Highlights d Repeated odor stimulation changes responses in the zebrafish olfactory cortex d Thes... more Highlights d Repeated odor stimulation changes responses in the zebrafish olfactory cortex d These changes are stimulus dependent and not observed in the olfactory bulb d The observed plasticity is abolished by an NMDA receptor antagonist d Odor representations are modified by passive sensory experience
Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate th... more Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate the striatal microcircuitry and possibly orchestrate local dopamine release. We expressed GCaMP6s, a genetically encoded calcium indicator (GECIs), selectively in CINs, and used microendoscopes to visualize the putative CIN assemblies in the dorsal striatum of freely moving mice. The GECI fluorescence signal from the dorsal striatum was composed of signals from individual CIN somata that were engulfed by a widespread fluorescent neuropil. Bouts of synchronous activation of the cholinergic neuropil revealed traveling-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 GECIexpressing CINs in acute striatal slices in conjunction with multiphoton imaging or widefield imaging that emulates the microendoscopes' specifications. The ability to detect fluorescent transients associated with individual action potential was constrained by the long decay constant of GECIs (relative to common inorganic dyes) to slowly firing (< 2 spikes/s) CINs. The microendoscopes' resolving power and sampling rate further diminished this ability. Additionally, we found that only back-propagating action potentials but not synchronous optogenetic activation of thalamic inputs elicited observable calcium transients in CIN dendrites. Our data suggest that only bursts of CIN activity (but not their tonic firing) are visible using endoscopic imaging, and that the spatiotemporal neuropil patterns are a physiological measure of the collective recurrent CIN network spiking activity. .
Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neurona... more 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.
The Journal of the Acoustical Society of America, 1999
Barn owls use the interaural time difference (ITD) for locating sounds in azimuth and the interau... more Barn owls use the interaural time difference (ITD) for locating sounds in azimuth and the interaural level difference (ILD) for locating sounds in elevation. Neurons in the optic tectum have spatially restricted receptive fields. Recently, Keller et al. [Hearing Res. [bold 118], 1334 (1998)] ...
Complex movements require accurate temporal coordination between their components. The temporal a... more 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 approximately 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 degrees, 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.
The olivo-cerebellar system has been implicated in temporal coordination of task components. Here... more 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.
Neurones are noisy elements. Noise arises from both intrinsic and extrinsic sources, and manifest... more Neurones are noisy elements. Noise arises from both intrinsic and extrinsic sources, and manifests itself as fluctuations in the membrane potential. These fluctuations limit the accuracy of a neurone's output but have also been suggested to play a computational role. We present a detailed study of the amplitude and spectrum of voltage noise recorded at the soma of layer IV-V pyramidal neurones in slices taken from rat neocortex. The dependence of the noise on holding potential, synaptic activity and Na+ conductance is systematically analysed. We demonstrate that voltage noise increases non-linearly as the cell depolarizes (from a standard deviation (s.d.) of 0.19 mV at -75 mV to an s.d. of 0.54 mV at -55 mV). The increase in voltage noise is accompanied by an increase in the cell impedance, due to voltage dependence of Na+ conductance. The impedance increase accounts for the majority (70%) of the voltage noise increase. The increase in voltage noise and impedance is restricted to the low-frequency range (0.2-2 Hz). At the high frequency range (5-100 Hz) the voltage noise is dominated by synaptic activity. In our slice preparation, synaptic noise has little effect on the cell impedance. A minimal model reproduces qualitatively these data. Our results imply that ion channel noise contributes significantly to membrane voltage fluctuations at the subthreshold voltage range, and that Na+ conductance plays a key role in determining the amplitude of this noise by acting as a voltage-dependent amplifier of low-frequency transients.
The cerebellum has been implicated as a major player in producing temporal acuity. Theories of ce... more 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 DCN’s 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, 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 inferior olive, rather than by direct olivary excitation. Moreover, we suggest that the DCN response profile is determined primarily by the number of concurrently active Purkinje cells, 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 Purkinje cells state transitions, while largely ignoring simple spikes from individual Purkinje cells. Future research should aim at quantifying the contribution of Purkinje cell state transitions to DCN activity, and the interplay between the different afferent systems that drive DCN activity.
Membrane ion channels and synapses are among the most important computational elements of nerve c... more 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 sigma = 0.33 +/- 0.28 mV at 10 mV hyperpolarization from the resting potential to sigma = 0.59 +/- 0.3 at a depolarization of 10 mV. At the dendrite, the noise increased from sigma = 0.34 +/- 0.28 to sigma = 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.
We have recently demonstrated using fMRI that a region within the human lateral occipital complex... more We have recently demonstrated using fMRI that a region within the human lateral occipital complex (LOC) is activated by objects when either seen or touched. We term this cortical region LOtv for the lateral occipital tactile-visual region. We report here that LOtv voxels tend to be located in sub-regions of LOC that show preference for graspable visual objects over faces or houses. We further examine the nature of object representation in LOtv by studying its response to stimuli in three modalities: auditory, somatosensory and visual. If objects activate LOtv, irrespective of the modality used, the activation is likely to reflect a highly abstract representation. In contrast, activation specific to vision and touch may reflect common and exclusive attributes shared by these senses. We show here that while object activation is robust in both the visual and the somatosensory modalities, auditory signals do not evoke substantial responses in this region. The lack of auditory activation in LOtv cannot be explained by differences in task performance or by an ineffective auditory stimulation. Unlike vision and touch, auditory information contributes little to the recovery of the precise shape of objects. We therefore suggest that LOtv is involved in recovering the geometrical shape of objects.
A central goal of modern neuroscience is to obtain a
mechanistic understanding of higher brain f... more 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.
Highlights d Repeated odor stimulation changes responses in the zebrafish olfactory cortex d Thes... more Highlights d Repeated odor stimulation changes responses in the zebrafish olfactory cortex d These changes are stimulus dependent and not observed in the olfactory bulb d The observed plasticity is abolished by an NMDA receptor antagonist d Odor representations are modified by passive sensory experience
Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate th... more Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate the striatal microcircuitry and possibly orchestrate local dopamine release. We expressed GCaMP6s, a genetically encoded calcium indicator (GECIs), selectively in CINs, and used microendoscopes to visualize the putative CIN assemblies in the dorsal striatum of freely moving mice. The GECI fluorescence signal from the dorsal striatum was composed of signals from individual CIN somata that were engulfed by a widespread fluorescent neuropil. Bouts of synchronous activation of the cholinergic neuropil revealed traveling-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 GECIexpressing CINs in acute striatal slices in conjunction with multiphoton imaging or widefield imaging that emulates the microendoscopes' specifications. The ability to detect fluorescent transients associated with individual action potential was constrained by the long decay constant of GECIs (relative to common inorganic dyes) to slowly firing (< 2 spikes/s) CINs. The microendoscopes' resolving power and sampling rate further diminished this ability. Additionally, we found that only back-propagating action potentials but not synchronous optogenetic activation of thalamic inputs elicited observable calcium transients in CIN dendrites. Our data suggest that only bursts of CIN activity (but not their tonic firing) are visible using endoscopic imaging, and that the spatiotemporal neuropil patterns are a physiological measure of the collective recurrent CIN network spiking activity. .
Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neurona... more 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.
The Journal of the Acoustical Society of America, 1999
Barn owls use the interaural time difference (ITD) for locating sounds in azimuth and the interau... more Barn owls use the interaural time difference (ITD) for locating sounds in azimuth and the interaural level difference (ILD) for locating sounds in elevation. Neurons in the optic tectum have spatially restricted receptive fields. Recently, Keller et al. [Hearing Res. [bold 118], 1334 (1998)] ...
Complex movements require accurate temporal coordination between their components. The temporal a... more 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 approximately 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 degrees, 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.
The olivo-cerebellar system has been implicated in temporal coordination of task components. Here... more 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.
Neurones are noisy elements. Noise arises from both intrinsic and extrinsic sources, and manifest... more Neurones are noisy elements. Noise arises from both intrinsic and extrinsic sources, and manifests itself as fluctuations in the membrane potential. These fluctuations limit the accuracy of a neurone's output but have also been suggested to play a computational role. We present a detailed study of the amplitude and spectrum of voltage noise recorded at the soma of layer IV-V pyramidal neurones in slices taken from rat neocortex. The dependence of the noise on holding potential, synaptic activity and Na+ conductance is systematically analysed. We demonstrate that voltage noise increases non-linearly as the cell depolarizes (from a standard deviation (s.d.) of 0.19 mV at -75 mV to an s.d. of 0.54 mV at -55 mV). The increase in voltage noise is accompanied by an increase in the cell impedance, due to voltage dependence of Na+ conductance. The impedance increase accounts for the majority (70%) of the voltage noise increase. The increase in voltage noise and impedance is restricted to the low-frequency range (0.2-2 Hz). At the high frequency range (5-100 Hz) the voltage noise is dominated by synaptic activity. In our slice preparation, synaptic noise has little effect on the cell impedance. A minimal model reproduces qualitatively these data. Our results imply that ion channel noise contributes significantly to membrane voltage fluctuations at the subthreshold voltage range, and that Na+ conductance plays a key role in determining the amplitude of this noise by acting as a voltage-dependent amplifier of low-frequency transients.
The cerebellum has been implicated as a major player in producing temporal acuity. Theories of ce... more 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 DCN’s 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, 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 inferior olive, rather than by direct olivary excitation. Moreover, we suggest that the DCN response profile is determined primarily by the number of concurrently active Purkinje cells, 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 Purkinje cells state transitions, while largely ignoring simple spikes from individual Purkinje cells. Future research should aim at quantifying the contribution of Purkinje cell state transitions to DCN activity, and the interplay between the different afferent systems that drive DCN activity.
Membrane ion channels and synapses are among the most important computational elements of nerve c... more 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 sigma = 0.33 +/- 0.28 mV at 10 mV hyperpolarization from the resting potential to sigma = 0.59 +/- 0.3 at a depolarization of 10 mV. At the dendrite, the noise increased from sigma = 0.34 +/- 0.28 to sigma = 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.
We have recently demonstrated using fMRI that a region within the human lateral occipital complex... more We have recently demonstrated using fMRI that a region within the human lateral occipital complex (LOC) is activated by objects when either seen or touched. We term this cortical region LOtv for the lateral occipital tactile-visual region. We report here that LOtv voxels tend to be located in sub-regions of LOC that show preference for graspable visual objects over faces or houses. We further examine the nature of object representation in LOtv by studying its response to stimuli in three modalities: auditory, somatosensory and visual. If objects activate LOtv, irrespective of the modality used, the activation is likely to reflect a highly abstract representation. In contrast, activation specific to vision and touch may reflect common and exclusive attributes shared by these senses. We show here that while object activation is robust in both the visual and the somatosensory modalities, auditory signals do not evoke substantial responses in this region. The lack of auditory activation in LOtv cannot be explained by differences in task performance or by an ineffective auditory stimulation. Unlike vision and touch, auditory information contributes little to the recovery of the precise shape of objects. We therefore suggest that LOtv is involved in recovering the geometrical shape of objects.
A central goal of modern neuroscience is to obtain a
mechanistic understanding of higher brain f... more 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.
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Papers by Gilad Jacobson
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.
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.