Integrated Optogenetic and Electrophysiological Dissection of Local Cortical Circuits In Vivo

2011 ◽  
pp. 339-355 ◽  
Author(s):  
Jessica A. Cardin
Keyword(s):  
Cortical Circuits

Opposing roles for neurotrophin-3 in targeting and collateral formation of distinct sets of developing cortical neurons

Development ◽  
1999 ◽  
Vol 126 (15) ◽  
pp. 3335-3345
Author(s):  
V. Castellani ◽  
J. Bolz
Keyword(s):  
Cortical Neurons ◽  
Developmental Stages ◽  
Axonal Guidance ◽  
Cortical Circuits ◽  
Axonal Branching ◽  
Guidance Cue ◽  
Neurotrophin 3 ◽  
Cortical Membranes ◽  
Opposing Effects

Neurotrophin-3 and its receptor TrkC are expressed during the development of the mammalian cerebral cortex. To examine whether neurotrophin-3 might play a role in the elaboration of layer-specific cortical circuits, slices of layer 6 and layers 2/3 neurons were cultured in the presence of exogenously applied neurotrophin-3. Results indicate that neurotrophin-3 promotes axonal branching of layer 6 axons, which target neurotrophin-3-expressing layers in vivo, and that it inhibits branching of layers 2/3 axons, which avoid neurotrophin-3-expressing layers. Such opposing effects of neurotrophin-3 on axonal branching were also observed with embryonic cortical neurons, indicating that the response to neurotrophin-3 is specified at early developmental stages, prior to cell migration. In addition to its effects on fiber branching, axonal guidance assays also indicate that neurotrophin-3 is an attractive signal for layer 6 axons and a repellent guidance cue for layers 2/3 axons. Experiments with specific antibodies to neutralize neurotrophin-3 in cortical membranes revealed that endogenous levels of neurotrophin-3 are sufficient to regulate branching and targeting of cortical axons. These opposing effects of neurotrophin-3 on specific populations of axons demonstrate that it could serve as one of the signals for the elaboration of local cortical circuits.

scholarly journals Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories

2020 ◽  
Author(s):  
Sarah Melzer ◽  
Elena Newmark ◽  
Grace Or Mizuno ◽  
Minsuk Hyun ◽  
Adrienne C. Philson ◽  
...  
Keyword(s):  
Auditory Cortex ◽  
Differential Expression ◽  
Vasoactive Intestinal Peptide ◽  
Cortical Circuits ◽  
Gastrin Releasing Peptide ◽  
Neuropeptide Receptors ◽  
Selective Targeting ◽  
Cortical Microcircuits ◽  
Grp Receptor

SummaryDisinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory and excitatory neurons suggests that each circuit motif is controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a newly-developed genetically-encoded GRP sensor and trans-synaptic tracing we reveal that GRP regulates VIP cells via extrasynaptic diffusion from several putative local and long-range sources. In vivo photometry and CRISPR/Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and that GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

scholarly journals Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Balázs B Ujfalussy ◽  
Judit K Makara ◽  
Tiago Branco ◽  
Máté Lengyel
Keyword(s):  
Cortical Neurons ◽  
Activity Patterns ◽  
Pyramidal Cells ◽  
Cortical Circuits ◽  
Functional Link ◽  
Synaptic Inputs ◽  
Two Photon ◽  
Highly Nonlinear ◽  
Efficient Integration

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits.

scholarly journals The March of Epileptic Activity across Cortex is Limited (for a While) by the Powerful Forces of Surrounding Inhibition

2007 ◽  
Vol 7 (5) ◽  
pp. 138-139 ◽  
Author(s):  
Carl E. Stafstrom
Keyword(s):  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Cortical Circuits ◽  
Single Mechanism ◽  
Speed Of Propagation ◽  
Epileptiform Events ◽  
Propagation Velocities ◽  
Feedforward Inhibition

Modular Propagation of Epileptiform Activity: Evidence for an Inhibitory Veto in Neocortex. Trevelyan AJ, Sussillo D, Watson BO, Yuste R. J Neurosci 2006;26(48):12447–12455. What regulates the spread of activity through cortical circuits? We present here data indicating a pivotal role for a vetoing inhibition restraining modules of pyramidal neurons. We combined fast calcium imaging of network activity with whole-cell recordings to examine epileptiform propagation in mouse neocortical slices. Epileptiform activity was induced by washing Mg2+ ions out of the slice. Pyramidal cells receive barrages of inhibitory inputs in advance of the epileptiform wave. The inhibitory barrages are effectively nullified at low doses of picrotoxin (2.5–5 μM). When present, however, these inhibitory barrages occlude an intense excitatory synaptic drive that would normally exceed action potential threshold by approximately a factor of 10. Despite this level of excitation, the inhibitory barrages suppress firing, thereby limiting further neuronal recruitment to the ictal event. Pyramidal neurons are recruited to the epileptiform event once the inhibitory restraint fails and are recruited in spatially clustered populations (150–250 μm diameter). The recruitment of the cells within a given module is virtually simultaneous, and thus epileptiform events progress in intermittent (0.5–1 Hz) steps across the cortical network. We propose that the interneurons that supply the vetoing inhibition define these modular circuit territories. Feedforward Inhibition Contributes to the Control of Epileptiform Propagation Speed Trevelyan AJ, Sussillo D, Yuste R. J Neurosci 2007;27(13):3383–3387. It is still poorly understood how epileptiform events can recruit cortical circuits. Moreover, the speed of propagation of epileptiform discharges in vivo and in vitro can vary over several orders of magnitude (0.1–100 mm/s), a range difficult to explain by a single mechanism. We previously showed how epileptiform spread in neocortical slices is opposed by a powerful feedforward inhibition ahead of the ictal wave. When this feedforward inhibition is intact, epileptiform spreads very slowly (100 μm/s). We now investigate whether changes in this inhibitory restraint can also explain much faster propagation velocities. We made use of a very characteristic pattern of evolution of ictal activity in the zero magnesium (0 Mg2+) model of epilepsy. With each successive ictal event, the number of preictal inhibitory barrages dropped, and in parallel with this change, the propagation velocity increased. There was a highly significant correlation ( p < 0.001) between the two measures over a 1,000-fold range of velocities, indicating that feedforward inhibition was the prime determinant of the speed of epileptiform propagation. We propose that the speed of propagation is set by the extent of the recruitment steps, which in turn is set by how successfully the feedforward inhibitory restraint contains the excitatory drive. Thus, a single mechanism could account for the wide range of propagation velocities of epileptiform events observed in vitro and in vivo.

scholarly journals Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

2016 ◽  
Vol 113 (46) ◽  
pp. E7287-E7296 ◽  
Author(s):  
Abhishek Banerjee ◽  
Rajeev V. Rikhye ◽  
Vincent Breton-Provencher ◽  
Xin Tang ◽  
Chenchen Li ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Time Course ◽  
Pyramidal Neurons ◽  
Reversal Potential ◽  
Mutant Mice ◽  
Loss Of Function ◽  
Cortical Circuits ◽  
Recombinant Human Insulin ◽  
Cortical Pyramidal Neurons

Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. Targeted recordings reveal that parvalbumin-expressing (PV+) interneurons in mutant mice have reduced responses. PV-specific MeCP2 deletion alone recapitulates effects of global MeCP2 deletion on cortical circuits, including reduced pyramidal neuron responses and reduced response reliability and selectivity. Furthermore, MeCP2 mutant mice show reduced expression of the cation-chloride cotransporter KCC2 (K+/Cl− exporter) and a reduced KCC2/NKCC1 (Na+/K+/Cl− importer) ratio. Perforated patch recordings demonstrate that the reversal potential for GABA is more depolarized in mutant mice, but is restored by application of the NKCC1 inhibitor bumetanide. Treatment with recombinant human insulin-like growth factor-1 restores responses of PV+ and pyramidal neurons and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.

scholarly journals Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

2013 ◽  
Vol 111 (1) ◽  
pp. 510-514 ◽  
Author(s):  
K. V. Kuchibhotla ◽  
S. Wegmann ◽  
K. J. Kopeikina ◽  
J. Hawkes ◽  
N. Rudinskiy ◽  
...  
Keyword(s):  
Neurofibrillary Tangle ◽  
Cortical Circuits

scholarly journals Spatiotemporal constraints on optogenetic inactivation in cortical circuits

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nuo Li ◽  
Susu Chen ◽  
Zengcai V Guo ◽  
Han Chen ◽  
Yan Huo ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Inhibitory Neurons ◽  
Dependent Manner ◽  
Cortical Circuits ◽  
Neuronal Populations ◽  
Multiple Length Scales ◽  
Dose Dependent ◽  
Reduced Activity

Optogenetics allows manipulations of genetically and spatially defined neuronal populations with excellent temporal control. However, neurons are coupled with other neurons over multiple length scales, and the effects of localized manipulations thus spread beyond the targeted neurons. We benchmarked several optogenetic methods to inactivate small regions of neocortex. Optogenetic excitation of GABAergic neurons produced more effective inactivation than light-gated ion pumps. Transgenic mice expressing the light-dependent chloride channel GtACR1 produced the most potent inactivation. Generally, inactivation spread substantially beyond the photostimulation light, caused by strong coupling between cortical neurons. Over some range of light intensity, optogenetic excitation of inhibitory neurons reduced activity in these neurons, together with pyramidal neurons, a signature of inhibition-stabilized neural networks ('paradoxical effect'). The offset of optogenetic inactivation was followed by rebound excitation in a light dose-dependent manner, limiting temporal resolution. Our data offer guidance for the design of in vivo optogenetics experiments.

scholarly journals Ontogeny of the VIP+ interneuron sensory-motor circuit prior to active whisking

2020 ◽  
Author(s):  
Cristiana Vagnoni ◽  
Liad J. Baruchin ◽  
Filippo Ghezzi ◽  
Sara Ratti ◽  
Zoltán Molnár ◽  
...  
Keyword(s):  
Long Range ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Cortical Circuits ◽  
Motor Processing ◽  
Efferent Connections ◽  
Sensory Motor ◽  
Sensory Evoked ◽  
Inside Out

ABSTRACTDevelopment of the cortical circuits for sensory-motor processing require the coordinated integration of both columnar and long-range synaptic connections. To understand how this occurs at the level of individual neurons we have explored the timeline over which vasoactive intestinal peptide (VIP)-expressing interneurons integrate into mouse somatosensory cortex. We find a distinction in emergent long-range anterior-motor and columnar glutamatergic inputs onto layer (L)2 and L3 VIP+ interneurons respectively. In parallel, VIP+ interneurons form efferent connections onto both pyramidal cells and interneurons in the immediate column in an inside-out manner. Cell-autonomous deletion of the fate-determinant transcription factor, Prox1, spares long-range anterior-motor inputs onto VIP+ interneurons, but leads to deficits in local connectivity. This imbalance in the somatosensory circuit results in altered spontaneous and sensory-evoked cortical activity in vivo. This identifies a critical role for VIP+ interneurons, and more broadly interneuron heterogeneity, in formative circuits of neocortex.

scholarly journals Syngap1 Dynamically Regulates the Fine-Scale Reorganization of Cortical Circuits in Response to Sensory Experience

2020 ◽  
Author(s):  
Nerea Llamosas ◽  
Thomas Vaissiere ◽  
Camilo Rojas ◽  
Sheldon Michaelson ◽  
Courtney A. Miller ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Cortical Plasticity ◽  
Neurodevelopmental Disorder ◽  
Spike Timing ◽  
Sensory Cortex ◽  
Fine Scale ◽  
Cortical Circuits ◽  
Population Activity ◽  
Cellular Processes

AbstractExperience induces complex, neuron-specific changes in population activity within sensory cortex circuits. However, the mechanisms that enable neuron-specific changes within cortical populations remain unclear. To explore the idea that synapse strengthening is involved, we studied fine-scale cortical plasticity in Syngap1 mice, a neurodevelopmental disorder model useful for linking synapse biology to circuit functions. Repeated functional imaging of the same L2/3 somatosensory cortex neurons during single whisker experience revealed that Syngap1 selectively regulated the plasticity of a low-active, or “silent”, neuronal subpopulation. Syngap1 also regulated spike-timing-dependent synaptic potentiation and experience-mediated in vivo synapse bouton formation, but not synaptic depression or bouton elimination in L2/3. Adult re-expression of Syngap1 restored plasticity of “silent” neurons, demonstrating that this gene controls dynamic cellular processes required for population-specific changes to cortical circuits during experience. These findings suggest that abnormal experience-dependent redistribution of cortical population activity may contribute to the etiology of neurodevelopmental disorders.

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