Nathaniel N. Urban

The multifarious hippocampal mossy fiber pathway: a review

The hippocampal mossy fiber pathway between the granule cells of the dentate gyrus and the pyramidal cells of area CA3 has been the target of numerous scientific studies. Initially, attention was focused on the mossy fiber to CA3 pyramidal cell synapse because it was suggested to be a model synapse for studying the basic properties of synaptic transmission in the CNS. However, the accumulated body of research suggests that the mossy fiber synapse is rather unique in that it has many distinct features not usually observed in cortical synapses. In this review, we have attempted to summarize the many unique features of this hippocampal pathway. We also have attempted to reconcile some discrepancies that exist in the literature concerning the pharmacology, physiology and plasticity of this pathway. In addition we also point out some of the experimental challenges that make electrophysiological study of this pathway so difficult.Finally, we suggest that understanding the functional role of the hippocampal mossy fiber pathway may lie in an appreciation of its variety of unique properties that make it a strong yet broadly modulated synaptic input to postsynaptic targets in the hilus of the dentate gyrus and area CA3 of the hippocampal formation.

Reciprocal intraglomerular excitation and intra- and interglomerular lateral inhibition between mouse olfactory bulb mitral cells

How patterns of odour‐evoked glomerular activity are transformed into patterns of mitral cell action potentials (APs) in the olfactory bulb is determined by the functional connectivity of the cell populations in the bulb. We have used paired whole‐cell voltage recordings from olfactory bulb slices to compare the functional connectivity of mitral cells to the known anatomy of the mitral cell network. Both inhibitory and excitatory coupling were observed between pairs of mitral cells. Inhibitory coupling was seen as an increased frequency of small, asynchronous GABAergic IPSPs following APs in the presynaptic cell. Excitatory coupling was short in latency, beginning about 1.3 ms after the presynaptic AP and was mediated by both NMDA and AMPA receptors. Mitral cell pairs were coupled by excitation if and only if their apical dendrites terminated in the same glomerulus. The excitatory coupling between mitral cells resembles conventional fast synaptic transmission in its time course, amplitude and latency, despite the absence of evidence for anatomically defined synapses between mitral cells.

Reliability, synchrony and noise

The brain is noisy. Neurons receive tens of thousands of highly fluctuating inputs and generate spike trains that appear highly irregular. Much of this activity is spontaneous - uncoupled to overt stimuli or motor outputs - leading to questions about the functional impact of this noise. Although noise is most often thought of as disrupting patterned activity and interfering with the encoding of stimuli, recent theoretical and experimental work has shown that noise can play a constructive role - leading to increased reliability or regularity of neuronal firing in single neurons and across populations. These results raise fundamental questions about how noise can influence neural function and computation.

Intrinsic biophysical diversity decorrelates neuronal firing while increasing information content

Although examples of variation and diversity exist throughout the nervous system, their importance remains a source of debate. Even neurons of the same molecular type have notable intrinsic differences. Largely unknown, however, is the degree to which these differences impair or assist neural coding. We examined the outputs from a single type of neuron, the mitral cells of the mouse olfactory bulb, to identical stimuli and found that each cells spiking response was dictated by its unique biophysical fingerprint. Using this intrinsic heterogeneity, diverse populations were able to code for twofold more information than their homogeneous counterparts. In addition, biophysical variability alone reduced pair-wise output spike correlations to low levels. Our results indicate that intrinsic neuronal diversity is important for neural coding and is not simply the result of biological imprecision.

Action potential propagation in mitral cell lateral dendrites is decremental and controls recurrent and lateral inhibition in the mammalian olfactory bulb

In the mammalian main olfactory bulb (MOB), the release of glutamate from lateral dendrites of mitral cells onto the dendrites of granule cells evokes recurrent and lateral inhibition of mitral cell activity. Whole-cell voltage recordings in the mouse MOB in vivo and in vitro show that recurrent and lateral inhibition together control the number, duration, and onset of odor-evoked action potential (AP) firing in mitral cells. APs in mitral cells propagate into the lateral dendrites and evoke a transient increase in dendritic calcium concentration ([Ca2+]), which is decremental with distance from the soma, and increases with AP number. These results suggest that the extent of AP propagation in lateral dendrites of mitral cells, along with the concomitant dendritic Ca(2+) transient, controls the amplitude of lateral and recurrent inhibition and thus is a critical determinant of odor-specific AP patterns in the MOB.

Correlation-induced synchronization of oscillations in olfactory bulb neurons.

Oscillations are a common feature of odor-evoked and spontaneous activity in the olfactory system in vivo and in vitro and are thought to play an important role in information processing and memory in a variety of brain areas. Theoretical and experimental studies have described several mechanisms by which oscillations can be generated and synchronized. Here, we investigate the hypothesis that correlated noisy inputs are able to generate synchronous oscillations in olfactory bulb mitral cells in vitro. We consider several alternative mechanisms and conclude that olfactory bulb synchronous oscillations are likely to arise because of the response of uncoupled oscillating neurons to aperiodic but correlated inputs. This mechanism has been described theoretically, but we provide the first experimental evidence that such a mechanism may underlie synchronization in real neurons. In physiological experiments, we show that this mechanism can generate gamma-band oscillations in populations of olfactory bulb mitral cells. This mechanism synchronizes oscillatory firing by using shared fast fluctuations in stochastic inputs across neurons, without requiring any synaptic or electrical coupling. We discuss the properties and limitations of synchronization by this mechanism and suggest that it may underlie fast oscillations in many brain areas.

Activity-dependent gating of lateral inhibition in the mouse olfactory bulb

Lateral inhibition is a circuit motif found throughout the nervous system that often generates contrast enhancement and center-surround receptive fields. We investigated the functional properties of the circuits mediating lateral inhibition between olfactory bulb principal neurons (mitral cells) in vitro. We found that the lateral inhibition received by mitral cells is gated by postsynaptic firing, such that a minimum threshold of postsynaptic activity is required before effective lateral inhibition is recruited. This dynamic regulation allows the strength of lateral inhibition to be enhanced between cells with correlated activity. Simulations show that this regulation of lateral inhibition causes decorrelation of mitral cell activity that is evoked by similar stimuli, even when stimuli have no clear spatial structure. These results show that this previously unknown mechanism for specifying lateral inhibitory connections allows functional inhibitory connectivity to be dynamically remapped to relevant populations of neurons.

Lateral inhibition in the olfactory bulb and in olfaction

Lateral inhibition in the olfactory bulb is mediated by circuits that involve reciprocal dendrodendritic connections between mitral and granule cells. Because of the properties of these connections and also because odor stimuli are not represented in an obviously topographic fashion, questions have been raised about whether the function of local inhibition in the olfactory bulb can be compared to the function of inhibition in other brain areas. Here, I propose an analysis of local inhibition in the olfactory bulb based on the simplification that olfactory bulb circuitry can be thought of as implementing a simple linear two-dimensional filter. This analysis highlights some important characteristics of the circuitry of the olfactory bulb and suggests that the function of lateral inhibition in the olfactory bulb may be to compensate for generalized, spatially distributed activation that otherwise may obscure the specific, discrete patterns of glomerular activation seen across the olfactory bulb.

Adult neurogenesis and specific replacement of interneuron subtypes in the mouse main olfactory bulb

BackgroundNew neurons are generated in the adult brain from stem cells found in the subventricular zone (SVZ). These cells proliferate in the SVZ, generating neuroblasts which then migrate to the main olfactory bulb (MOB), ending their migration in the glomerular layer (GLL) and the granule cell layer (GCL) of the MOB. Neuronal populations in these layers undergo turnover throughout life, but whether all neuronal subtypes found in these areas are replaced and when neurons begin to express subtype-specific markers is not known.ResultsHere we use BrdU injections and immunohistochemistry against (calretinin, calbindin, N-copein, tyrosine hydroxylase and GABA) and show that adult-generated neurons express markers of all major subtypes of neurons in the GLL and GCL. Moreover, the fractions of new neurons that express subtype-specific markers at 40 and 75 days post BrdU injection are very similar to the fractions of all neurons expressing these markers. We also show that many neurons in the glomerular layer do not express NeuN, but are readily and specifically labeled by the fluorescent nissl stain Neurotrace.ConclusionThe expression of neuronal subtype-specific markers by new neurons in the GLL and GCL changes rapidly during the period from 14–40 days after BrdU injection before reaching adult levels. This period may represent a critical window for cell fate specification similar to that observed for neuronal survival.

Selective reduction by dopamine of excitatory synaptic inputs to pyramidal neurons in primate prefrontal cortex

We have employed in vitro physiological methods to investigate dopaminergic modulation of excitatory synaptic transmission in monkey prefrontal cortex (PFC) circuits. We show that combined activation of D1‐like and D2‐like dopamine receptors results in the reduction of extracellular stimulation‐evoked isolated EPSCs in layer 3 pyramidal neurons. Using paired recordings from synaptically connected pyramidal neurons we have determined the basic properties of unitary synaptic connections between layer 3 pyramids in the primate PFC and, interestingly, we found that dopamine does not reduce synaptic transmission between nearby pairs of synaptically coupled PFC pyramidal neurons. This input specificity may be a critical aspect of the dopaminergic regulation of recurrent excitatory circuits in the PFC.