Gap junctions compensate for sublinear dendritic integration in an inhibitory network

Electrically coupled inhibitory interneurons dynamically control network excitability, yet little is known about how chemical and electrical synapses regulate their activity. Using two-photon glutamate uncaging and dendritic patch-clamp recordings, we found that the dendrites of cerebellar Golgi interneurons acted as passive cables. They conferred distance-dependent sublinear synaptic integration and weakened distal excitatory inputs. Gap junctions were present at a higher density on distal dendrites and contributed substantially to membrane conductance. Depolarization of one Golgi cell increased firing in its neighbors, and inclusion of dendritic gap junctions in interneuron network models enabled distal excitatory synapses to drive network activity more effectively. Our results suggest that dendritic gap junctions counteract sublinear dendritic integration by enabling excitatory synaptic charge to spread into the dendrites of neighboring inhibitory interneurons.     

Dendritic spikes and their inhibition in alligator Purkinje cells

Alligator Purkinje cells generate action potentials in the peripheral dendritic tree, after synaptic depolarization via superficial parallel fibers. These action potentials are inhibited at the dendrite level by preceding parallel-fiber volleys at close intervals. We conclude that this inhibition is produced by the activation of the inhibitory interneurons of the molecular layer, the stellate cells, which establish synaptic contacts with the dendrites of the Purkinje cells.     

Filtering of visual information in the tectum by an identified neural circuit

The optic tectum of zebrafish is involved in behavioral responses that require the detection of small objects. The superficial layers of the tectal neuropil receive input from retinal axons, while its deeper layers convey the processed information to premotor areas. Imaging with a genetically encoded calcium indicator revealed that the deep layers, as well as the dendrites of single tectal neurons, are preferentially activated by small visual stimuli. This spatial filtering relies on GABAergic interneurons (using the neurotransmitter γ-aminobutyric acid) that are located in the superficial input layer and respond only to large visual stimuli. Photo-ablation of these cells with KillerRed, or silencing of their synaptic transmission, eliminates the size tuning of deeper layers and impairs the capture of prey.     

Electrotonic coupling between pyramidal cells: a direct demonstration in rat hippocampal slices

Intracellular recordings from pairs of neurons in slices of rat hippocampus directly demonstrated electronic coupling between CA3 pyramidal cells. When two neurons were impaled simultaneously (as verified by subsequent double staining with horseradish peroxidase), current pulses injected into one cell caused voltage changes in other cells. These interactions were bidirectional. Fast prepotentials, historically thought to represent spike activity in dendrites, resulted from action potentials in other electronically coupled pyramidal cells. These data directly demonstrate electrotonic coupling between neurons in the mammalian brain and indicate that some fast prepotentials are coupling potentials. Coupling between pyramidal cells could mediate synchronization of normal rhythmic activity and of burst discharges during seizures.     

Locally synchronized synaptic inputs

Synaptic inputs on dendrites are nonlinearly converted to action potential outputs, yet the spatiotemporal patterns of dendritic activation remain to be elucidated at single-synapse resolution. In rodents, we optically imaged synaptic activities from hundreds of dendritic spines in hippocampal and neocortical pyramidal neurons ex vivo and in vivo. Adjacent spines were frequently synchronized in spontaneously active networks, thereby forming dendritic foci that received locally convergent inputs from presynaptic cell assemblies. This precise subcellular geometry manifested itself during N-methyl-D-aspartate receptor-dependent circuit remodeling. Thus, clustered synaptic plasticity is innately programmed to compartmentalize correlated inputs along dendrites and may reify nonlinear synaptic integration.     

Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex

A puzzling feature of the neocortex is the rich array of inhibitory interneurons. Multiple neuron recordings revealed numerous electrophysiological-anatomical subclasses of neocortical gamma-aminobutyric acid-ergic (GABAergic) interneurons and three types of GABAergic synapses. The type of synapse used by each interneuron to influence its neighbors follows three functional organizing principles. These principles suggest that inhibitory synapses could shape the impact of different interneurons according to their specific spatiotemporal patterns of activity and that GABAergic interneuron and synapse diversity may enable combinatorial inhibitory effects in the neocortex.     

Variability in spike trains during constant and dynamic stimulation

In a recent study, it was concluded that natural time-varying stimuli are represented more reliably in the brain than constant stimuli are. The results presented here disagree with this conclusion, although they were obtained from the same identified neuron (H1) in the fly's visual system. For large parts of the neuron's activity range, the variability of the responses was very similar for constant and time-varying stimuli and was considerably smaller than that in many visual interneurons of vertebrates.     

Directional specificity in the regeneration of lamprey spinal axons

After spinal transection in ammocoetes (lamprey larvae) 4 to 5 years old, functional recovery is accompanied by a limited regeneration in which axons grow as far as 5 millimeters beyond the scar. In axotomized giant interneurons labeled intracellularly with horseradish peroxidase 16 to 120 days after transection, 74 percent of regenerating neurites grew in their normal projection pattern, rostal and contralateral to the cell body. One third of the neurites originated anomalously from posterior dendrites. Despite their initial abnormal orientation, 80 percent of these neurites looped contralaterally and rostrally to assume the normal projection path. The directional specificity persisted when giant interneurons were located in islands formed by double simultaneous cord transection. This limited regeneration seems to be characterized by directional selectivity that cannot be attributed to nonspecific influences, such as a tendency of neurites to grow in an already established direction or a trophic effect of the zone of injury.     

Olfactory bulb response of rabbit

An approach to understanding the properties of dendrites is to record the response of the olfactory bulb where the dendrites of mitral cells form the glomeruli. After the stimulations of the bulb and nasal mucosa, the responses appear different, but they are fundamentally composed of three successive potentials, suggesting that the last one is the action potential of glomerular dendrites.     

The cellular basis of GABA(B)-mediated interhemispheric inhibition

Interhemispheric inhibition is thought to mediate cortical rivalry between the two hemispheres through callosal input. The long-lasting form of this inhibition is believed to operate via γ-aminobutyric acid type B (GABA(B)) receptors, but the process is poorly understood at the cellular level. We found that the firing of layer 5 pyramidal neurons in rat somatosensory cortex due to contralateral sensory stimulation was inhibited for hundreds of milliseconds when paired with ipsilateral stimulation. The inhibition acted directly on apical dendrites via layer 1 interneurons but was silent in the absence of pyramidal cell firing, relying on metabotropic inhibition of active dendritic currents recruited during neuronal activity. The results not only reveal the microcircuitry underlying interhemispheric inhibition but also demonstrate the importance of active dendritic properties for cortical output.     

Compartmentalized and binary behavior of terminal dendrites in hippocampal pyramidal neurons

The dendritic arbor of pyramidal neurons is not a monolithic structure. We show here that the excitability of terminal apical dendrites differs from that of the apical trunk. In response to fluorescence-guided focal photolysis of caged glutamate, individual terminal apical dendrites generated cadmium-sensitive all-or-none responses that were subthreshold for somatic action potentials. Calcium transients produced by all-or-none responses were not restricted to the sites of photolysis, but occurred throughout individual distal dendritic compartments, indicating that electrogenesis is mediated primarily by voltage-gated calcium channels. Compartmentalized and binary behavior of parallel-connected terminal dendrites can greatly expand the computational power of a single neuron.     

Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons

Voltage clamp recordings and noise analysis from pyramidal cells in hippocampal slices indicate that N-methyl-D-aspartate (NMDA) receptors are tonically active. On the basis of the known concentration of glutamate in the extracellular fluid, this tonic action is likely caused by the ambient glutamate level. NMDA receptors are voltage-sensitive, thus background activation of these receptors imparts a regenerative electrical property to pyramidal cells, which facilitates the coupling between dendritic excitatory synaptic input and somatic action potential discharge in these neurons.     

Rats smell in stereo

It has been hypothesized that rats and other mammals can use stereo cues to localize odor sources, but there is limited behavioral evidence to support this hypothesis. We found that rats trained on an odor-localization task can localize odors accurately in one or two sniffs. Bilateral sampling was essential for accurate odor localization, with internasal intensity and timing differences as directional cues. If the stimulus arrived at the correct point of the respiration cycle, internasal timing differences as short as 50 milliseconds sufficed. Neuronal recordings show that bulbar neurons responded differentially to stimuli from the left and stimuli from the right.     

Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition

The temporal resolution of neuronal integration depends on the time window within which excitatory inputs summate to reach the threshold for spike generation. Here, we show that in rat hippocampal pyramidal cells this window is very narrow (less than 2 milliseconds). This narrowness results from the short delay with which disynaptic feed-forward inhibition follows monosynaptic excitation. Simultaneous somatic and dendritic recordings indicate that feed-forward inhibition is much stronger in the soma than in the dendrites, resulting in a broader integration window in the latter compartment. Thus, the subcellular partitioning of feed-forward inhibition enforces precise coincidence detection in the soma, while allowing dendrites to sum incoming activity over broader time windows.     

Preparing and motivating behavior outside of awareness

The mere activation of the idea of a behavioral act moves the human body without the person consciously deciding to take action. In an experiment, we showed that people subliminally primed with the concept of exertion were faster to squeeze a hand grip forcefully but expended more effort when the subliminal primes were directly accompanied by consciously visible positive stimuli. These findings demonstrate the human capacity to rely on mental processes in preparing and motivating behavior outside of awareness.     

Bilateral symmetry and interneuronal organization in the buccal ganglia of Aplysia

Principles of functional organization of the bilaterally symmetric buccal ganglia of Aplysia were studied in 20 identified cells used as a reference population. Four of the identified cells (two in each ganglion) are multiaction interneurons, each of which innervates six identified ipsilateral follower cells, mediating cholinergic excitation to one cell and cholinergic inhibition to five others. Bilateral coordination is effected by common inputs to all four interneurons. Ipsilateral pairs of interneurons are electrotonically coupled and produce identical synaptic actions on their common follower population. This apparent redundancy of interneuronal action leads to feed-forward summation, eliciting amplified synaptic output from each interneuron pair.     

Specialized inhibitory synaptic actions between nearby neocortical pyramidal neurons

We found that, in the mouse visual cortex, action potentials generated in a single layer-2/3 pyramidal (excitatory) neuron can reliably evoke large, constant-latency inhibitory postsynaptic currents in other nearby pyramidal cells. This effect is mediated by axo-axonic ionotropic glutamate receptor-mediated excitation of the nerve terminals of inhibitory interneurons, which connect to the target pyramidal cells. Therefore, individual cortical excitatory neurons can generate inhibition independently from the somatic firing of inhibitory interneurons.     

Receptor potentials from hair cells of the lateral line

Intracellular recordings from hair cells in the tail lateral line of mudpuppy Necturus maculosus show receptor potentials less than 800 microvolts, peak to peak, from stimuli that are considered large compared to natural stimuli. The hair cells are in neuromasts that are sensitive at the time of recording and are identified by both in vivo and in vitro examination of intracellular staining.     

Neuronal activity regulates diffusion across the neck of dendritic spines

In mammalian excitatory neurons, dendritic spines are separated from dendrites by thin necks. Diffusion across the neck limits the chemical and electrical isolation of each spine. We found that spine/dendrite diffusional coupling is heterogeneous and uncovered a class of diffusionally isolated spines. The barrier to diffusion posed by the neck and the number of diffusionally isolated spines is bidirectionally regulated by neuronal activity. Furthermore, coincident synaptic activation and postsynaptic action potentials rapidly restrict diffusion across the neck. The regulation of diffusional coupling provides a possible mechanism for determining the amplitude of postsynaptic potentials and the accumulation of plasticity-inducing molecules within the spine head.     

Segregation of axonal and somatic activity during fast network oscillations

In central neurons, information flows from the dendritic surface toward the axon terminals. We found that during in vitro gamma oscillations, ectopic action potentials are generated at high frequency in the distal axon of pyramidal cells (PCs) but do not invade the soma. At the same time, axo-axonic cells (AACs) discharged at a high rate and tonically inhibited the axon initial segment, which can be instrumental in preventing ectopic action potential back-propagation. We found that activation of a single AAC substantially lowered soma invasion by antidromic action potential in postsynaptic PCs. In contrast, activation of soma-inhibiting basket cells had no significant impact. These results demonstrate that AACs can separate axonal from somatic activity and maintain the functional polarization of cortical PCs during network oscillations.