.g. memory impairment) in mouse models of Down syndrome (DS). Yet the mechanisms that drive such exaggerated synaptic inhibition and their behavioral effects remain unclear. Here we report the existence of bidirectional alterations to the synaptic inhibition on CA1 pyramidal cells in the Ts2Cje mouse model of DS which are associated to impaired spatial memory. Furthermore, we identify triplication of the kainate receptor (KAR) encoding gene Grik1 as the cause of these phenotypes. Normalization of Grik1 dosage in Ts2Cje mice specifically restored spatial memory and reversed the bidirectional alterations to CA1 inhibition, but not the changes in synaptic plasticity or the other behavioral modifications observed. We propose that modified information gating caused by disturbed inhibitory tone rather than generalized overinhibition underlies some of the characteristic cognitive deficits in DS.

Inhibitory neuronal changes following a mixed diffuse-focal model of traumatic brain injury.

Traumatic brain injury (TBI) can result in excitation: inhibition imbalance, as well as a range of chronic neurological deficits. However, how TBI affects different interneurons, and how this relates to behavioral abnormalities, remains poorly understood. This study examined the effects of a mixed diffuse-focal model of TBI, the lateral fluid percussion injury (LFPI), on interneurons, 8 weeks post-TBI in rats. Brains were labeled with antibodies against calbindin, parvalbumin, calretinin, neuropeptide Y, and somatostatin, and the number of interneurons were assessed in the cortex and hippocampus following LFPI. LFPI caused a reduction in the numbers of interneurons mediating both perisomatic and dendritic inhibition in the somatosensory cortex. In hippocampus, there were heterogenous changes in the number of interneurons while motor cortex, showed no obvious loss in any of the subsets of interneurons after TBI. In parallel to the investigations of changes in the number of interneurons, we also investigated the long-term behavioral consequences of LFPI. Behaviorally, rats given an LFPI displayed transient reduction in performance in motor tasks and were significantly impaired in reversal learning in the water maze task post-TBI. We also report here progressive neurodegeneration in cortex and hippocampus indicated by Fluoro-Jade C in the different brain areas examined after injury. Our findings suggest differential vulnerability of inhibitory neurons to LFPI in the different brain areas examined after injury. These data will aid in evaluation of new treatments for TBI and help target specific neuronal subtypes as a function of injury time and type.

Improving the Recall Performance of a Brain Mimetic Microcircuit Model

The recall performance of a well-established canonical microcircuit model of the hippocampus, a region of the mammalian brain that acts as a short-term memory, was systematically evaluated. All model cells were simplified compartmental models with complex ion channel dynamics. In addition to excitatory cells (pyramidal cells), four types of inhibitory cells were present: axo-axonic (axonic inhibition), basket (somatic inhibition), bistratified cells (proximal dendritic inhibition) and oriens lacunosum-moleculare (distal dendritic inhibition) cells. All cells’ firing was timed to an external theta rhythm paced into the model by external reciprocally oscillating inhibitory inputs originating from the medial septum. Excitatory input to the model originated from the region CA3 of the hippocampus and provided context and timing information for retrieval of previously stored memory patterns. Model mean recall quality was tested as the number of stored memory patterns was increased against selectively modulated feedforward and feedback excitatory and inhibitory pathways. From all modulated pathways, simulations showed recall performance was best when feedforward inhibition from bistratified cells to pyramidal cell dendrites is dynamically increased as stored memory patterns is increased with or without increased pyramidal cell feedback excitation to bistratified cells. The study furthers our understanding of how memories are retrieved by a brain microcircuit. The findings provide fundamental insights into the inner workings of learning and memory in the brain, which may lead to potential strategies for treatments in memory-related disorders.

Amplifying the redistribution of somato-dendritic inhibition by the interplay of three interneuron types.

GABAergic interneurons play an important role in shaping the activity of excitatory pyramidal cells (PCs). How the various inhibitory cell types contribute to neuronal information processing, however, is not resolved. Here, we propose a functional role for a widespread network motif consisting of parvalbumin- (PV), somatostatin- (SOM) and vasoactive intestinal peptide (VIP)-expressing interneurons. Following the idea that PV and SOM interneurons control the distribution of somatic and dendritic inhibition onto PCs, we suggest that mutual inhibition between VIP and SOM cells translates weak inputs to VIP interneurons into large changes of somato-dendritic inhibition of PCs. Using a computational model, we show that the neuronal and synaptic properties of the circuit support this hypothesis. Moreover, we demonstrate that the SOM-VIP motif allows transient inputs to persistently switch the circuit between two processing modes, in which top-down inputs onto apical dendrites of PCs are either integrated or cancelled.