Andrea Hasenstaub

Turning on and off recurrent balanced cortical activity

The vast majority of synaptic connections onto neurons in the cerebral cortex arise from other cortical neurons, both excitatory and inhibitory, forming local and distant ‘recurrent’ networks. Although this is a basic theme of cortical organization, its study has been limited largely to theoretical investigations, which predict that local recurrent networks show a proportionality or balance between recurrent excitation and inhibition, allowing the generation of stable periods of activity. This recurrent activity might underlie such diverse operations as short-term memory, the modulation of neuronal excitability with attention, and the generation of spontaneous activity during sleep. Here we show that local cortical circuits do indeed operate through a proportional balance of excitation and inhibition generated through local recurrent connections, and that the operation of such circuits can generate self-sustaining activity that can be turned on and off by synaptic inputs. These results confirm the long-hypothesized role of recurrent activity as a basic operation of the cerebral cortex.

Neocortical Network Activity In Vivo Is Generated through a Dynamic Balance of Excitation and Inhibition

The recurrent excitatory and inhibitory connections between and within layers of the cerebral cortex are fundamental to the operation of local cortical circuits. Models of cortical function often assume that recurrent excitation and inhibition are balanced, and we recently demonstrated that spontaneous network activity in vitro contains a precise balance of excitation and inhibition; however, the existence of a balance between excitation and inhibition in the intact and spontaneously active cerebral cortex has not been directly tested. We examined this hypothesis in the prefrontal cortex in vivo, during the slow (<1 Hz) oscillation in ketamine–xylazine-anesthetized ferrets. We measured persistent network activity (Up states) with extracellular multiple unit and local field potential recording, while simultaneously recording synaptic currents in nearby cells. We determined the reversal potential and conductance change over time during Up states and found that the body of Up state activity exhibited a steady reversal potential (−37 mV on average) for hundreds of milliseconds, even during substantial (21 nS on average) changes in membrane conductance. Furthermore, we found that both the initial and final segments of the Up state were characterized by significantly more depolarized reversal potentials and concomitant increases in excitatory conductance, compared with the stable middle portions of Up states. This ongoing temporal evolution between excitation and inhibition, which exhibits remarkable proportionality within and across neurons in active local networks, may allow for rapid transitions between relatively stable network states, permitting the modulation of neuronal responsiveness in a behaviorally relevant manner.

Inhibitory Postsynaptic Potentials Carry Synchronized Frequency Information in Active Cortical Networks

Temporal precision in spike timing is important in cortical function, interactions, and plasticity. We found that, during periods of recurrent network activity (UP states), cortical pyramidal cells in vivo and in vitro receive strong barrages of both excitatory and inhibitory postsynaptic potentials, with the inhibitory potentials showing much higher power at all frequencies above approximately 10 Hz and more synchrony between nearby neurons. Fast-spiking inhibitory interneurons discharged strongly in relation to higher-frequency oscillations in the field potential in vivo and possess membrane, synaptic, and action potential properties that are advantageous for transmission of higher-frequency activity. Intracellular injection of synaptic conductances having the characteristics of the recorded EPSPs and IPSPs reveal that IPSPs are important in controlling the timing and probability of action potential generation in pyramidal cells. Our results support the hypothesis that inhibitory networks are largely responsible for the dissemination of higher-frequency activity in cortex.

Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential

Traditionally, neuronal operations in the cerebral cortex have been viewed as occurring through the interaction of synaptic potentials in the dendrite and soma, followed by the initiation of an action potential, typically in the axon. Propagation of this action potential to the synaptic terminals is widely believed to be the only form of rapid communication of information between the soma and axonal synapses, and hence to postsynaptic neurons. Here we show that the voltage fluctuations associated with dendrosomatic synaptic activity propagate significant distances along the axon, and that modest changes in the somatic membrane potential of the presynaptic neuron modulate the amplitude and duration of axonal action potentials and, through a Ca2+-dependent mechanism, the average amplitude of the postsynaptic potential evoked by these spikes. These results indicate that synaptic activity in the dendrite and soma controls not only the pattern of action potentials generated, but also the amplitude of the synaptic potentials that these action potentials initiate in local cortical circuits, resulting in synaptic transmission that is a mixture of triggered and graded (analogue) signals.

State changes rapidly modulate cortical neuronal responsiveness.

The responsiveness of cortical neurons is strongly and rapidly influenced by changes in the level of local network activity. In rodent somatosensory cortex, increases in network activity increase neuronal responsiveness to the intracellular injection of brief conductance stimuli but paradoxically decrease responsiveness to brief whisker deflections. However, whisker stimulation frequently evokes long-lasting changes in the level of local circuit activity. The ability of stimuli to successfully evoke prolonged increases in circuit activity is associated with both an increase in the amount of conductance evoked by a whisker stimulus and an increase in action potential responsiveness to whisker stimulation. In addition, brief whisker stimuli presented during periods of high network activity evoke postsynaptic potentials containing a greater proportion of inhibition, consistent with an increased efficiency in the activation of inhibitory mechanisms during the Up state. In contrast, during prolonged and variable whisker stimulation, increased network activity is associated with an increase in overall responsiveness, dynamic range, output gain, and correlation between action potential response and speed of whisker movement. We conclude that stimulus-evoked or spontaneous alterations in cortical state can influence neuronal responsiveness in a complex manner, resulting in large changes in which, and how, sensory stimuli are represented.

Metabolic cost as a unifying principle governing neuronal biophysics

The brain contains an astonishing diversity of neurons, each expressing only one set of ion channels out of the billions of potential channel combinations. Simple organizing principles are required for us to make sense of this abundance of possibilities and wealth of related data. We suggest that energy minimization subject to functional constraints may be one such unifying principle. We compared the energy needed to produce action potentials singly and in trains for a wide range of channel densities and kinetic parameters and examined which combinations of parameters maximized spiking function while minimizing energetic cost. We confirmed these results for sodium channels using a dynamic current clamp in neocortical fast spiking interneurons. We find further evidence supporting this hypothesis in a wide range of other neurons from several species and conclude that the ion channels in these neurons minimize energy expenditure in their normal range of spiking.

Contrast Dependence and Differential Contributions from Somatostatin- and Parvalbumin-Expressing Neurons to Spatial Integration in Mouse V1

A characteristic feature in the primary visual cortex is that visual responses are suppressed as a stimulus extends beyond the classical receptive field. Here, we examined the role of inhibitory neurons expressing somatostatin (SOM+) or parvalbumin (PV+) on surround suppression and preferred receptive field size. We recorded multichannel extracellular activity in V1 of transgenic mice expressing channelrhodopsin in SOM+ neurons or PV+ neurons. Preferred size and surround suppression were measured using drifting square-wave gratings of varying radii and at two contrasts. Consistent with findings in primates, we found that the preferred size was larger for lower contrasts across all cortical depths, whereas the suppression index (SI) showed a trend to decrease with contrast. We then examined the effect of these metrics on units that were suppressed by photoactivation of either SOM+ or PV+ neurons. When activating SOM+ neurons, we found a significant increase in SI at cortical depths >400 μm, whereas activating PV+ neurons caused a trend toward lower SIs regardless of cortical depth. Conversely, activating PV+ neurons significantly increased preferred size across all cortical depths, similar to lowering contrast, whereas activating SOM+ neurons had no systematic effect on preferred size across all depths. These data suggest that SOM+ and PV+ neurons contribute differently to spatial integration. Our findings are compatible with the notion that SOM+ neurons mediate surround suppression, particularly in deeper cortex, whereas PV+ activation decreases the drive of the input to cortex and therefore resembles the effects on spatial integration of lowering contrast.

Cell type-specific control of neuronal responsiveness by gamma-band oscillatory inhibition.

Neocortical networks are composed of diverse populations of cells that differ in their chemical content, electrophysiological characteristics, and connectivity. Gamma-frequency oscillatory activity of inhibitory subnetworks has been hypothesized to regulate information processing in the cortex as a whole. Inhibitory neurons in these subnetworks synchronize their firing and selectively innervate the perisomatic compartments of their target neurons, generating both tonic and rapidly fluctuating inhibition. How do different types of cortical neurons respond to changes in the level and structure of perisomatic inhibition? What accounts for response heterogeneity between cell types, and are these response properties fixed or flexible? To answer these questions, we use in vitro whole-cell recording and dynamic-clamp somatic current injection to study six distinct types of cortical neurons. We demonstrate that different types of neurons systematically vary in their receptiveness to fast changes in the structure of inhibition and the range over which changes in inhibitory tone affect their output. Using simple neuron models and model neuron hybrids (dynamic clamp), we determine which intrinsic differences between cell types lead to these variations in receptiveness. These results suggest important differences in the way cell types are affected by gamma-frequency inhibition, which may have important circuit level implications. Although intrinsic differences observed in vitro are useful for the elucidation of basic cellular properties and differences between cell types, we also investigate how the integrative properties of neurons are likely to be rapidly modulated in the context of active networks in vivo.

Asymmetric effects of activating and inactivating cortical interneurons

Bidirectional manipulations – activation and inactivation – are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is the notion that tonic activation and inactivation will both produce valid, internally consistent insights into interneurons’ computational roles. Here, using single-unit recordings in auditory cortex of awake mice, we show that this may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed that Sst+ inactivation increased response gain, while Pvalb+ inactivation weakened tuning and decreased information transfer, implying that these neurons support delineable computational functions. But activating Sst+ and Pvalb+ interneurons revealed no such differences. We used a simple network model to understand this asymmetry, and showed how relatively small changes in key parameters, such as spontaneous activity or strength of the light manipulation, determined whether activation and inactivation would produce consistent or paradoxical conclusions regarding interneurons’ computational functions. DOI: http://dx.doi.org/10.7554/eLife.18383.001

Caudal Ganglionic Eminence Precursor Transplants Disperse and Integrate as Lineage-Specific Interneurons but Do Not Induce Cortical Plasticity

The maturation of inhibitory GABAergic cortical circuits regulates experience-dependent plasticity. We recently showed that the heterochronic transplantation of parvalbumin (PV) or somatostatin (SST) interneurons from the medial ganglionic eminence (MGE) reactivates ocular dominance plasticity (ODP) in the postnatal mouse visual cortex. Might other types of interneurons similarly induce cortical plasticity? Here, we establish that caudal ganglionic eminence (CGE)-derived interneurons, when transplanted into the visual cortex of neonatal mice, migrate extensively in the host brain and acquire laminar distribution, marker expression, electrophysiological properties, and visual response properties like those of host CGE interneurons. Although transplants from the anatomical CGE do induce ODP, we found that this plasticity reactivation is mediated by a small fraction of MGE-derived cells contained in the transplant. These findings demonstrate that transplanted CGE cells can successfully engraft into the postnatal mouse brain and confirm the unique role of MGE lineage neurons in the induction of ODP.