Gilad A. Jacobson

Amygdala interneuron subtypes control fear learning through disinhibition

Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV+ interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM+ interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV+ and SOM+ interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.

Circuit Neuroscience in Zebrafish

A central goal of modern neuroscience is to obtain a mechanistic understanding of higher brain functions under healthy and diseased conditions. Addressing this challenge requires rigorous experimental and theoretical analysis of neuronal circuits. Recent advances in optogenetics, high-resolution in vivo imaging, and reconstructions of synaptic wiring diagrams have created new opportunities to achieve this goal. To fully harness these methods, model organisms should allow for a combination of genetic and neurophysiological approaches in vivo. Moreover, the brain should be small in terms of neuron numbers and physical size. A promising vertebrate organism is the zebrafish because it is small, it is transparent at larval stages and it offers a wide range of genetic tools and advantages for neurophysiological approaches. Recent studies have highlighted the potential of zebrafish for exhaustive measurements of neuronal activity patterns, for manipulations of defined cell types in vivo and for studies of causal relationships between circuit function and behavior. In this article, we summarize background information on the zebrafish as a model in modern systems neuroscience and discuss recent results.

A model of the olivo-cerebellar system as a temporal pattern generator

The olivo-cerebellar system has been implicated in temporal coordination of task components. Here, we propose a novel model that enables the olivo-cerebellar system to function as a generator of temporal patterns. These patterns could be used for timing of motor, sensory and cognitive tasks. The proposed mechanism for the generation of these patterns is based on subthreshold oscillations in a network of inferior olivary neurons and their control by the cerebellar cortex and nuclei. Our model, which integrates a large body of anatomical and physiological observations, lends itself to simple, testable predictions and provides a new conceptual framework for olivo-cerebellar research.

Invariant phase structure of olivo-cerebellar oscillations and its putative role in temporal pattern generation.

Complex movements require accurate temporal coordination between their components. The temporal acuity of such coordination has been attributed to an internal clock signal provided by inferior olivary oscillations. However, a clock signal can produce only time intervals that are multiples of the cycle duration. Because olivary oscillations are in the range of 5–10 Hz, they can support intervals of ≈100–200 ms, significantly longer than intervals suggested by behavioral studies. Here, we provide evidence that by generating nonzero-phase differences, olivary oscillations can support intervals shorter than the cycle period. Chronically implanted multielectrode arrays were used to monitor the activity of the cerebellar cortex in freely moving rats. Harmaline was administered to accentuate the oscillatory properties of the inferior olive. Olivary-induced oscillations were observed on most electrodes with a similar frequency. Most importantly, oscillations in different recording sites retained a constant phase difference that assumed a variety of values in the range of 0–180°, and were maintained across large global changes in the oscillation frequency. The inferior olive may thus underlie not only rhythmic activity and synchronization, but also temporal patterns that require intervals shorter than the cycle duration. The maintenance of phase differences across frequency changes enables the olivo-cerebellar system to replay temporal patterns at different rates without distortion, allowing the execution of tasks at different speeds.

Implications of functional anatomy on information processing in the deep cerebellar nuclei

The cerebellum has been implicated as a major player in producing temporal acuity. Theories of cerebellar timing typically emphasize the role of the cerebellar cortex while overlooking the role of the deep cerebellar nuclei (DCN) that provide the sole output of the cerebellum. Here we review anatomical and electrophysiological studies to shed light on the DCNs ability to support temporal pattern generation in the cerebellum. Specifically, we examine data on the structure of the DCN, the biophysical properties of DCN neurons and properties of the afferent systems to evaluate their contribution to DCN firing patterns. In addition, we manipulate one of the afferent structures, the inferior olive (IO), using systemic harmaline injection to test for a network effect on activity of single DCN neurons in freely moving animals. Harmaline induces a rhythmic firing pattern of short bursts on a quiescent background at about 8 Hz. Other neurons become quiescent for long periods (seconds to minutes). The observed patterns indicate that the major effect harmaline exerts on the DCN is carried indirectly by the inhibitory Purkinje cells (PCs) activated by the IO, rather than by direct olivary excitation. Moreover, we suggest that the DCN response profile is determined primarily by the number of concurrently active PCs, their firing rate and the level of synchrony occurring in their transitions between continuous firing and quiescence. We argue that DCN neurons faithfully transfer temporal patterns resulting from strong correlations in PCs state transitions, while largely ignoring the timing of simple spikes from individual PCs. Future research should aim at quantifying the contribution of PC state transitions to DCN activity, and the interplay between the different afferent systems that drive DCN activity.

A paradoxical isopotentiality: a spatially uniform noise spectrum in neocortical pyramidal cells

Membrane ion channels and synapses are among the most important computational elements of nerve cells. Both have stochastic components that are reflected in random fluctuations of the membrane potential. We measured the spectral characteristics of membrane voltage noise in vitro at the soma and the apical dendrite of layer 4/5 (L4/5) neocortical neurons of rats near the resting potential. We found a remarkable similarity between the voltage noise power spectra at the soma and the dendrites, despite a marked difference in their respective input impedances. At both sites, the noise levels and the input impedance are voltage dependent; in the soma, the noise level increased from σ = 0.33 ± 0.28 mV at 10 mV hyperpolarization from the resting potential to σ = 0.59 ± 0.3 at a depolarization of 10 mV. At the dendrite, the noise increased from σ = 0.34 ± 0.28 to σ = 0.56 ± 0.30 mV, respectively. TTX reduced both the input impedance and the voltage noise, and eliminated their voltage dependence at both locations. We describe a detailed compartmental model of a L4/5 neuron with simplified electrical properties that successfully reproduces the difference in input impedance between dendrites and soma and demonstrates that spatially uniform conductance-base noise sources leads to an apparent isopotential structure which exhibits a uniform power spectra of voltage noise at all locations. We speculate that a homogeneous distribution of noise sources insures that variability in synaptic amplitude as well as timing of action potentials is location invariant.

Synthesizing spatially complex sound in virtual space: an accurate offline algorithm.

The study of spatial processing in the auditory system usually requires complex experimental setups, using arrays of speakers or speakers mounted on moving arms. These devices, while allowing precision in the presentation of the spatial attributes of sound, are complex, expensive and limited. Alternative approaches rely on virtual space sound delivery. In this paper, we describe a virtual space algorithm that enables accurate reconstruction of eardrum waveforms for arbitrary sound sources moving along arbitrary trajectories in space. A physical validation of the synthesis algorithm is performed by comparing waveforms recorded during real motion with waveforms synthesized by the algorithm. As a demonstration of possible applications of the algorithm, virtual motion stimuli are used to reproduce psychophysical results in humans and for studying responses of barn owls to auditory motion stimuli.

Experience-Dependent Plasticity of Odor Representations in the Telencephalon of Zebrafish

Sensory systems balance stability and plasticity to optimize stimulus representations in dynamic environments. We studied these processes in the olfactory system of adult zebrafish. Activity patterns evoked by repeated odor stimulation were measured by multiphoton calcium imaging in the olfactory bulb (OB) and in telencephalic area Dp, the homolog of olfactory cortex. Whereas odor responses in the OB were highly reproducible, responses of Dp neurons adapted over trials and exhibited substantial variability that could be attributed to ongoing activity and to systematic changes in neuronal representations following each stimulus. An NMDA receptor antagonist did not affect the magnitude of odor responses but strongly reduced the variability and experience-dependent modification of odor responses in Dp. As a consequence, odor representations became stable over trials. These results demonstrate that odor representations in higher brain areas are continuously modified by experience, supporting the view that olfactory processing is inseparable from memory, even in the absence of reinforcement.

Neural Circuits: Random Design of a Higher-Order Olfactory Projection

A recent study in Drosophila has found that the connectivity between the first olfactory processing center, the antennal lobe, and one of its targets, the mushroom body, is apparently random. This supports the idea that the mushroom body is designed for learning arbitrary odor features.

Wave-like activity patterns in the neuropil of striatal cholinergic interneurons in freely moving mice represent their collective spiking dynamics

Cholinergic interneurons (ChIs) are believed to form synchronous cell assemblies that modulate striatal microcircuitry and possibly orchestrate local dopamine release. We expressed genetically encoded calcium indicators (GECIs) selectively in ChIs and visualized dorsal striatum in freely moving mice using microendoscopes. Bouts of synchronous activation of the cholinergic neuropil revealed wave-like patterns of activity that preceded the signal from individual somata. To investigate the nature of the neuropil signal and why it precedes the somatic signal, we target-patched GECI-expressing ChIs in acute striatal slices while imaging them with single- and multiphoton microscopy. We found that only back-propagating action potentials but not synchronous optogenetic activation of thalamic inputs elicits observable calcium transients in ChI dendrites. Our data suggest that the spatiotemporal neuropil patterns are a newly described physiological measure of the collective recurrent ChI network activity.